causes of nocturnal headaches include drug withdrawal,
temporal arteritis, sleep apnea, oxygen desaturation,
pheochromocytomas, primary and secondary neoplasms,
communicating hydrocephalus, subdural hematomas, subacute
angle-closure glaucoma, and vascular lesions. Migraine,
cluster, hypnic, and chronic paroxysmal hemicrania are
other primary headaches that can cause awakening from
sleep. Hypnic headaches only occur during sleep. Migraine
typically has associated symptoms and very uncommonly
only occurs during sleep. Cluster headaches have autonomic
symptoms and may occur during the day as well as during
sleep. Chronic paroxysmal hemicrania occurs both during
the day and at night, lasts for less than 30 minutes,
and occurs 10 to 30 times a day.
and excessive daytime sleepiness are the most common
symptoms of obstructive sleep apnea (OSA). Morning headaches
are three times more common in those with OSA than in
the general population and may occur in 36% of those
during sleep occurs in up to 20% of the population as
determined by visible tooth wear. Sleep bruxism is most
common in children between the ages of 3 and 12 years
and in adults between the ages of 19 and 45 years. Individuals
are unaware of this behavior, which produces audible
sounds in about 20% of episodes. Some patients report
morning jaw discomfort and tension-type headaches that
improve as the day goes on. Causes include dental factors,
psychologic and emotional factors, and systemic disorders.
Occlusal bite splints protect against damage. Medications
that can be helpful at bedtime include propranolol,
L-dopa, bromocriptine, and, for acute exacerbations,
Deprivation and Sleeping In
of sleep can trigger migraine and tension-type headaches.
In one study, 38.8% of medical and dental students reported
headaches due to sleep deprivation. Some migraineurs
find sleeping later than their usual time of awakening
is a trigger.
to Relieve Migraine
migraineurs obtain relief from acute attacks by sleeping.
In one study, 28% could terminate a migraine with sleep.
occurs in 28% of children with migraine and 5% of controls.
Children with migraine also have a greater incidence
of night terrors.
of exploding head syndrome awaken people from sleep
with a sensation of a loud bang in the head, like an
explosion. Ten percent of cases are associated with
the perception of a flash of light. The episodes take
place in healthy individuals during awakenings without
evidence of epileptogenic discharges.
normally occurs in the brain during development and
aging. However, diseases such as Parkinson's, Alzheimer's,
Lou Gehrig's and Huntington's. in which neuronal death
occurs at an accelerated rate, have caught the attention
of both scientists and the public, because of the devasting
outcome of these diseases on the individual and their
high cost to society. Current therapies for neurodegenerative
diseases do not offer cures, and are ameliorative rather
than restorative. However, neuroscience research has
led to the identification of genes involved in neuronal
differentiation, growth and survival, as well as to
genes involved in genetic forms of these diseases. Consequently,
gene transfer into the CNS is an emerging field likely
to lead to novel therapeutic approaches for neurodegenerative
diseases in which disease progression is retarded or
The pathology of Prakinoson's disease is characterized
by the loss of dopamine (DA) neurons in the substantia
nigra pars compacta, with consequent depletion of DA
in the striatum. With this pathology being focal and
toxins being available that selectively kill DA neurons,
well-characterized animal models of Parkinson's disease
have long been available, and have been used in the
evaluation of gene therapy strategies. Such studies
represent several approaches, including delivery of
genes to increase the synthesis of DA or DA receptors
and genes that code for neuroprotective and growth-promoting
disease (PD) affects approximately 1% of people over
the age of 50, with nearly 500,000 patients in the United
States. The cardinal symptoms of PD include bradykinesia
or akinesia, rigidity, resting tremor, and postural
instability. Rigidity is clinically detected as increased
resistance to passive movement and is caused by tonic
contraction of muscles. Resting tremor is caused by
a rapid alternating contraction of opposing muscle groups,
often observed in the forearm and hand as a "pill
rolling" tremor. Life expectancy in PD patients
is similar to that of age-matched controls; however,
even with medical therapy, 80% of patients are disabled
within 10 yr of diagnosis.
etiology and pathogenesis of PD are unknown. Although
the majority of cases are sporadic, are large kindred
with autosomal dominant inheritance of PD has shown
linkage to chromosome 4q21-q23. The causative gene,
once identified, should provide insight into the pathogenesis
of both hereditary and sporadic cases. DA neurons may
be in PD because of a combination of oxidative stress,
excitotoxicity, mitochondrial abnormalities, and calcium
toxicity. Reactive oxygen species, generated from auto-oxidation
and metabolism of DA, can cause DA neuron death by damaging
cell membranes, proteins, and DNA. Excitatory amino
acids such as glutamate can increase intracellular calcium
(Ca) concentrations. Mitochondrial abnormalities, which
have been observed in patients with PD, can impair energy
production and cause loss of ion gradients, including
Ca. Elevated intracellular Ca may lead to cell death
through activation of Ca-dependent proteases.
Current pharmacologic therapies for PD are aimed at
ameliorating symptoms, primarily through augmenting
DA neurotransmission. L-DOPA (1-dihydroxyphenylalanine),
in conjunction with the peripheral decarboxylase inhibitor
carbidopa, has been the mainstay of PD therapy for decades.
L-DOPA crosses the blood-brain barrier and is converted
to DA by DOPA decarboxylase in remaining DA neurons,
non-DA neurons, and glia. DA levels can also be augmented
by inhibition of DA metabolism with deprenyl, a monoamine
oxidase B inhibitor, or by inhibition of catechol-O-methyl-transferase.
DA agonists, such as bromocriptine, directly activate
D1 and D2 receptors on striatal neurons. Other drugs
that improve symptoms such as anticholinergics and amantadine,
indirectly compensate for reduced DA levels by altering
neurotransmission in the basal ganglia.
L-DOPA and other therapies do not prevent the continued
degeneration of DA neurons, and side effects, such as
dyskinesias and the on-off phenomenon occur in the majority
of patients. As a result, additional therapies are being
studied in animal models and PD patients. Experimental
therapies include pallidotomy, a surgical procedure
that creates a compensatory lesion in basal ganglia
circuitry. Patients with unilateral pallidotomy show
reductions in L-DOPA-induced dyskinesias and on-off
fluctuations, as well as some improvement in tremor,
rigidity, and bradykinesia, but not postural instability.
Transplantation of DA neuron containing fetal ventral
mesencephalon to the striatum has improved symptoms
in some patients, and may work by local, continuous
release of DA in the striatum and reconstruction of
some circuitry. Transplantation of cells genetically
modified to produce L-DOPA or DA, or direct modification
of host tissue with genes encoding L-DOPA or DA synthesizing
enzymes, are alternative strategies to transplantation
of fetal tissue that are being investigated in animal
models of PD. Molecules with neuroprotective potential,
including antioxidants, antagonists of NMDA or other
excitatory amino acid receptors, inhibitors of nitric
oxide synthase (NOS), and neurotrophic factors, are
also under investigation.
MODELS OF PARKINSON'S DISEASE
well-characterized animal models of parkinson's disease
are available for evaluating novel therapies. Transection
of the medial forebrain bundle, which contains nigrostriatal
and mesolimbic DA axons, causes a reduction of DA phenotypic
markers and cell death in the substantia nigra and ventral
tegmental area. Injection of the neurotoxin 6-hydroxydopamine
into the striatum, medial forebrain bundle, or substantia
nigra results in a selective loss of DA neurons. 6-OHDA
is an analog of DA that is concentrated in DA neurons
through uptake by the high-affinity DA transporter.
6-OHDA undergoes auto-oxidation, generating hydroxyl
radical, hydrogen peroxide, and superoxide anion, molecules
that damage lipids, proteins, and DNA, and lead to cell
death. Injection of 6-OHDA into the rat striatum produces
a progressive loss of DA neurons over several weeks;
injection into the medial forebrain bundle or substantia
nigra produces a rapid loss of DA neurons. MPTP causes
parkinsonian symptoms in humans, nonhuman primates,
and mice, following its oxidation to MPP+ by MAO-B.
MPP+ enters DA neurons by high-affinity uptake through
the DA transporter and interferes with ATP production
by inhibiting complex I of the mitochondrial electron
Unilateral chemical or physical lesions of the nigrostriatal
pathway result in an imbalance in the levels of DA and
DA receptors between the two striatae, with behavioral
sequelae. For example, DA stores are depleted and striatal
postsynaptic DA receptors are upregulated on the lesioned
side. Animals exhibit rotational behavior in response
to amphetamine and DA agonists, such as apomorphine,
that is readily quantifiable. In addition, unilaterally
lesioned animals exhibit deficits in contralateral limb
use in several spontaneous behaviors. MPTP-lesioned
nonhuman primates exhibit symptoms similar to humans
with parkinson's disease, including bradykinesia or
akinesia, resting tremor, and rigidity.
In addition to chemical or physical lesions of DA neurons,
another model of Parkinson's disease is the weaver mutant
mouse. Following normal DA innervation of the striatum,
approx 75% of DA neurons in the substantia nigra degenerate,
with a parallel loss of striatal DA. The weaver phenotype
results from a point mutation in the pore region of
the G protein activated inwardly rectifying potassium
channel subunit, GIRK2. Potassium channels containing
the weaver GIRK2-subunit are not selective for potassium,
but also conduct sodium, which may cause depolarizatioon
leading to excitotoxicity in DA neurons.
REPLACEMENT GENE THERAPIES
DA neurons die in Parkinson's disease, the synthesis
of DA is reduced. The rate limiting enzyme for DA biosynthesis
is tyrosine hydroxylase, which catalyzes the conversion
of the amino acid L-tyrosine to L-DOPA. This reaction
requires the cofactor tetrahydrobiopterin, the synthesis
of which is rate-limited by GTP-cyclohydrolase I (GC).
L-DOPA is rapidly converted to DA by AADC. DA is subsequently
concentrated into synaptic vesicles by the vascular
amine transporter. DA acts as an end product inhibitor
of TH by competing with BH4 for the cofactor binding
site. In Parkinson's disease, orally administered L-DOPA
is absorbed into the blood stream, crosses the blood-brain
barrier, and is converted to DA by AADC in remaining
DA nerve terminals and in other neurons and glia. The
fluctuations in response to oral L-DOPA to the striatum,
and thus the irregular production of DA. Replacement
of the TH gene, perhaps along with other DA biosynthetic
enzymes, by gene therapy approaches may lead to continuous
local production of DA. This strategy may not produce
the motor fluctuations and peripheral side effects with
orally administered L-DOPA.
Vivo Enzyme Replacement Gene Therapy
variety of cell lines and primary cells, including fibroblasts,
myoblasts, and astrocytes, are readily genetically modified
in vitro by transfection methods or by viral vectors.
The TH gene has been introduced into a variety of cells,
including the fibroplast cell lines 208F, NRK-49F, NIH3T3,
and CVI; a rat endocrine cell line; rat primary fibroblasts;
rat primary astrocytes; an immotralized human fetal
astrocyte cell line, SVG; and neural cells derived from
the rat ventral mesencephalon immorrtalized with a temperature-sensitive
oncogene. In most studies, retroviral vectors with the
TH cDNA driven by the cytomegaloviral (CMV) promoter
or a retroviral long-terminal repeat (LTR) promoter
were utilized to genetically modify the cells, although
calcium phosphate transfection and infection with a
defective herpes simplex virus-1 (SV-1) vector have
also been used. Production and release of L-DOPA by
TH-expressing fibroblasts in vitro occurred only in
BH4 is added to the medium, consistent with the lack
of expression of GC in fibroplasts. Retroviral transduction
of both the TH and GC genes into fibroplasts resulted
in synthesis of BH and L-DOPA. Unlike fibroblasts, primary
astrocytes expressing TH release L-DOPA in the absence
of exogenous BH4. The amount of L-DOPA released by cells
in vitro in the medium is much higher than that contained
in cells, suggesting that L-DOPA is constitutively released
by fibroblasts. Cocultured TH-expressing fibroblasts
and AADC-expressing fibroblasts produced and released
DA in vitro in the presence of BH4, indicating that
L-DOPA and DA cab readily diffuse in and out of fibroblasts.
Transplantation of cells genetically modified to express
TH into the 6-OHDA denervated striatum of rats reduced
opamorphine-induced rotation behavior, but transplantation
of unmodified cells or cells expressing a reporter gene
failed to do so. These results suggest that grafted
cells produce and release L-DOPA in the presence of
host-derived BH4 L-DOPA is subsequently converted to
DA by host AADC, and the increased DA reduces DA-receptor
supersensitivity on the lesioned side, thus reducing
apomorphine-induced rotation behavior. L-DOPA and DA
levels were increased by TH-expressing NIH3T3fibroblasts,
as measured by in vivo microdialysis. However, transplanted
NRK-49F fibroblasts expressing TH did not synthesize
detectable L-DOPA unless BH4 was perfused into the striatum.
No DA and only low levels of L-DOPA are observed following
transplantation of TH-expressing primary fibroblasts.
Thus, endogeneous BH4 levels in the DA-depleted striatum
might, in some situations, be inadequate to activate
TH. Transplantation of fibroblasts modified to express
both TH and GC resulted in measurable L-DOPA and DA
production and reduce apomorphine rotation; however,
in this study, fibroblasts expressing only TH or unmodified
firboblasts reduced apomorphine rotation to the same
extent. Retroviral-mediated TH-and GC-transgene expression
is rapidly downregulated in vivo. Only a small percentage
of grafted astrocytes and fibroblasts were TH-immunoreactive
2 wk after grafting, and L-DOPA production decreased
over 95% 2 wk after grafting of TH-and GC-expressing
fibroblasts. Additonally, the behavioral improvement
observable at 2 wk is reduced at 6 - 8 wk.
1 : Gene Therapy in Animal Models of Parkinson's Disease
Biological effect Refs
Ex vivo Gene Therapy Approaches
vivo Gene Therapy Approaches
Protection of soma
improved behavior, DA transporters
Ex vivo Gene Therapy Approaches
Fibroblast-TH ? Apomorphine rotation
Fibroblast-TH ? Apomorphine rotation
Neural cell-TH ? Apomorphine rotation
Astrocyte-TH ? Apomorphine rotation
MPP + Rat I - BDNF Protection of soma 63
MPP + Fibroblast-BDNF ? SN DA levels 64
6-ODHA, BHK-GDNF Sprouting of fibers 68
partial Astrocyte-BDNF Improvement in rotation 67
6-ODHA, Fibroblast-BDNF Protection of soma, fibers 66
6-ODHA, Fibroblast-GDNF Protection of soma 69
MFB Fibroblast-BDNF No effect 65
Unlesioned Fibroblast-BDNF ? DA turnover, sprouting
Chromaffin/NGF-astrocyte cografts Protective/stimulatory
Chromaffin/NGF-fibroblast cografts ? Survival/differentiation
PC12cells+NGF Protective ( survival) 76.77
II.In vivo Gene Therapy Approaches
6-OHDA HSV-TH ?Apomorphine rotation 27
6-OHDA AAV-TH ?Apomorphine rotation 28
6-OHDA Lipofectin-TH ?Apomorphine rotation 30
6-OHDA Ad-TH ?Sensorimotor asymmetry 29
Normal Ad-D2R ? Receptor density 31
6-OHDA Ad-GDNF Protection of soma 81,82,
6-OHDA AAV-GDNF ? DA, improved behavior, 85
? DA transporters
6-OHDA AAV-GDNF Protection of soma 87
vivo gene therapy approaches also have been applied
to a small number of non-human primates. A temperature-sensitive
immortalized neural cell line derived from rat embyonic
d 14 ventral mesencephalon was modified to express TH
with a retrovirus vector. These cells were grafted into
the striatum of two Macaco mulata monkeys immunosuppresed
with cyclosporin, and previously rendered hemi-parkinsonian
with unilateral intracarotid infusion of MPTP. Apomorphine
rotation behavior improved in both monkeys, and grafted
cells survived and expressed TH, as demonstrated by
immunocytochemistry. Autologous primary fibroblasts
retrovirally transduced with a TH gene under the Moloney
murine leukemia virus (MMLV) LTR and grafted into the
striatum of MPTP-lesioned monkeys expressed TH 4 mo
after grafting, as demonstrated by immunocytochemistry
and in situ hybridization.
vivo Enzyme Replacement Gene Therapy
alternative approach to grafting cells modified ex vivo
is to genetically modify host tissue by injecting vectors
encoding the transgene of interest to the CNS. Long-term
behavioral effects have been observed in the 6-OHDA-lesioned
rat following injectiono f an HSV-1 amplicon vector
and an adeno-associated virus (AAV) vector encoding
TH. HSV-TH improved apomorphine rotation behavior 65%
from 2 wk to 1 yr after vector injection; HSV-LacZ,
encoding the reporter enzyme - galactosidase, was without
effect. DA release induced by high extracellular potassium
was 300% greater in HSV-TH, compared to HSV-LacZ-or
vechicle-injected rats, as measured by in vivo microdialysis
at 4-6 mo. Despite considerable behavioral improvement,
transgene expression was limited. Six to 16 mo after
injection of HSV-TH, 5-300 TH-immuno reactive cells
were observed in the striatum. TH mRNA was amplified
by reverse transcription polymerase chain reaction from
3 of 10 rats 1 mo after HSV-TH. Injection of AAV-lacZ
and AAV-TH resulted in transgene expression for at least
3 and 4 mo, respectively, as detected by X-gal histochemistry
and TH immunocytochemistry, respectively. In 6-OHDA-lesioned
rats, AAV-TH reduced apomorphine rotation behavior approx
35% at 5 and 10 wk after injection, compared to AAV-LacZ
and vehicle-injected rats. An adenovirus-encoding TH
decreased sensorimotor asymmetry in lesioned rats. Striatal
injection of a lipofectin-plasmid DNA complex encoding
TH under the simian viral (SV40) early promoter reduced
apomorphine turning by 46% 3 - 15 d after injection
in the 6-ODHA lesioned rat; injection of plasmid alone
or lipofectin alone had no effect. Only in lipofectin
TH plasmid-injected rats were TH-immunoreactive cells
and TH mRNA amplified by RT-PCR observed in the striatum.
In monkey, injection of AAV-TH or AAV-LacZ resulted
in expression in neurons for at least 3 mo. At early
time-points, 14,000 - 31,000 - ßgalactosidase-expressing
cells were observed per injection site.
Another in vivo gene therapy approach applicable to
Parkinson's disease is to increase dopamine D2 receptor
expression in the striatum, which is known to be reduced
in late-stage Parkinson's disease. An adenoviral vector
encoding the D2R, under control of the CMV promoter
injected into the normal rat striatum, increased D2R
density in a focal area round the injection site, as
demonstrated by receptor autoradiography with [3H]-
THERAPIES WITH NEUROTROPHIC FACTORS
studies of DA neurons in culture showed that neuronal
growth and morphology can be differently influenced
by signals from glial cells in target vs nontarget brain
regions. Subsequently, the plasticity and potential
for regeneration and sprouting inherent to DA neurons
in adult brain were realized from transplantation and
injury studies. These studies prompted the search for
specific DA neurotrophic factors. To date, more than
20 neurotrophic factors have been reported for DA neurons.
These include members of several growth factor families
operating through different intracellular signaling
mechanisms, including the TGFß- superfamily, the
neurotrophins, cytokines, and mitogenic growth factors.
Some factors, such as glial cell line derived neurotrophic
factor and brain-derived neurotrophic factor, act directly
on DA neurons in vitro; others, such as fibroblast growth
factor, mediate effects on DA neurons through astrocytes.
The identification of factors with potent DA trophic
activities in vitro led to the concept of using these
as therapeutic agents for Parkinson's disease, as reviewed
previously. Results of studies utilizing rat, mouse,
and nonhuman primate models of Parkinson's disease,
in which large amounts of recombinant DA neurotrophic
factor proteins have been injected or infused in to
the brain, support the therapeutic efficacy of these
substances. For example, GDNF, the most potent DA neurotrophic
factor yet identified, protects DA neurons from death
and loss of phenotypic markers, and ameliorates parkinsonian
behaviors in several animal models of Parkinson's disease.
In the MPTP-treated mouse, GDNF partially prevented
MPTP-induced decline in striatal DA levels, DA cell
number, and TH-IR fiber density. GDNF-treated mice also
exhibited increased motor behavior. In rat, GDNF maintained
the DA phenotype against 6-ODHA-induced damage. GDNF
infused into the substantia nigra 5 wk after 6-ODHA
completely reversed apomorphine-induced rotation, increased
the number of TH-IR neurons, and normalized DA levels
in the substantia nigra. Repeated injections of GDNF
just above the substantia nigra in rats with a progressive
DA lesion resulting from striatal injection of 6-ODHS
also protected DA neurons from cell death. In the hemi-parkinsonian
Rhesus monkey, GDNF injected into substantia nigra,
caudate nucleus, or lateral ventricle improved bradykinesia,
rigidity, and tremor. Moreover, unilaterally injected
GDNF protected against the effects of MPRP bilaterally,
increasing DA somal size and the density of TH-IR fibers.
DA levels in the substantia nigra also were increased
in hemi-Parkinsonian monkeys after an intraventricular
injection of GDNF. In addition, GDNF injection into
normal Rhesus monkey caudate upregulated the DA system.
In rats with a physical lesion of the medial forebrain
bundle, repeated injections of GDNF near the substantia
nigra increased DA cell survival to 85%, compared to
53% in control injected rats. Although the reported
effects of GDNF are remarkable, other DA neurotrophic
factors, such as BDNF, FGF, and NT-3, also have effects
on DA neurons in vivo, BDNF increased DA turnover and
DA neuronal activity, and both BDNF and NT-3 ameliorated
the development of parkinsonian behaviors in the rat.
Several mitogenic factors, including EGF, aFGF, and
bFGF, also promoted recovery in the 6-OHDA-lesioned
rat and the MPTP-treated mouse.
2 : Dopaminergic Neurotrophic Factors
- Superfamily members
- modest effects
the therapeutic efficacy of DA neurotrophic factors
is well founded in animal models of Parkinson's disease,
there are practical considerations to their application
in humans. Because Parkinson's disease is progressive,
it is likely that long-term trophic support for the
diseased DA neurons will be required. Neurotrophic factors
are labile substances that are unable to cross the blood
- brain barrier in significant amounts. Therefore, their
therapeutic use for Parkinson's disease will require
development of methods for delivering these factors
continuously to the DA neurons in the substantia nigra
in a manner that is safe, minimally invasive, and that
does not elicit effects on other types of neurons. Alternatively,
pharmacological approaches targeted to neurotrophic
factor receptors may be developed; however, these would
be expected to affect all cell types that express the
receptor. Repeated injections of recombinant neurotrophic
factors into the human brain are unlikely to be practical,
and are likely to elicit deleterious side effects over
the long term. In this respect, clinical trials in which
neurotrophic factors were administered in large amounts
in the periphery were stopped because of unanticipated,
intolerable side effects. In addition, one patient with
Alzheimer's disease experienced the side effects of
weight loss, pain, and sleep disturbances following
intraventricular infusion of nerve growth factor. Gene
therapies for delivering neurotrophic factors to the
CNS have the potential to circumvent or even eliminate
the drawbacks of recombinant protein therapies. By transferring
neurotrophic fact genes to the CNS, there is the potential
of producing these vital substances in a continuous
manner, or even in a regulatable manner through the
use of regulatable promoters. Moreover, expression of
a factor may ultimately be confined to a specific cell
type through the use of a cell-specific promoter.
Vivo Neurotrophic Factor Gene Therapy
first studies applying gene therapy with neurotrophic
factors to Parkinson's disease used ex vivo gene therapy,
implanting various types of cells into the striatum
following retroviral transduction with neurotrophic
factor genes in vitro. Cell lines, as well as primary
fibroblasts, myoblasts, and astrocytes, including human
astrocytes, are amenable to transfection and retroviral
transduction with neurotrophic factors. Rat-I fibroblasts
are primary rat astrocytes secrete bioactive BDNF following
retroviral infection, as shown by an in vitro bioassay
of embryonic DA neurons. Implantation of BDNF-secreting
cells in animal models of Parkinson's disease ameliorate
the effects of neurotoxins acting through either oxidative
stress or mitochrondrial toxicity. For example, BDNF-secreting
fibroblasts grafted near the rat substantia nigra protected
approx 80% of the DA neurons from MPP+ injected into
the striatum, compared to only 35% protection in rats
grafted with control fibroblasts. In addition, DA levels
in the substantia nigra were increased, although DA
turnover remained unaffected. BDNF-secreting fibroblasts
grafted into the striatum of unlesioned rat increased
DA turnover. Implantation of BDNF-secreting fibroblasts
1 wk prior to 6-ODHA lesion completely protected DA
cell bodies in the substantia nigra for up to 3 wk,
and partially protected DA terminals in the rat striatum,
as determined by binding of 3H-mazindole to DA uptake
sites. In contrast, implantation of BDNF-secreting fibroblasts,
either into the striatum or substantia nigra did not
protect DA neurons from 6-ODHA injected into the medial
forebrain bundle. Astrocytes have also been used to
deliver BDNF tot he 6-ODHA lesion of the substantia
nigra, reduced motor asymmetry as evaluated by apomorphine-induced
rotational behavior in the absence of effects on DA
cell survival or fiber density in the striatum.
Ex vivo gene therapy with GDNF has been tried with rat
fibroblasts and encapsulated baby hamster kidney cells.
Following calcium phosphate transfection of a GDNF expression
plasmid, BHK cells were encapsulated in a polymer. Bioactive
GDNF was secreted from these capsules, as judged by
increased survival and neurite outgrowth of embryonic
DA neurons grown in medium conditioned by the capsules.
In rats partially lesioned with 6-OHDA, implantation
of capsules into the striatum induced in growth of DA
fibers into the capsules; however, behavioral improvement
was not apparent and effects on DA cell survival were
not studied. In another study, rat firboblasts transduced
with the human GDNF gene and grafted near the substantia
nigra protected DA neurons from a medial forebrain lesion
with 6-OHDA, as judged by counting neurons positive
for c-ret, a component of the GDNF receptor.
Another ex vivo gene therapy approach is that of combining
genetically engineered cells with grafts of other cell
types. For example, adrenal chromaffin cells are catecholaminergic
cells that secrete high levels of DA when grown in the
absence of glucocorticoids. Although chromaffin cells
were for a period of time considered to be an ideal
replacement for DA neurons, and were experimentally
used in human with Parkinson's disease, these cells
survive poorly when grafted into the brain. However,
if provided with a source of NGF, chromaffin cell survival
in the brain is improved. Taking this observation to
the gene therapy level, rat chromaffin cells cografted
with astrocytes or primary fibroblasts retrovirally
transduced with the NGF gene improved survival and neuronal
differentiation of the chromaffin cells. In addition,
chromaffin cells cografted with NGF-astrocytes improved
amphetamine-induced rotational behavior in the 6-OHDA-lesioned
rat. Polymer-encapsuled BHK fibroblasts, transfected
with an NGF construct under control of the metallothionein
promoter and transplanted into the rat striatum, increased
grafted chromaffin cell survival 20-fold from young
and old donors, and improved apomorphine rotation behavior.
Futhermore, chromaffin cell survival and apomorphine
rotation behavior were improved with striatal, but not
intraventricular, implants of the polymer-encapsulated
NGF-BHK cells. Neuronal differentiation and survival
of PC12 pheochromocytoma cells grafted into the 6-OHDA-lesioned
rat striatum were also improved by transducing the cells
with an NGF-retrovirus or NGF under control of a zinc-inducible
Grafting human fetal mesencephalon is an experimental
approach presently being tried in Parkinson's disease
patients. Although reports of improved symptoms in these
patients are encouraging, the survival of DA neurons
in these grafts is only 5-6%. In rat, providing exogeneous
BDNF to fetal mesencephalic grafts enhanced DA neuronal
survival and process outgrowth. Similarly, injection
of 4.5 µg GDNF every third day for 3 wk adjacent
to fetal mesencephalic grafts increased the survival
of DA neurons twofold, increased the density of TH+
fibers 50 - 100%, and enhanced graft function based
on amphetamine-induced rotation behavior. No one has
yet applied gene therapy to improve survival of grafted
DA neurons, although this is an interesting possibility.
Vivo Neurotrophic Factor Gene Therapy
vivo gene therapy with neurotrophic factors for Parkinson's
disease is an area ripe for investigation. Several classes
of viral vectors are being investigated as means for
delivering neurotrophic factor support for DA neurons,
including Aav, Ad, and HSV-1; however, few publications
on this topic have appeared to date. In our studies,
we have observed a significant effect of an adenovirus
harboring human GDNF on protecting DA neurons from degeneration.
Ad-GDNF was injected either just above the rat substantia
nigra or into the striatum, 1 wk prior to a progressive
6-ODHA striatal lesion. At 6 wk after the lesion, the
number of surviving DA neurons was increased approximately
threefold in rats injected with Ad-GDNF, compared to
rats injected with Ad-LacZ or an Ad-mutant GDNF lacking
bioactivity or rats that remained untreated. In addition,
these studies showed that nanogram quantities of GDNF
were produced in the injection site when 3x107 plaque-forming
units of Ad-GDNF were injected. This level of GDNF is
well above that required to activate GDNF receptors.
Injection of Ad-GDNF into the striatum in this model
also resulted in improvement in amphetamine-induced
rotation at 12 d after 6-OHDA. Using a variation of
the progressive lesion model, in which 6-OHDA was injected
bilaterally, During and colleagues injected AAV harboring
the rat GDNF gene unilaterally into the striatum. The
AAV-GDNF treated rats, but not the AAV-LacZ injected
rats, developed asymmetry in response to amphetamine
and apomorphine, and showed improved motor abilities
on several behavioral tasks. In addition, in vivo microdialysis
at 12 wk after vector injection showed potassium and
nomifensine - induced increases in DA in the AAV-GDNF
group, suggesting an enhancement of DA neurotransmission
in remaining DA terminals. The same vector was also
injected into the caudate of two African Green monkeys
partially lesioned with MPTP. ß- CIT spectroscopy
to image DA transporters showed small increases of 9
and 19% over values obtained before the therapy in the
two monkeys, again suggesting a protective effect on
DA terminals. Similar effects have been reported for
Ad-GDNF and AAV-GDNF. HSV vectors have not yet been
specifically applied to Parkinson's disease. However,
Federoff and colleagues have injected as HSV vector
harboring LacZ under control of the TH promoter into
the striatum. Retrograde transport of the vector to
the SN was observed, with transgene expression specifically
limited to DA neurons. This approach may be well suited
to providing neurotrophic support to DA neurons in an
autocrine or paracrine manner.
therapy strategies for Parkinson's disease, aimed at
replacing DA synthesizing enzymes, or rejuvenating DA
neurons and slowing the progression of the disease through
neurotrophic factors, have been reviewed. The latter
approach is relevant to neurodegenerative diseases in
general, in which increased levels of neurotrophic factors
may not only slow the disease process, but may stimulate
regeneration or sprouting of remaining neurons. Further
technological advances are required to realize the potential
of gene therapy for Parkinson's disease. There is no
vector presently available that provides long-term,
stable gene expression in the brain in the absence of
cytotoxic effects. Consequently, new generation vectors
need to be developed that not only lead to stable gene
expression, but that also minimize hot cellular and
humoral responses. For the current state of the art
of vectors, the reader is referred to other chapters
in this volume and to several recent reviews. It is
imperative that vectors be shown to be safe and efficacious
in nonhuman primate brain, and, ultimately, in the human
The cellular complexity of the CNS provides another
challenge. Vectors harboring genes driven by cellular
promoters have the potential of expressing a transgene
specifically is one phenotypically defined cell population.
In the case of neurotrophic factor therapies for Parkinson's
disease, this cell could be the diseased DA neuron itself,
although it is not known whether neurotrophic factors
acting in an autocrine manner are effective in CNS neurons.
The neurotrophic factor could be expressed in DA target
neurons, such as enkephalin-or somatostatin-synthesizing
striatal neurons, where it would be released, taken
up by DA terminals, and retrogradely transported. In
this respect, several DA neurotrophic factors are retrogradely
transported. In this respect, several DA neurotrophic
factors are retrogradely transported. In this respect,
several DA neurotrophic factors are retrogradely transported
by DA neurons, including GDNF, BDNF, and bFGF. Trophic
factor expression could also be targeted to astrocytes,
which would in turn secrete trophic support in the vicinity
of the DA neuron. It is not presently known which cellular
site offers the best trophic support for CNS neurons.
Another potential of viral vectors is the possibility
of including regulatable promoters for the regulation
of transgene expression through peripheral drug administration
or through endogenous molecules whose levels are altered
by disease or injury. For some diseases or injuries
to the nervous system, transient increases in neurotrophic
support may be optimal; for others, chronic support
may be needed. However, affective or cognitive disorders
could potentially result from chronically increased
levels of neurotrophic factors in the CNS, and these
are difficult to predict from animal studies. If such
side effects of gene therapy were to occur, the inclusion
of a regulatable promoter or a killer gene in the vector
construct could be used to turn off expression or to
kill infected cells. For these reasons, systematic studies
on optimal ways to deliver and regulate genes in the
CNS, expecially in primate CNS, are crucial.
In the parkinsonian brain, DA neurons degenerate over
a prolonged period, and the etiology underlying this
degeneration is unknown. The elucidation of genes involved
in hereditary forms of PD, as well as genes that increase
risk for this disease, will result in additional targets
of gene therapy and novel animal models. Although the
therapies reviewed here show promise, it is not known
how closely current rodent and nonhuman primate models
of Parkinson's disease, in which DA neurons are chemically
or physically damaged, mimic idiopathic Parkinson's
disease. The answer to this can come only form the application
of these therapies to the human parkinsonian brain.
Hemodynamic Manipulation in the Treatment of Brain Ischemia
Brain ischemia is a common pathophysiologic entity.
In some circumstances, its role in producing a neurologic
deficit is unequivocal, as in embolization from an ulcerated
carotid atheroma to an intracranial artery or severe
systemic hypotension from cardiac asystole. However,
its impact spreads far beyond such obvious clinical
disorders. Unrecognized brain ischemia probably contributes
to the development of neurologic deficits in many other
settings, such as an expanding intracerebral hematoma
or other mass lesion and severely elevated intracranial
treatment of acute brain ischemia continues to receive
considerable attention from clinical and laboratory
investigators. Although a comprehensive regimen for
preventing brain infarction has not been defined, much
has been learned the can improve the clinical outcome.
The primary objectives of treatment are to improve blood
flow to the ischemic area and to increase the resistance
of brain tissue to metabolic injury. Improving circulation
reduces the size of the ischemic area and enhances the
delivery of agents intended to increase metabolic resistance
This chapter focuses on methods for increasing blood
flow to ischemic areas. The primary emphasis is on the
treatment of incomplete focal ischemia, the kind most
often encountered clinically by neurologists and neurosurgeons.
PRINCIPLES OF BLOOD FLOW
Poiseuille's law states that volume flow rate is directly
proportional to the product of the pressure differential
between the ends of the tube and the fourth power of
the radius of the tube, and is inversely proportional
to the product of the length of the tube and the viscosity
of the fluid. In simpler terms, this mans that the volume
flow rate can be altered by changing the driving pressure,
the radius or length of the tube, or the viscosity of
the fluid. Although Poiseuille's law generally applies
to blood flow, it must be remembered that blood is non-Newtonian
fluid and that perfusion is normally pulsatile. Thus,
blood viscosity varies with the velocity of flow (29).
Furthermore, brain blood flow increases with conversion
from nonpulsatile to pulsatile perfusion in the presence
of a constant range of perfusion pressures (48).
Circulation of blood appears to be more complex in the
microvasculature than in larger vessels. Fahraeus and
Lindquist (12) found that Poiseuille's law did not accurately
predict the flow of blood through tubes of progreassively
smaller diameter: As vessel diameter decreased to the
40 mm range (that of arterioles), blood viscosity decreased.
They ascribed this phenomenon to a reduction in hematocrit.
Dintenfass (11) subsequently found that when the radius
of the tube was 5 to 7 mm (approximately that of capillaries),
blood viscosity stopped decreasing; with further reductions,
viscosity increased markedly.
Our understanding of the mechanisms that regulate intracranial
circulation is incomplete. Under normal circumstances,
the brain regulates blood flow in accordance with its
metabolic needs (38). Regional blood flow is regulated
by constriction or dilatation of precapillary arterioles;
it increases or decreases in response to neuronal metabolic
activity. These regional fluctuations are thought to
be partly the result of changes in local pH, carbon
dioxide tension, and tissue metabolite levels. Brain
blood flow is also greatly influenced by changes in
systemic arterial CO2 (i.e.CO2 reactivity). Under normal
circumstances, brain blood flow remains within a constant
range throughout the physiologic range of systemic arterial
blood pressure. During severe ischemia, the mechanisms
controlling blood flow break down as the arterial system
reaches a state of maximal dilatation. As blood flow
decreases, CO2 reactivity and autoregulation are progressively
impaired and cease when the ischemic threshold is crossed
(2,18). Impairment of CO2 reactivity and autoregulation
may persist in varying degrees for months or years after
the ischemic event whether or nor maximum vasodilatation
persists (33, 34).
Methods of enhancing blood flow to ischemic areas are
based on out knowledge of the principles of tubular
flow and hemorrheology. It is currently possible to
increase perfusion pressure, dilate conducting arteries,
and alter blood viscosity. The results of some experimental
studies support the validity of these approaches in
the treatment of brain ischemia, but many questions
ramain regarding their effectiveness in reducing infarct
size and their application in specific clinical settings.
Increasing systemic arterial blood pressure to raise
cerebral perfusion pressure would appear to be a logical
component of the treatment of brain ischemia. Arteries
in an area of focal ischemia due to proximal vascular
occlusion are connected, through collateral channels
that vary greatly in size and number, to arteries in
the nonischemia. Despite the presence of these interconnecting
vessels, perfusion pressure is lower in the ischemia
area that in the nonischemic area (45). An increase
in systemic arterial blood pressure would be expected
to increase pressure in the collateral arterial conducting
system proximal to the occluded artery and in surrounding
areas, thereby increasing the pressure differential
and augmenting flow into the ischemia area. Whether
or not this phenomenon reduces the extent of ischemic
tissue damage depends on the adequacy of the collateral
circulation and the severity of the ischemia.
The effects of changes in systemic arterial blood pressure
on the brain circulation in experimental ischemia have
been investigated extensively, but the treatment of
ischemia with hypertension has received surprisingly
little attention. Waltz (49) studied the effects of
varying systemic arterial blood pressure on cortical
blood flow in cats undergoing acute middle cerebral
artery (MCA) occlusion. In nonischemic cortex, blood
flow remained relatively constant despite changes in
systemic arterial blood pressure. In ischemic cortex,
blood flow paralleled blood pressure at normotensive
and hypontensive levels; at hypertensive levels (means
arterial blood pressure to 120 mm Hg,) it increased
but never reached the baseline levels of nonischemic
cortex. With further increases in systemic arterial
pressure, cortical blood flow decreased.
Symon et al (43) evaluated the effects of pharmacologically
induced hypertension on cerebral blood flow (CBF) in
baboons undergoing acute MCA occlusion. These studies
clearly showed a link between the degree of ischemia
and the extent of autoregulatory impairment. Autoregulation
was partially preserved in ischemic area with greater
than 40% of basal flow (ollateral zones) and was absent
in areas with less than 20% of basal flow (core area
of ischemia). Hypotension induced by exsanguination
further reduced CBF in the ischemic zone, whereas pharamacologically
induced hypertension increased flow. Like Waltz (49),
Symon et al (43) found a limit to the favorable effects
of hypertension on CBF. When the mean arterial blood
pressure rose 50 mm Hg or more above normal preexisting
pressure, CBF in the ischemic zone decreased.
Symon et al (43) made additional important observation
during reperfusion. CBF was imparied during reperfusion
after severe ischemia. CBF was also measured after restoration
of normal systemic arterial blood pressure in baboons
subjected to MCA occlusion followed by 2 hours of hypotension.
CBF levels after restoration of blood pressure did not
recover to levels observed immediately after MCA occlusion
and before induction of hypotension; but CBF levels
after restoration of blood pressure correlated with
the severity of ischemia observed during the hypontensive
period. Clearly, hypotension had an additive deleterious
effect on blood flow during reperfusion. These findings
confirmed the observations of other (1) that changes
in the microcirculation in areas of severe ischemia
may prevent adequate reperfusion. This secondary impairment
in blood flow has been called the "no-reflow phenomenon"
Hope et al (16) measured somatosensory evoked potentials
and local CBF in baboons subjected to MCA occlusion.
Increasing the mean systemic arterial blood pressure
pharamacologically by an average of 40 mm Hg significantly
improved the evoked potentials and local CBF. Hypertensive
therapy elicited a similar response in a small group
of patients with ischemic neurologic deficits after
Denny-Brown (10) was probably the first to report that
hypertensive therapy improved acute brain ischemia.
Others have described similar observations, but most
of the studies were uncontrolled, and the reports anecdotal.
The effect of hypertensive therapy on acute focal brain
ischemia has not yet been systematically evaluated in
a clinical setting.
During the past few years, pharmacologically induced
hypertension has be come a major component in the treatment
of ischemic neurologic deficit after subarachnoid hemorrhage
(SAH). The current tendency to operate on a ruptured
intracranial aneurysm within hours or days of SAH has
largely eliminated the potential risk of rebleding due
to hypertensive therapy. The results of studies in which
hypertension has been used to treat this condition have
been encouraging (4,30,34). In most of these reports,
hypertension was combined with hypervolemia. Beneficial
effects were not achieved in some patients until very
high blood pressure levels (e.g. 240 mm Hg systolic
blood pressure) were reached.
Careful monitoring and manipulation of systemic arterial
blood pressure are essential in patients with acute
brain ischemia. Allowing systemic arterial blood pressure
to decrease below initially observed levels further
reduces blood flow in ischemic areas and must be avoided.
Although the role of hypertensive therapy is less well
defined than in patients with SAH, the weight of the
evidence strongly favors its application for patients
with SAH. The guidelines for its use in patients with
brain ischemia due to vascular occlusion have yet to
Hypertensive therapy is not without risk. For example,
pharmacologically induced hypertension may not be tolerated
in patients with heart disease and could precipitate
rebleeding from an untreated intracranial aneurysm.
Hypertensive therapy initiated after prolonged delay
could worsen brain edema or produce hemorrhage, particularlly
if infarction has already occurred or if reperfusion
is induced in a previously severely ischemic area, such
as after dissolution of an embolism.
Total body blood volume varies with many factors including
age, sex, bodyweight, fat content, activity, position,
medications, and disease. Blood volume may by reduced
in many persons already at risk for stroke. In patients
with SAH, both red blood cell mass and total blood volume
are often substantially reduced (27). These changes
are thought to be partly the result of bed rest, supine
duresis, negative nitrogen balance, decreased erythropoiesis,
and iatrogenic blood loss. Systemic secretion of casoconstricting
catecholamines that accompanies SAH is also considered
an important factor in reducing intravascular volume.
Most patients with acute ischemic stroke are hypovolemic
at admission (13).
Maintaining intravascular volume appears to be an important
factor in improving the outcome of patients with acute
ischemia after a recent SAH. Hypovolemia increases the
likelihood of relative or absolute systemic hypotension,
which could further reduce blood flow in the ischemic
area. However, the role of hypervolemia in treating
brain ischemia has not yet been established. On the
basis of Poiseuille's law, it is difficult to explain
how hypervolemia per se would improve brain blood flow
without a concomitant increase in perfusion pressure,
dilatation of conducting arteries, or reduction of blood
Some experimental studies (20) have related improved
brain blood flow and outcome in ischemia to an increase
in cardiac output induced by hypervolemia. In this setting,
pulse pressure is augmented by the increased cardiac
stroke volume. Raising pulse pressure might have favorable
effects on blood flow in ischemic brain (48). However,
another series of experimental studies showed that expanding
intravascular volume without hemodilution did not improve
cortical blood flow in areas of focal cerebral ischemia
despite a significant rise in the cardiac output (51).
Decreased blood volume after SHA appears to increase
the risk of symptomatic vasospasm. Solomon et al (37)
found subnormal blood volume in 86% of patients with
symptomatic vasospasm but in only 13% of patients with
asymptomatic angiographic vasospasm. A number of clinical
reports, although largely anecdotal, appear to show
a considerable reduction of morbidity from vasospasm
when aggressive steps are taken in increase intravascular
volume (4,30,37). But there is no compelling evidence
that hypervolemia is better than normovolemia in treating
ischemic symptoms after SAH.
Systemic hypervolemia is unlikely to have any direct
effect on blood volume in the ischemic area. expansion
of blood volume in the brain microcirculation is an
early and consistent response to ischemia. When perfusion
pressure and blood flow drop below the normal range,
the brain arterial system dilates, spontaneously producing
a state of reactive hypervolemia in the ischemic area.
as blood approaches the ischemic threshold, vasodilatation
and volume expansion of the microcirculation are already
maximal and autoegulation and CO2 reactivity are lost.
Consequently, it is unclear what benefit systemic volume
expansion would have on the microcirculation in and
around an ischemic area of brain, except indirectly
by its effect on blood pressure.
Cerebral arteries and arterioles in an ischemic area
lose their autoregulatory capacity and Co2 reactivity
and becomes maximally dilated (38,43). Conducting arteries
in surrounding areas retain their reactivity either
fully or partially depending on their proximity to the
ischemic focus. These observations gave rise to the
hypothesis that blood flow in the ischemic area could
be anhanced by dilating the conducting collateral channels.
The findings of subsequent studies, however, have not
supported this hypothesis.
The early studies focused on the effects of CO2 on the
brain circulation in experimental and clinical ischemia.
In 1968, Lassen and Palvolyi (22) reported a further
decrease in blood flow "in some brain regions in
patients with acute cerebral vascular diseases."
They attributed this response to a reduction in perfusion
pressure in collateral vessels produced by arterial
dilatation in nonischemic brain. This response was called
the "intracerebral steal syndrome." They also
observed an inverse response, the "Robin Hood"
or "inverse steal" syndrome, where hypocapnic
provoked an increase in blood flow shunted to poor ischemic
areas in association with vasoconstriction and decrese
in flow in rich nonischemic areas. Most subsequent reports
have confirmed these observation.
Symon (41,42) and Brawley and his associates (7,8),
measured the luminal pressure in arteries beyond the
point of experimental occlusion of a mojor brain artery.
During inhalation of CO2, arterial pressure decreased.
Using a thermocouple technique, Brawaley et al (7,80
also showed a concomitant further reduction of cortical
blood flow in the ischemic area.
A few studies have show improved blood flow in ischemic
areas during CO2 inhalation. For example, Yamamoto et
al (52) performed fluorescein angiography and measured
microregional CBF in dogs undergoing occlusion of a
cortical artery. When the dogs breathed 5% CO2 and 95%
oxygen, collateral flow improved and the ischemic area
was consistently reduced in size. Hyperventilation that
lowered arterial CO2 made the ischemia area larger by
reducing collateral flow. Using autoadiography to study
rats subjected to MCA occlusion, Jones* found a significant
increase in cortical blood flow in the territory of
the occluded vessel with high arterial CO2 levels (i.e.
60 torr). The results of such studies indicate that
the effects of elevated arterial CO2 levels on the brain
circulation in ischemia are variable and may be unpredictable.
Clinical studies have never demonstarted significant
benefit from induced hypercarbia.
Interest in the use of vasodilating agents to improve
blood flow in ischemia brain was rekindled with the
introduction of prostacyclin, a prostaglandin derivative,
and the dihydropyridine group of calcium-entry blocking
agents. Prostacyclin is a very potent vascular smooth
muscle relaxant that is produced primarily in endothelial
cells; it also reduces platelet adhesiveness. Intravenous
injection or topical application to normal cortex causes
intense arterial dilatation and a marked increase in
blood flow. Unfortunately, prostacyclin has not consistently
improved blood flow in experimental studies of brain
ischemia (5), nor has it reduced the neurologic morbidity
of ischemia in controlled clinical trials (17,23,28).
Nimodipine and nicardipin are dihydropyridine derivatives
that have been extensively evaluated in experimental
studies of ischemia. Both agents selectively dilate
brain arteries and increase brain blood flow under normal
circumstances. Their effects on blood flow during ischemia,
however, have varied; the most consistent benefit is
seen during recirculation after temporary focal ischemia
(6,15). In studies of ischemia after SHA from aneurysm
rupture (3,26), nimodipine improved the clinical outcome
despite the lack of any angiographic evidence or reduction
in the severity of vasospasm. Nimodipine, it has ben
surgested, may exert a beneficial effect in brain ischemia
by preventing toxic calcium accumulation in the cytoplasm
of ischemic neurons and glia. The relative lack of binkding
affinity of dihydropyridine derivatives to neuronal
and glial plasma membranes, however, reduces the likelihood
of that possibility (36).
is a physical property of fluids that determines the
internal resistance to shear forces. Blood viscosity
is not constant (29). Blood is a non-Newtonian fluid:
Its viscosity varies with the rate of flow. Slow-moving
blood has a higher viscosity that the same blood moving
rapidly. Hematocrit, erythrocyte rigidity, and plasma
fibrinogen concentration also affect blood viscosity.
Blood viscosity increases logarithmically with increasing
hematocrit. Hematocrit, and consequently viscosity of
blood, in the cerebral microcirculation is normally
70% to 80% of that in the large vessels (21).
Brain blood flow decreases with hematocrit levels above
50% and increases with hematocrit levels below 30% (14,46).
This compensatory increases allows adequate oxygen delivery
in normal subjects even when hamatocrit is as low as
20%. In a patient with an occluded brain artery and
limited collateral circulation, a similar compensatory
increase would not be possible; more severe impairment
of oxygen delivery and greater tissue damage could result.
The relationship of blood viscosity to the pathogenesis
and treatment of brain ischemia is of considerable interest.
Studies have shown that a hematocrit level greater than
50% increases the risk of stroke (19,47). Other clinical
and experimental studies have suggested that optimizing
blood viscosity can limit tissue damage during an ischemic
event (13,50,51). Hematocrit might also be a factor
in the impairment of reperfusion after ischemia. Yield
stress - the minimal force required to start blood flowing
once it has been stationary - increases in relation
to the third power of the hematocrit (29). Consequently,
an elevation of hematocrit might prevent the restoration
of blood flow after transient ischemia.
The optimal hematocrit for patients with brain ischemia
has not been determined. Recent studies suggest that
it is probably about 35% (13,14,29,49,50,51). To achieve
this level, hematocrit can be quickly reduced by the
intravenous administration of low-molecular-weight dextran,
albumin, or saline. Blood can be removed concomitantly
by venesection if normovolemic hemodilutioh is desired.
Transfusions of packed erythrocytes can be given to
raise the hematocrit when it is below 35%.
Experimental studies have consistently demonstrated
improved blood flow and reduced infarct size after treatment
with low-molecular-weight dextran (50). These beneficial
effects have been attributed o the lowering of blood
viscosity through hemodilution and to the reduction
of platelet adhesiveness. The clinical use of low-molecular-weight
dextran in acute brain ischemia has many advocates,
but most of the reports have been anecdotal.
The Scandinavian Stroke Study Group conducted a stratified
randomized multicenter trial in 15 hospitals (35). Patients
who had an acute ischemic stroke within 48 hours of
admission and a hematocrit of 38% to 50% were randomized
to hemodilution and control groups. The results showed
no benefit from normovolemic hemodilution (mean hematocrit
reduction, 6.9%) maintained by venesectiona and in fusion
of low-molecular-weight dextran. The failure to improve
neurologic outcome does not mean that this form of therapy
is without potential benefit in other situations. Undoubtedly,
many of the patients treated in the Scandinavian study
already had irreversible brain injury when treatment
was initiated. Further studies are needed toe evaluate
this therapeutic approach in a more acute setting and
to define potentially respnsive subgroups of patients.
is the hyperosmolar agent used most frequently in the
treatment of acute brain ischemia. Experimentally, this
agent has been shown to have a beneficial effect on
the microcirculation and infarct size when it is given
early in the course of the ischemic event (24,25). These
favorable effects are not seen when mannitol is given
after ischemic breakdown of the blood - brain barrier
or irreversible brain injury has occurred.
Several mechanisms have been proposed to explain the
action of mannitol. It increases blood osmolality, which
appears to retard early brain swelling and maintain
flow through the microcirculation (24,25). Mannitol
reduced erythrocyte transit through the capillary bed
(9). The rapid administration of mannitol transiently
reduces blood viscosity by lowering the hematocrit.
Lower viscosity would also improve flow in ischemic
areas. Muizelaar and associates (31,32) suggested that
mannitol decreases blood viscosity and increases blood
flow in nonischemic brain and that the arteries in nonischemic
areas undergo secondary constriction to keep blood flow
constant. They postulated that arterial constriction
in nonischemic areas, rather than water conduction deiven
by an osmotic gradient, is primarily responsible for
the reduction of ICP after mannitol infusion. These
changes could also act to improve blood flow in ischemic
areas by decreasing ICP and thereby increasing perfusion
pressure and by producing an inverse steal syndrome.
Report of the clinical efficacy of mannitol in brain
ischemia are preliminary and anecdotal. It is unlikely,
based on experimental evidence, that the delayed administration
of mannitol would have a protective effect. The clinical
applications for treatment of acute stroke therefore
appear to be limited. Mannitol has frequently been given
to patients by neurosurgons when temporary artery occlusion
is needed for clipping of an intracranial aneurysm.
Suzuki et al (39,40) have used mannitol extensively
in combination with dexamethasone and vitamin E (the
"Sendai cocktail") with good results in both
expeimental and uncontrolled surgical studies.
Brain ischemia is a frequently encountered problem.
In the past, patients with impending or evolving infarction
were generally believed to be beyond help and were managed
supportively. Although it is difficult to prove a beneficial
effect in any given patient, the findings of experimental
and clinical studies suggest that the morbidilty and
mortality from acute ischemia might be reduced by optimizing
systemic circulatory factors. Brain ischemia must be
treated early if tissue necrosis is to be prevented
or limited. In the usual clinical setting, treatment
is often started too late to be effective. In patients
undergoing cerebral vascular surgery with a potential
risk of ischemia, the circulatory and hemodynamic state
of the patient can be optimized in anticipation of the
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medication Indications for treatment
unprovoked epileptic seizures that are not separated
seizure in patients with:
- A relevant underlying brain lesion or neurologic
- A specific epileptic syndrome and an unprovoked
seizure that will eventually
need treatment, such a juvenile myoclonic epilepsy.
risks and benefits of both treatment and no treatment
have been discussed extensively with the patient.
patient understands that the drug must be taken
regularly and continued for at less 3 years from
the time of the last seizure, and the about 40%
of patients will need to take anti-epileptic medication
lifelong, depending on the seizure syndrome and
of anti-epileptic drug therapy
to control seizures with the lowest effective dose
that causes no adverse effects.
goal is not to achieve the quoted 'therapeutic drug
A 'therapeutic' drug level may not be effective
or therapeutic for some patients;
higher, so-called 'toxic' levels may be required.
- A so-called 'therapeutic' drug level may be toxic
for others, and seizures may
be controlled with so-called 'sub-therapeutic' levels.
with low dose and increase slowly until the desired
therapeutic effect (i.e. seizure control) is achieved
or until adverse effects of the drug occur, whichever
the response primarily on clinical grounds.
of anti-epileptic drug:
the single most appropriate drug for the seizure type
§ Carbamazepine and v
are the first line treatments for focal epliepsies.
is the first line treatment for generalized epliepsies.
is also very effective for generalized epliepsies.
and clonazepam still have a place, but barbiturates
are now used less.
lamotrigine, topiramate, tiagabine and gabapentin
are of proven benefit in 25-50% of patients with refractory
partial seizures. It is not clear which is the most
effective drug but vigabatrin is not recommended because
it may cause constriction of the visual fields.
is only used for juvenile abscence epilepsy.
cost of newer anti-epileptic drugs (e.g. lamotrigine,
topirmate, gabapentin, tiagabine, vigabatrin) is about
10 times greater than older drugs (phenobarb, phenytoin).
mechanism of action. Increases synthesis and slows
the breakdown of GABA.
for the primary generalized epilepsies, particularly
tonic-clonic seizures, abscences and myoclonus.
effective as carbamazepine and phenytoin for partial
seizuers, especially is secondary generalization.
as a 40 mg/ml syrup for pediatric or nasogastric tube
use, crushable 100 mg tablets, and 200 mg and 500
mg eneric-coated tablets.
half-life: 6-9 hours, so may be administered as two
or three divided doses daily.
dose in adults: 200 mg twice daily (bd), given after
meals to minimize gastric irritation, and increasing
to 400 mg bd after 2 days, if tolerated. The full
pharmacologic action may not occur for some weeks.
can be increased slowly to I g three times daily (tds)
if necessary and tolerated.
of blood levels is often not necessary as three is
a poor relation between serum concentrations and anti-epileptic
efficacy or toxicity.
interactions: increases concentrations of other anti-epileptic
drugs such as carbamazepine (and its metabolities)
and phenobarbitone (phenobarbital), by inhibiting
their metabolism, and decreases plasma levels of phenytoin;
it is a minor inhibitor of oxidative metabolism but
is not a liver enzyme induce.
effect: tremor, weight gain due to appetite simulation,
and thinning or loss of hair. Congnitive impairment
is uncommon. Stupor and encephalopathy, although potentially
dangerous, are rare idiosyncraic effects and may be
due to acumulation of ammonia. The prothrombin time
can be prolonged but not sufficient to cause bleeding.
Liver toxicity, in the form of a microvesicular steatosis,
may occur idiosyncratically, particularly, in young
children and when combined with other (anti-epileptic)
drugs. Other adverse efects include anorexia, dyspepsia,
nausea, vomiting and rash (predictable), and acute
pancreatitis, thrombocytopenia, hyperammonemia, teratogenicity
used in 1964.
for the prophylaxis of generalized tonic-clonic and
partial seizures but not for absence o myoclonic epilepsy
(which it may aggravate).
as 100 mg and 200 mg tablets, or 200 and 400 mg controlled-release
tablets that are helpful for avoiding peak-dose adverse
half-life: 24-45 hours initially but after continued
long term use it falls to about 9 (8-24) hours.
drug must be introduced in a low dose to offset mild
neurotoxicity (sedation, vertigo, ataxia, diplopia,
nausea, headache). The usual starting dose in adults
in 100 mg three times daily, or preferably, half a
200 mg or 400 mg controlled-release tablet twice daily
for 2 days, followed by half a tablet in the morning
and a whole tablet at night, and further increases
if necessary, aiming to maintain the plasma level
within the therapeutic range and control seizures
(rather than waiting for another seizure to occur).
Even with this cautious approach and the development
of tolerance some patients are unable to remain on
carbamazepine because of neurotoxicity. In addition
a morbilliform skin rash limits its usefulness in
5-8% of patients.
- Dose-related: neuroptoxicity (dizziness, double
vision, unsteadiness), nausea,
vomiting, cardiac arrhythmia and orofacial dyskinesia.
- Idiosyncratic: skin rash (5-8% of patients), agranulocytosis,
syndrome of antidiuretic hormone secretion (leading
to fluid retention and
hyponatremia) hepatotoxicity, photosensitivity, Stevens-Johnson
lupus-like syndrome, thrombocytopenia and pseudolymphoma.
major inducer of hepatic cytochorme P450 activity.
Variable autoinduction of metabolism accounts for
the wide range of doses and for the substantial interindividual
variation in concentration found with the same dose.
interactions: carbamazepine accelerates the clearance
of itself (i.e. it induces its own metabolism), ethosuximide,
clonazepam, clobazam, corticosteroids, theophylline,
haloperidol, warfarin and hormones. So, most women
taking the oral contraceptive pill require daily estrogen
in a dose of 50 ug. Mutual enzyme induction or inhibition
with phenobarbitone (phenobarbital), phenytoin, or
primidone can result in a small rise or fall in steady-state
concentrations or either of both drugs. The metabolism
of carbamazepine is inhibited, causing neurotoxicity,
by sodiukm valproate, cimetidine, danazol, dextropropoxphene
(propoxyphene), diltiazem, erythromycin, issoniazid,
used as an antiepileptic drug in 1938.
for generalized tonic-clonic and partial seizures.
longer a drug of first choice, particularly in young
women, because it may cause cosmetic changes (gum
hyperplasia, acne, hirsutism, and facial coarsening),
as well as sedation and unfavorable effects on cognitive
function (e.g. attention, memory).
as a 6 mg/ml suspension, as chewable 50 mg tablets,
and as capsules of 30mg and 100 m.
half-life: about 24 (9-40) hours.
of only a few drugs with zero order kinetics at theraoeutic
dosage - as the concentration P - 450 enzyme system
to metabolize the drug becomes saturated (usually
at around 300mg/day), and so a small increment in
dose cn poduce a large rise in serum level. Conversely,
the circulation concentration may fall precipitously
when the dose is modesly reduced.
dose for children: 5mg/kg daily, for adults starting
and maintenance dose: 300mg daily, given as a single
dose or in divided doses. (Note, this is not the loading
dose that is required for status epilepticus.)
seizures continue, an increment of 30mg is appropriate
particularly if the serum concentration is above 12mg/1
effects: mental slowing, unsteadiness of gait, slurred
speech and tremor, and physical examination reveals
gaze-evoked nystagmus and tandem gait ataxia. Other
predictable adverse effects include nausea, anorexia,
vomiting, dyspepsia, cognitive impairment, depression,
aggression, drowsiness, headache, paradoxical seizures,
megaloblastic anemia, hyperglycemia, hypocalcemia,
osteomalacia and neonatal hemorrhage. Prolonged use
is associated with coarsening of facial features,
gum hyperplasia (98), acne and hirsutism.
effects include blood dycrasia, lupus-like syndrome,
reduced serum IgA, pseudolymphoma (Iymphadenopahy),
rash, Stevens-Johnson syndrome, Dupuytren's contracture,
hepatomegaly and hepatotoxicity and teratogenicity.
Long term use may cause peripheral neuropathy, cerebellar
degeneration due to purkinje cell loss and osteomalacia.
interaction: an enzyme inducer and may reduce the
efficacy of many lipid-soluble drugs such as other
anti-epileptic drugs, anticoagulants, coticosteroids,
cyclosporine, oal contraceptives, and therophylline.
Its metabolism may be inhibited, causing neurotoxicity
by enzyme inhibitors such as allopurinol, amiodarone,
chloramphenicol, cimetidine, imipramine, isoniazid,
metronidazole, phenothiazines and sulfonamides.
been used an anti-epileptic drug since 1912.
widely available and as good as carbamazepine and
phenytoin in controlling generalized tonic-clonic
and partial seizures.
drawback: its effect on cognition and behavior: fatigue,
listlessness and tiredness in adults and insomnia,
hyperkinesia, and aggression in children (and sometimes
in elderly patients). Subtle impairments of mood,
memory and learning can occur in all age groups.
dose varies from 90 to 300mg/day.
plasma half life of 3-4 days; can therefore be taken
as a single daily dose.
adults, it should be restricted to patients who cannot
tolerate first-line anti-epileptic drugs or as an
adjunct to first line therapy in refractory epilepsy.
can lead to temporary increase in seizure frequency.
Methylphenobarbitone (mephobarbital) is metabolized
to phenobarbitone (phenobarbital), and is given it twice
the dose of phenobarbitone but co gers no special advantage.
Primidone is metabolized to phenobarbitone (phenobarbital)
and phenylethlmalonamide, both of which are pharmacologially
active. Efficacy is similar to that of phenobarbitone.
1,4 benzodiazepine (like diazepam).
for generalized tonic-clonic and myoclonic seizures,
and generalized absence (petit mal) epilepsy and partial
more sustained and effective anti-epileptic activity
than diazepam (Valium) but tolerance develops.
as 0.5mg and 2.0mg tablets.
varies from 0.5-4.0mg three times daily.
plasma half life of 20-40 hours.
effects include sedation, irritability, and aggression.
patients benefit from long term treatment and nearly
half have an exacerbation of seizures when the drug
is withdrawn, particularly if pre-existing brain damage.
sedative than clonazepam and diazepam but still commonly
cause tiredness as well as depression and iritability.
a limited role as a long term anti-epileptic drug
(like clonazepam) but can do effective as a short
term treatment to 'cover' for special events such
as holidays, weddings and surgery and for catamenial
single dose if 10-30mg can also be helpful it taken
immediately after the first seizure in patients who
have regular clusters of generalized tonic-clonic
and partial seizures.
field defects are the most common serious adverse
effect, which limits the use of this drug.
voltage-gated sodium channels and reduces the release
of glutamate, an excitatory amino acid neurotransmitter
implicate in the pathophysiology of epilepsy.
in both partial and generalized tonic-clonic and absence
seizures in adults and children.
weak inhibitor of dihydrofolate reductase, so long
term therapy may disturb folate metabolism.
not significantly induce or inhibit hepatic oxidative
drug-metabolizing enzymes, nor affect the plasma concentrations
of concomitant anti-epileptic drug.
induced by anti-epileptic drugs that induce liver
enzymes such as carbamazepine, phenytoin and phenobarbiton
(phenobarbital) (half-life about 15 hours).
inhibited by sodium valproate (half-life about 60
half-life: about 29 hours (mean).
largely as an N-glucuronide conjugate.
as 5mg dispersible, 25mg, 50mg, 100mg, and 200mg standard
dose in patients not taking sodium valproate is 25mg
once a day for 2 weeks, followed by 100 mg per day
given in two divided doses for 2 weeks. Thereafter,
the dose should be increased to achieve the optimal
response. The usual maintenance dose is 200-400 mg
per day in two divided doses.
dose in patients taking sodium valproate is 25mg every
alternate day for 2 weeks, followed by 25mg once a
day for 2 weeks. The usual maintenance dose is 100-200mg
a day, given once a day or in two divided doses.
effects: a generalized maculopapular skin rash appears
within 4 weeks of generally starting treatment in
about 2-5% of patients. The incidence of rash is proportional
to the rapidity with which the drug is commenced.
It usually resolves after immediate withdrawal of
lamotrigine, after which the drug can be re-introduced
slowly. Rarely, serious skin rashes such as Stevens-Johnson
syndrome and angiodema have been reported. Some patients
complain of insomnia which can be minimized by giving
the second dose in the afternoon. Dose-related adverse
effects include dizziness, headache, diplopia, ataxia,
somnolence, nausea, asthenia, blurred vision and vomiting.
GABA-related amino acid.
of action: uncertain; it may after L-type voltage-depandent
when used in doses of 1800mg/day and as an 'add-on'
treatment in reducing the frequency of seizures by
more than half in about 40% of patients with complex
partial seizures and 60% with secondarily generalized
effective for absence seizures.
as 300mg and 400mg capsules.
maintenance dose: 1200-2400 mg/day, but higher doses
may be more effective.
not seem to interact with other anti-epileptic drugs.
effects on cognitive function may arise with higher
only for absence seizures; not effective against generalized
require a dose of 20-40 mg/kg per day but lower weight-related
doses are used in adults. In children over 6 years
of age, I is started with a dose of 250mg capsules
twice daily, increasing if necessary to three of four
effects include drowsiness and bone marrow depression.
sulfamate derivative structurally unique among anti-epileptic
decreases the number of action potentials in spontaneous
epileptiform bursts and reduces burst duration in
cultured hippocampal neurons, suppressing intrinsic
bursting of proximal subiculum neurons, and reducing
voltage-gated sodium currents in cultured cerebellar
elevated levels of excitatory amino acids, glutamate
as adjunctive therapy for partial seizures, in Lennox-Gastaut
syndrome and possibly some primary generalized epilepsies
such as drop attacks. It is not helpful for, and may
aggravate, absence seizures.
to be commenced gradually, with 25mg alternate days
at night or daily at night, other wise adverse cognitive
effects may be prohibitive. Cognitive disturbances
may manifest as slowed speech (and even mimic dysphasia
and dysnomia) and a vulnerability to behavioral disturbances
(i.e. cranky, not the same person). Other adverse
effects include weight loss, renal stones in 1% of
patients and a theoretical risk of teratogenicity.
derivative of nipecotic acid the potently and selectively
inhibits neuronal and glial GABA uptake. It specifically
inhibits the GABA transporter GAT-1 and interacts
only weakly with GABA receptors.
against partial and generalized convulsive seizures.
be contraindicated in generalized absence epilepsy.
A single agent (monotherapy) generally achieves satisfactory
seizure control without significant adverse effects
in about half of patients. Although another
15-20% attain better control with the addition of
a second anti-epileptic drug, it is often better to
strive for seizure control with monotherapy by gradually
introducing another agent and then gradually withdrawing
the initial agent. Overall, about 70% of patients
can be controlled with monotherapy.
of antiepileptic medication
drug withdrawal should be considered in patients who
have been free of seizures for 2 years or longer;
taking anti-epileptic drugs long term is incovenient
and costly, and associated with adverse cognitive
and behavioral effects, so it is essential to ascertain
whether they are still necessary or not.
withdrawal is not likely to be successful (i.e. seizures
- Late age to onset (>16 years of age).
- Mental retardation.
- Symptomatic epilepsy (i.e. underlying untreated
- Certain epileptic syndromes, such as juvenile myoclonic
unprovoked seizures have occurred.
- Family history of epilepsy.
- Slow wave activity or focal epileptiform activity
on EEG prior to medication
- History of atypical febrile seizures.
are no definite predictors of recurrence but EEG findings
of epileptiform activity prior to, or during, drug
withdrawal are highly predictive of a further seizure
if anti-epileptic medication is ceased. Relapses may
also occur in patients with normal EEGs however.
of any anti-epileptic drug must always be gradual
in a step-wise fashion, over at least 6 weeks (and
probably months for barbiturates) because abrupt withdrawal
may provoke rebound
AND OTHER PROTHROMBOTIC STATES
of the blood that predispose to recurrent venous and
possibly arterial thrombosis.
heterogeneous disorder, both in terms of its clinical
manifestations and range of autoantiboides, which is
characterized by thrombosis, recurrent miscarriage,
or both, in association with persistent positive laboratory
tests for antiphospholipid antibody : lupus anticoagulant
(LA), anticardiolipin antibody (ACA), or both, on repeated
studies. Thrombocytopenia is an occasional feature.
are a family of antibodies which are specific for
several plasma proteins, such as human prothrombin
and ß2 glycoproteins, which may bind to phospholipid
and ACA are different APAs but occur together in about
60% of patients with the phospholipid antibody syndrome;
in the remaining 40%, only one is present.
are immunoglobulins which interfere with one or more
of the in vitro phospholipid-dependent tests of coagulation
activated partial thromboplastic time, dilute Russell
viper venom time, dilute prothrombin time, and kaolin
clotting time. They therefore slow the rate of thrombin
generation and therefore clot formation in vitro.
are detected by immunoassay, most commonly enzyme-linked
1 - 40% or so of ischemic stroke/TIA patients have
raised circulating IgG or IgM anticardiolipin antibodies
and/or the lupus anticoagulant, depending on the selection
of patients, the timing of the blood sample after
the onset of cerebral ischemia, the laboratory methods,
and what level is deemed 'normal'. However, only a
few of these patients have some or all of the constellation
of features known as the APA syndrome.
: any age.
are typically 'bland' and may be found in vessels of
any size and on heart valves, such as the mitral valve
leaflets. There is no evidence of inflammation of the
paradoxical association between the presence of autoantibodies
with in vitro anticoagulant effects and the occurrence
of a prothrombotic state is not fully understood. Patients
with antiphospholipid syndrome have evidence of persistent
coagulation activation and, as stated above, vascular
occlusion is due to thromboembolism or embolization
from sterile vegetation on heart valves, and not vasculitis.
It is unlikely that a single prothrombotic mechanism
operates. Possible mechanisms include :
of the protein C system : the most likely cause of
venous thrombosis : APAs interfere with activated
protein C down-regulation of factors Va and VIIIa,
resulting in an acquired activated protein C resistance.
of the antithrombin III heparin sulfate down regulation
of serine proteases : some APAs have specificity for
heparin sulfate found on the surface of endothelial
of tissue factor expression by endothelial cells.
some cases the APAs may represent an epiphenomenon.
No evidence of other underlying disease.
with rheumatic and connective tissue disorders : systemic
lupus erythematosus (SLE) : about 30 - 40% of patients
with SLE have LA ; rheumatoid arthritis ; systemic
sclerosis ; temporal arteritis ; Sjogren's syndrome
; psoriatic arthropathy ; Behect's syndrome; others.
vascular site can be affected so there is a wide range
of clinical manifestation :
syndrome : livedo reticularis, stroke-like episodes
ulceration of the ankles and skin necrosis.
stroke, or multifocal encephalopahty due to arterial
or venous thrombosis in any sized vessel. Venous thromboembolic
events account for about 70% of cases and arterial
events the remaining 30%. The most common site for
arterial thrombi is the cerebral circulation.
- like headaches.
spontaneous miscarriage/fetal loss due to intrauterine
death in the latter part of the first trimester or
early second trimester.
foetal growth retardation.
- onset pre - eclampsia.
Post - infectious thromboembolic events.
for Antiphospholipid Syndrome or any other
Suspected Procoagulant state (Thrombophilia)
(<50 years) and no other cause found for TIA or
history or family history of premature arterial or
venous thrombosis, especially if unusual sites (cerebral,
mesenteric, hepatic veins).
history of recurrent miscarriages.
full blood picture or blood film (e.g., thrombocytopenia).
positive : may be a false positive in the presence
of ACAs because cardiolipin is the antigen used in
the VDRL assay. However, the VDRL is positive in only
about 25% of patients with APLAb.
blood count and film.
assays for lupus anticoagulant (LA)
partial thromboplastin time (APTT) : lacks sensitivity
but remains the most appropriate screening test for
the LA. A prolonged APTT that fails to correct when
affected plasma is mixed with normal plasma implies
inhibition of the clotting system rather than deficiency
of a component, and is the laboratory hallmark of
Russell's viper venom time (dRVVT) : prolongation
of the dRVVT will not correct with the addition of
normal plasma in the presence of LA. For confirmation,
a platelet neutralization procedure, to show the dependence
of phospholipid inhibitors, should be performed.
clotting time test : also detects LA, but it is not
as sensitive as the dRVVT, and sensitivity is highly
thromboplastin inhibition test.
are indirect coagulation assays sensitive to the phospholipid-dependent
steps of blood coagulation. At least tow assays, with
sensitive reagents and techniques must be used, most
commonly the APTT with another test.
antibody (ACA) : detected by means of solid-phase
immunoassay, such as enzyme linked immunosorbent assay
(ELISA) or raido immunoassay (RIA), employing cardiolipin
or other negatively charged phospholipids as the antigen
to measure antibody concentration and binding avidity.
phospholipids, e.g., phosphatidyl serine.
to ß2 GPI.
thrombophilia diagnostic blood tests
S antigen level.
V Leiden genetic analysis or activated protein C resistance
G202 10A mutation.
protein levels, serum protein electrophoresis and
plasma viscosity : indicated in patients with elevated
ESR or suspected hyperviscosity syndrome.
electrophoresis/sickle test : indicated in appropriate
racial groups to detect sickle cell trait or disease.
diagnosis is usually established from routine first
line investigation and standard thrombophilia screening
and diagnostic tests.
be diagnosed on the basis of a single raised titer of
ACA in the serum. The titer must be substantially raised
on several occasions and associated with not just cerebral
ishcemia but also with some combination of deep venous
thrombosis, recurrent miscarriage, livedo reticularis,
cardiac valvular, thrombocytopenia and migraine.
sequential steps are necessary to establish the diagnosis
of LA :
1. Demonstration of an abnormal phosopholipid (PL) dependent
coagulation test (e.g., APTT, dRVVT).
2. Proof that the abnormality in step 1 is due to an
3. Establishing the PL-dependence of the inhibitor.
4. Ruling out other coagulopathies.
stroke due to a procoagulant state
can be very difficult to attribute confidently the cause
of the ischemic stroke to the hematologic disorder if
the patient has other disease that could have caused
More often than not, the hematologic disorder is one
of several factors predisposing to thrombus formation,
such as coexistent activated protein C resistance, or
coexistent athero-thrombosis, trauma or dehydration.
Irrespective, the hematologic disorder frequently needs
treating in its own right.
; no controlled trials of aspirin, anticoagulants, or
immunosuppressive therapy have been undertaken.
term anticoagulant therapy, INR : 2.5, if risks considered
to be outweighed by benefits. Otherwise antiplatelet
24 000 units per day s.c. and aspirin 75 mg per day.
Low molecular weight heparin may cause les sosteoporosis,
heparin-induced thrombocytopenia, and bleeding events
than standard heparin and does not require blood monitoring.
but limited studies suggest a high rate of recurrent
stroke and other vascular events in patients with ischemic
stroke and the antiphospholipid syndrome.
Quantitive abnormalities of formed blood
rubra vera (primary polycythemia) :
- Hematocrit >0.50 in males and >0.47 in females,
provided the patient is rested, normally hydrated,
and the blood has been taken without venous occlusion.
- Raised red cell mass.
- Increased whole blood viscosity, raised platelet
count, and enhanced platelet activity, may cause TIAs,
cerebral infarction and intracranial hemorrhage.
(iron deficiency and presumably other types) :
- If severe, usually causes non-specific neurologic
symptoms such as generalized weakness, poor concentration
and faintness but in the presence of severe arterial
disease, it may provoke focal cerebral ischemia.
- May predispose to cerebral arterial or venous occlusion
because of increased whole blood viscosity.
- More commonly is associated with intracranial hemorrhage
because of the hemostatic defect or CNS leukemic infiltration.
L-asparaginase treatment for leukemia can cause both
cerebral ischemia and hemorrhage.
- can present like a stroke but the neurologic involvement
soon becomes diffuse and progressive.
- Platelet count >500 x 1009/1, causes arterial
and venous thrombosis.
- Headache with transient focal and non focal neurologic
disturbances are the most common neurologic symptoms.
- Occasionally, platelet function is defective predisposing
- Other causes of thrombocytes should be excluded:
malignancy, splenectomy or hyposplenism, surgery and
other trauma, hemorrhage, iron deficiency, infections,
polycythemia rubra vera, myelofibrosis and leukemia.
abnormalities of formed blood elements
cell (SC) disease :
- Tschemic stroke is common in homozygotic children
and young adults ; intracranial hemorrhage may also
- Stroke is rare in heterozygotic adults, and usually
in the context of a hypoxia - provoked sickle-cell
- Small and large arteries, and veins, are occluded
by thrombi as a result of the rigid red blood cells,
raised whole blood viscosity, thrombocytosis, impaired
fibrinolytic actiivty, and arterial stenosis due to
fibrous profileration of the intima; the last can
be detected in the MCA with transcranial doppler and
is predictive stroke.
- may also be complicated by stroke.
nocturnal hemoglobinuria :
- very rare :
- intracranial venous thrombosis is more common than
- Anemia, abdominal pain, recurrent deep venous thrombosis,
dark urine, hemolysis and a low platelet and granulocyte
count are recognized features.
macroglobulinemia, multiple myeloma and perhaps cryoglobulinemia
- Most commonly cause the 'hyperviscosity syndrome',
a global encephalopahty characterized by headache,
ataxia, diplopia, dysarthria, lethargy, poor concentration,
drowsiness and coma, visual blurring, and deafness.
The retina shows dilatation and tortuosity of the
veins, venous occlusions, papilledema and hemorrhages
; similar symptoms may also be due to uremia, hypercalcemia
or lymphoma complicating the paraproteinemia.
- Arterial or venous cerebral infarction may occur
if vessels become occluded by acidophilic material
which are probably precipitants of the abnormal plasma
- Intracranial hemorrhage also occurs due to reduced
Impaired reactivity of platelets, perhaps as a result
thrombin and activated factors, X, IX, XI, and XII
(but not VII).
important mediator of the anticoagulant effect of
heparin ; heparin increases the activity of antithrombin
III by 100-fold. Indeed, heparin resistance is a clue
to low antithrombin III activity.
may be inherited, or acquired as a result of severe
liver disease, intravascular thrombosis, the nephrotic
syndrome, or use of medications such as L-asparaginase
of the oral contraceptive pill.
vitamin K-dependent plasma protein that is synthesized
in the liver in an inactive form.
activated by thrombin in the presence of calcium,
it inhibits the procoagulant activity of factor Va
and factor VIIIa and inactivates plaminogen activator
may be inherited as an autosomal dominant trait, or
acquired as a result of warfarin therapy or severe
liver disease, disseminated intravascular coagulation
and acute thrombosis. Accounts for about 10% of cases
of venous thrombosis.
to activated protein C is commonly used by an autosomal
dominant inherited mutation in the factor V gene,
which was disocvered in Leiden, the Nehterlands, in
1994; hence the inherited defect is called the Leiden
factor V mutation. Accounts for 15-50% of cases of
cofactor of protein C ; free protein S increases the
affinity of protein C for phospholipid and enhances
the inactivation of factors Va and VIIIa by activated
may be inherited as an autosomal dominant trait, or
acquired as a result of warfarin therapy, severe liver
disease, and the nephrotic syndrome. Accounts for
about 5% of cases of venous thrombosis.
deficiency of coagulation inhibitors, activated protein
C resistance, and hereditary abnormalities of fibrinolysis
: plasminogen deficiency and / or abnormality
in which spontaneous and recurrent venous thrombosis
and rarely, arterial thrombosis are presenting or
relevance of low levels of these natural anticoaulants
in the etiology and prognosis for many patients with
ischemic stroke of 'no other cause' is uncertain so
the potential benefits of any treatment are uncertain.
arise attributing the cause of the stoke to one of
these conditions :
- Familial deficiency of antithrombin III, protein
C and protein S are not uncommon in the general population
so the hypercoagulation state may be coincident and
not a sole or contributing cause of the stroke. Therefore,
the patient must be properly assessed and other potential
causes of ischemic stroke must be considered and excluded
- Low levels of these coagulation factors may be caused
by the acute stroke itself or its treatment the acute
stroke itself or its treatment so the results must
be confirmed by repeated testing on several later
- Acute stroke is associated with activation of procoagulant
and fibrinolytic pathways, as manifest by a significant
decrease in functional antithrombin III and plasminogen
and an increase in thrombin-antithrombin complex,
total protein S, tissue plasminogen activator, plasminogen
activator inhibitor 1, and D-dimer.
II (prothrombin) mutation (G20210A)
A mutation in the prothrombin gene results in elevated
prothrombin levels and carries a nearly threefold increased
risk of venous thrombosis, but does not appear to be
associated with an increased risk of arterial thrombosis
and ischemic stroke.
States of Uncertain cause
thrombocytopenic purpura (TTP)
hemolytic anemia, thrombocytopenia, fever, and renal
failure are characteristic.
microthrombi cause infarcts in many organs, including
symptoms in 90% of cases, and are the presenting symptoms
encephalopathy, rather than a stroke syndrome, is
the usual presentation.
patient is unwell with malaise, fever, skin purpura,
renal failure, proteinuria, hematuria, thrombocytopenia,
hemolytic anemia and fragmented red blood cells.
CT may be normal, or show infarcts, or occasionally
intracerebral hemorrhage, more commonly due to heparin
treatment than the disease itself.
status epilepticus is another treatable cause of altered
mental status in these patients.
abnormalities of coagulation of firbinolysis are commonly
found, particularly in patients with metastases.
About 2% of patients with cancer have a TIA or stroke
at some stage.
causes of ischemic stroke or TIA include :
coagulopathy mediated by intravascular mucinosis,
low-grade disseminated intravascular coagulation,
or the patient's chemotherapy.
of non-infected heart valve vegetations.
or septic emboli, sometimes with aneurysm formation.
compression or invasion of neck arteries.
of neck arteries.
as an acute or subacute global encephalopathy, rather
than stroke-like episodes, in a very sick patient.
brain scan reveals widespread hemorrhagic infarcts
platelet count, low plasma fibrinogen, raised fibrin
degradation products and raised D-dimer point to the
and the puerperium
relative risk of stroke in the pregnant woman is 13
times the risk in the non-pregnant woman of the same
age, but he absolute risk of stroke in the last trimester
of pregnancy and the puerperium is no more than 30 per
100 000 deliveries. About three-quarters of ischemic
strokes are due to arterial occlusion and one quarter
venous occlusion. Causes include :
embolism from the venous system of the pelvis of legs.
dissection during labor.
or fat embolism
estrogen dose oral contraceptive use is associated
with a threefold increased risk of TIAs and stroke.
But the absolute risk is very small.
risk is greater in women who are older, who smoke
and who have other vascular risk factors such as hypertension.
high doses of estrogen given to elderly men for treatment
of prostatic cancer and male survivors of MI increase
their risk of vascular death.
may paradoxically lead to thrombus formation and thrombocytopenia
by two mechanisms :
I consists of a transient decrease in platelet count
1 - 5 days after heparin is started and is thought
to be due to reversible clumping of platelets.
II is a persistent depression of the platelet count
beginning 3-22 days after the introduction of heparin
which is thought to be mediated by IgG antibodies
against a heparin -platelet membrane complex.
be complicated by ischemic stroke, perhaps due to 'hypercoagulability'
: loss of antithrombotic proteins in the urine.
and intravenous immunoglobulin
cause hypercoagulability and ischemic stroke, perhaps
by altering blood viscosity, hemorrheology, platelet
aggregability or clotting factor levels.
cause ischemic stroke but is more likely to cause defibrination
endocarditis (stenosis or regurgitation).
thrombotic (marantic) endocarditis.
- Sacks endocarditis.
stenosis / sclerosis/ classification.
heart disease (particularly with right to left shunt)
manipulation / surgery / catheterization / valvuloplasty
risk of embolism.
of potential cardiac sources of embolism in patients
with first-ever ischemic stroke*
AF : 13%.
- Without rheumatic heart disease : 12%
- With rheumatic heart disease : 1%.
regurgitation : 6%.
(<6 weeks) myocardial infarction : 5%.
valve : 1%.
stenosis : 1%.
embolism : 1%.
of the above : 20%.
sources of uncertain significance : aortic stenosis/
sclerosis ; mitral annulus calcification, mitral valve
prolapse and son on : 11%.
PAG, Warlow CP, Jones LN, Starkey IR (1989) Predisposing
factors for cerebral infarction : The Oxford Community
Stroke Project. BMJ, 298 : 75 - 80.
all cardiac sources of embolism pose equal threats.
all emboli are of the same size of the same material.
The most common cause of cardioembolic stroke, accounting
for up to 12% of all ischemic strokes, and an even greater
proportion of ischemic strokes in the very elderly where
its frequency in the population is highest. Atrial fibrillation
is the cause of stroke in many of these patients but
it is not always the cause because :
possible causes of stroke, which may also be the cause
of the AF, such as ischemic heart disease and hypertension,
are present in about 20% of fibrillating stroke patients.
AF patient have lacunar syndromes.
about 13% of non-rheumatic fibrillating patients have
detectable thrombus in the left atrium and it is unknown
if these patients have a higher stroke risk than those
without detectable thrombi.
a few case the AF is caused by the stroke.
average absolute risk of stroke is uncoagulated non-rheumatic
AF patients is about 5% per annum and about 12% per
annum in unanticoagulated firbillating TIA / stroke
patients. The risk of stroke among patients in AF is
variable ; some are at particularly high risk and others
at particularly low risk of embolization.
factors for embolization in AF patients
risk : no other detectable heart disease.
mitral valve disease.
cerebral or systemic embolic event.
ventricular systolic dysfunction.
left atrium defined by echocardiography.
echo contrast in the left atrium, probably a consequence
of blood stasis.
atrial thrombi, left atrial appendage size and dysfunction,
and various hemostatic variables are perhaps adverse
risk factors also.
AF : probably depends on frequency and duration of
episodes of AF
heart disease is common in patients with TIA and ischemic
stroke : about 20 - 40% have a past history of MI or
current angina. Stroke may occur in up to 5% of patients
with recent acute myocardial infarction, due to :
of left ventricular mural thrombus.
hemorrhage secondary or thrombolysis, anticoagulants
of catheter thrombus during coronary angioplasty /
non-cardiac cause of stroke.
the acute period, the risk of stroke is much lower,
about 1% in the first year, perhaps higher if there
is persisting left ventricular thrombus. Chronic left
ventricular aneurysm after MI often contains thrombus
but embolization is uncommon.
risk of embolism is above 2% per annum for all prosthetic
valves, provided patients with mechanical valves are
valves have a higher risk of embolism that tissue
valves, but there is no difference in stroke risk
between the difference in stroke risk between the
different types of mechanical valve.
Bjork - Shiley tilting disc valves have disintegrated
and embolized pieces to the brain.
mitral valves are more prone to thrombosis than arotic
enodcarditis is a potential risk for any type of prosthetic
mitral stenosis / regurgitation is a well recognized
cause of left atrial dilation causing thrombus formation
and embolism to the brain.
valves also degenerate so even patients in sinus rhythm
who have no thrombus in the left atrium are at risk
of embolism of degenerate and sometimes calcific fragments
of valve into the circulation.
may also occur as a result of infective endocarditis
and intracerebral hemorrhage due to anticoagulation
in these patients.
sclerosis/ calcification of the arotic and mitral valves
These may also be a source of embolism in some patients
but unless calcific emboli are seen in the retina or
on CT it is difficult to attribute confidently the TIA
or ischemic stroke to this condition, which is very
common in normal elderly people.
valve (or leaflet) prolapse
mitral valve prolapse is not a cause of embolism from
the heart to the brain. It is only likely to be relevant
to the etiology of an ischemic stroke or TIA if it is
complicating infective endocarditis, AF, gross mitral
regurgitation, or thrombus in the left atrium. Prolapse
may be familial and associated with various inherited
disorders of connective tissue.
cardiomyopathies are well recognized causes of intracardiac
thrombus, particularly the dilated type rather than
hypertrophic subaortic stenosis. Many are familial.
be associated with intracardiac thrombus and embolism,
particularly if bradycardia alternates with tachycardia,
or the patient is in AF.
be complicated by thrombus and embolism to the brain.
associated with a patent foramen ovale and so has
the potential for paradoxical embolism from the venous
system. The presence of both atrial septal aneurysm
and patent foramen ovale increases the risk of recurrent
embolism from the venous system, or right atrium
; present in about 10% of normal people.
the uncommon cause of ischemic stroke ; although bubbles
can be shown to move from the right to the left side
of the heart frequently, it must be rare for venous
thrombus to do so without also going to the lungs,
or at least to be able to make a certain diagnosis
of such an event during life.
recent study of 581 patients, aged 18 - 55 years,
with ischemic stroke of unknown origin in the preceding
3 months has shown that after 4 years the risk of
recurrent stroke was 2.3% among patients with patent
foramen ovale alone, 15.2% among patients with both
a patent foramen and atrial septal aneurysm, and 4.2%
among patients with neither of these cardiac abnormalities.
There were no recurrences among patients with atrial
septal aneurysm alone.
arterial venous malformation
in isolation or as part of hereditary hemorrhagic
are clubbing, cyanosis, hemoptysis, bruit over the
chest and a 'coin lesion' on the chest x-ray.
are the most common heart tumor and most occur in
the left atrium.
may cause :
- Constitutional upset : malaise, weight loss, anemia,
raised ESR and hypergammaglobulinemia.
- TIA or ischemic stroke : embolism of tumor or complicating
- Primary intracerebral or subarachnoid hemorrhage
: myxomatous emboli to sites of earlier symptomatic
or even asymptomatic embolic occlusions can cause
fusiform and irregular aneurysmal dilatations at these
sites which can rupture.
hydatid cysts and intracranial calcification due to
primary oxalosis are even rarer causes of embolism
to the brain, the former with the subsequent development
of intracranial cysts.
chest injury :
be associated with left ventricular thrombus and embolization.
stroke occurs when large emboli impact permanently
in the internal carotid artery or trunk of the MCA.
anterior circulation infarction occurs when smaller
emboli impact in a distal branch of the anterior of
circulation infarction occurs when moderate or small
sized emboli impact in the tip of the basilar artery
or one of its branches.
of the brain or eye.
: Some emboli do not occlude arteries completely or,
if they do, there is sufficient collateral circulation
to maintain tissue integrity.
following strongly suggest embolism from the heart
particularly calcific emboli, visible in the retina.
infarction in other organs.
CT brain Scan
or multiple wedge-shaped cortical /subcortical infarcts,
with or without hemorrhage transformation.
density in the middle or basilar artery on the non-contrast
CT suggestive of blood clot or calcium.
in the territory of the tip of the basilar artery
or superior cerebellar artery.
(electrocardiograph) : AF, IHD
cortical / subcortical cerebral infarcts in different
cortical / subcortical infarct or hemorrhage infarct,
or striatocapsular infarct and no carotid lesion on
EKG or CXR evidence of heart disease.
<45 years and no cause found for TIA or stroke.
echocardiographic technique for detecting various cardiac
and aortic valve vegetations.
heart valve malfunction.
arch atherothrombosis / dissection.
Transcranial doppler. Detection of intravenously injected
air bubbles is less invasive, more specific, but not
quite so sensitive ; galactose particle suspension increases
Patients may have two or more competing causes of cerebral
ischemia, such as carotid stenosis and atrial fibrillation,
so one cannot always be sure which is the cause in an
from the heart to the brain or eye
More likely to be the cause of ischemic stroke or TIA
identified cardiac source of embolism, particularly
one with a substantial embolic risk.
events in more than one arterial territory, particularly
if more than one organ is involved.
evidence clinically or by angiography of arterial
disease in the neck.
emboli in the retina.
emboli on brain CT
vascular risk factors
other explanation for the stroke.
flow infarction / ischemia
transformation of the infarct.
risk of embolism
or rheumatic AF.
risk of embolism
foramen ovale with no evidence of deep venous thrombosis.
Of acute ischemic stroke of suspected cardioembolic
anticoagulants very likely to be worthwhile
Start as soon as possible
TIA or ischemic stroke with complete recovery within
1 -2 days + high risk of embolism.
time to start unclear
Non-disabling ischemic stroke, no hemorrhagic transformation
of the infarction, and AF.
anticoagulants probably worthwhile
Best time to start anticoagulants unclear
MI within past few weeks and confirmed ischemic stroke
ischemic stroke and AF.
or no antithrombotic therpay ; anticoagulants not worthwhile
Law risk of recurrent cardioembolic stroke without anticoagulants
disease with a low risk of embolism
non-cardiac lesion more likely cause of cerebral infarct
: severe ipsilateral carotid stenosis ; likely disease
of intracranial small vessels.
to gain from long term anticoagulation
cholesterol embolization syndrome
severely disabled before the stroke.
or predicted to be severely disabled in the long term.
risk of cererbal hemorrhage on anticoagulants
cerebral infarct with midline shift and / or evidence
of major hemorrhagic transformation on brain CT.
to comply poorly with anticoagulation therapy and
its monitoring after discharge.
depend on individual circumstances and are seldom absolute.
severe hypertension :
- Systolic pressure over 26.7 kPa (200 mgHg).
- Diastolic pressure over 16 kPa (120 mgHg).
bleeding lesions :
- Active peptic ulcer.
- Esophageal varices.
- Intracranial aneurysms
- Proliferative retinoapthy.
- Recent organ biopsy.
- Recent trauma or surgery to head, orbit, spine.
- Recent stroke, but patient has not had a brain CT
scan or MRI.
- Confirmed intracranial or intraspinal bleeding.
- History of heparin - induced thrombocytopenia or
warfarin planned :
- Homozygous protein C deficiency.
- History of warfarin - related skin necrosis.
- Uncooperative / or unreliable patients.
- Risk of falling.
- Unable to monitor INR.
effects of heparin
Local minor complications of subcutaneous heparin at
complications of intravenous heparin at cannula site
at cannula site.
patient mobility because of infusion lines and pump.
- Type I : dose and duration related, reversible,
mild, usually asymptomatic, not serious and often
- Type II : idiosyncratic, allergic, severe. Affects
3 - 11% of patients treated with intravenous heparin
and less than 1% of patients treated with subcutaneous
low frequency postural tremor which is absent at rest
and not associated with the clinical signs of parkinsonism
or other neurologic deficits.
8 (95% CI : 4 - 14% 100 000/year.
(lifetime) : 0.3 - 1.7%.
of onset : bimodal : young adults (median about 15
years) and elderly.
: M = F.
No characteristic pathological or biochemical findings.
: autosomal dominant inheritance (50% of patients)
via a penetrant autosomal dominant gene. The responsible
gene(s) remain unknown.
: probably the same entity as hereditary ET.
central source of oscillation that is influenced by
somatosensory reflex pathways.
olivocerebellar oscillation and activation of cerebellothalamocortical
pathways probably have an important role in the generation
and transmission of the tremor because :
- functional imaging studies reveal increased olivary
glucose metaboism and increased blood flow bilaterally
in the cerebellum and red nuclei and contralaterally
in the globus pallidus, thalamus and primary sensorimotor
cortex of patients with essential tremor.
- Lesions of the ipsilateral cerebellum diminish essential
- Ventrointermediate thalamotomy or microstimulation
is thought that the cerebellum introduces an error
in the timing of muscle bursts during voluntary movement,
and repeated corrective movements lead to tremor.
or action tremor of the finer, hands, and forearms
when they are help outstretched against gravity, or
used for specific, usually visually-guided, manual
- 12 cycles per second.
but may be asymmetric.
body parts involved in about half of cases : the head,
tongue, lips, voice, face, and trunk; and postural
tremor of lower limbs.
but the amplitude may fluctuate.
by emotional upset such as excitement and anger.
temporarily by alcohol, in small quantities, in about
half of patients.
sign (a rhythmic resistance to passive movements of
a limb about a joint when there is a voluntary action
of another body part).
of 'terminal' tremor due to cerebellar disease
(3-5 cycles per second).
in a horizontal plane.
present at rest.
with action and progressively increases during a voluntary
kinetic tremor, which is tremor during any form of
movement; 'intention' or 'treminal' tremor is the
pronounced exacerbation of kinetic tremor toward the
end of goal-directed movement.
head may be affected, but usually as titubation
to propranolol and diazepam.
6 (3-7) cycles per second.
increased with posture or action.
the limbs and head.
to levodopa and anticholinergic medications.
-10 cycles per second
and limbs involved.
: appears 8 - 12 hours after last drink.
to diazepam and chlordiazepoxide.
derangements, such as thyrotoxicosis
- 20 cycles per second.
and upper limbs involved
and signs of metabolic disturbance.
to correcting metabolic disturbance.
Physiologic Tremor (EPT)
rapid 8 - 12 Hz small amplitude, barerly visible, postural
tremor, typically of the upper limbs, which occurs as
a normal phenomenon during muscle contraction. EPT manifests
as apostural and kinetic hand tremor. iT can be difficult
to distinguish between EPT and early stages of hereditary
ET in a young person. There is no current reliable way
of making this distinction but the family history can
be a clue.
is directed to correction of the underlying medical
or cessation of any contributing drug. If idiopathic
EPT becomes inconvenient or socially embarrassing, propranol
may be helpful.
high frequency bilaterally synchronous tremor of legs
and trunk when standing still.
not be detected easily without palpation of the leg
may only complain of unsteadiness when standing.
to clonazepam and, in some cases, pramipexole ; ET
does not respond to clonazepam.
position - specific or task-specific tremors (including
occupational tremors and primary writing tremor)
the appearance of localized ET but the task specificity
respond to anticholinergics.
several tremor with features of a parkinsonian rest
marked exacerbation during movement.
always associated with lesions of the red nucleus
but may result from lesions of the ipsilateral cerebellar
dentate nucleus or superior cerebellar peduncle in
commonly seen in multiple sclerosis.
asymmetric postural tremor is probably a form of dystonia.
voice tremor may be due to laryngeal dystonia and
other dytonias of the vocal apparatus.
variations in tremor frequency.
and inconsistent behavioral characteristics.
or social factors
A clinical diagnosis based on the long duration of symptoms
; positive family history ; lack of rigidity, bradykinesia
or other neurologic signs ; symmetry; and alcohol responsiveness.
Diagnostic criteria (predominantly for research purposes)
bilateral tremor on maintaining posture, typically
of the outstretched upper limbs of more than 5 years
duration. It is absent at rest, not made strikingly
worse with movement and is not associated with extrapyramidal
or cerebellar signs.
definite evidence of sudden onset.
direct or indirect trauma to the brain, spinal cord
or relevant part of the peripheral nervous system
in the preceding 3 months.
recent exposure to tremorgenic drugs.
in a state of drug withdrawal.
neurologic examination other than tremor.
history or clinical evidence suggestive of psychogenic
origins of tremor.
evidence of stepwise deterioration.
: same as above
more than 3 years
evidence of isolated or localized tremors such as
primary orthostatic tremor, isolated voice tremor,
isolated position-specific or task-specific tremor,
or isolated tongue or chin tremor.
Patients satisfy the criteria for definite or probable
tremor but exhibit other neurologic disorders or other
neurologic signs of uncertain significance.
Monosymptomatic and isolated tremors of uncertain relation
tremors and isolated tremors of the voice, tongue, head
and legs have all been considered part of the spectrum
of ET but it may be that the label 'ET'' is not appropriate
for these diverse disorders whose etiologies are not
Not all patients require treatment ; only those severely
Propranolol and primidone have been shown in controlled
trials to afford a partial reduction in tremor amplitude
in about two-thirds of cases, and are the mainstay of
10 - 40 mg mane or bd, or metroprolol 25 mg or bd,
or metoprolol 25 mg twice daily with 25 mg increments
to effect or until a maximum of 50 mg three times
daily, leads to variable improvement. About half of
patients experience a reduction in tremor amplitude
of up to 50%. The effect is greatest on postural limb
tremor. However, not all patients are helped and the
tremor is seldom abolished. There is little point
in prescribing a nocte dose. Adverse effects and relative
contraindications for propranolol include heart failure,
bradycardia, hypotension and asthma. The mechanisms
of action of propranolol is thought to be blockade
of peripheral skeletal muscle ß2 receptor. ß1
blockade is less effective than propranolol.
50 - 250 mg daily if necessary, if propranolol is
ineffective or contraindicated. May be as effective
as beta blockers but adverse effects are common. Care
is required when introducing primidone because of
nausea, sedation and unsteadiness, which may be sufficiently
severe to warrant stopping the drug. A low starting
dose minimizes adverse effects, particularly if taken
in the evening before retiring. There appears to be
no added benefit to increasing the daily dose beyond
in doses of 0.1 - 0.9 mg daily.
with alcohol responsive tremors may find judicious
use of alcohol to be helpful before social engagements.
drugs that may be helpful but also have adverse effects
include clonazepam, alprazolam, flunarizine, clozapine,
nicardipine, and carbonic anhydrase inhibitors such
as methisnozole and acetazolamide. Gabepentin is currently
undergoing evaluation for the treatment of tremor.
Botulinum toxin can be injected locally into the splenius
capitus to reduce 'no-no' tremor without adverse effects,
but it does not work well when injected into forearm
muscles for wrist tremor.
thalamotomy is usually employed only for the most
severe tremors because of the significant risks of
adverse effects, particularly with bilateral operations.
About 70-90% of patients experience some relief from
stimulation with chronically implanted electrodes,
positioned with the use of intraoperative recordings
in the nucleus ventralis intermedius of the thalamus,
confers lower risk. High frequency stimulation, controlled
by a subcutaneously implanted box on the chest wall,
is thought to produce its beneficial effect by inducing
depolarization block. Good results have been achieved
in the vast majority of patients. It is hoped that
the benefits will be maintained with longer term follow-up.
randomized comparison of thalamotomy and thalamic stimulation
found that both were effective in relieving drug resistant
tremor but thalamic stimulation produced greater functional
improvement. Bilateral thalamic stimulation may have
a lower complication rate than bilateral thalamotomy.
Dysarthria and aphonia complicate up to 20 - 25 % of
bilateral thalamic lesions, though with stimulation
speech improves when the stimulator is switched off.
is slowly progressive but seldom becomes severe.
de-efferented state whereby patients are aware of themselves
and their environment but are unable to respond due
to loss of motor and speech function.
supranuclear lesion of the descending corticospinal
tracts, usually in the ventral portion of the brain
stem, below the level of the IIIrd cranial nerve nuclei,
causes paralysis of the muscles innervated by the
lower cranial nerves and peripheral nerves.
widespread nuclear or infranuclear (lower motor neuon)
disease of motor nerves.
Ventral brain stem lesion
pontine myelinolysis, following profound hyponatremia
and consciousness are preserved because the brainstem
tegmentum, including the reticular formation and oculomotor
nerves and pathways are spared.
to open the eyes and move them, and blink, in order
to try and communicate.
or MRI brain scan : ventral pontine or midbrain lesion.
investigations, as appropriate, to ascertain the cause.
is clinical, based on the presence of total paralysis
of the limbs and muscle innervated by the lower cranial
nerves, but with the ability of the patient to open
and close the eyes voluntarily and in response to commands,
and to respond to verbal and sensory stimuli by blinking.
can see, hear and feel everything so are sensitive to
what staff are saying. They are also very frustrated
that they cannot move.
of complications of immobility : pneumonia, deep vein
thrombosis, contractures, urinary tract infection.
: physiotherapy, swallowing and speech therapy, occupational
therapy, psychologic support and therapy.
is poor. Some patient recover, usually with residual
A symptoms complex, or syndrome, than manifests as discrete
episodes of headache associated with other features
of sensory sensitivity.
· Women : 33% (95% CI:31 - 37%).
· Men : 13% (95% CI : 12 - 16%).
· Women : 25% (95% CI : 23 - 29%).
· Men : 7.5% (CI : 7 - 9%).
· Higher in Caucasians than Africian Americans,
· Onset is nearly always before age 50 years;
25% begin in childhood.
· Peak incidence at age 10 - 12 for males and
14 - 16 years for females.
· Peak prevalence at age 50 years for men and
35 years for females.
· Attacks commonly increase in frequency at the
menopause, but may decrease.
· Children : M- F
· Adolescents and adults : F>M = 2 - 3:1.
A combination of genetic factors and environmental factors
; first degree relatives of probands with migraine without
aura have a twofold increased risk of migraine without
aura compared with the general population ; the probandwise
concordance rate is higher in monozygotic than dizygotic
Largely genetic ; first degree relatives of probands
with migraine with aura have a fourfold increased risk
or migraine with aura compared with the general population
; the probandwise concordance rate is higher in monozygotic
than dizygotic twins. However, environmental factors
are also important as the pairwise concordance rate
is less than 100% in MZ twin pairs.
hemiplegic migraine (FHM)
A rare autosomal dominant subtype of migraine with aura.
Genes for FHM map of chromosomes 19p 13 and 1q but some
families with FHM do not link to either locus, indicating
genetic heterogeneity of FHM. The CACNa1A gene at 19p13
encodes the a subunit of a brain specific P/Q type voltage-dependent
calcium channel, suggesting that migraine may be a 'cerebral
Triggered by the action of a multitude of environmental
and biochemical factors on the cerebral cortex or hypothalamus;
the premonitory symptoms of elation, yawning or a craving
for sweet foods, experienced by about 25% of patients,
suggest hypothalamic activation.
stress and tension.
changes : fall in estradiol levels at menstruation
idiosyncrasies / allergies : rich foods, red wines,
specific dietary amines.
late in the morning.
such as alcohol, monosodium glutamate, and anti-anginal
activated cerebral cortex and hypothalamus stimulate
brain stem nuclei, dorsal raphe nuclei and locus coeruleus
and tirgger the trigeminovascular reflex which constitutes
serotonergic and noradrenergic pathways that project
from the brain stem to the cortical microcirculation
and the spinal trigeminal nucleus and spinal cord.
Axons of the first division of the trigeminal nerve,
which innervate the pain-sensitive intracranial structures,
depolarize as a result of direct neuronal activation
or vasodilation of dural and cerebral arteries, or both,
leading to central transmission of nociceptive pain
signals to bipolar neurons in the trigeminal ganglion
and on to the trigeminal nucleus in its most caudal
extent in the caudal medulla and the dorsal horn of
the spinal cord at C1 and C2. Impulses are then transmitted
to the ventroposteriomedial nucleus of the thalamus
via the quintothalamic tract, from where they are relayed
to the cortex.
Stimulation of the trigeminal ganglion leads to the
release of powerful vasodilator neuropeptides such as
calcitonin gene-related peptide from trigeminal neurons
that innervate the cranial circulation. This peptide
is not only a vasodilator but it also mediate a sterile
neurogenic inflammation within the dura mater.
aura and headache
the onset of aura, regional cerebral blood flow to the
clinically involved part of the brain is reduced by
about 20% and reduced neuronal activity spreads in a
wave across the cerebral cortex, usually beginning in
the occipital region and slowly moving forward.
Migraine headaches begins while regional cerebral blood
flow is reduced. Platelets in the blood release serotonin,
and this leads to platelet aggregation. During the headache,
the level of a vasodilator peptide. GGRP increases in
the external jugular venous blood, and some intracranial
arteries become dilated and inflamed. Vascular dilatation
and neurogenic inflammation is believed to be responsible
for the pulsatile nature of the headache.
Migraine attacks can be ameliorated by activating 5-hydroxytryptamine
1 D presynaptic receptors within the vessel wall, thus
blocking release of vasoactive neurpeptides, causing
vasoconstriction of certain cerebral and dural arteries,
and inhibiting depolarization of trigeminal axons, functionally
blocking activation of trigeminal perivascular nerve
one : prodrome
in 25 - 50% of migraineurs.
onset and evolution over up to 24 hours.
dulled perception, irritability, withdrawal, cravings
for particular foods , frequent yawning, elation and
two : aura
- 25% of migraine attacks are associated with aura.
symptoms most commonly : blurred vision, flashing
lights or shimmering zigzag lines of light, sometimes
around an area of impaired vision or blindness in
a part of the visual field of one or both eyes.
: tingling or pins and needles, or less commonly numbness,
in the face, arm, hand or leg.
: difficulty understanding and expressing specch.
onset, symptoms 'build up' or progress over 5 - 10
minutes, then subside within 5 - 60 minutes.
within 60 minutes by headache ; the aura may continue
to the headache phase.
three : headache
Present in most, but not all migraine attacks.
in two-thirds of patients, and bilateral in one-third.
region commonly, spreading to occipital region.
activity / movement.
tenderness on the affected side.
(90% of patients).
awareness of sensation such as smell and noise.
retention at onset, and polyuria as headache subsides.
- 72 hours.
2 - 6 hours in children, and 6 - 24 hours in adults.
four : postdrome
For up to 24 hours after the headache has subsided,
most migraineurs feel tired 'drained' or 'washed out',
with aching muscles. Others however, become euphoric
for a period of time.
Migraine is paroxysmal ; clearly defined episodes recur
as often as 4 - 6 times each month.
Family history of migraine is present in more than half
Less than 5 % of migraineurs,
Monocular, rather than binocular hemianopic visual disturbance.
of > 1 of the ocular cranial nerves, usually the
IIIrd nerve, at the height of a migraine headache.
paralysis usually resolves but may persist after recurrent
entity does not embrace a transient dilatation or
constriction of one pupil as this is quite commonly
seen during severe migraine attacks.
cause of the cranial neuropathy in ophthalmoplegic
migraine is probably transient ischemia of the cranial
Gradual onset and evolution over several minutes of
brainstem, cerebellar and visual disturbances, often
acompanied or followed by headache and syncope.
preceding or occurring with a migraine headache.
family history of hemiplegic migraine is often present
and the gene is located on chromosome 19 or 1.
focal neurologic symptoms persisting beyond 24 hours
after the cessation of migraine headache. Cranial
CT or MRI scan shows features consistent with cerebral
cause is probably arterial thrombosis, provoked by
arterial spasm and a procoagulant state.
Just before menstruation, plasma estradiol levels fall
rapidly below about 20 ng/ml which sets in motion a
series of changes that culminate in the onset of migraine
in about 60% of women migraineurs and exclusively at
that time in about 14%. Migraine is relieved by pregnancy
in about 60% of women, many, but not all, of whom have
a history of menstrual migraine.
and vomiting are common but the child may be unable
to describe the symptoms and may simply appear pale,
ill, limp, and inert, complaining of poorly localized
up to 38.5 C may be present so that the suspicion
of appendicitis or mesenteric adenitis often arises.
than accept a label of 'bilious attack' or 'periodic
syndrome', recurrent headaches or vomiting attacks
in children which may develop at times of excitement
or stress should be considered as possibly migrainous
and not psychosomatic.
Abrupt onset of headache ('thunderclap headache')
exertional or sex headache.
precipitous rise in blood pressure : drug induced
obstruction of the CSF pathways.
carotid or vertebral artery dissection.
or daily headache
headache : just headache, and sometimes mild photophobia
and phonophobia but no other features of sensory sensitivity.
migraine / tension headache.
- rebound headache : a periodic daily bilateral headache
that has gradually increased in frequency, and changed
in character from the typical migraine headaches,
in concurrence with increasing consumption and misuse
of analgesic drugs, particularly those which also
aura without headache (acephalgic migraine)
autosomal dominant arteriopathy with subcortical infarction
only be necessary if headache is suspected to be secondary
to another disorder.
symptoms' include :
- Onset above age 50 years.
- Aura without headache.
- Aura symptoms of acute onset without spread.
- Aura symptoms that are very brief or unusually long.
- Aura symptoms that are stereotyped.
- Sudden increases in migraine frequency or change
in migraine characteristics.
- High fever.
- Abnormal neurologic examination.
role of imaging in patients with suspected migraine
is to exclude structural causes for the headache such
as AVMs or tumors. A contrast enhanced CT scn is satisfactory
for this, and is usually normal. If MRI is performed,
the T2W image occasionally shows areas of altered
signal in the white matter which may be residual ischemic
changes following a recent or prolonged attack, or
may rarely be due to CADASIL. The appearance is non-specific
least 5 attacks.
last 4-72 hours if untreated or unsuccessfully treated.
least two of :
- Unilateral headache.
- Pulsating headache.
- Moderate or severe headache.
- Headache aggravated by routine physical activity.
least one of :
- Nausea, with or without vomiting.
Avoid precipitating / triggering factors
Identify these by keeping a dairy if necessary.
of the acute migraine attack
in a quiet dark room.
fluids if severely dehydrated.
analgesics and antiemetic / prokinetic compounds
as early as possible, and wait 40 minutes. If headache
persists, try a specific treatment such as ergotamine
1 mg capsule or sumatriptan 50 mg tablet, and wait >
1 hour. If headache persists, repeat.
and prokinetic compounds if nausea and vomiting are
a problem. Metoclopramide is preferable because it improves
the oral absorption of other drugs and may have a favorable
central effect. If vomiting is severe, suppositories
of domperidone, prochlorperazine, or chlorpromazine
may be helpful.
analgesic drugs :
- Aspirin 2 or 3 x 300 mg chewable tablets orally.
- Paracetamol 2x500 mg tablets orally.
- Compound codeine - containing analgesic but may cause
or exacerbate nausea.
non-specific drugs :
- Chlorpromazine : intramuscular, but long term considerations.
- Narcotic analgesic use is highly controversial, not
evidence-based, and is associated with prominent adverse
effects and a high risk of dependency. Most patients
who require narcotics are misusing analgesics or ergots.
- Lignocaine infusion : may be indicated for prolonged
severe migraine unresponsive to other therapy or for
rebound headache. Procedure: a 12-lead EKG is obtained
and examined before and 30 - 60 minutes after starting
the infusion. Lignocaine is delivered by a pump device
at a rate of 2 mg/ min. The patient is attached to a
bedside cardiac monitor, and a rhythm strip is obtained
every 5 minutes for the first 30 minutes, then every
15 minutes for 3 hours, and thereafter every 2 hours.
Pulse rate and blood pressure are measured every 5 minutes
for 3 hours, and thereafter every 2 hours while the
patient is awake. The infusion is maintained until the
patient has been headache free for at least 12 hours.
The duration of infusion should not exceed 14 days.
Contraindications include significant heart disease,
epileptic seizures, or allergic reaction to lignocaine.
adrenergic agoinsts with potent 5-HT1 receptor afinity.
Also stimulants of dopamine D2 receptors in brainstem
and gut, and vascular adrenergic and 5-HT2 receptors
exists in several forms :
- 1 mg capsule of ergotamine tartrate, or combined
- 2 mg tablet of ergotamine tartrate combined with
caffeine and an antiemetic.
mesylate can also be given orally, or more effectively,
by suppository, inhalation, sublingual, intramuscular
and intravenous routes.
in about half of cases.
two doses at intervals of 2 - 6 hours are ineffective,
no more should be given for that attack.
include poor oral and rectal bioavailability ; frequent,
long-lasting adverse effects; and risk of headache
and ergotism with chronic recurrent use.
drug of choice in a limited number of migraine sufferers
who have infrequent or long duration headaches and
are likely to comply with dosing restrictions. For
most migraine sufferers requiring specific migraine
treatment, a triptan is generally a better option
from both an efficacy and side-effect perspective.
and potent agonists of 5-HTIB, ID, IF, and to some extent
5-HTIA receptors. Antimigraine effects are mediated
of firing of cells in trigeminal nuclei.
of dural neurogenic inflammation and plasma extravasation.
of meningeal, dural, cerebral or pial vessels.
- generation triptans : sumatriptan :
specific and selective agonist of 5-HTID presynaptic
receptors on cranial blood vessels, inhibiting trigeminal
neuronal firing at the trigeminal nerve ending.
as subcutaneous injection, oral tablets, nasal spray,
and rectal preparations.
sumatriptan injection :
- Bioavailability : 96%.
- Therapeutic plasma levels : within 10 minutes.
- 79% of patients improved at 2 hours after injection
; 71% improved within 1 hour.
- 60% of patients pain-free at 2 hours after injection;
43% pain-free after 1 hour.
· Oral sumatriptan tablets :
- Bioavailability : 14%.
- Therapeutic plasma levels : within 30 - 90 minutes.
- 59% of patients improved at 2 hours after tablets.
- 29% of patients pain-free at 2 hours.
sumatriptan is more effective than conventional treatment
with aspirin and metoclopramide or oral ergotamine
plus caffeine, particularly in the second and third
attacks, suggesting greater consistency for sumatriptan.
of headache occurs iwthin 24 - 48 hours in about one-third
of responders to sumatriptan. Repeated drug administration
is usually effective, but he headache may recur again.
effects of sumatriptan are common but are usually
mild and short-lived. The most frequent are tingling,
pareshtesias, and warm sensations in the head, neck,
chest, and limbs; less frequent are dizziness, flushing,
and neck pain or stiffness. The risk and intensity
is greater with the fixed subcutaneous formulation.
'Chest-related symptoms' include short-lived heaviness
or pressure in the arms and chest, shortness of breath,
chest discomfort, anxiety, palpitations, and, very
rarely, chest pain. The mechanism is unknown. The
risk of sumatriptan-induced myocardial ischemia in
the absence of coronary artery disease appears to
-generation triptans :
2.5 mg, 5 mg : similar to oral sumatriptan.
2.5 mg : slower action and perhaps fewer and less
severe adverse effects, but lower efficacy.
10 mg, 40 mg : better efficacy and consistency, and
12.5 mg : similar efficacy, better consistency and
20 mg, 40 mg and 80 mg : 80 mg orally is more effective
than sumatriptan 100 mg orally with similar consistency
but lower tolerability.
: possibly lower efficacy than oral sumatriptan.
over oral sumatriptan :
bioavailability : 45-75%.
rapid therapeutic plasma levels : within 30 - 60 minutes.
potency at 5-HTIB / D receptor sites.
lipophilicity and brain penetratiion (hence, direct
attenuation of excitability of cells within the trigeminal
nuclei of the brainstem, as well as vasoconstriction
and peripheral inhibition of trigeminal perivascular
alternatives for patients who do not respond to oral
of these agents is consistently effective in all patients
and all attacks, and some cause disturbing adverse effects.
Rizatriptan 10 mg, eletriptan 80 mg, and almotriptan
12.5 mg provide the highest likelihood of success. Ergotamine
and sumatriptan should not be prescribed for patients
with suspected coronary artery disease, Prinzmetal variant
angina, or uncontrolled hypertension.
reduction through relaxation exercises and tapes,
meditation, yoga, swimming and similar strategies
will reduce migraine frequency in many patients.
exercise such as swimming.
in short courses by an experienced therapist can be
a useful adjunct to other strategies in some patients.
indication for prophylactic therapy is when the patient
needs it. This is usually when the migraine attacks
are frequently interfering with their life and recurring
every 2 weeks or so and not responding quickly and
adequately to acute treatment.
is limited : at most about half of patients will have
a reduction in attack frequency of half or more.
effects occur commonly.
choice of prophylactic agent is primarily determined
by the patient and which potential adverse effects
are most acceptable.
the adverse effect profile of each drug with the patient
and determine their preference. Asthma and weight
gain and are by far the major concerns.
realistic expectations with the patient before starting
: the medication may reduce the frequency of attacks
but uncommonly abolishes attacks, and so occasional
breakthrough attacks requiring acute treatment will
slowly, with dosage increments every 7 - 10 days to
minimize adverse effects.
patients to persist for at least 3 months to adequately
trial the drug and because most adverse effects become
less prominent with time.
on with a drug free interval to reassess the frequency
and severity of migraine attacks.
standard prophylactic therapy, as above, before hormone
bromocriptine therapy, 2.5 mg tds, added to the existing
prophylactic regime may be beneficial. Adverse effects,
such as light-headedness and nausea can be minimized
by gradual introduction of medication, beginning with
1.25 mg daily and followed by daily incremental 1.25
mg increases over 1 week to full dosage.
anti-inflammatory drug, such as diclofenac 50 mg bd
commencing 24 hours before anticipated menstruation
of a gel containing 1.5 mg estradiol to the skin 48
hours before the expected onset of menstruation.
implantation of estradiol pellets, starting with 100
mg, inhibits ovulation and maintains estradiol levels,
while regular monthly periods can by induced by cyclical
oral progestogens. Depoprovera, a different oral contraceptive
pill, or 3 monthly cycles of the oral contraceptive
pill are alternative strategies.
citrate, 10-20 mg daily preceeding and during menstruation
may help; tamoxifen competes at estrogen an anti-estrogen
binding sites and is a calcium channel blocker. However,
the anti-estrogenic effect in young women, such as
osteoporosis, is an obvious problem with this strategy.
is paroxysmal. Clearly defined episodes of migraine
recur as often as three or six times each month but
sufferers remain symptom-free between attacks.
frequency of migraine attacks may increase until it
develops into chronic daily headache, often as the
result of stress or the over-use of ergotamine or
symptoms frequently change over time.
severity of the attacks often diminish with time and
in some patients the attacks cease in latter years,
particularly after the menopause in women.
some women however, attacks increase in frequency
at the menopause.
occurs in 70% of pregnancies.
young women, below the age of 25 years, the relative
risk of ischemic stroke among migraineurs is increased,
particularly among those taking the oral contraceptive
pill, but the absolute risk is extremely by small.
absence of any adaptive response to the external environment
and any evidence of a functioning mind which is either
receiving or projecting information, in a patient
who has long periods of wakefulness.
clinical condition of unawareness of self and environment
in which the patient brethes spontaneously, has a
stable circulation, and shows cycle of eye closure
and eye opening which may stimulate sleep and waking.
be transient stage in the recovery from coma or it
may persist until death.
continuing or persistent vegetative state
diagnosis based on a high degree of clinical certainty
that the continuing vegetative state is irreversible;
usually a continuing vegetative state for more than
12 months after head injury and more than 6 months
following other causes of brain damage.
this state is one of the most important aspects of
attempting to assess prognosis early in coma.
: 10 000 to 25 000 adults and 400 - 1000 children in
damage to part or all of the cerebral hemispheres,
with an intact brain stem.
occur with damage to the more rostral part of the
main patterns :
axonal injury, typically as a sequel to severe closed
head trauma, giving rise to degeneration of the white
matter throughout the cerebral hemispheres.
laminar necrosis of the cerebral cortex, following
global cerebral hypoxia or ischemia.
stage of degenerative brain disorders : Alzheimer's
and aware of the surroundings but breathes spontaneously,
without mechanical support, and has stable circulation.
times the eyes are closed and the patient appears
asleep, at other times the eyes are open and they
seem to be awake.
be aroused by painful or prominent stimuli, opening
the eyes if they are closed, increasing the respiratory
rate, or occasionally grimacing or moving the limbs.
the eyes are open the eyelids may blink in response
to any threat to the eye.
range of spontaneous movement may occur such as roving
eye movements, chewing, teeth-grinding, groaning,
grunting and even swallowing is possible. More distressingly,
patients may smile, shed tears, moan or scream, without
any discernible reason. Sometimes, the head and eyes
turn fleetingly to follow a moving object or sound.
posture may be decorticate or decerebrate.
reflexes, oculocephalic are usually preserved.
reflexes such as pouting and sucking reflexes, grasp
reflex, and withdrawal reflexes to pain may be present.
stimuli may provoke an extensor or a flexor response.
responses are commonly extensor.
medical practitioners experienced in assessing disturbances
of consciousness and awareness should separately assess
the patient (this includes discussion with other medical
and nursing staff, relatives and carers about the reactions
and responses of the patient, and to ensure that the
patient is not sentient) and document their findings
and conclusions in the medical record. If there is nay
uncertainty about the diagnosis of the permanent vegetative
state, then a re-assessment should be undertaken at
a later date.
cause for the syndrome has been established
effects of sedative, anesthetic and neuromuscular
blocking drugs have been excluded by the passage or
time or by appropriate analysis of body fluids
metabolic causes have been corrected or excluded as
evidence of awareness of self or environment at any
time. No volitional response to visual, auditory,
tactile or noxious stimuli, and no evidence of language
comprehension or expression.
of eye closure and eye opening which may stimulate
sleep and waking shall be present.
and brain stem function is sufficiently preserved
to ensure the maintenance of respiration and circulation.
clinical feature include :
non-purposeful reflex movements in response to external
- Apparent smiling.
- Facila 'grimacing' to painful stimuli.
- Watering of the eyes,
- Startle myoclonus
- Occasional movements of the head and eyes towards
a peripheral sound or movement.
- Purposeless movement of the limbs and trunk.
pupillary and corneal responses
of visual fixation and ability to track moving objects
with the eyes or show a 'menace' response.
eye movements may be present.
or dysconjugate tonic eye movement, without corrective
saccades in response to ice water caloric testing.
deep tendon reflexes and plantar responses.
and other signs of spasticity may be present.
of bladder and bowel.
in syndrome : a brainstem a lesion disrupts the voluntary
control of movement but arousal and the content of
movement but arousal and the content of awareness
are not abolished. Patients are able to communicate
by movement of the eyes or eyelids.
: most patients who are in 'coma' for weeks, months
or years are in a continuing vegetative state.
death : implies the irreversible loss of all brainstem
functions. It is in a sense, the converse of PVS,
in which brainstem functions survives while the function
of the cerebral hemispheres is lost or gravely impaired.
Brain death is followed, within hours or days, despite
intensive care, by cardiac arrest.
mutism : a state of profound apathy with evidence
of preserved awareness and attentive visual pursuit,
giving an unfulfilled 'promise of speech'. The responsible
lesions often involve the medical frontal lobes.
or MRI head scan : may show non-specific focal or
diffuse abnormalities, brain atrophy, and hydrocephalus.
photon emission computed tomography (SPECT) and positron
emission tomography )PET) : show a reduction in cerebral
studies : EEG, somatosensory evoked potentials
(SSEPs), and electrodermal techniques ; very variable
results. Often these studies provide evidence of some
cortical activity, reminding us that an accurate clinical
diagnosis of vegetative state does not imply cortical
silence. They are of little value in predicting outcome,
other than early EEG evidence of burst suppression
and SSEP evidence of an absent N20 potential.
findings are diagnostic of the permanent vegetative
by the age of the patient, underlying cause and the
duration of the vegetative state.
outlook is better in children, and after traumatic
brain injury. If the cause is not head injury, there
is very little hope of recovery of sentience after
3 months and none after 6 months.
the cause is head injury, a longer time should elapse
before being confident that the chances of recovery
are extremely low.
the diagnosis of a permanent vegetative state by (1)
identifying the clinical state of the patient, (2) the
cause for the syndrome, and (3) the lapse of time. Because
many patients entering a vegetative state emerge from
it within a few weeks or months, supportive early management
is usually appropriate. The diagnosis of a permanent
vegetative state implies that recovery cannot be achieved
and further therapy is futile. It merely prolongs an
insentient life for the patient and a hopeless vigil
for relatives and carers.
nursing or home care
oxygenation, circulation and nutrition.
complicating factors such as infection and hypoglycemia.
discussion with, education of, relatives and carers
about the cause, clinical state, 'hopeless' prognosis,
artificial means of administering food and fluid.
to withdraw nutrition, hydration and other life-sustaining
medication such as insulin for diabetes, should currently
be referred to the court before any action is taken.
not to intervene with cardio-pulmonary resuscitation
or prescribed antibiotics are clinical decisions,
but they should take account of, and respect, the
views of the relatives, carers and patient, if known,
whether formally recorded in a written document or
role of sensory stimulation remains uncertain, despite
the writings for Hippocrates : 'the patient in state
of coma should be spoken to in a loud voice, splashed
with cold water and exposed to bright light'.
of the brain is an inevitable and natural process and
is not necessarily accompanied by an intellectual impairment.
Often, however, the brain undergoes considerable macroscopic
and microscopic changes that are invariably accompanied
by alterations in neurochemistry and function. A clear
answer as to a possible link between ageing of the brain
and pathological processes that underlie dementia, particularly
Alzhemier's disease, has not yet been established. However,
in many ways Alzheimer's disease can be considered as
an acceleration of the ageing process.
changes, brain weight and volume
postmortem the dura, which is often very densely adherent
to the calvaria, is slack because of reduction in the
size of the brain. Over the age of 60 years, there is
often thickening of the lepotmeninges, particularly
in the parasagittal region where they often have a distinctly
gelatinous appearance. An inconstant feature is prominence
of the arachnoid granulations which may in the posterior
frontal and parietal regions produces shallow identations
of the inner table of calvaria.
degree of cerebral atrophy is commonly present over
the age of 60 years but is not an invariable accompaniment
in the ageing process. When present, there is narrowing
of gyri and widening of sulcei, particularly at the
vertex in relation there is also an excessive amount
of cerebrospinal fluid.
weight and volume of the normal brain are maximal between
the ages of 15 and 60 years; thereafter, there is a
gradual onset of this atrophic process beginning earlier
in women than in men. After the age of 50 years this
loss of brain weight amounts of approximately 2 - 3%
per decade over the next four decades. An assessment
of the amount of atrophy can be guaged from the ration
of brain to skull volume which remains constant at about
95% upto the age of 60 years. Thereafter, even in intellectually
normal people, there is variation and this ratio may
fall to 80% by the 10 th decade.
adult brain weighs between 1200 and 1600 g with an average
of 1400 g in men and 1250men and 1250 g in women. The
weight remains fairly constant throughout middle age,
but after the age of 65 years it tends to decline, the
mean loss being about 100g. As the Intracranial volume
is not routinely measured post mortem, a considerable
reliance is placed on the weight of the brain at autopsy
as an index of cerebral atrophy. However, it should
be noted that both weight and volume change during fixation
in 10% formol saline, both increasing by some 10% over
a 2 - 3 week period.
additional difficulty in interpretation of volume and
weight loss in the ageing brain in the recognition of
the so called secular effect, as a result of which mean
body heights and brain weights have increased progressively
over the past 50 - 100 years. In some elderly subjects,
therefore, a reduction in brain weight may atleast in
part be due to the individual having had a small brain.
The best way of assessing the true significance of a
reduced weight is to determine the ration between brain
volume and intracranial cavity volume, as both are closely
related to each other between the ages of 15 and 60
years. A useful index as to whether or not a brain is
atrophied is to measure the ration between the weight
of the whole fixed brain and that of the whole fixed
hindbrain the former usually being between eight and
10 times greater than the latter.
vivo imaging of the ageing brain has shown widening
of sulci and some enlargement of the ventricular system.
However, hydrocephalus is not a consistent finding.
Sometimes in the small brain the ventricles maintain
their normal relative size, while in other cases of
cerebral atrophy, the brain is not much reduced in size
yet the ventricles are enlarged. This is one of the
reasons why it is not possible to make a confident diagnosis
of normal pressure hydrocephalus post mortem. In general,
however, the volumes of the lateral and third ventricles
increase progressively with age, rising from a mean
of about 15ml in teenagers to 55ml over the age of 60
years. Likewise, autopsy studies have shown that the
size of the ventricles increases with age, particularly
above 60 years, and that in general the ventricles of
the elderly are larger than those of young subjects.
the absence of obstruction, increases in the volume
of the ventricles and subarachnoid space are indicative
of a reduction in the volume of the brain, but the precise
contributions of this atrophy by grey and white matter
have been difficult to establish, although increasing
precision is being obtained by quantitative techniques.
For example, it has been calculated that there is a
progressive reduction in hemispheric volume from the
age of 20 years with a greater than in women. Initially,
there is a greater reduction in the volume of grey matter
than in white matter, but thereafter more in white than
in grey. This greater loss of white matter is probably
accounted for by loss of neurons, with their myelinated
axons having a greater volume than the space occupied
by the cell body and dendrites. Such changes are clearly
of importance when considering the neuropathology of
dementia, and although in Alzheimer's disease there
is generalized atrophy of the cortex with commensurate
enlargement of the ventricular system, there are undoubted
exceptions, particularly in the very elderly when the
changes may be no greater than those found in intellectually
consideration will be given to the vascular changes
found in the ageing brain, but at this stage it should
be noted that small recent or old infarcts are not infrequently
present in the brains of intellectually normal subjects.
This should indicate the need for great caution in attributing
dementia, even in the oldest subjects, solely to one
or a small number of cerebral infarcts.
histological examination there may be a variety of changes
affecting neurones, glia and blood vessels. The findings,
however, are by no means constant; for example, there
is variable loss of neurones and special silver impregnations
have demonstrated that there is often some loss of dendritic
processes in the intact neurones. An increased amount
of lipofusion in neurones is the rule. An almost invariable
finding is an increase of astrocytic nuclei in the subcortical
digitate white matter, but staining of myelin is usually
preserved. Other features are a subpial and subependymal
astrocytosis, and the presence of numerous corpora maylaceae
throughout the central nervous system, but particularly,
immediately deep of the ependyma and throughout the
central nervous system, but particularly, immediately
deep of the ependyma and throughout the spinal cord.
Commonly, there are deposits of calcium in the walls
of small blood vessels in the basal ganglia. Other more
specific abnormalities include the presence of neuritic
plaques in grey matter, the occurrence of occasional
examples of granulovacuolar degeneration, neurofibrillary
degeneration and Hirano bodies. Some of these changes
are described in more detail below.
seems reasonable to presume that marked atrophy associated
with ventricular enlargement in the ageing brain is
due to changes in the numbers of nerve cells and their
size. However, the assessment is difficult because of
variability in the same region in different individuals.
However, certain trends can be identified in which particular
nuclei are prone to atrophy with increasing age, that
is, particular areas of the cerebral cortex and Purkinje
cells in the cerebellum, whereas others nuclear groups
retain their original numbers and size, that is brainstem
of the findings are still uncertain because of wide
variations in the observations from different studies.
However, it seems certain that some neuronal populations
show cell loss and shrinkage. Others may show shrinkage
without significant loss and yet others show neither
shrinkage nor loss. The development of computerized
image analysers, particularly when combined with editing
capability, has allowed more precise studies to be undertaken
from which it has been concluded that there is a loss
of neurones in some areas of the neocortex with increasing
age. In spite of wide variations in total neuronal counts,
it has been concluded from a detailed study in a group
of elderly patients that there was a 10% reduction in
nerve cell counts and that in addition, more consideration
had to be given to neuronal shrinkage. More recently,
further consideration has been given to the fact that
neuronal shrinkage and not neuronal loss is one of the
more significant changes which occur in the neocortex
of the ageing brain.
studies have also been carried out on brain areas other
than the neocortex. For example, it is generally accepted
that there is a loss of pyramidal cells in the hippocampus
with increasing age. There is, however, some difference
of opinion as to the amount of this loss and whether
all sectors of the hippocampus are equally involved.
For example, it has been calculated that there is 31%
loss of neurones in the hilum of the dentate fascia
and 52% loss of neurones in the subiculum between the
ages of 13 and 85 years, and the neuronal population
within the CA1 sector of the hippocampus reduces by
between 3.6 and 6.2% per decade.
view of the likely importance of the subcortical nuclei
that produce neurotransmitters required in cognition,
various attempts have been made to compare changes in
similar sites between age- and sex - matched controls,
and in dements. One area of particular interest is that
of the basal nucleus of Meynert, which is the main source
of cholinergic fibres to the cortex. Differences of
opinion exist, however, ranging from minimal neuronal
loss in adult life to a steady decline with age.
hindbrain is not exempt from changes either. For example,
considerable loss of Purkinje cells has been found in
the cerebellum of individuals over the age of 60 years.
Within the brainstem some nuclear groups, such as the
inferior olive and the nuclei of the abducent and trochlear
nerves, are stable with increasing age, whereas others
such as the locus ceruleus - the main supply of cortical
noradrenergic fibres - show variable loss.
of function may be due not only to neuronal loss, but
also atrophy of the soma and the dendritic tree, as
well as loss of synapses. The use of human postmortem
material has created difficulties in interpretation
largely because so-called dendritic changes in the elderly
have also been seen in young control subjects. Nevertheless,
a possible progressive series of changes has been described
in the dendritic trees of the pyramidal cells in the
cortex of the temporal and frontal lobes. These include
loss of dendritic spines, swellings, varicosities and
distortions of the horizontal branches, followed by
progressive swelling of the cell body, loss of basal
dendrites and of branches of the apical shaft, and terminal
branches. Finally, the apical shaft is lost, the cell
body disappears and there is an astorcytosis. Use of
the Golgi-Cox method, which is relatively free from
postmorterm artefact, has shown that the pyramidal neurones
of the parahippocampal gyrus can undergo considerable
dendritic growth in normal old age: a similar conclusion
has been reached for pyramidal cells of the cortex.
The application of immunocytochemistry has identified
changes in synaptic density with age. For example, a
20% reduction in presynaptic terminals of subjects over
the age of 60 years has been established using antibodies
to synaptophysin. Such studies serve to confirm the
general observation of a 20% reduction in presynaptic
terminals in the frontal cortex with ageing by electron
microscopy. Such studies have suggested that despite
such losses, the synaptic density may be maintained
by the remaining neurones undergoing sprouting. An additional
mechanism by which function is maintained in some regions
of cortex is an increase in synaptic contact length
for those synapses that remain.
appears to increase in amount in neurones at certain
sites. It is first seen in the inferior olivary neurones
in infancy and may be found in the spinal cord of children.
The amount tends to rise with increasing age, particularly
in the cranial and spinal motor nuclei, the red nucleus,
parts of the thalamus and globus pallidus, and in the
dentate nucleus of the cerebellum. In contrast, relatively
small amounts of lipofuscin are seen in the cells of
the occipital cortex and in purkinje cells of the cerebellum.
is a cytoplasmic organelle which measures about 1µm
in diameter and is a type of lysosome in which non-metabolizable
substances accumulate: it stains red with Sudan dyes
and is periodic acid-Schiff (PAS) positive. It is membrane
- bound and usually has an electron - dense and electron
- light component, which presumably is responsible for
its light yellow colour. It is a normal organelle and
it has been suggested that as the amount of lipofuscin
increases there is a loss of Nissl substance followed
by marked reductions in cytoplasmic RNA, sufficient
perhaps to lead to cell atrophy and death. However,
there does not appear to be any relationship between
the amount of lipofuscin and neuronal loss, as loss
of neurones in old age is also common in sites where
lipofusin is present in only small amounts. That there
may indeed be a relationship between the accumulation
of lipofuscin and loss of function is suggested by the
finding that there is an excessive amount of lipofuscin
in the brains of dements compared with matched controls.
addition to lipofuscin there is an accumulation of neuromelanin
with ageing, particularly in the substantia nigra and
locus ceruleus. As the amount of neuromelanin increases
with advancing years, there may be up to a 50% loss
of pigmented neurones as part of the normal ageing process.
The neuronal loss appears to be greatest in those containing
the most pigment, but whether or not the accumulation
of the pigment is directly associated with changes that
presage cell death is nor clear.
more recently described change is an increase in the
prevalence of granular bodies that react with antibodies
to ubiquitin. These bodies are located principally in
the medial portion of each temporal lobe and they are
considered to be located in dystrophic neurites. Immunoreactive
structures that are again ubiquitin positive are found
increasingly in the glia of white matter. Other changes
that have been described include an altered expression
of phsophorylated neurofilament antigen and an increase
of a - and ß - crystallin cytoplasmic molecules
thought to act as a chaperone and as a stabilizer of
intraneuronal degenerative change is difficult to see
in haematoxylin and eosin-stained sections. Other techniques
have therefore been employed, one of the more successful
being that of Congo red, which stains tangles a deep
pink colour and at the same time renders them birefringent
under polarized light. Various silver impregnation techniques
also readily identify them and, more recently, antibodies
to the various constituents of the tangle have been
employed. The great majority of tangles are particularly
well demonstrated by antitau antiserum.
light microscopy the configuration of the tangles is
largely determined by the site and type of neurone affected.
For example, in the small pyramidal neurones of the
cortex, tangles are seen to extend from the base of
the cell towards the apical dendrite. In larger pyramidal
cells, many resemble a skein of wool, whereas tangles
in the hippocampus may have a more complex configuration.
In subcortical structures, including the upper brainstem,
globoid forms are commonly seen. As the tangle enlarges,
the nucleues and any pigments become displaced, until
eventually the boundaries of the cell become ill defined
and only the tangle remains. In these circumstances
the tangle often acquires additional immunoreactive
properties staining with ß-A4 amyloid.
microscopic studies have shown that neurofibrillary
tangles are made up of filaments that measure 20 mm
across with a regular constriction of 10 mm occurring
every 80 mm. Although initially thought to be twisted
tubules, later studies showed that the appearances were
due to paired filaments wound in a double helix. Although
tangle formation in normal old age consists predominantly
of paired helical filaments they may also be associated
with straight tubules within the same neurone or straight
filaments. Paired helical filaments derive from components
in the normal neuronal cytoskeleton, containing not
only sequences from neurofilaments and microtubule-associated
proteins, but also antigenic determinants which are
unique to them. Current evidence suggests that the abnormal
phosphorylation of the tau protein could play an important
role in tangle formation.
tangles not only occur in normal ageing but also in
Alzheimer's disease and in a variety of other neurodegenerative
disorders, such as progressive supranuclear palsy. Within
the normal ageing process, they are uncommon in non-demented
subjects, being found in greatest numbers in the corticomedial
portion of the amygdaloid nucleus and in the cortex
of the anteromedial part of the temporal lobe: the number
increases with age. Particular emphasis has been placed
recently on the occurrence of neurofibrillary tangle
formation in the entorhinal cortex in normal ageing
and the fact that it is unusual to find them to any
great extent in the neocortex of normal old age in the
absence of dementia.
tangles are a prominent feature of Alzheimer's disease,
but are also found in adults with Down's syndrome where
they are present in most subjects who are over 30 years
of age. They are also present in large numbers in the
parkinsonian demmentia complex of Guam and in the amyotrophic
lateral sclerosis of Guam, as well as in other instances
of motor neurone disease. They are also found in subacute
sclerosing panencephalitis, head injury and dementia
pugilistica. In all these disorders the neurofibrillary
tangle shows the same configuration of paired helical
filament. The only exceptions are certain instances
of motor neurone disease and in progressive supranuclear
palsy, in which conditions the tangles consist predominantly
of straight fibrils rather than paired helical filaments.
nature and origin of the tangles remain unclear, although
it has been suggested that tangles contain the same
protein as the amyloid of blood vessels and plaques,
despite the fact that ultrastructurally the neurofibrillary
tangle does not resemble amyloid fibrils. Conversely,
immunocyto-chemical studies indicate that tangles share
antigenic determinants for neurofilaments with microtubules
and tau protein. These studies tend to suggest that
neurofibrillary tangles form as a result of defective
assembly of micro-tubules and/or neurofilaments, which
result from abnormal phosphorylation of tau or neurofilaments.
change, which is largely restricted to the pyramidal
cells of CA1 of the hippocampus, consists of one or
more intracytoplasmic vascuoles measuring some 2 - 5
m in diameter. Multiple vacuoles are common when they
may displace the nucleus and normal cytoplasmic organelles:
they occasionally occur in association with neurfibrillary
tangles. They are easily seen in haematoxylin and eosinstained
sections but are strikingly obvious when present in
silver-stained preparations. Electron microscopy shows
a dense granular core embedded in a translucent matrix,
which in turn appear to be separated from the rest of
studies have shown that some of the granules react with
antibodies to phosphorylated neuro-filaments, tubulin,
tau and ubiquitin. Such an antigenic profile suggests
that the vacuoles are autophagic structures in which
cytoskeletal components are being degraded.
studies have shown that granulovacuolar degeneration
is uncommon before the age of 65 years, but its frequency
increases even in non-demented subjects, to the extent
that it is present in some 75% by the ninth decade.
The number of pyramidal cells in the hippocampus showing
this change increases to some 20% in demented subjects.
They have been described in other diseases, including
young adults with Down's syndrome and in the amyotrophic
lateral sclerosis and parkinsonian dementia complex
of Guam. Granulovacuolar degeneration may also be present
in tuberous sclerosis. Whereas in these conditions the
changes are limited to the hippocampus, granulovacuolar
degeneration is present in the nuclei of the brainstem
in progressive supranuclear palsy.
a haematoxylin and eosin-stained sections avoid structures
measuring between 10 and 30 m in length and 9 m across
may be seen easily, although often they are mistaken
for columns of red cells. They are present most commonly
in the pyramidal cells of the hippocampus. Up to middle
age only the occasional body is seen, but late in life
they are numerous. Since their original description
they have been found in a variety of disease including
Pick's disease, and they are particular abundant in
microscopically they are made up of parallel filaments
60 - 100 m in length which alternate with lengths of
sheet-like material. Immunohistochemistry has shown
that Hirano bodies share epitopes for actin and the
actin-associated proteins tropomycin, - actionin and
vinculin and that a small proportion of the bodies also
react with antibodies to tau protein, These observations
suggest that Hirano bodies result from an abnormal configuration
in the neuropil
these are thread - like structures found in the neurophil
of grey matter. In normal ageing they are usually restricted
to structures in the medial parts of the temporal lobes.
They are found in the dendrities of neurons that contain
neurfibrillary tangles and electron microscopically
they contain straight straight tubules. Immunocytochemically,
their profile is similar to that of neurofibrillary
also as dendritic and amyloid plaques, these name emphasize
the two most striking components of may plaques found
in old age, since most consists principally of a central
core of amyloid-like material surrounded by swollen
abnormal neurites. Large numbers of these structures
are found in the brains of patients with Alzheimer's
disease, and small numbers of so-called neuritic plaques
and large numbers of related non-neutritc plaques are
found in the brains of non- demented older people
appearance of plaques differs depending upon the staining
method used. For example, they are difficult to see
in haematoxylin and eosin-stained preparations, but
are easily seen in either frozen or paraffin-embedded
sections using silver impregnation techniques. The amyloid
component of these plaques can be seen readily by Congo
red or thiflavin S techniques. More recently, immunohiso-chemistry
has revealed immunostaining for - A4 amyloid protein
in non - neuritic plaques in many aged non-demented
subjects. Similarly, - A4 amyloid plaques have also
been demonstrated in dementia pugilistica and progressive
supranuclear palsy, two conditions that had previously
been thought to be characterized by neurofibrillary
tangle formation in the absence of plaques.
classic neuritic plaque measures between 5 and 20 mm
in a diameter and in silver-stained preparations consists
of a dark central core surrounded by an irregular clear
halo, beyond which there is an envelope of granular
filamentous or rod-like structures, which like the core,
are argophilic. Their size and configuration may vary
depending on the state of development of the plaque
and the plane of section. Plaques are commonly discrete,
whereas in other areas they appear to fuse together
into large irregularly shaped structures and less commonly,
the appearances may be of ill-defined areas of faintly
granular background. Ultrastructural studies have shown
that the central core is composed of amyloid fibrils
which stain positively with Congo red, while the outer
rim consists of a mixture of abnormal distended neuritic
processes intermingled with astrocytes and microglia.
Since the earliest studies it seems likely that the
central part of the plaque always contains fibrils of
amyloid, but many of the larger neuritic processes contain
paired helical filaments, and that neuritic processes
may well originate from dendritic sprouting of neurones
affected by tangle formation.
stages in the light microscopic formation of a neuritic
plaque have been described. In the first stage the primitive
plaque consists of abnormal neurites intermingled with
the fibre-forming astrocytes and microglial cells. The
second stage is the mature plaque which has all the
typical constituents of the central core of the amyloid,
neurites, microglia and astrocytes. The last stage,
which is the 'burn-out' plaque, is composed mainly of
amyloid. Recently another form of plaque has been described
in which there is a diffuse deposition of amyloid unassociated
with central compacted amyloid or abnormal unassociated
with central compacted amyloid or abnormal neurites.
These lesions have been called diffuse plaques, preamyloid
deposits, senile plaque like structures and diffuse
senile plaques. This type of plaque is commonly found
throughout the cortical mantle occurring amongst other
discrete classic plaques. They are also found, however,
in areas of the brain where classical plaques are few,
such as the brainstem and cerebellum. Such plaques have
also been found in dementia pugilistica and in progressive
supranuclear palsy - both conditions which previously
had been thought to be characterized by neurofibrillarly
tangle formation in the absence of plaques. The relationship
between this diffuse type of plaque and classic plaque
formation is not known.
- neuritic senile plaques are rarely found in the brains
of normal young and middle-aged subjects. However, they
are commonly present in small numbers in those over
60 years of age. Immunocytochemical techniques using
antibodies to the -A4 peptide show evidence of plaque
formation rising with age from about 20% in the sixth
decade to 90 - 100% in centenarians. In the most mildly
affected cases plaques are found in isolated areas in
the cortex of the frontal and anterior temporal lobe
and in the structures comprising the medial parts of
the temporal lobes. Neuritic plaques, when present,
tend to occur in the deeper layers of the cortex and
in the non-neuritic cases in the superficial layers
where they are located between vertically orientated
clusters of neuronal apical dendrites. In a recent study
Sparks et al. showed that brains from non-demented subjects
were significantly more likely to contain senile plaques
if the subject had died of coronary heart disease than
those who had died from other causes. Some studies have
found numerous neocortical plaques in elderly non-demented
subjects sufficient to have met Khachaturian criteria
forms of Alzheimer's disease, especially when examining
material obtained after autopsy which has been incompletely
possible importance in the light of what has been noted
already is that when many plaques are seen in non-demented
subjects, neurofibrillary tangles within cortical neurones
were either rare or absent, whereas in the majority
of cases of Alzheimer's disease, tangle formation is
extensive throughout the cortex.
astrocytes and microglia become more prominent in the
human brain with increasing age. For example, age-associated
increase in the numbers of astrocytes as demonstrated
by glial fibrillary acidic protein immunohistochemistry
becomes evident in the eighth decade. Such changes are
found not only in cortex but also in subcortical structures
and in relation to blood vessels and the ventricular
system. Activated astrocytes elaborate in neurotrophic
cytokine, S 100 protein, that has been implicated in
the development of neuritic plaques in Alzheimer's disease.
With normal ageing there are increased numbers of S
100 protein immunoreactive astrocytes in human cerebral
also show age-associated changes, activated forms expressing
the cytokine interleukin - 1 being significantly increased
in numbers in the brains of non-demented individuals
with an age of 60 years. The numbers of enlarged cells
with processes increase with age while no significant
increase is seen in the number of non-enlarged, non-activated
forms. Concomitant with these changes in microglial
number and morphology, there are significant age-associated
increases in tissue levels of interleukin - 1 messenger
RNA. As the microglial over-expression of interleukin
- 1 has been implicated in the pathogenesis of Alzheimer's
disease, these age-associated increases may contribute
to the increasing incidence of Alzheimer's disease with
amylaceae are round, basophilic PAS-positive structures
5 - 20 m in diameter that lie within astrocytic processes
in the subependymal and subpial areas especially in
the basal ganglia, medial parts of the temporal lobe
and posterior columns of the spinal cord. They are unusual
in the first decade of life, but are universal by the
age of 40 years. Although they are essentially identical
to the polyglucosan bodies and the Lafora bodies, their
significance in normal ageing remains obscure.
in neurotransmitter activity
cholinergic neurones of the central nervous system play
an important role in learning and/or memory has been
stimulated by two separate lines of evidence. Firstly
patients with Alzheimer's disease sustain severe loss
of cortical choline acetyltransferase; and secondly,
there is atrophy of the basal nucleus of Meynert, and
it is form the subcortical nucleus that most of the
cholinergic innervation on the cerebral cortex originates.
Such reports have led to the formulation of the cholinergic
hypothesis that 'these disturbances play an important
role in the memory loss and related cognitive problems
associated with old age and dementia'.
and neuropathological studies have shown that there
are neurotransmitter abnormalities other than in the
cholinergic system. For example, there are deficits
in both the noradrenergic and serotoninergic systems
that corresond with the loss of noradrenergic cells
from the locus ceruleus and of serotoninergic cells
from the raphe nuclei. There have also been reports
of reduction in certain neuropeptides.
and other studies clearly show that there are disturbances
in several neurotransmitter systems and that the cholinergic
hypothesis of memory loss, even in the ageing process
and Alzheimer's disease, may prove to be an over-simplification.
Nevertheless, the neuroanatomical inter-relationship
between the frontal cortex, nucleus basalis, hippocampus
and amygdala has been implicated as contributing a functional
role in the loss of memory in the elderly and Alzheimer's
disease. It is to be expected, therefore, that in vivo
imaging techniques such as positron emission tomography
will play an increasingly prominent role in the demonstration
of regional cerebral metabolic abnormalities and their
correlation overtime with neuropsychological performance.
changes are found commonly in the ageing brain. However,
very few quantitative studies have been undertaken,
although comparison have been made on the amount and
distribution of infarction between dements and non-demented
old people. Cerebrovascular changes are common causes
of admission to hospital in the elderly. The incidence
of stroke rises rapidly with increasing age, some 80%
of cases occurring in patients over the age of 65 years.
studies have shown that in normotensive subjects atheroma
does not usually affect cerebral blood vessels less
that 2 mm in diameter, such as those supplying the basal
ganglia and thalamus.
similar to those found in hypertension occur in the
elderly, comprising fibrous replacement of muscle and
fragmentation of the elastic tissue. As a consequence
the walls of arteries become thickened, longer, more
tortuous and rigid. In blood vessels of 1 mm diameter
or less, in addition to hypertrophy of the media, the
intima becomes thickened by a concentric increase in
connective tissue. In the smallest arteries the intimal
change predominates and may result in narrowing of the
lumen. In contrast to the dilatation seen in the large
arteries there may be hyaline thickening of arterioles
which gradually extends over the whole circumference
and when severe replaces all structures except the endothelium.
are small cavities measuring between 3 and 20 mm in
diameter occurring principally within the diencephalon
and brainstem. Lacunae of small diameter are commonly
seen in the basal ganglia of the ageing brain. Although
some 90% of lacunae are associated with hypertension,
they may be found in some 9% of normotensive subjects.
They consist of expanded perivascular spaces consequent
upon rarefaction and disintegration of the neuropil
around the blood vessel. The cavity is normally empty,
containing very few cells and is limited by a narrow
band of astrocytosis. The term etat lacunaire is used
for the cavities if numerous in the grey matter, and
etat crible for similar cavities if numerous in the
centrum semi ovale and other richly myelinated regions.
The pathogenesis of lacunae is not clear, although a
number of mechanisms are probably operating. For example,
it has been suggested that they are the result of spiral
elongations of small intracerebral arteries under the
effects of raised blood pressure, whereas Fisher, in
a series of publications, found that they could be attributed
to occlusive vascular disease, the small lesions appearing
to be due to lipohyalinosis and the larger to atheroma
(miliary) aneurysms have been demonstrated using radiological
techniques in both hypertensive and normotensive patients
post mortem. Such techniques have demonstrated microaneurysms
in small arteries and are seen as out-pouching to the
vessel wall. Such aneurysms are uncommon under the age
of 50 years and occur most commonly in the brains of
hypertensive patients. However, some microaneurysms
have been observed in the brains of normotensive patients
but not to the same extent as in elderly hypertensive.
This suggests that microaneurysms form as part of the
normal ageing process, but that this is accentuated
many instances these are found at autopsy and appear
not to have been associated with clinical signs or symptoms
and in particular without any loss of, or deterioration
in, higher mental function. Often these lesions are
small and are most commonly found in the basal ganglia
and brain stem. The larger the lesion the more of them
there are, and their strategic location predisposes
to the entity of multifarct dementia which is responsible
for some 15% of cases of dementia over the age of 65
years. They also contribute to a further 10% of cases
of dementia in association with Alzheimer's disease.
term leukoaraiosis is used to describe changes in periventricular
white matter seen on computed tomography in both demented
and in elderly normal subjects. These changes are usually
symmetrical and appear histologically as hyaline arteriosclerosis
of blood vessels, astrocytosis and partial loss of myelinated
axons and oligodendrocytes. These appearances are thought
to represent incomplete infarction confined to white
matter, possibly consequent to hypoperfusion due to
vascular disease. some of these patients are demented,
but many show no intellectual deficits. However, patients
with leukoaraiosis are more likely to have had strokes
in the past and are more likely to have strokes in the
future, suggesting an association with vascular disease.
- like material occurs not only in the centre of neuritic
plaques but also in the walls of small blood vessels,
meninges and cortex, staining brightly eosinophilic
in haematoxylin and eosin-stained preparations. If the
complete circumference of the blood vessel is involved,
the artery appears as a thickened homogeneous tube,
the walls of which become congophilic when stained with
Congo red. Such staining also makes it briefringent
in polarized light.
angiopathy is uncommon in normal subjects under the
age of 60 years, the prevalence thereafter rising to
about 30%. The cortex of the parietal and occipital
lobes is more commonly affected than that of the frontal
region, although rarely there is involvement of the
brainstem. Changes in normal old age are usually mild
and it is much more frequent in cases of Alzheimer's
disease than in long surviving Down's syndrome.
- matched control brain
is increasing awareness of the importance of selecting
normal control material for tissue-based studies of
neurological disorders of the elderly. A described above,
some age-associated changes are clearly pathological,
for example cerebral infarction, while others are not,
for example the presence of diffuse plaques and neurofibrillary
tangles and corpora amylacea. Therefore, the selection
of material for any given study requires the application
of inclusion/exclusion criteria that need to be defined
at the outset.
consideration include race and gender differences in
the ageing brain. For example, the age-associated changes
of plaques and tangles of normal elderly subjects is
said to be similar in American Caucasian and East African
black populations but is less frequent in the Chinese
population of Hong Kong. There is also evidence that
the vascular changes comprising leukoaraiosis and small
vessel disease are more common in the brains of elderly
Japanese, Chinese and American black than in white people.
Differences in the brain between men and women have
also been noted. It is difficult to identify sex-specific
changes that are age associated, although there is some
evidence that the neuroendocrine and neurotransmitter
functions of certain nuclei in the hypothalamus are
the context of brain banks the importance of control
material has been stressed. A recent review entitled
'What makes the brain bank go round?' details the most
important aspects that need to be taken into accounting
when collecting and providing postmortem brain samples
for research. Not only should there be accurate matching
for anti- and postmortem factors, but there should also
be standardization of the brain area sampled, matched
in addition of age and sex, agonal state, lateralization,
seasonal variations, time of death, medication, postmortem
delay, fixation and storage time. Although the analysis
of postmortem human data is difficult, there is nevertheless
an increasing appreciation that rapid freezing techniques
of materials derived from patients who have died suddenly
are eminently suitable for neurochemical and molecular
biological techniques and as long as the confounding
influences are recognized and built into the design
of the study, comparison of disease tissue with appropriate
matched controls yields worthwhile information.
recent years there has been an increasing requirement
to quantify changes based on reporducible objective
and precise methods in order to allow comparisons between
the normal and psychometric and neurochemical data derived
from the diseased brain. Such methods have been reviewed
with a particular emphasis on methods for measuring
the volume of the cranial cavity, the brain and its
component parts, and methods for estimating the volume
fraction of numerical density of particular structures
in microscopical sections. The more traditional methods
have now largely been replaced.
definition 'blood-brain barrier' is somehow restrictive,
as it only emphasizes the role that the microvascular
endothelial cells perform in the brain in preventing
access to the nervous tissue. In recent years, however,
it has become increasingly evident that the endothelial
cells of the brain microvascular do not just isolate
the brain from the blood, but play a pivotal role in
maintaining the constancy of the internal milieu of
the brain . This is achieved by preventing the entry
into the brain of substances which could interfere with
neurotransmission, but also by active regulation of
the transport of those compounds which are essential
for the maintenance of normal brain function. The aim
of this chapter is to extend the concept of the barrier
beyond that of an impermeable wall and to try to analyse
the reason why the microvascular endothelium is essential
for the maintenance of normal brain function.
and development of the concept of a barrier
observation, at the end of the nineteenth century, that
'something' was preventing the access of substances
from blood to brain led tot he development of the concept
of the blood-brain barrier. In the 1880s Ehrlich noticed
that trypan blue injected intravenously stained most
of the organs in the body excluding the brain. He concluded
that the brain had low affinity for the dye he had injected.
Whilst his experiment demonstrated the fundamental property
of the barrier, his conclusions were simplistic. Goodman,
20 years or so later, proved that when the same dye
was injected into the cerebrospinal fluid the brain
became blue, but the other organs did not. This time
the conclusion was reached that a permeability barrier
separated the blood and the brain. In between those
two crucial experiments much work continued showing
the different effect of neurotoxins injected into the
blood stream or directly into the brain. In particular.
Lewandowsky studied the effect of sodium ferrocyanide,
a known lipid-insoluble compound. This was non-toxic
when injected intravenously, but highly toxic when injected
directly into the brain. Perhaps he was the first to
put forward the concept of a barrier as it is now under
stood. However, almost 60 years passed before the anatomical
basis of the blood-brain barrier could be fully elucidated.
of the barrier
the late 1960s a classical series of studies by Rese
and Karnovsky and Brightman and Reese using electron
microscopy demonstrated the fundamental anatomical properties
of the brain endothelial cells which create the passive
barrier isolating the blood from the brain interstitial
fluid. This passive barrier results from the presence
of tight junctions that seal together the endothelial
cells impeding intercellular passage of substances.
Furthermore, the brain capillaries do not have fenestrations,
and they contain very few pinocytotic intracellular
vesicles, suggesting that transcellular vesicular transport
is almost absent.
the site of the barrier resides in the particular properties
of the endothelial cells, a number of specialized structures
participate in the maintenance of the barrier complex.
Around the capillaries a basement membrane, rich in
collagen, supports the endothelial cells. Within the
context of the basement membrane specialized cells,
the pericytes, are in strict contact with the endothelial
cells. The pericytes, which extend their processes around
the capillaries, are contractile cells, but it is believed
that under some circumstances they may have a phagocytic
function. The perivascular cells, also in close contact
with the basement membrane, are, most probably, pure
phagocytic cells, as they are part of the resident brain
microglia. The astrocytes, through their foot processes,
are, however, the cellular elements which share most
of the contact with the outer aspect of the basement
membrane and endothelial cells.
close relationship between the astrocytes and the anatomical
side of the barrier has been the object the numerous
studies which have suggested that astrocytes are essential
in the indication and maintenance of the barrier properties.
Both in Vitro and in vivo the presence of astrocytes
induces endothelial cells to acquire properties of a
permeability barrier. Conversely, in brain tumours changes
in the astrocyte-endothelial relaitonship correlate
with the well known alteration in the permeability of
cerebral capillaries. The blood-brain barrier is not
present in the entire brain as there are structures
outside the barrier, such as the circumventricular organs
and the pituitary gland. In these regions, specialized
neurones, involved in the regulation of the hormonal
systems, come in contact with the blood and can detect
and respond to the levels of circulating hormones in
of the blood-brain barrier
belief that the blood-brain barrier develops during
the early years of life has been amply revisited in
recent years. Most of the difficulties in determining
the timing of blood-brain barrier development have been
generated by the different gestational periods of the
various animal models, different time of barrier development
in relation to the anatomical site, and the tracer and
technique used ot assess permeability. The vascular
plexus on the surface of the embryonic brain, which
will give origin to the intracerebral capillaries, does
not seem to possess blood-brain barrier properties.
When the vessels migrate into the brain and the astroglial
foot processes envelope the capillaries, the gap between
the endothelial cells closes and the tight junctions
develop. Although the tightness of the junction and
the exclusion from the brain of plasma proteins appear
very early, other barrier properties develop later at
different times. The immature brain seems to be more
permeable to small molecules and amino acids than the
adult brain. Whether this differential permeability
is just expression of the progressive maturation of
the blood-brain barrier, or whether it responds to clear
development needs, is not clear. There are suggestions,
however, that the early isolation of the brain from
plasma protein is essential for the proper development
of neuronal connectivity, while continued permeability
to small molecules would allow diffusion of essential
substrates required by the fetal and neonatal brain.
The endothelial proliferation and the induction of barrier
properties appear to be different processes regulated
by different factors. While the former is probably under
the control of soluble angiogenic substances, the latter
occurs only when the endothelial cells penetrate the
brain parenchyma and are enveloped by the astrocyte
freely permeable to the blood-brain barrier
the factors that influence the ability of a solute to
cross the blood-brain barrier, the lipid solubility
is probably the most important. Lipid-soluble compounds
dissolve into the lipid membrane of the endothelial
cells enter the brain by simple diffusion. It must be
emphasized that diffusion does not require energy and
that the limiting factor to diffusion is the difference
in concentration of either side of the brain endothelial
cells, as molecules will move from an area of higher
to one of lower concentration. Most neuroactive compounds,
such as ethanol, diazepam and nicotine, are highly lipid
soluble and enter the brain so rapidly that the only
limiting factor to their uptake is the cerebral blood
flow. In fact, the passage of any substance from blood
to brain will depend not only upon the permeability
of that particular substance, but also upon the surface
area of the capillaries available for the exchange with
the brain. Therefore the PS product defines the rate
at which a product enters the brain.
highly permeable substances which are almost completely
extracted from the blood in a single passage through
the brain, the factor that mostly controls the diffusion
into the brain is how much, and how fast, that substance
can be delivered to the brain itself. Therefore, in
this paradigm the limiting factor is, infact, the cerebral
blood flow. This is the conceptual basis for the use
of highly permeable substances such as xenon or iodoantipyrine
for measurement of cerebral blood flow. It should not
be forgotten, however, that although highly lipid soluble,
a substance can be bound to plasma proteins and therefore
prevented from crossing the blood-brain barrier. In
this situation the permeability, predicted on the basis
of the lipid solubility, will not correspond to the
actual penetration on the brain. Anticonvulsants such
as phenobarbital and phenytoin belong to this group
of compounds. Brain function is dependent upon a constant
supply of oxygen which is highly permeable and rapidly
diffuse into the brain. Similarly, the free, rapid diffusion
of carbon dioxide compared to the more controlled entry
of hydrogen ions means that the pH of the brain interstitial
fluid is dependent on the concentration of carbon dioxide.
exchanges extremely rapidly across the blood-brain barrier
by diffusion. Whilst is the peripheral circulation,
the hydorstatic pressure drivers water out of the capillary
bed, in the cerebral circulation, due to the tightness
of the capillary endothelium, osmotic forces assume
much more relevance than the hydrostatic ones. The use
of mannitol in clinical practice is based on this principle.
Mannitol crosses the blood-brain barrier extremely slowly,
and thus by increasing the osmolarity of the plasma
on the luminal side of the barrier, water will more
unidirectionally from brain to blood. It is obvious
that for this mechanism to be operational, an intact
blood-brain barrier is required since an alteration
of the permeability of the endothelial cells will lead
to an increased passage of mannitol from blood to brain,
resulting in an increased brain osmolarity and a consequent
abolition of the antioedema effect.
permeability of non-diffusible molecules
substances which are essential to the functioning and
the structural integrity of the brain are polar compounds
and therefore non-lipid soluble. Specialized carrier-mediated
transport on the luminal side of the endothelial cells
ensures that these substances are infact transported
in the brain. The carrier-mediated transport for glucose
is the best studied. It does not require energy and
therefore does not work against concentration gradient
and is stereo-specific, since D-glucose but not L-glucose
can be transported. The Glut- 1 transporter has a differential
expression with expression of the transporter since
in chronic hypoglycaemia it is upregulated, while on
the contrary, in models of non-obese diabetes, the transporter
is downregulated. Therefore, the level of Glut-1 activity
in endothelial cells forming the barrier is modulated
by blood glucose levels and by the metabolic activity
of the area served by the capillaries ensuring that
the metabolic requirements of individuals brain areas
smiliar arrangements allows large neural L-amino acids
such as tryptophan and phenylalanine to enter into the
brain quickly. These are essential for the synthesis
of neuro-transmitters within the central nervous system
and cannot be synthesized directly within brain tissue.
In contrast, the entry of small neutral amino acids,
such as glycine and ?- aminobutyric acid, is restricted.
These compounds are synthesized by neurones for use
as neurotransmitters, and hence the entry of circulating
glycine and GABA is prevented. Similarly, the acidic
amino acids, such as glutamate and asparate, which have
an essential role in neurotransmission and are implicated
in excitotoxic damage, cross the blood-brain barrier
extremely slowly, their levels within the brain being
maintained by metabolic processes intrinsic to the brain.
The basic amino acids lysine and arginine are transported
across the barrier by a carrier similar to that utilized
by the large neutral amino acids. There is therefore
a free passage for amino acids required as precursors
and metabolic intermediates, whilst those amino acids
with direct neuromodulatory action are restricted by
the absence of a specific carrier.
first suggestion that the brain endothelial cells do
not play a merely passive role in limiting the passage
of substances, but might have an active metabolic function
in regulation the brain environment, derives from an
anatomical observation. Oldendoff et al. demonstrated
that the cerebral endothelial cells have five times
more mitochondria than capillaries elsewhere in the
body suggesting a high metabolic rate. Active, energy-requiring
transport at the blood-brain barrier contributes to
the regulation of the ionic milieu of the brain. The
particular position of the Na+/K+ - adenosine triphosphatase
on the abluminal side of the brain endothelial cells
confers to the endothelium almost an epithelial - like
property. By exchanging sodium and potassium, the capillary
endothelial cells can secrete fluid into the brain and
contribute to the composition of the intersitial fluid.
This system permits the maintenance of a potassium level
within the extracellular space of the parenchyma lower
than that of the plasma even during periods when plasma
potassium levels are changing. As changes in extracellular
potassium will directly affect neuronal excitability,
it is essential that this is highly regulated.
presence within the brain endothelial cells of specific
enzymatic systems confers the property which has been
defined as the enzymatic blood-brain barrier. This is
particularly relevant for the detoxification of potentially
damaging compounds or for the metabolic activation of
prodrugs. The most important area in which the enzymatic
properties of the barrier play a role is in the treatment
of Parkinson's disease using 3,4-dilhydroxy-L-phenylalanine.
Dopamine is not transported across the blood-brain barrier,
but L-dopa, the precursor to dopamine, is rapidly taken
up via the neutral amino acid transporter and converted
to dopamine by dopa-decarboxylase within the endothelial
cells. The formation of dopamine in the periphery is
minimized by simultaneous administration of the dopa-decarboxylase
inhibitor carbidopa thus reducing the requirement for
high systemic doses of L-dopa. This does not pass through
the barrier, but inhibits dopa-decarboxylase in other
tissues. The endothelial cells contains a number of
enzymes utilized by the liver to metabolizes drugs and
toxins and thus protect the brain form the harmful effects
of such compound.
it is conceivable that the endothelial cells would play
a role in the metabolism of neurotransmitters derived
from neuronal activity. The endothelial cells contain
monoamine oxidase, cholinesterase and GABA transaminase,
all of which are responsible for the breakdown of neurotransmitters,
and thus the enzymatic capability of the endothelial
cells is utilized by the brain itself to regulate neuronal
activity. Last, but not least, the endothelial cells
can produce substances which may influence the activity
and properties of neighboring cells.
of their size and polarity, proteins are not expected
to cross the blood-brain barrier and, infact, most proteins
are excluded from the brain. The formation of vasogenic
oedema following the breakdown of the blood-brain barrier
is produced by the increased osmotic pressure produced
by unregulated protein accumulation in the brain parenchyma.
However, specific transporters have been described for
substances such as insulin, transferrin and interleukin
- 1. When these substances bind to the transporter,
the luminal membrane of the endothelial cells will invaginate
allowing a vesicular transport to take place.
of the blood-brain barrier
wide variety of receptors are expressed on brain microvessels
suggesting that the barrier, transport and enzymatic
function can be regulated by endogenous mechanisms.
Probably the best example of this regulation is the
demonstration that blood-brain barrier permeability
to water can be altered by the noradrenervic innervation
from the locus ceruleus. In fact, ablation of the locus
cerules abolishes the Na+/K+ - ATPase activity in brain
capillaries and thus active control of electrolyte balance
may be lost. Other examples of regulation include the
ability of atrial natriuretic peptide to increase the
blood-brain barrier permeability to water. The tightness
of the junction can also be influenced by hormones and
neurotransmitters. Dexamethasone, progesterone and corticotrophin
may all be responsible for increasing the tightness
of the junction in normal animals. Conversely, activation
of the pathways which result in an increase in calcium
concentration within the endothelial cells could be
the final common pathway for an increase in permeability
deriving from action of 5-hydroxytryptamine or activation
of the B2-bradykinin receptors. Obviously, the destruction
of the endothelial cell membrane by any pathological
process would lead to the alteration of the passive
permeability of the barrier; the mechanism advocated
for the alteration of the blood-barrier produced by
the action of free radicals, such as that occurring
after cerebral ischaemia.
recent years, a growing importance in the regulation
of the activity of the barrier has also been attributed
to message coming directly from the brain and acting
at the brain vascular interface. Among the possible
substances which act as a messenger, cytokines have
acquired a major role. For example, both tumour necrosis
factor alpha and interleukin - 1ß are rapidly
produced in response to injury. Both cytokines are able
to induce the expression of intercellular adhesion molecule
-1, a protein on the cell surface which mediates leucocyte
adhesion to the endothelial cells. Following binding
to ICAM-1, leucocytes will pass through the endothelial
cell layer into the brain and instigate an inflammatory
reaction. Parallel induction of nitric oxide production
and free radical formation will enhance the inflammatory
reaction whilst producing an alteration in the barrier
properties of the endothelial cells. The complex interaction
between cytokines and free radicles on blood-brain barrier
permeability and function is an area of growing interest
to the understanding of the pathophysiology of a number
of conditions and may represent a potential site for
blood-brain barrier is formed by a complex interaction
between the endothelial cells of most cerebral capillaries
and specialized astrocytes within the brain parenchyma.
The role of the barrier is not solely to isolate the
brain from the circulating blood, but to provide a selective
crossing point for those substances required in order
to maintain normal brain function whilst excluding substances
prejudicial to neuronal survival. Additionally, the
barrier actively contributes to the maintenance of a
constant extracellular environment within the brain
even in the presence of fluctuating peripheral ionic
concentrations. The properties of the barrier may be
exploited for therapeutic benefit, but they present
a significant difficulty in the design of centrally
neuroactive drugs. An alteration of the barrier therefore
results in serious consequences for the continued functioning
of the central nervous system.
oedema is one of the most frequent diagnoses based on
computed tomography (CT) or magnetic resonance imaging
(MRI) in neurosurgical patients, in particular in intensive
care patients. In clinical practice this diagnosis is
rarely questioned. Various existing treatment modalities
directed against brain oedema formation such as application
of steroids, mannitol or controlled hyperventilation
are mostly symptomatic. However, their mode of action,
treatment dosage and their therapeutic effects are controversial.
reason for this is the early and uncritical use of the
term 'brain oedema', leading to an overestimation of
this potentially life-threatening complication. Some
years ago, clinical deterioration of neurosurgical patients
following head injury, tumour removal or aneurysm clipping
was explained by the presence of brain oedema or brain
swelling, since it was often difficult to diagnose brain
oedema clearly by CT or MRI. The therapeutic consequence
was mostly sterotype: steroids were administered, a
high-dose osmotherapy or uncontrolled hyperventilation
was performed. However, it has to be kept in mind that
neurological deterioration can also be related to other
pathological processes, for example, extension of an
infarct, enlargement of a haematoma, cerebral vasospasm
and so on. The diagnosis of brain oedema is based on
complex pathophysiological changes in blood-brain barrier
function, regulation of brain cell volume and release
of toxic mediator substances.
aim of this chapter is to contribute to a critical use
of the term 'brain oedema', and to understand pathophysiological
mechanisms of brain oedema formation, possibly leading
to a more targeted, while still symptomatic, therapy
of brain oedema.
are several detailed reviews and monographs recommended
for the study of cerebral oedema, brain cell volume
regulation and the blood-brain barrier.
to Pappius (1974) brain oedema is defined as an increase
in brain water content leading to an increase in tissue
volume. This simple definition clearly distinguishes
brain oedema from hydrocephalus and cerebral atrophy
as well as 'brain swelling' due to an increase in cerebral
blood volume, a state which is rarely proven but often
incriminated if intracranial pressure rises or is increased.
brain oedema and cerebral swelling by vascular engorgement
concern the Monro-Kellie doctrine: the intracranial
contents consists of four distinct compartments, the
intracellular space, interstitial fluid, cerebrospinal
fluid (CSF) and blood. Expansion of any of these compartments
either leads to a compensatory decrease of another or
produces an increase in intracranial pressure. Thus,
brain oedema and brain swelling are closely connected
to an increase in intracranial pressure, its physiology
blood-brain barrier is an essential factor for the regulation
of normal brain volume. The state of the blood-brain
barrier is an important feature in distinguishing different
types of brain oedema. Thus, the term blood-brain barrier
shall briefly be explained anatomically and functionally.
existence of a barrier between blood and brain was first
demonstrated by Paul Ehrlich in the late nineteenth
century. Ehrlich injected trypan blue, a vital dye,
intravascularly and noted that the brain was not stained,
in contrast to all other organs of the body. Thereafter,
Goldmann injected trypan blue into the CSF and observed
that only the brain was stained and no other organ.
These simple experiments demonstrated the presence of
a barrier between brain and blood and that there is
no barrier between brain and CSF.
many years the anatomical substrate for the blood-brain
barrier was unclear. Although Spatz and Krogh had proposed
that cerebral vasculature was responsible for the formation
of this barrier, it had also been proposed that the
close attachment of astrocytic foot processes around
cerebral capillaries, or the basement membrane surrounding
these capillaries, might form the anatomical basis for
the blood-brain barrier. In 1967 Reese and Karnovsky,
using electron microscopy, studied the distribution
of horseradish peroxidase given intravenously. They
proved that the vascular endothelial cells are tightly
connected to each other by so-called 'tight junctions'
forming the anatomical substrate of the blood-brain
barrier. Moreover, there are no transendothelial channels
and there is no pinocytotic activity in cerebral endothelial
endothelial cells are metabolically highly active. They
are five times richer in mitochondria than other endothelial
cells and contain various enzymes known to metabolizes
neurotransmitters and their precursors. Thus, the endothelial
cells might also be actively involved in removing substances
from the interstitial space. These endothelial cells
are equipped with various receptors for hormones and
neurotransmitters suggesting that endothelial function
is regulated in many ways.
are only a few small areas within the brain void of
any blood-brain barrier, as for example the pituitary
gland and circumventicular organs. These areas are important
for the regulation of systemic hormone systems. In these
areas endothelial cells are fenestrated and tight junction
blood-brain barrier limits the passage or entrance of
numerous substances into the brain, but vital metabolic
substrates can pass the barrier easily and metabolic
wastes can also be removed.
amount of a substance which can enter the brain depends
on its permeability, capillary surface area, the concentration
of the substance and the time the substance is present
blood flow (CBF) is the determining variable of uptake
for highly permeable substances. In contrast, uptake
of low permeability substances is mainly diffusion limited.
is highly dependent on lipid solubility. Lipid-soluble
compounds can enter the brain by simple diffusion, whereas
polar compounds cannot. They require carrier systems,
such as facilitated diffusion, cotransporters or active
pumps. Proteins are large, polar molecules which do
not move easily across the blood-brain barrier. Oxygen
and carbon dioxide rapidly diffuse across the blood
-brain barrier due to their lipid solubility. The glucose
transport system is one of the most important transport
systems of the blood-brain barrier, since the almost
exclusive source of energy for the brain is glucose.
There are other specific carrier systems for amino acids
and nucleic acid precursors, referred to as facilitated
diffusion transport system.
water quickly crosses the barrier by simple diffusion
and there is constant exchange of water between blood
and brain . About 50% of total brain water can be exchanged
within seconds by bidirectional diffusion. On the other
hand, the blood-barrier impedes the accumulation of
water in the brain due to a high reflection coefficient
other organs, flux of water within the brain is only
limited by osmotic pressure and not by hydrostatic pressures,
due to the tightness of the blood-brain barrier. Nevertheless,
the osmotic driving force is rather powerful. Since
a difference of 1 mmol is equivalent to 20 mmHg of hydrostatic
pressure, a difference of only 20 mmol even surpasses
the capillary hydrostatic pressure of about 30 mmHg.
As a consequence, brain water content is primarily influenced
by osmolar forces, providing the blood-brain barrier
is intact. If, however, barrier function is disturbed,
hydrostatic pressure gradients prevail.
the turn of the century, Reichardt (1905) introduced
the term 'brain oedema' in a first attempt to differentiate
between oedema and brain swelling. It was not until
the 1950s and 1960s that brain oedema was classified
into two major types by the neuropathologist Igor Klatzo
(1967). His fundamental experimental work enabled the
classification of brain oedema on pathophysiological
grounds. The state of the blood-brain barrier is one
keystone of this differentiation. If the blood-brain
barrier breaks, a so-called 'vasogenic' brain oedema
develops. Cellular injury without blood-brain barrier
disturbance is called 'cytotoxic'. Fishman (1975) added
to these prototypes a third entity called 'interstitial'
or 'hydrocephalic' oedema. A fourth type of oedema is
due to osmotic imbalances where there is neither injury
to endothelium nor to astrocytes and neurones.
induce and imitate the vasogenic type of oedema, Klatzo
(1967) used a 'cold injury'. In this experimental model
the cortex of the animal is frozen, a cortical necrosis
develops surrounded by a border in which the endothelial
lining is damaged and the blood-barrier breaks down.
Thus, it can also be called 'open barrier oedema'. It
is characterized by a protein-rich exudate derived from
plasma due to increased permeability of vessels to albumin
and other plasma proteins. In this context, it is interesting
to note that mere opening of the blood-brain barrier
does not induce the vasogenic type of oedema, for example
during hypertonic crises there is distension of endothelial
cells and blood-brain barrier opening but no, or only
minimal, development of brain oedema in its strict sense.
The same holds true for osmotic opening of the barrier
in which the endothelial cell lining is shrunk by infusion
of hypertonic solutions. Other factors must be associated
with barrier opening leading to oedema. It has been
hypothesized that mediator substances which are released
or generated within the necrotic focus or its border
rim may be responsible. For many years, the cold injury
model has been used as an experimental model for traumatic
contusion. Traumatic brain oedema is a complex phenomenon
that is not well modelled by the cold injury, as discussed
below. It has always been criticized that this type
of lesion and the developing oedema cannot be transferred
easily to the clinical situation following trauma, ischaemia,
infection or metastases. This model, however, has provided
insights into the development and resolution of clinical
forms of oedema associated with blood-brain barrier
damage, as seen in metastases and abscesses. Thus, it
has been shown that the entry port for vasogenic oedema
is within and around the focus, and the oedema front
propagates through the white matter to the ventricles,
probably because of less packing of cells within the
white as compared to the gey matter. Excision of the
necrotic focus, the cold lesioned area itself, resulted
in cessation of oedema formation. Even if the excised
tissue was reinserted, there was no oedema is vessels
in an around the focus, and it could well be that there
are mediators, either from the necrotic focus or the
blood enhancing blood-brain barrier damage the oedema
defined the cytotoxic prototype of oedema as cellular
swelling associated with a decreasing extracellular
space while the endothelial cell lining, that is, the
blood-brain barrier, is still intact. Swelling of cellular
elements is a typical characteristic. Cytotoxic oedema
is characterized by an increase in cellular volume,
not simply due to a toxic state, and therefore is preferably
called cellular oedema. Contrary to vasogenic oedema,
the blood-brain barrier remains intact in this type
principle, there are three mechanisms responsible for
neuronal and glial cell swelling.
1. Increased sodium permeability of the cell membrane
with increase Na+ influx into the cell.
2. Dysfunction or failure of the sodium - potassium
- adenosine triphophatase pump.
3. Membrane energy depletion followed by a failure of
the active ion pumps.
mechanisms, single or in combination, cause cellular
swelling. A simplistic model is to describe cell swelling
in the brain as 'pump leak equilibrium' distance. Under
normal conditions, the influx of osmotically active
solutes is equilibrated by their active elimination.
This avoids an accumulation of solutes within the cell;
immediate cell swelling would follow due to high membrane
permeability to water molecules. The increased membrane
permeability of Na+ ions in cellular oedema causes a
shift of the 'pump leak equilibrium'. The Na+ influx
along the electrochemical concentration gradient cannot
be compensated by the active Na+ pump. Further pathological
conditions, for example ischaemia with energy depletion,
lead to a complete pump failure.
are several causes for the increased Na+ permeability
in cellular oedema. The excitotoxic amino acid glutamate
plays an important role. Increased concentration of
glutamate in the extracellular space, for example in
ischaemia or head injury, interact with glutamate receptor
of the cell membrane and stimulate the opening of Na+
channels. The efforts of the cell to maintain or re-establish
the extracellularly low glutamate concentrations, finally
leads to energy depletion followed by failure of cell
volume control. The presence of high concentrations
of glutamate and K+ ions, for example after terminal
depolarization of brain cells in ischaemia, stimulates
clearance mechanisms of glial cells. Astrocytes have
high-affinity transporters for glutamate to guarantee
fast clearance from the extracellular space. The active
transport of one glutamate molecule is coupled to a
simultaneous influx of two or three Na+ ions. This process
is regarded as a compensatory function of glial cells
to maintain and restore extracellular homeostasis may
lead to cell swelling by itself.
is not only glutamate but also increased concentrations
of lactic acid that induces cell swelling. This process
is a similar compensatory mechanism to normalize the
intracellular pH. The elimination of H+ in exchange
for Na+ leads to a net accumulation of Na+, thus causing
failure of the active Na+/K+ - ATPase pump the accumulated
Na+ ions cannot be eliminated but further increase the
oedema, present in cerebral ischaemia, hypoxia, after
trauma or due to toxins, is an important manifestation
of secondary brain damage. A mere shift of the interstitial
fluid into cells of the brain parenchyma does not change
brain volume, but further cell swelling increases brain
volume and therefore intracranial pressure. Consequently,
at least a minimal CBF is necessary to promote the process
of oedema formation.
term was introduced by Fishman. It occurs if CSF outflow
is obstructed while there is still production of CSF
leading to an increase in ventricular pressure and causing
subsequent ventricular dilation. The increase in hydrostatic
pressure in the ventricles drives CSF into the periventricular
tissue and the increased hydrostatic pressure stops
drainage of interstitial fluid. Thus, the periventricular
areas released with CSF. CT scanning and MRI illustrate
'periventricular lucencies' or increased signal intensities
water diffuses easily across the blood-brain barrier,
osmotic gradients between blood and tissue play an important
role. It has been stated above that brain water content
is primarily controlled by osmolar forces, providing
the barrier is intact. Thus, it is easy to understand
that all states with low plasma osmolarity can lead
to water accumulation within the brain and osmotic brain
oeema. Hyperosmolar states, for example, are seen if
there is inappropriate secretion of antidiuretic hormone
or a disequilibrium following dialysis. Osmotic brain
oedema is neither vasogenic nor cytotoxic. There is
no blood-brain barrier opening nor a cytotoxic mechanism.
Of decisive importance for the development of osmotic
brain oedema is the speed at which osmotic imbalances
develop, since concentration or dilution of osmolarity
within the brain can be compensated if osmolar gradients
develop slowly. The hyperosomolar syndrome is of particular
clinical importance, for example, following dehydration
or systemic disturbances of the water and electrolyte
system. Under these conditions, increases in osmolarity
of cerebral tissue are associated with symptoms such
as drowsiness. If such hyperosmolar states are corrected
too rapidly by infusion of isotonic or even hypotonic
solutions, the brain swells due to osmotic brain oedema.
This can even cause a critical increase in intracranial
pressure, herniation and finally brain death. Thus,
it is recommended that plasma osmolarity is reduced
cerebral ischaemia with reperfusion there is also an
osmotic component of brain oedema. With reperfusion
the hypertonic tissue is perfused with isotonic blood
causing an additional diffusion of water into the hypoxic/ischaemic
classic experimental model for the study of ischaemic
brain odema is stroke induced by clipping of the middle
cerebral artery. With sensitive volume gauges allowing
monitoring of the displacement of the cortex, incipient
swelling can be detected after 1 - 2 min following vascular
brain oedema is composed of various oedema prototypes,
developing from cellular, vasogenic and osmotic components.
Important factors determining the formation of ischaemic
cerebral oedema are the duration and depth of the ischaemia,
as well as the quality and quantity of reprefusion.
long as flow remains above a critical threshold, water
and electrolyte content of brain tissue remain normal
even if electrophysiological disturbances are already
present. Below this threshold, the water and electrolyte
homeostasis is disturbances are already present. Below
this threshold, the water and electrolyte homeostasis
is disturbed. The threshold for oedema development is
species dependent and oedema develops when blood flow
decreases below a threshold of about 10ml/100g/min.
At these low flow values, ion exchange pumps break down.
Ischaemic oedema is characterized by the initial uptake
of water and electrolytes from blood and CSF, followed
by a breakdown of the blood-brain barrier, making it
permeable to serum proteins in cases of irreversible
tissue damage. Oedema, in consequence, is initially
cytotoxic and later vasogenic.
interval when the vasogenic type supervenes is not clearly
defined. During the initial 3 - 6h of ischaemia the
blood-brain barrier remain impermeable to the passage
of conventional barrier tracers such as Evans blue.
ischaemia is absolute and blood flow zero, for example
during a cardiac arrest, cellular oedema, mostly derived
from the extracellular space, develops after a few minutes.
The endothelial cells swell by taking up sodium and
water from the interstitial fluid due to increased membrane
permeability. Up to this stage the process is potentially
reversible, but with stepwise sequence of organelle
failure the threshold for survival is reached.
is no net increase in brain water as long as CBF is
not re-established to serve as the water source. During
ischaemia there is an increase in tissue osmolality.
Following reperfusion there is a rapid increase in extracellular
fluid and cerebral water content associated with a corresponding
rise in intracranial pressure.
ischaemia followed by reperfusion is characterized by
a biphasic development of oedema. During the first hours
after ischaemia the cellular component dominates and
the blood-brain barrier remains intact, demonstrated
by the absence of Evans blue leakage, a marker for the
vasogenic component. The second phase starts several
hours after ischaemia, when the blood-brain barrier
becomes permeable to serum proteins and blood serum
extravasates into the brain leading to oedema formation.
This vasogenic phase lasts much longer and is associated
with clinical deterioration.
contrast to complete ischaemia there is no biphasic
odema formation during continuous incomplete ischaemia.
Instead, oedema develop e s progressively over a 24
- 48h period. During the first 4-12h of incomplete ischaemia,
the blood-brain barrier remains intact but subsequently
of ischaemic oedema, as described above, requires a
certain amount of persisting blood flow, which functions
as a reservoir of fluid and electrolytes taken up by
the brain. During complete ischaemia, as induced by
cardiac arrest, this reservoir is restricted to the
CSF compartment, and ischaemic brain swelling, in consequence,
is minor. However, as soon as recirculation is restored
after a period of ischaemia the brain swells abruptly,
and remains swollen. This postischaemic brain oedema
is proposed as one of the factors responsible for postischaemic
recirculation disturbances and hence for the irreversibility
of ischaemic brain damage.
many years it has been known that intracranial hypertension
is a frequent complication of traumatic brain injury.
In more than 50% of patients dying from brain trauma
there is a refractory increase in intracranial pressure.
However, to what extent brain oedema contributes to
this process has been debated. In the pre-CT era brain
oedema was often held responsible for fatalities. This
opinion has since been modified. The widely accepted
assumption was that there is development of vasogenic
brain oedema following traumatic brain injury, with
a maximum on day 2 - 3 post-trauma. Since steroids were
used very effectively to reduce peritumoral brain oedema
which is of clear vasogenic origin, steroids were also
tested to treat severe head injury in general, not simply
pericontusional oedema. While there were initially two
positive studies with steroids following severe head
injury, three subsequent controlled trials were unable
to show a beneficial effect on mortality or clinical
outcome. Thus, steroids have been abandoned and are
now not part of the standard protocols to treat severe
head injury. Nevertheless, there is very recent evidence
that steroids given in very high doses might ameliorate
the clinical course of patients with cerebral contusions
and perifocal oedema.
assumption that vasogenic brain oedema is a major factor
following trauma was one reason to use Klatzo's cold
injury to model focal contusion experimentally. Unfortunately,
some of the results obtained using this model were too
easily transferred to the clinical situations. More
recently, the contribution of vaosgenic oedema to severe
head injury has again been intensely debated.
a critical review, Miller and Corales questioned the
significance of post-traumatic oedema. Based on experimental
data obtained with the fluid percussion model of traumatic
brain injury and CT observations made clinically in
the early post-traumatic period, they concluded that
the very early post-traumatic intracranial hypertension
observed experimentally is related to a state of hypertension
observed experimentally is related to a state of hyperaemic
CBF. This corresponds to an increase in Hounsfield units
in CT scanning and 'diffuse brain swelling' in patients.
A few hours after fluid percussion injury there was
no increase in cerebral water content. The authors then
asked: brain oedema as a result of head injury - fact
or fallacy? Meanwhile, numerous experimental investigations
have clarified that there is brain oedema in various
models of head injury including fluid percussion brain
injury and that it takes time to develop brain oedema.
question of diffuse brain swelling due to vascular engorgement,
especially in the very early post-traumatic period,
is still not solved. Very recent studies of Marmarous
et al, using MRI techniques for non-invasive tissue
water and cerebral blood volume measurements indicated
that brain water was increased while blood volume decreased.
These studies provide compelling evidence that the major
contributor to early brain swelling is rain oedema and
not blood volume. These studies, however, did not differentiate
between intra- or extracellular water accumulation.
positron emission tomography studies could not demonstrate
increased intracranial blood volume. In addition, it
is now widely accepted that the very early hyperaemic
response to brain injury is followed by hypoperfusion
on the first post-traumatic day.
is no doubt that there is perifocal or pericontusional
brain oedema following trauma. For a long time this
pericontusional oedema has been regarded as vasogenic.
There is, however, only limited blood-brain barrier
damage and uptake of contrast media, both in CT and
MRI patients. Thus, it has been speculated that pericontusional
oedema is also cellular/cytotoxic. Indeed, recent experimental
studies using the weight drop technique or the controlled
cortical impact injury indicate that there is both opening
of the blood-brain barrier and vasogenic as well as
cellular/cytotoxic oedema. Following controlled cortical
impact injury the extent of cellular/cytotoxic oedema
is even more pronounced than the vasogenic component
of brain oedema
judge and interpret clinical and experimental studies
of brain oedema it is important to know the principles
of various methods of measuring brain oedema and their
potential errors. Tissue water content can be measured
directly in experimental animals or small surgical tissue
samples. Other techniques can be calibrated against
actual tissue water determinations. Thus, they can also
be used to give quantitative data in contrast to indirectly
measuring techniques like blood-brain barrier permeability
studies, electrical impedance and CT.
is the 'gold standard' technique to determine tissue
water content. It is highly reliable and other techniques
should be compared to this. A sample of brain tissue
is taken, weighed immediately after removal and then
desiccated in an oven for at least 24h. After equilibration
to room air the sample is reweighed. The loss of weight
indicates the total tissue water. This a very simple,
although time-consuming, investigation that requires
a reasonable amount of tissue. Since this technique
measures total water content of a specimen it cannot
distinguish between intra-or extracellular accumulation
of water or oedema.
et al. described the technique of specific densitometry.
Two liquids of different densities are put on top of
each other in a cylinder and a gradient is established
by slowly mixing these liquids. Thereby a linear density
gradient is obtained which is calibrated by standards
of known specific gravity. Thereafter, small specimens
of tissue are dropped into the density column and will
settle until they reach their isogravimetric point.
Thus, many investigators simply give the specific gravity
value as an index of tissue water content which can
be calculated if the amount of solid is known.
technique is erroneous if samples of different protein
contents are compared. The technique is especially suitable
and valid for measuring cellular/cytotoxic oedema.
is the most useful clinical tool to image the brain
. MRI uses the ability of protons to be magnetized.
Since the majority of hydrogen atoms are within water
molecules, MRI predominantly images water in various
tissues. Although many attempts have been made to differentiate
between extra- and intracellular water using MRI, this
is still not feasible on a routine basis.
normal brain with an intact blood-brain barrier, the
capillaries are impermeable to intravascularly injected
contrast agents. Dural vessels and structures in which
capillaries are fenestrated allow diffusion of contrast
material into the extracellular space. Also, tumor tissue
lacking an intact blood-brain barrier enhances due to
accumulation of the paramagnetic contrast medium in
the interstitial space. Tumour capillaries in gliomas
may have a near-normal structure with an intact blood-brain
barrier, so that such tumours will not enhance with
contrast. In more malignant gliomas, however, formation
of capillaries is stimulated whose endothelia are fenestrated
and therefore, have no blood-brain barrier- these tumours
do enhance. Metastatic lesions equipped with non- CNS
capillaries that are similar to their tissue of origin
virtually always enhance. Extra-axial tumours arise
from tissue whose capillaries lack tight junctions and,
consequently, these tumours enhance. Usually, there
is no correlation between MRI or CT enhancement and
angiographic findings of hypervascularity, although
it has been suggested that the vascular pooling in angioplastic
neoplasm may represent 20 - 30% of the noted enhancement.
It is important that a lack of enhancement does not
necessarily signify lack of tumour and one cannot use
enhancement to separate tumour from oedema in infiltrative
gliomas or anaplastic astrocytomas. On MRI, oedema is
seen as high intensity abnormality on T2-weighted images.
This 'oedema' pattern is a reflection of a combination
of tumour and oedema on histology.
understanding of the spread and resolution of brain
oedema under clinical conditions is closely connected
to CT. CT scanning is capable of visualizing even small
changes in absorption of X-rays on a regional basis
due to brain oedema. Comparative analyses between CT
density and changes of brain water content demonstrated
that it is possible to detect brain oedema if cerebral
water content is elevated by 1.3%. This is equivalent
to a decrease of 1 Hounsfield unit in CT density. Investigations
of tissue water content and CT density in patients with
severe head injury have confirmed these close correlations.
Nevertheless, there are also obvious problems in differentiating
between oedema and low-grade gliomas, as there are also
attenuations in Hounsfield units. Moreover, it is not
possible to distinguish between cellular/cytotoxic oedema
and brain infarction.
increase in permeability is visualized by contrast enhancement.
CT scanning was shown to be useful in the investigation
of the resolution of vasogenic oedema around metastases
and abscesses by studying the rate of penetration of
intravenous injected contrast media into the tissue
and their spread towards the ventricles.
of tissue uptake of dyes bound to proteins, contrast
media and radiolabelled proteins indicate blood-brain
barrier damage and therefore, vasogenic oedema. The
easiest technique to demonstrate vasogenic oedema is
intravenous administration of Evans blue dye. It binds
to albumin and enters the brain only in areas where
the blood-brain barrier is defective. Thereafter, it
spreads within the tissue due to bulk flow and diffusion.
Uptake of Evans blue is therefore a technique that may
provide both a qualitative as well as quantitative assessment
of vasogenic oedema. Quantitative assessment of Evans
blue uptake can be achieved by extraction and colorimetric
substances like I-labelled albumin or C aminoisobutyric
acid have also been used to determine breakdown of the
blood-brain barrier experimentally, Clinically mTc-
or Rb-labelled markers are used in CT or PET scanning.
the electrical impedance of tissue can be used for studying
the development of cellular/cytotoxic swelling. This
technique uses a low-frequency alternating current which
is transmitted extracellularly, thus estimating the
size of the extracellular space. This technique was
used experimentally to study the development of cellular
brain oedema in ischaemia and cytotoxic oedema following
administration of glutamate. It is not applicable for
are two important differences between brain oedema and
oedema in other tissues, one being the state of the
blood-brain barrier as described above and the fact
that oedema development in the brain is limited because
the intracranial compartment is a closed container with
only minimal facilities for expansion. Thus, oedema
development will soon cause an increase in intracranial
pressure which, in turn, causes an increase in intracranial
pressure which, in turn, causes a decrease in cerebral
perfusion pressure and a decrease in cerebral perfusion
pressure and a decrease in cerebrovasclar resistance
followed by an increase in cerebral blood volume resting
in increasing intracranial pressure. This vicious circle
illustrates the fact that brain oedema can ultimately
lead to cerebral herniation and finally brain death.
intracranial situation is particularly dangerous if
there are changes in vascular permeability leading to
vasogenic oedema and loss of cerebral autoregulation
as seen in very severe cases of traumatic brain injury.
Under these circumstanses as evaluation in systemic
blood pressure causes an increase in both vasogenic
oedema and vascular volume. Taken together, brain oedema
development may often affect CBF either locally or globally
and influence intracranial pressure. Conversely, there
are other important causes of an increase in intracranial
pressure such as hematoma or an increases in cerebral
blood volume due to hypercapnia amongst others. Thus,
a significant rise in intracranial pressure should always
be further evaluated by CT scanning.
cerebral insults which are associated with cellular/cytotoxic
and vasogenic oedema formation are also often associated
with a release of substances which might promote or
enhance the oedema process. Such compounds are called
'mediators'. The understanding of their pathophysiology
is indispensable for the development of specific and
more effective methods of treatment. Mediator substances
may be formed from inert precursors or released in effective
concentrations to the extracellular space where these
compounds are usually not present or found only in minimal
concentrations. Mediator formation is likely to occur
in damaged brain tissue, for example contusions or infarcted
tissue. The substances may then spread into primarily
undamaged perifocal tissue where they can induce secondary
processes like opening of the blood-brain barrier, alterations
of the cerebral microcirculation or cytotoxic cell swelling.
Extravasation of plasma-borne factors as active mediators
or precursors can also occur.
identify such factors, a number of criteria should be
met (a) these substances should be found to induce cellular
swelling or blood-brain barrier damage if administered
to the brain ; (b) they should be formed or released
under pathological conditions; and (c) inhibition of
the release, formation or function of these mediator
compounds should prevent or reduce brain oedema.
considerable number of substances have been discussed
such as glutamate, lactate, H+, K+, arachidonic acid
and metabolites, oxygen free radicals, histamine and
possible involvement of glutamate, H+ ions, potassium
ions and lactate for the development of cellular/cytotoxic
oedema are depicted. Ultimately, there is also an uptake
of calcium by the cells associated with cellular swelling
and rupture of cell membranes. Thus, the intracellular
release of calcium has been invoked as the final common
pathway to cell death. This process is also accompanied
by a release of AA, polyunsaturated free fatty acids
and oxygen free radicals. Experimentally, it has been
shown that AA induces both cellular swelling and also
leads to a breakdown of the blood-brain barrier. Thus,
AA is proposed as a mediator substance of vasogenic
as well as cellular/cytotoxic oedema. AA induces as
unspecific opening of the blood-barrier for small and
large tracers, but only moderate vasomotor responses.
Since effective AA concentrations have been detected
following brain injury within the oedema fluid, AA appears
to be an important mediator of oedema formation. However,
it is difficult specifically to inhibit the release
of AA which might be considered as a potential therapeutic
avenue. Nevertheless, inhibition of phsopholipase A2
by steroids and other compounds might explain some beneficial
effects of these substances.
radicals are also believed to be involved in the generations
of cellular/cytotoxic oedema. Their noxious effect on
blood-brain barrier function has been debated. While
it has been shown that there is certainly release or
generation of free radicals following acute cerebral
insults associated with oedema formation, their inhibition
by various substances such as aminosteroids, superoxide
dismutase, melatonin and others, moderately reduced
brain oedema formation in various experimental models,
but did not significantly affect the clinical course
following severe head injury. The Kallikrein - kinin
system, and its active polypeptide bradykinin, could
also play an important role as mediator of vasogenic
oedema. Bradykinin is capable of inducing oedema if
administered to the brain. There is formation of kinins
following brain injury and it is possible to reduce
oedema formation by specifically inhibiting kinin release,
at least experimentally. Oedema formation is supposed
to be caused by an increase in blood-brain barrier permeability
to small solutes, supported by an increase in blood
pressure in the microcirculation due to arterial dilatation
and venous construction. Therapeutic studies with synthetic
kinin antagonists in severely head injured patients
have recently exerted moderate beneficial effects.
amines, such as serotonine, histamine and polyamines,
could also be involved in vasogenic oedema formation.
A potential role for leukotrienes has been controversial.
They are potent constrictors of cerebral vessels if
administered from the extravascular side and in most
studies there was neither alteration in blood-brain
barrier function due to leukotrienes, nor formation
together, glutamate, lactate, H+, K+, AA and free radicals
are the most pertinent mediators of cellular/cytotoxic
oedema. Kinins, AA and histamine seem to be the most
intriguing mediators of vasogenic brain oedema. There
are, however, a number of additional potential mediator
compounds that might be considered to be like cytokines,
for example tumour necrosis factor or p olyamines, thrombin
of oedema on brain function
well localized or mild in degree, brain oedema is associated
with little or no clinical evidence of brain dysfunction;
however, when it is severe it causes focal or generalized
signs of brain dysfunction.
following infusion oedema of the brainstem, electrophysiological
alterations are moderate at best. In fact, it is not
likely that oedematous tissue becomes hypotoxic, unless
the intercapillary distance increase. Microscopic studies
suggest that vasogenic oedema could alter neuronal function
due to widening of the extracellular space separating
adjacent foot processes from their neurones and synapses,
described in the while matter as lamellar blebs. With
resolution of oedema these changes reverse.
and resolution of oedema are dynamic processes. Oedema
production is estimated to be 0.09 - 1.63 ml/h in metastases
and 0.42 - 3.39 ml/h in gliomas, based on CT scan analyses
in patients. The speed of edema propagation ranged in
this population from 0.2 to 2.2mm/h
are three main mechanisms by which the pathologically
accumulated oedema fluid is removed from the tissue,
depending on oedema location and type.
It is widely accepted that the predominant portion
of vasogenic oedema fluid is reabsorbed into the cerebral
ventricles. Marmarou et al. found that the clearance
of radioiodinated cat serum albumin leaving the brain
occurred at 87.14% into the CSF and only 19.96% into
the blood. Thus, 'vascular clearance' is minimal,
in the acute state at least, and oedema resolution
occurs mainly via bulk flow into the CSF.
second mechanism, 'vascular' oedema resolution, involves
uptake of proteins and ions by capillary cells, reducing
the osmotic gradient between tissue and cerebral vessels
and leading to a diffusion of water molecules back
across the blood-brain barrier. This implies in intact
third pathway of oedema resolution, in cellular oedema,
needs a normalized cellular metabolism with sufficient
energy sources to rebalance the ionic imbalances responsible
for intracellular water accumulation.
In vasogenic and hydrocephalic oedema, oedema clearance
into the CSF is studied in detail. The oedema fluid,
of a composition similar to plasma, passes through
extra-cellular channels along a pressure gradient
from the site of blood-brain barrier breakdown from
grey to white matter. The driving force for the spread
of oedema fluid is a pressure gradient. Initially,
a relatively high pressure is required to open the
channels and gain access to performed pathways of
low resistance, for instance the perivascular space,
but once open for spreading of oedema only little
hydrostatic pressure is necessary.
metastases with a small perifocal oedema the amount
of oedema resolution within the tissue averages 0.0086
ml/h/cm3, probably representing the reabsorption of
oedema fluid into capillaries within the oedematous
tissue. In large tumours with pronounced perifocal oedema
the main fraction of oedema fluid is drained into the
ventricular, and to a less extent into the subarachnoid
swelling describes a physiological condition of the
brain accompanied by high intracranial pressure that
is potentially life-threatening. Frequently, the terms
'brain swelling' and 'oedema' are used similarly, probably
because 'oedema' arises from the Greek word 'oedema'
which means swelling. At the turn of the century, Reichardt
tried to differentiate brain swelling from oedema. If
the surface of a brain cut was wet, 'oedema' was diagnosed,
whereas a dry brain cut was called 'brain swelling'
or 'swollen brain'.
the late 1960s, brain swelling has been attributed to
an increased blood volume secondary to vasoparalysis.
There is, however, little evidence for this assumption.
At least in trauma, the 'diffuse brain swelling' seen
immediately after trauma is probably not due to vascular
engorgement and an increase in cerebral blood volume
but rather due to brain oedema, be it cellular or vasogenic.
Studies combining non-invasive tissue water measurement
by MRI and cerebral blood volume techniques are focusing
on this issue.
swelling due to vascular engorgement and increased cerebral
blood volume has also been blamed for the often observed
intracranial pressure rise seen in children after severe
head injury. CT scans in these children are characterized
by increased CT densities and signs of diffuse brain
conditions associated with brain oedema
variety of clinical conditions are associated with oedema
formation, the presence of which may be a major causes
of clinical deterioration. Most often, the oedema in
a particular clinical condition consists of various
oedema proto-types. Vasogenic oedema is predominantly
observed around brain tumours, abscesses and haemorrhages,
and is seen in the later stages of infarction. There
are several causes of cellular oedema, for example ischaemia
and hypoxia. Osmotic oedema is observed for example,
in acute hypoosmolar states, osmotic disequilibrium
syndromes occurring with haemodialysis and diabetic
ketoacidosis. Interstitial oedema is a typical feature
oedema is a common occurrence in patients with malignant
gliomas, meningiomas and metastatic tumours. The predominant
oedema type associated with brain tumours is classified
as vasogenic. Responsible for this is the formation
of tumour capillaries deficient of a functioning blood-brain
barrier and often with fenestration, rather than the
active destruction of intact cerebral capillaries by
tumour invasion. Consequently, plasma proteins and other
macromolecules pass freely into the intersitial extracellular
space. The precise mechanism of peritumoral oedema formation
remains poorly understood, but it is presumed to be
related to the production of a vascular permeability
factor known to be associated with gliomas. The grade
of peritumoral oedema is often closely related to the
degree of malignancy of the brain tumour, location of
the tumour and extent of venous involvement.
oedema develops in approximately 50% of meningiomas.
It is more common with large lesions but may be extensive
with small ones. Studies have indicated its presence
is significantly correlated with either the meningioma
blood supply coming in some degree from cerebral pial
arteries, or with its venous drainage connecting to
cortical veins. While varying amounts of oedema may
be present with any of the meningoma cell types, fibroplastic
and transitional cell tumours have been reported to
have only mild to moderate degrees of oedema. Severe
oedema tends to be associated with meningiomas of the
syncytial or angioblastic cell types and tend to be
hyperintensive on T2-weighted images.
glioblastomas an extensive mass effect mainly due to
fairly extensive oedema, usually apparent in the adjacent
white matter, is often seen even in relatively small
tumour masses. As with all infiltrative gliomas, there
is no clear miscroscopic margin showing where tumour
cells stop and reactive gliosis, oedema or normal brain
begins. Therefore, what is termed 'oedema' is more accurately
described as 'tumour plus oedema'.
are notoriously surrounded by massive amounts of oedema,
often extending far from the site of a relatively small
metastatic focus. The extent of associated oedema has
no direct relationship to the size of the metastasis.
Usually, metastatic lesions are distinguishable from
their associated oedema on both CT and MRI and intravenous
contrast clearly shows the metastasis to separate from
the surrounding oedema. On MRI, a metastasis is typically
a focus of variable intensity surrounded by high-intensity
oedema. The oedema accompanying metastases does not
usually cross the corpus callosum, nor does it involve
cortex, features which often help to distinguish this
lesion from primary infiltrative brain malignancies.
Regardless of the appearance of the enhancement, there
is in general a greater degree of oedema associated
with a metastatic focus if compared to the oedema associated
with most of the benign entities, as well as compared
to edema associated with primary gliomas.
frequent clinical condition associated with oedema is
the brain abscess. Oedema surrounding an abscess may
be greater in volume than the abscess itself, and may
cause much of the associated mass effect. With MRI,
due to the sensitivity of T2-weighted images to alterations
in tissue water, earlier detection of cerebritis and
brain abscess is possible, compared to CT. on T1-weighted
images of a bacterial abscess, oedema is moderately
hypointense surrounding a marked hypointense central
focus with a hyperintense rim. On T2-weighted images
the signal intensities are quite variable.
trauma is a complex of a variety of cerebral lesions,
including contusion, haematoma, subarachnoid haemorrhage
and diffuse axonal injury. Development of oedema depends
on the kind of primary lesions and concomitant conditions,
such as hypoxia and/or ischaemia. Probably both oedema
types, the vasogenic and cytotoxic component, are present
around haemorrhagic contusions, independent of the primary
and, eventually, secondary injury mechanisms. Most frequently,
pericontusional oedema is present, responsible for the
often extensive mass effect with midline shift in such
cerebral haematoma causes compression of surrounding
tissue, reading perfusion and therefore oxygen delivery
from oxygenated blood to these regions. Therefore, similar
processes as described in traumatic brain injury occur.
Oedema is frequently revealed both on CT and MRI and
is more prominent around acute haematomas compared to
subacute or chronic haematomas. As in trauma, both cellular
and vasogenic oedema components are prominent. Recently,
evidence is growing that thrombin is an important mediator
of oedema surrounding intracerebral haematomas.
focal oedema is commonly seen on CT and MRI following
focal or large-volume irradiation. When radiation necrosis
is present, mass effect and oedema are common findings
with clinical evidence of focal neurological abnormality
and raised intracranial pressure. Microscopically, the
lesion shows characteristic vascular changes and white
matter pathology. The delayed form, generally seen after
treatment of malignant gliomas, has its onset usually
from 6 months to 2 years after treatment and may - in
the case of a significant mass effect and oedema - demand
surgical decompression. Radiation -induced peritumoral
necrosis and vascular changes can occur sooner than
the typical 1-year interval, for example acute radiation
encephalitis can show a disrupted blood-brain barrier
and enhance dramatically on MRI. Again, radiation -
induced brain oedema is a composite mixture of cellular
and vasogenic oedema.
situations with vascular dysfunction may ultimately
lead to oedema formation, for example circulatory arrest,
cerebral vasospasm, emboli and venous sinus obstruction.
An example of a thromboembolic occlusion of the right
middle cerebral artery with concomitant ischaemic oedema
is demonstrated. Hypoxia after cardiac arrest or asphyxia
may result in cerebral energy depletion, and therefore,
cellular swelling with increased intracellular osmoles
which induce rapid entry of water into cells. In clinical
practice, however, hypoxia-induced oedema is rare and
described only after longer periods of insufficient
vasospasm associated with subarachnoid haemorrhage may
reduce local CBF and cause incomplete ischaemia. Venous
sinus obstruction may occur as a result of infection,
from direct occlusion by trauma or surgery, invasion
by tumor such as a meningioma or pathological thrombosis
usually seen with hypercoagulable states. If large or
abrupt, the stasis will diminish or obstruct flow through
the arterial capillary bed and produce cerebral ischaemia
and infarction involving the venous territories. The
resulting increase in hydrostatic pressure will produce
a mixture of vasogenic and cellular oedema.
oedema has been reported in pseudotumour cerebri, a
disease often affecting obese younger women with typical
symptoms of elevated intracranial pressure, such as
headache, nausea, vomiting, diplopia, ataxia or altered
consciousness and always with optic disc swelling. There
is still discussion over whether or not brain oedema
syndrome, a neurological disorder of children, is characterized
by fulminant hepatic failure, a rapid progressive encephalitis
and severe intracranial hypertension, with brain oedema
as a major and often fatal complication. The classic
cytotoxic cerebral oedema is present. Electron microscopic
features are cellular swelling of astrocytic foot processes
and intralamellar myelin blebs.
multiple sclerosis, gadolinium enhancement, especially
in the acute phase, indicates blood-brain barrier opening
due to inflammation in the white matter and spinal cord.
encephalopathy is a syndrome consisting of headache,
seizures, visual changes and other neurological disturbances
in patients with markedly elevated systemic blood pressure.
Acute hypertensive encephalopathy is probably caused
by failure of autoregulatory vasoconstriction with focal
for general dilation of small arteries and arterioles.
This is associated with an increased CBF, dysfunction
of the blood-brain barrier and formation of vasogenic
oedema that is thought to cause clinical symptoms. Oedema
generally resolves after reduction of blood pressure.
of brain oedema
of brain oedema is largely sympotmatic. Most of the
treatment modalities used are directed towards a decrease
in intracranial pressure.
date, only steroids are used as a 'specific' therapy
of peritumoral oedema, and perhaps the oedema around
abscesses. All other modalities are either used to dehydrate
the brain or decrease cerebral blood volume. Therapeutic
option to reduce brain oedema or intracranial pressure,
their mechanisms, advantage and disadvantage
the early 1960s corticosteroids have been used to treat
brain oedema associated with brain tumours, metastases
and abscesses. A common feature of these processes is
a blood-brain barrier dysfunction with consecutive vasogenic
brain oedema formation. It has thus been postulated
that corticosteroids are 'sealing' the endothelial lining
in and around tumours and metastases. In line with this
assumption, it has been shown that extravasation of
plasmatic markers into brain tissue decreases following
steroid treatment. The exact mechanism of 'endothelial
sealing', however, is unknown. Certainly, there are
other well known mechanisms of corticosteroids which
might contribute to the antioedematous effect, like
'stabilization' of lysosomal membranes, induction of
various enzymes, inhibition of CSF secretion, inhibition
of release of AA as well as lipid hydroperoxides. It
could also be that corticosteroids are interfering with
granulocytes and other inflammatory mechanisms operative
in and around abscesses.
corticosteroids are highly effective in reducing peritumoral
oedema, they are less effective in abscesses; their
effect on the perifocal oedema around contusions is
still under debate and there is certainly no effect
on post-ischaemic oedema. The fact that the perifocal
oedema around contusions is of cytotoxic origin to a
great extent, might explain that the efficacy of steroids
to treat perifocal pericontusional oedema is limited
osmodiuretics, for example 20% mannitol, increase plasma
osmolarity and dehydrate the brain due to the osmotic
gradient. This effect is not confined to oedematous
tissue, but effective all over the brain. A second mechanism
of mannitol is associated with the ensuing haemodilution
and initially increased total blood volume. Thereby,
mannitol causes an increase in CBF which is followed
by an autoregulaotry constriction of cerebral vessels
and a consecutive decrease in cerebral blood volume.
By this, intracranial pressure is effectively reduced.
has been argued that mannitol infusion might cause a
'rebound phenomenon'. It is postulated that mannitol
molecules may enter the tissue in cases of a defective
blood-brain barrier. Once in the extracellular space
mannitol might bind water molecules after dissipation
of the osmotic gradient and thus lead to an increase
of water content after mannitol has been cleared from
the plasmatic compartment. This 'rebound phenomenon'
has, however, been controversial. In clinical practice,
mannitol is given abundantly and the rebound phenomenon
is not observed. Also, repeated doses of mannitol are
usually given to treat intracranial hypertension following
severe head injury where the blood-brain barrier defect
has probably been overestimated.
is potentially nephrotoxic so it should not be given
if the plasma osmolarity exceeds 320 mmol/l.
is buffering substance which is used to treat acidosis
and when given intravenously leads to a significant
decrease in intracranial pressure. Apart from the buffering
of intracellular acidosis, a diuretic effect of the
substance has been postulated. THAM has been demonstrated
to be beneficial in reducing brain oedema following
cerebral ischaemia. It could well be that this substance
is in fact interfering with the mechanisms of cellular/cytotoxic
oedema following ischaemia. Consequently, THAM has been
used to treat traumatic brain oedema and post-traumatic
intracranial hypertension. Similarly to steroids, THAM
could not be shown to be clinically useful regarding
the neurological outcome of severely head injured patients
in general. Thus, treatment with THAM has been abandoned.
Moreover, it has recently been reported that THAM administration
may cause a decreased cerebral oxygenation due to vasoconstriction.
Nevertheless, it may remain a therapeutic option to
decrease intracranial pressure under certain circumstances.
decreasing CSF, cerebral blood volume and intracranial
simplest method to reduce intracranial pressure is to
drain CSF. This is certainly a very effective method
as long as there is CSF in the ventricles to drain.
of CSF production by furosemide or the carbonic anhydrase
inhibitor acetazolamide also decreases intracranial
pressure. Their effects is time-limited and it is not
advisable to use them on a long - term basis.
following therapeutic modalities have in common that
they decrease intracerebral blood volume, thereby reducing
intracranial pressure. Thus, these therapeutic options
do not directly pressure. Thus, these therapeutic options
do not directly interfere with brain oedema.
causes cerebral vasodilation and an increase of cerebral
blood volume with brain swelling which should be strictly
avoided. Conversely, hyperventilation causing hypocapnia
reduces cerebral blood volume by vasoconstriction. Hyperventilation
is called 'moderate' if the arterial Pco2 is between
30 and 35 mmHg, and called 'forced' if the arterial
Pco2 drops below 30 mmHg. Since hypocapnia causes vasoconstriction,
there is always a danger of inducing cerebral ischaemia
by this manoeuvre. This is in fact imminent if arterial
Pco2 is below 30 mmHg. It is now possible to control
cerebral oxygenation either by monitoring of oxygen
saturation in the jugular bulb or by direct measurement
of the partial pressure of tissue oxygen. It has been
suggested therefore, that such techniques should be
used to monitor forced hyperventilation in order to
prevent cerebral maloxygenation.
hypothermia has attracted enormous interest. Decades
ago it had already been used to decrease cerebral metabolism
and thus local tissue demands for substrate supply.
Thereby hypothermia decreases CBF and cerebral blood
volume as well as intracranial pressure. Hypothermia
has been shown to be very effective in various experimental
situations of acute brain injury, ischaemic and traumatic.
Clinical trials have yet to show whether this procedure
is also efficacious in a clinical setting. It should
be mentioned that hypothermia is a considerable technical
effort with numerous side-effects, for example interference
also decreases cerebral metabolism, CBF and cerebral
blood volume. It has also been postulated that barbiturates
might interfere with mediator mechanisms of brain oedema,
like AA release, free radical generation and so on.
Barbiturates should generally not be given to severely
head injured patients but only in cases where intracranial
hypertension cannot be controlled by CSF drainage, mannitol
and hyperventilation. Barbiturates bear the risk of
arterial hypotension, thus potentially decreasing cerebral
decompression of the brain must be mentioned. Obviously,
tumour excision removes the source of oedema and decompression
has also recently been a revival of interest in removing
haemorrhagic contusions in severely head injured patients
with intracranial hypertension.
a massive bony decompression combined with an enlargement
of the dura might be useful to cope with brain swelling
due to ischaemic brain oedema following MCA occlusion
or diffuse brain swelling in traumatized patients, especially
in children and adolescents. Again, this is a symptomatic
therapy aimed at preventing the secondary deleterious
effects of brain oedema.
with mediators of brain oedema.
date, there are various compounds known to interfere
with different mediator mechanisms of brain oedema which
are efficiently reducing brain edema under experimental
conditions. However, clinically, their effect is either
moderate or non-existent. As mentioned above, steroids
and barbiturates may interfere with lipid peroxidation,
while aminosteroids and superoxide dismutase inhibit
oxygen free radical generation. Clinical trials with
the latter agents have not been encouraging and these
substances have thus been abandoned. Conversely, calcium
antagonists, nimodipine in particular, were shown no
improve neurological outcome following subarachnoid
haemorrhage and may also be of benefit in patients with
traumatic subarachnoid haemorrhage. This effect is probably
not related to vasospasm, but rather is a 'neuroprotective'
property of the agent. It might be hypothesized that
nimodipine also interferes with cellular/cytotoxic oedema
generation in ischaemia and trauma.
the moment various glutamate receptor antagonists are
being tested both experimentally and clinically following
stroke and brain trauma. The crucial role of glutamate
in cellular/cytotoxic oedema has been mentioned before.
Needless to say, this is a fundamental rational approach
which might prove the concept of excitotoxicity and
cytotoxic brain oedema.
with inflammatory processes, like inhibition of cytokines
as, for example, by tumour necrosis factor and so on,
might be another potential avenue to search for a more
rational treatment under certain circumstances.
oedema is an important factor determining the course
of numerous cerebral diseases. The distinction between
different prototypes of oedema is helpful for the understanding
of oedema formation and resolution. Under clinical conditions,
there is most often a combination of cellular/cytotoxic
oedema with extracellular vasogenic oedema. Oedema itself
is not necessarily harmful and is principally reversible.
It may, however, lead to an increase in intracranial
pressure and decreased cerebral perfusion pressure,
and eventually to herniation. Under clinical conditions,
brain oedema is diagnosed by CT and MRI supplemented
by contrast enhancement to visualize a defect of the
blood brain barrier, that is, the vasogenic oedema component.
Treatment of cerebral oedema is still largely symptomatic.
Steroids are clearly useful for the treatment of peritumoral
oedema incluidng abscesses, while their predominant
mode of action is still unclear. All other modalities
to reduce brain oedema are primarily directed towards
a generalized dehydration of the brain or to decrease
cerebral blood volume and intracranial pressure. Further
progress towards a more specific antioedematous treatment
can only be made if our knowledge about oedema formation
and inhibition of oedema-mediating substances and processes
clinical manifestation of cancer are usually non-specific
- eg, anorexia, malaise, weight loss, fever - or are
due to local effects of tumor growth either in the primary
site or at a distant site. The term "paraneoplasia"
has been coined to denote the remote effects of malignancy
that cannot be attributed either to direct invasion
of metastatic lesions. These syndromes may be the first
sign of a malignancy and may affect up to 15% of patients
paraneoplastic syndromes are of considerable clinical
importance for the following reasons :
may accompany relatively limited neoplastic growth
and provide an early due to the presence of certain
types of cancer.
course of the paraneoplastic syndrome usually parallels
the course of the tumor. Therefore, effective treatment
should be accompained by resolution of the syndrome,
and conversely, recurrence of the cancer may be
heralded by return of systemic symptoms.
metabolic or toxic effects of the syndrome may constitute
a more urgent hazard to life than the underlying
paraneoplastic syndromes are usually caused by the secretion
of proteins not normally associated with a cancer's
normal tissue equivalent. Clinical findings may resemble
those of primary endocrine, metabolic, hematologic,
or neuromuscular disorders. The mechanisms for such
remote effects can be classified into three groups :
(1) effects initiated by a tumor product, (2) effects
due to the destruction of normal tissues by tumor products,
and (3) effects due to unknown mechanisms such as unidentified
tumor products or circulating immune complexes stimulated
by the tumor. Even such nonspecific symptoms as fever
and weight loss are truly paraneoplastic and are due
tot he production of specific factors by tumor cells
or by normal cells in response to the tumor.
syndromes associated with ectopic hormone production
are the best-characterized entities. Tumor cells secrete
a hormone or prohormone that may be of a higher or lower
molecular weight that may be of a higher or lower molecular
weight than hormones secreted by the more differentiated
normal endocrine cell. This ectopic hormone production
by cancer cells is believed to result form activation
of genes in malignant cells that are normally suppressed
in most somatic cells. A single syndrome such as hypercalcemia
may be due to more than one of a variety of causes.
Effective antitumor treatment usually results in return
of the serum calcium to normal, though additional therapy
may be required. Several neurologic paraneoplastic syndromes
have been found to be caused by the production of antineuronal
antibodies that circulate in the serum and spinal fluid.
It is thought that the underlying tumor expresses a
similar antigen, resulting in production of a cross-reactive
antibody. Treatment of the underlying tumor usually
results in only modest improvement of the neurologic
deficit. Examples of antineuronal antibodies include
the anti-Hu antibody causing sensory neuropathy or encephalitis,
associated with small cell cancer of the lung; the anti-Yo
antibody causing cerebellar degeneration, associated
most often with breast or gynecologic malignancies;
the stiff man syndrome, associated with breast cancer;
and the anti-Purkinje cell antibodies causing cerebellar
ataxia, associated with Hodgkin's disease as well as
gynecologic breast, and lung cancers.
well-described paraneoplastic syndromes include those
involving the skin with or without other organ involvement,
hematologic syndromes and those involving the kidneys,
the gastrointestinal tract, and the joints.
most common cancer associated with paraneoplastic syndromes
is small -cell cancer of the lung. This is thought to
be due to its neuroectodermal origin.
A unilateral, lower motor neuron facial paralysis that
is probably due to active viral inflammatory demyelination
of the facial nerve causing swelling and secondary nerve
ischemia within the facial canal.
The most common cause of facial paralysis.
: 20 - 30 per 100 000 persons per year.
: any age
: M = F
of the facial nerve is present within the subarachnoid
space, composed largely of lymphocytes with associated
demyelination or axonal destruction or both.
of autopsy material have shown latent herpes simplex
virus (HSV) in the geniculate ganglia of humans.
acute viral inflammatory demyelination within the
facial canal, causing swelling of the nerve within
the facial canal and secondary ischemia.
HSV is the strongest association: reactivation of
HSV 1 genomes. HSV might be present in the geniculate
ganglia where it could cause a facial nerve palsy
when the virus travels down the nerve axon, perhaps
infecting the Schwann cells.
- Epstein - Barr virus
: fivefold increased risk
: threefold increased risk
viral prodrome is present in about 60% of patients.
behind the ear, evolving over about 48 hours before
reaching a plateau.
facial weakness of lower motor neuron type follows
the pain, and may be associated with excessive tearing
due to weakness of the orbicularis oculi (which normally
holds the lacrimal puncta against the conjunctiva)
facial numbness is a common symptom, but objective
sensory testing is normal.
may be altered.
to sound (hyperacusis) may be increased, such as when
using a telephone.
motor neuron facial weakness
unilateral lower motor neuron facial weakness, without
other neurologic deficits.
facial nerve infections : herpes viruses (e.g., reactivation
of the varicella-zoster vitrus (Ramsay Hunt syndrome):
vesicles in the ear from which varicella-zoster virus
can be easily recovered; seroconversion often, with
increase in specific antibody to VZV); Lyme disease.
facial neuropathy due to small vessel disease (e.g.
bone tumors: metastatic, invasive meningioma
gland tumors or infections
motor neuron facial weakness
usually necessary, unless there is doubt about the
A light preponderance of elevated titres against HSV,
compared with controls but increased titres are the
exception rather than the rule.
Inconsistently shows mildly elevated cell counts and
when a brain lesion is suspected (e.g. when more than
an isolated lower motor neuron facial palsy is present).
scans are more sensitive than CT brain scan of the
posterior fossa, which is limited by bone artifacts.
gadolinium-induced enhancement of the facial nerve
in acute causes of Bell's palsy.
are used to amplify viral genomic sequences from endoneurial
fluid collected from the facial nerve or tissue of
the posterior auricular muscle innervated by the facial
nerve is patients undergoing decompressive surgery.
one study, HSV type 1 genomes were amplified from
the nerve or muscle tissue of 11 of 14 patients with
Bell's palsy. However, PCR does not distinguish between
viral genomes that are present in a latent state and
those that are present because of reactivated virus
in the course of a productive infection.
Electroneurography may be used to prognosticate recovery,
but not to make the diagnosis.
clinical diagnosis of exclusion:
motor neuron facial weakness (peripheral facial nerve
other neurologic deficits.
apparent cause, other than a herpes simplex virus,
after prolonged follow-up (until the condition has
resolved or fresh clues to a specific cause appear).
Controversial, party because of the good prognosis of
the untreated condition and the failure of controlled
trials to prove a beneficial effect on long term outcome:
Nevertheless, steroids are used empirically by some
neurologists to :
pain that is sometimes an early failure
progression of incomplete to complete paralysis.
denervation in cause of complete paralysis
the time to recovery
development of abnormal synkinesias.
is likely that any benefit obtained is due to steroids
used early in the course. The usual regime is prednisolone,
25mg per day, orally, for 1 week, with patient review
on completion. Corticosteroids should not be used when
contraindications exist, such as diabetes, hypertensions,
peptic ulcer disease, osteoporosis, glaucoma, or pregnancy
May be effective if the underlying cause is herpes virus
infection. More data are needed from a large, randomized
controlled and blinded trial with at least 12 months'
There is no proven place for adjunctive therapies or
surgical decompression of the facial nerve in Bell's
if the cornea is not adequately protected.
can be avoided by using artificial tears, instilling
lubricating paraffin ointment, and taping (rather
than padding) the eye closed at night.
glasses should be worn outdoors.
advice should be sought if the patient reports eye
discomfort or the eye becomes irritated despite the
toxin injection into the eyelid levator to weaken
it may be considered if conservative measures fail.
is rarely necessary in cooperative patients.
- 80% of patients recover completely. In these cases,
recovery usually begins within 8 weeks and is complete
by 6 - 12 months. The most favorable prognostic sign
is an incomplete rather than complete facial palsy.
If weakness in severe or complete, recovery commencing
within 3 weeks is a favorable sign. The longer the delay
in return of movement the poorer the recovery.
of incomplete recovery are :
other than in or around the ear(i.e. back of head,
hypertension, diabetes or pyschiatric illness.
winking' and other abnormal facial movements caused
by aberrant reinnervation of the muscles of facial
expression by regenerating facial nerve fibers. (i.e.
tears' (rare): an excessive flow of tears when eating,
caused by aberrant reinnervation of the lacrimal gland
by regenerating facial nerve fibers.
facial palsy occurs in about 10% of patients. If this
occurs, alternative causes should be excluded, such
as diabetes, sarcoidosis, tumors, or infection.
heterogeneous group of disorders characterized by histologic
evidence of inflammation, and often necrosis, of blood
vessels and clinico-pathologic evidence of brain ischemia
or, less commonly, hemorrhage.
: any age
: either sex
arteries (aorta and its primary branches) Takayasu¡¦s
Large and medium ¡V sized arteries Giant cell
¡V sized and small muscular arteries
systemic necrotizing angiitides
angiitis and granulomatosis of Churg-Strauss.
associated with other systemic diseases
¡V Degos disease.
angiitis associated with connective tissue disease
Systemic lupus erythematosus.
connective tissue disease
isolated angiitis of the CNS
granulomatous angiitis of the CNS.
vessels (arterioles, capillaries, venules)
Exogenous stimuli proved or suspected:
- Drug-induced angiitides.
- Henoch ¡V Schonlein purpura.
- Serum sickness and serum sickness ¡V like reactions.
- Angiitis associated with infectious diseases.
antigens likely to be involved:
- Angiitis associated with neoplasms (particulary lymphoid
- Angiitis associated with other underlying diseases
- Angiitis associated with congenital deficiencies of
the complement system (hypocomplementemic angitis).
- Mixed cryoglobulinemia.
- Cutaneous angiitides.
subacute or chronic inflammation in the arterial and/or
wall with or without granuloma formation and necrosis.
A distinctive chronic inflammatory reaction of blood
vessels characterized by a predominance of modified
macrophages which are aggregated into nodular clumps
referred to as granulomas and which respond to foreign
bodies by coalescing to form giant cells that often
conglomerate around the
Inflammation and necrosis (usually fibrinoid necrosis)
of vessel walls.
Focal or multi-focal cerebral infarction
primary manifestation of disease or a secondary component
of another disorder such as connective tissue disease,
drug abuse, neoplasia or infection.
In situ formation or deposition of immune complexes
in blood vessel wall leading to activation of the
complement-mediated inflammatory response.
antibody-mediated damage via antibodies directed at
endothelial cells or other tissue components.
cellular cytotoxicity directed against blood vessels.
T lymphocytes directed at blood vessel components.
formation in blood vessel wall or adjacent to blood
(i.e. interleukin 1, TNF-alpha) expression of adhesion
vehicles for leukocytes on endothelial cells.
Infiltration of blood vessel wall or surrounding tissue
by microbiologic agents.
invasion of blood vessel by neoplastic cells.
of tissue dysfunction
Angiitis (Causing ischemia or hemorrhage)
Variable in onset, nature and duration.
are determined partly by the size and location of
the involved vessel(s).
commonly vasculitis presents as an acute or subacute
focal or diffuse encephalopathy or meningo-encephalopathy
with headache, altered mentation, seizures and cognitive
and behavioral abnormalities, with
multifocal neurologic signs.
Less commonly, patients present with a multiple sclerosis-like
picture, features of a rapidly progressive space-occupying
cranial neuropathies and rarely, with spinal cord
syndrome or stroke syndrome.
Systemic symptoms and signs may be present such as
malaise, weight loss, joint aches and pains, facial
: young : Takayasu¡¦s arteritis, SLE;
imaging brain parenchymal lesions. It may show:
Areas of increased signal on T2 and PDW images typically
in peripheral white matter and gray matter. There
may be evidence of hemorrhage in these lesions.
CT scan may be normal or show single or multiple non-enhancing
areas of low density, which may involves both cerebral
gray and white matter.
imaging arterial lesions:
May show areas of alternate narrowing and dilatation
of intracranial arterial branches, or areas of extracranial
In primary angiitis of the brain the small intracranial
arteries and arterioles are involved, whereas in vasculitis
complicating meningitis, tumors or other cause the
major basal intracranial arteries may be
involved. However, the angiogram may be normal even
vasculitis, particularly if the affected vessels are
<500 microns in diameter and
too small to be seen, so biopsy is strongly recommended.
Magnetic resonance angiography is not reliable enough
to confirm or exclude vasculitis; it is too prone
to flow-related artefacts and shows insufficient detail
to image the peripheral small arteries
satisfactorily. Spiral CT has not been widely evaluated.
of segmental narrowing of cerebral arteries on cerebral
Arteritis (non-infective, infective).
(drugs, subarachnoid hemorrhage, severe hypertension,
examination using low dose fluorescin angiography
with slit-lamp video microscopy of the anterior segment:
slowing of flow, multifocal attenuation of arterioles,
erythrocyte aggregates, area of
small vessel infarction, and multifocal segments of
intense leakage from post
capillary and collecting venules.
Antibodies against borreliosis*, salmonellosis, yersiniosis,
(Serum protein electrophoresis)*
- Cell count, total protein, glucose, quantitative
immunoglobulins, oligoclonal band analysis.
- Moderate mononuclear CSF pleocytosis
- CSF protein usually elevated to round 1 ¡V
1.5 g/1, but may be up to 5.8 g/1.
- Xanthochromia, hypoglycorrhachia and an elevated
CSF gammaglobulin with
oligoclonal banding of IgG have been reported.
The primary value of CSF studies is to exclude other
causes of a
APTT, dRVVT*: APLAb, SLE
Anticardiolipin antibodies*: APLAb, SLE
Angiotensin converting enzyme: sarcoidosis.
and beta 2-microgrobulin: sarcoidosis.
immunity : sarcoidosis, LG.
: frequently abnormal, showing generalized non-specific
activity of variable degree and location.
white-cell brain imaging: increased uptake and accumulation
in the brain imaging: increased uptake and accumulation
in the brain of indium-labelled leukocytes.
Cerebral or spinal cord biopsy establishes the diagnoses
in about 70% of cases
False-negative biopsies occur in about 30% of autopsy-proven
relatively low diagnostic yield from cortical biopsy
may be related
to the segmental nature of the lesions and the lack
of leptomeningeal tissue in the biopsy.
risk of serious morbidity from brain biopsy is about
0.5 ¡V 2.0%.
decision to biopsy is made on an individual basis;
if an extended period of treatment with potentially
hazardous immunosuppressant drugs is being considered,
then the need to establish an unequivocal tissue
diagnosis becomes of primary importance.
result of blood and CSF laboratory tests, EEG, brain
imaging with CT and MRI, and cerebral angiography are
neither sensitive nor specific but are usually essential
to role out infectious or malignant disease, which
can mimic CNS angiitis clinically.
diagnosis is made histologically. A combined leptomeningeal
and wedge cortical tissue biopsy, preferably of the
temporal tip of the non-dominant hemisphere and including
a longitudinally ¡V orientated surface vessel
is required. If organs other than the brain are affected,
biopsy specimens should be obtained.
decision to treat and how will depend on the clinical
condition and course of the patient and the philosophies
of the attending clinician. If the patient is well then
time is available to allow a period of observation
of the natural history of the disease. If the patient
is very sick, however, empirical immunosuppressive therapy,
may be commenced whilst awaiting biopsy confirmation.
Once the histologic diagnosis is confirmed then anti-inflammatory
and immunosuppressive therapy should be considered,
bearing in mind that the treatment of CNS angiitis is
inferred from clinical experience with
systemic angiits or intravenous glucocorticoid in divided
doses every 8 ¡V 12
the disease is controlled, reduce to one morning dose,
and thereafter, taper the daily dose as rapidly as clinical
disease permits. Ideally, patients should be slowly
converted to alternate day therapy with a single morning
dosage of short active glucocorticoid so as to minimize
adverse effects; prednisone doses of 15 mg daily given
before noon usually do not suppress the hypothalamic
pituitary axis. However, the disease may flare on the
day off steroids, in which case use the lowest single
daily dosage that suppresses disease.
Strategies to minimize adverse effects of steroid
Calcium for most patients to minimize osteoporosis.
D 50 000 units one to three times weekly if 24-h urinary
calcium excretion <120 mg,
replacement therapy if post-menopausal.
and biphosphonates may also be useful.
hypertension, edema and hypokalemia should be treated.
should be identified and treated early.
with influenza and pneumococcal vaccines are safe
and should be given if the disease is stable.
addition of cyclophosphamine to prednisolone may be
to minimize adverse effects of cyclophosphamide include:
Monitor the leukocyte count closely, keeping it above
3000 per cubic millimeter and the neutrophil count
about 1500 per microlitre.
severe neutropenia or bladder toxicity occurs despite
low doses of cyclophosphamide and a fluid intake of
>3 liters/day, azathioprine 1 ¡V 2 mg/kg
per day or methotrexate can be used successfully with
pulsed regimen of 10-15 mg/kg intravenously once every
4 weeks has less bladder toxicity that daily oral
doses but bone marrow suppression can be severe.
the disease has been controlled for a few months, taper
immunosuppressive agents and attempt to discontinue
them. The role of antiplatelet agents and anticoagulants
is uncertain. Campath- 1H
humanized monoclonal antibody treatment remains experimental.
approach to the patient with suspected CNS vasculitis
1. Is it cerebrovascular
2. Where is the lesion neuroanatomically?
3. What is the pathologic nature of the lesion: ischemic
4. What is the etiology of the lesion: have more common
disorders of the
arteries, heart and blood been excluded?
5. Are there other clinical features or investigation
results to indicate that this is part of a specific
6. If a syndrome is recognized and if it is associated
with an underlying disease or an offending antigen,
treat the underlying disease or remove the offending
antigen where possible.
7. Establish the histologic diagnosis of angiitis by
obtaining a tissue biopsy before committing the patient
to a long course of immunosuppressive medication.
8. Determine the extent of disease activity
9. Start treatment with appropriate agents in disorders
in which treatment is of proven benefit and is essential
10. In patient with systemic angiitis , start with glucocorticoid
Add a cytotoxic agent such as methotrexate or cyclophosphamide
if an adequate response does not result of if the disorder
is likely to respond only to cytotoxic agents, such
as Wegener¡¦s granulomatosis.
11. Avoid immunosuppressive therapy in disorders which
rarely result in irreversible organ system dysfunction
and which usually do not respond to such agents.
12. Closely follow patients for development of toxic
adverse effects of treatment.
13. Continually attempt to taper glucocorticoids to
an alternate day regimen and discontinuation when possible,
and to taper and discontinue cytotoxic drugs as soon
as is feasible upon induction of remission.
14. In the event of unacceptable adverse effects or
lack of efficacy, consider alternative agents such as
a derivative of the carbohydrate mannose, was introduced
as an osmotic diuretic over 30 years ago. Since then,
it has been successfully and eclectically employed in
many areas of medicine. These include transfusion medicine,
where it prolongs red blood survival in stored blood,
as a pharmaceutical excipient, e.g. with dantrolene,
in ophthalmology to reduce intraocular pressure, and
as a substitute glycine in urology. Mannitol has also
been employed as an adjunct to chemotherapy for intracranial
malignancies, where it is used to improve the penetration
of cytotoxic drugs given selectively via the carotid
artery. However, the areas in which it excites most
controversy and confusion are as a protective and therapeutic
agent in situations of neurological or renal compromise
and as a potential scavenger of free oxygen radicals.
This article attempts to review these roles and assess
the value of mannitol for these indications.
AND NEURO CRITICAL CARE
use of osmotic agents to reduce cerebral water content
was suggested by the work of Weed and McKibben in 1919.
They noted cerebral dehydration after hypertonic saline
in contrast to cerebral oedema following intravenous
distilled water. Amongst the earliest proponents of
osmotherapy, as it was then called, were Fremont-Smith
and Forbes, who used hyperosmolar urea of reduce intracranial
pressure (ICP) during neurosurgery in the late 1920s.
Mannitol was introduced in the early 1960s after urea
was found to be associated with rebound intracranial
hypertension. Since then, it has become the most widely
used agent to control ICP in both elective neurosurgery
and following traumatic brain injury (TBI).
MECHANISMS OF NERUOPROTECTIVE EFFECTS
Because mannitol is hyperosmolar relative to intracellular
fluid, intravenous administration results in movement
of 'free water' from the tissues into the plasma. There
is a more pronounced effect in the brain due to the
fact that the blood-brain barrier (BBB) differs from
all other capillaries membranes in being relatively
impermeable to mannitol, thus maintaining the osmotic
support of the osmotic theory, the work of Cascino'
has shown that even small changes in total brain water
content can translate into relatively large alterations
in brain volume. On the other hand, clinically significant
changes in brain water content can take up to 30 min
to develop, whereas the observed reduction in ICP following
mannitol usually far sooner. There is also a discrepancy
between the large amounts of mannitol needed to reduce
brain water experimentally and the much smaller doses
known to reduce ICP clinically. It is likely, therefore,
that any osmotic effect is more responsible for the
sustained, rather than immediate, reduction in ICP seen
with mannitol administration.
and Viscosity changes
Under normal physiological conditions, ICP is principally
determined by cerebral blood volume (CBV). In turn,
the CBV is controlled by a number of variables, the
most important of which are those influencing oxygen
delivery to the rain. These include cerebral perfusion
pressure (CPP), cerebral vascular resistance and blood
viscosity. When intracranial compliance is reduced,
such as after a traumatic brain injury (TBI), any manoeuvre
which improves oxygen delivery reduces CBV, and thus
ICP, by inducing vasoconstriction of cerebral blood
Mannitol probably improves oxygen delivery both by increasing
CPP and reducing blood viscosity. The increase in CPP
comes from its plasma expanding effect, which causes
an increased cardiac output. Factors favouring viscosity
reduction, include haemodilution, decreased adhesiveness
of red cells and increased red cell deformability, thereby
reducing resistance to capillary blood flow. These changes
are thought to be most responsible for the prompt reduction
in ICP seen clinically with mannitol, given that they
occur soon after administration.
action of mannitol
Mannitol could decrease ICP through a fall in CVP as
a result of the osmotic diuresis. However, this is unlikely
given that ICP reduction occurs long before the diuresis,
and a normal or elevated CVP is not incompatible with
a good response to mannitol. Even patients with renal
failure, who have a persistently elevated CVP, can have
a brisk reduction in ICP with mannitol.
and CSF production / resorption
Although never proven satisfactory and probably of little
significance, mannitol may increase resorption and reduce
production of CSF by increasing plasma osmolality. The
site of action is postulated to occur at the level of
the pial circulation or at the cerebral ventricles.
as an oxygen free radical scavenger
An additional, although theoretical, beneficial effect
of mannitol could be a reduction of ischemic damage
and oedema by a free radical scavenging action. This
may be as a result of specific interference with oedema
promoting factors or a reduction in brain tissue necrosis
from the primary injury.
IN TRAUMATIC BRAIN INJURY
seems that regardless of the intervention strategy chosen,
the outcome from a severe TBI is bleak. Nevertheless,
it is accepted that reducing a raised ICP is a useful
manoeuvre, the rationale being that a fall in ICP to
near normal limits improves CBF and CPP, and increases
oxygen delivery to the brain which, in turn, reduces
anaerobic glycolysis and hence cerebral oedema. Indeed,
one study showed that a persistently raised ICP resulted
in a mortality of > 90%, while successful reduction
of near normal limits decreased mortality of 26%.
Although mannitol has become the cornerstone of the
pharmacological management of raised ICP after TBI,
it has never been subjected to a controlled trial against
placebo. There has been one study comparing its efficacy
with barbiturates, where mannitol was shown to have
a better outcome mortality of 41% compared to 77% for
pentobarbital. Certain factors do indicate its ability
to produce a prompt, persistent reduction of ICP to
or below 15 mmHg, to reduce an initially high ICP of
>50 mmHg or the ability to maintain CPP at or below
limit of autoregulation. Diffuse widespread injuries
respond more than focal injury and there is a greater
benefit seen in patients < 40 years of age with an
initial systolic blood pressure > 90 mmHg. There
was a suggestion that mannitol was less effective after
loss of cerebral blood flow autoregulation, but this
is no longer thought to be the case.
It is becoming increasingly apparent, however, that
the relationship between ICP, CPP and development of
cerebral ischaemia is far clear-cut. Following TBI,
certain factors adversely influence CBF or contribute
directly to cerebral damage without having much effect
on ICP. These include loss of autoregulation, traumatic
vasospasm or neurochemical changes from elevated excitatory
amino acids. This suggests that, in addition to measuring
ICP, it is equally important to assess adequacy of the
CBF, and thus oxygen delivery to the brain. The development
of techniques such as somatosensory evoked potentials
and jugular bulb oxygen monitoring now makes this possible.
In the future, therefore, it is hoped that having a
multimodal approach to monitoring cerebral function
after a TBI will help direct therapeutic interventions,
including the use of mannitol, more appropriately so
as to optimise CPP further and ameliorate the consequences
of secondary ischaemic damage to the brain.
ISSUES FOR ADMINISTRATION OF MANNITOL
The initial dose of 2 g/kg was derived from a comparison
with urea. The recommended dose has fallen in recent
years to between 0.25 - 1 g/kg. Mannitol shows substantial
inter-patient variability, making it difficult to predict
an effective dose for every patient, but larger doses
appear to prolong the effect of ICP. Mannitol should
be used with caution in renal impairment as it is cleared
exclusively by the kidney.
and timing of administration
There is no firm consensus on this, although mannitol
is usually given by slow bolus infusion over 15 - 30
min to limit significant haemodynamic changes. There
is no fixed interval for repeat boluses, but it is usually
every 3 - 4 h, as this is the time taken for mannitol
to clear from the circulation if renal function is normal.
Tachyphylaxis may occure with more than 3 - 4 doses
per 24 h. Continuous infusion is best avoided as small
amounts of mannitol may pass into the brain and accumulate.
This could potentially result in reverse osmotic shift
with water entering the brain to compensate for the
increased osmolality with the consequence of increasing
cerebral oedema and exacerbating ICP.
Clinical indications for the use of mannitol in the
absence of ICP monitoring include signs of transtentorial
herniation or progressive neurological deterioration
not attributable to systemic pathology. Optimal criteria
based on ICP have not been clearly established. Smith,
for example, failed to show any improvement in outcome
after a severe head injury regardless of whether mannitol
was given only when ICP was > 25 mmHg or empirically
every 2 h until serum osmolality was 310 mOsm/1. Because
cerebral oedema occurs soon after the primary event,
it has been suggested that mannitol should be given
as soon as possible after injury, even if this is outside
a hospital setting. There have been reservations concerning
potential adverse haemodynamic effects, but these have
recently been questioned.
concurrent fluid therapy
Moderate fluid restriction is traditionally advocated
in the acute management of TBI. However, this has to
be balanced against the need for adequate fluid replacement
to prevent dehydration, particularly given the diuretic
effects of mannitol and the consequent risks of hyperviscosity
and renal impairment. The use of large volumes of hypotonic
0.45% saline solution over 4 --8 h have been advocated
to counteract the hyperosmolar effect of mannitol and
also promote its rapid clearance so limiting renal impairment.
Good hydration also maintains intravascular volume and
optimises blood pressure and CPP.
is some controversy concerning the importance and relevance
of potential complications, as outlined below.
Although mannitol usually increases blood pressure slightly,
it can occasionally cause a fall in blood pressure due
to a decrease in systemic vascular resistance. Possible
explanations for this include a fall in plasma pH, increased
release of atrial natriuretic factor (ANF), basophil
histamine release and direct impairment of the contractile
properties of vascular smooth muscle. Any hypotension
is usually transient, but it could compromise cerebral
perfusion to an extent that offsets any potential benefit
of mannitol. This is particularly true in volume depleted
patients or after multiple trauma with a closed head
injury, in whom even brief periods of hypotension correlated
with a poor outcome. In these cases, the benefits from
reducing ICP must be balanced against the risk of reducing
CPP. In really compromised patients, care must be taken
not to precipitate cardiac failure secondary to sudden
increases in ICP
Bolus infusions of mannitol can double CBV. This is
not usually clinically significant, however, as CBV
comprises such a small percentage of the total intracranial
space. Any increases in ICP are usually mild and transient
and are usually offset by the reduction in brain water
and CSF volume. Mild hyperventilation, often used in
TBI, also tends to conunteract any increases in CBV.
and electrolyte disturbances
Dehydration is often concealed as mannitol shifts fluid
into the intravascular compartment, thus preserving
circulating volume so that clinical signs of haemodynamic
compromise may not develop until intracellular dehydration
is severe. Generally, there is electrolyte depletion,
but it is proportionally much less than fluid loss.
Sodium may increase in the long term as a result of
the hyperosmolar state, but is often compensated by
an increase in ADH, a common finding in the critically
ill. Hyperkalaemia may also occur, rarely, from haemolysis.
and osmotic compensation
Sustained use of mannitol results in a hyperosmolar
state, which leads to movement of osmotically active
particles and electrolytes intracellularly. This increase
in osmotic activity within the cell counteracts the
dehydrating effect of hyperosmolar plasma and thus places
finite limits on the reduction of brain volume mannitol
can achieve. The threshold for osmotic compensation
is not precisely known, but is thought to be 25 mOsm/kg
above normal osmolality. Because of this, mannitol should
not be used when plasma osmolality exceeds 320 mOsm/1.
Cerebral oedema may occur if a hyperosmolar state is
reversed too quickly, and the speed of return to normal
osmolality should approximately match the duration of
the hyperosmolar state. Cautious use of isotonic saline
is safer than hypotonic fluids such as enteral feeds
or dextrose solutions.
Mannitol in excess of 200 g/day may cause acute renal
failure (ARF). This is more likely in the elderly, in
pre-existing renal failure and where patients are having
concomitant treatment with other diuretics. It is probably
due to structural and functional charges in the nephron,
but prompt haemodialysis usually results in complete
FUTURE ROLE OF MANNITOL FOR NEUROPROTECTION
has a well-established role in the short-term control
of ICP for intracranial surgery and after TBI and this
is the basis for its continued use. More recently, it
has been prompted as a 'small volume resuscitation fluid'
for cerebral protection and volume expansion in multiple
trauma patients. However, mannitol is being increasingly
challenged - by two other osmotic agents, glycerol and
Glycerol's effect on ICP and CPP are similar to those
of mannitol but appear to be more consistent and sustained.
Its diuretic action is less pronounced, favoring normovolaemia.
Glycerol crosses the BBB but there is minimal accumulation
in the cerebral tissues as it is metbolised by neuronal
cells. Reverse osmotic shift is not, therefore, thought
to be a risk. It may also provide nutritional support
to the damaged cells thus having a protein sparing action.
Its main side effect is haemolysis which can be limited
by using a low concentration, a slow infusion rate and
adding glucose, fructose or chloride to the solution.
It has been suggested that glycerol be used as the first
line treatment in the management of brain injured patients
with increased ICP and impaired CPP, while mannitol
is reserved for sudden increases in ICP.
Hypertonic saline is also being promoted as superior
to mannitol. It is as effective in reducing brain volume
and ICP in animal and human studies, in elective neurosurgery
and in brain injured children. More significantly, it
has also been found to be effective in reducing a raised
ICP refractory to treatment with mannitol. Hypertonic
saline also has the advantage of not significantly reducing
intravascular volume. The diuretic action of mannitol,
once considered beneficial, may, infact, worsen outcome
in TBI as the damaged brain appears to be exceptionally
vulnerable to a fall in CPP caused by hypovolaemia-induced
Thus, although mannitol is currently the most popular
osmotic agent, it may well be that hypertonic saline,
the original osmotic fluid first used by Weed and McKibben
almost a century ago, will become the treatment of choice
for raised intracranial pressure in the next millennium.
AND RENAL PROTECTION
1945, mannitol was experimentally found to induce diuresis
in dogs subjected to an ischaemic insult. This led to
the idea that it might be of value in preserving renal
function in humans. Since then, mannitol has been widely,
but controversially, used in prophylaxis and treatment
of acute renal failure (ARF).
MECHANISMS OF RENAL EFFECTS
is effectively inert and is freely filtered at the glomerulus
without being secreted or substantially re-absorbed.
Diruesis is brisk, with total body water loss up to
30% if the filtered amount. The precise mechanisms by
which the diuresis occurs have not been fully elucidated,
but include changes of systemic and renalhaemodynamics
as well as local effects at the glomerular and tubular
Following intravenous administration, mannitol is confined
mainly to the intravascular compartment causing a water
shift from the intracellular compartment. This leads
to intravascular volume expansion and to decreased plasma
oncotic pressure, blood viscosity and haematocrit, all
of which may improve renal perfusion. Mannitol increases
plasma levels of the vasodilatory hormone, atrial natriuertic
factor (ANF), probably as a result of intravascular
volume expansion and may have a syngergistic action
with it to improve renal perfusion.
Infusion of mannitol has been shown to improve renal
blood flow (RBF) and glomerular filtration rate(GRF)
by reducing renal vascular resistance (RVR). This effect
is explained mainly by a reduction in plasma viscosity,
although mannitol may also stimulate release of vasoactive
agents such as prostacyclin. This increased renal perfusion
is associated proportional increases in both cortical
and medullary blood flow. The latter may be responsible
for the loss of medullary hypertonicity observed during
osmotic diuresis, which could explain the inhibition
of salt and water resorption in the loop of Henle. Conversely,
high doses of mannitol may cause renal artery vasospasm
and increased RVR resulting in decreased renal perfusion,
which may paradoxically impair renal function.
There are conflicting accounts of the glomerular effects
of mannitol on GFR. Results vary according to the animal
model being studied and whether single nephrons or whole
kidneys are being assessed. In many in vitro studies,
mannitol has been shown to restore GFR of a hypoperfused
kidney to near normal values. Mechanisms proposed include
preferential dilatation of the afferent glomerular arteriole
due to suppression of renin release and intrarenal formation
of angiotensin II. Unfortunately, these protective effects
of mannitol on the GFR seen experimentally are not reflected
in the results seen in intact animals or normal volunteers
where, under circumstances of low renal perfusion, for
example, glomerular filtration remains unchanged or
even decreases with mannitol.
Renal ischaemia of whatever origin leads to tubular
cell oedema. This compresses the interstitial and vascular
spaces, resulting in poor renal perfusion and impaired
renal function. Mannitol has been shown to reduce tubular
cell swelling, particularly in the proximal tubule and
thick ascending limb of the loop of Henle and it is
assumed that this helps to maintain both tubular flow
and glomerular filtration. In addition, mannitol has
been found to increase intratubular pressure by increasing
the flow of urine which may also help maintain patency
of the tubulular lumen.
The diuresis seen with mannitol leads to reduced tubular
resorption of water and solutes. As resorption is an
energy requiring process, this reduction may be protective
in situations where impaired renal perfusion leads to
poor oxygen delivery. The precise cause of this effect
is unknown although it is probably unrelated to the
hyperosmolality of the solution, given that a glucose
infusion of similar osmolarity does not produce the
same protective effect as mannitol.
AND EFFECTS ON RENAL FUNCTION
there are good theoretical reasons for mannitol to have
a role in the prophylaxis and salvaging of renal function,
they are not convincingly supported by the available
evidence. There is a wide gap between the expectation
of mannitol's value and its observed clinical benefit,
although rigorous studies on its efficacy in the management
of renal failure are lacking. Such studies are often
difficult to conduct in view of the wide spectrum of
aetiologies, clinical settings and severity of ARF.
In addition, the criteria for successful treatment differ
between studies, and mortality is often due to other
Nevertheless, one area where mannitol has been found
to be invaluable is in preserving renal function and
reducing the incidence of ARF after cadaveric renal
transplantation. A number of well controlled prospective
studies have shown that mannitol in the perfusate of
a cadaveric kidney prior to transplantation substantially
reduced the incidence of both graft rejection and the
incidence of post-transplant ART. The same effect can
be seen if mannitol is given just prior to restoration
of blood flow to the transplanted kidney.
FOR THE PROPHYLAXIS OF ARF
than in renal transplantation, prophylactic mannitol
does not appear to have any significant protective effect
on renal function when given prophylactically. For example,
pre-dosing with mannitol prior to the use of radiocontrast
agents in interventional radiology has shown no protective
effect on renal function. Despite initial hopes, the
results have also been equally disappointing in preserving
renal function after surgical relief of obstructive
jaundice. Patients who have infrarenal cross clamping
during abdominal aortic aneurysm surgery are particularly
at risk of ARF, but here too, most studies have found
mannitol to be of little value with the exception of
one group who found a reduction in subclinical renal
injury as measured by albumin and N-acetylglucosamindase,
more sensitive markers of renal dysfunction.
Mannitol has also been used to preserve renal function
in rhabdomyolysis, which results in the release of nephrotoxic
myoglobin form severe muscle necrosis following a crush
injury. The renoprotective action of mannitol is thought
to be mediated through the diuretic action which has
the dual effect of increasing both urine flow and intratubular
pressure to overcome tubular obstruction from haem pigment
trapping and cast formation. These effects, however,
are not exclusive to mannitol and, in addition to there
being little evidence that mannitol improves outcome,
it has also been shown that expanding plasma volume
with other agents, such as glycerol and normal saline,
has similar renoprotective actions. As such, nowadays
the first line of treatment for prevention of myoglobinuric
ARF is volume expansion with saline.
FOR THE MANAGEMENT OF ACUTE RENAL FAILURE
established acute renal failure, mannitol is not only
ineffective but can be hazardous due to the risk of
fluid overload. Its role in early renal failure is less
clear as it can be difficult to determine whether patients
have pre-renal failure or have crossed the line into
established failure given that biochemical measurements
are too insensitive to be helpful in the early stages.
Some clinicians advocate mannitol therapy within 24
h of onset of oliguria. However, conversion of oliguria
to an non-oliguric state is no guarantee of prevention
of ARF, and the risk of progression remains high regardless
of whether mannitol has been given or not.
There are concerns that mannitol may acutally increases
the risk of ARF by increasing renal artery oxygen consumption.
Despite receiving approximately 20% of cardiac output,
the kidney is very susceptible to ischaemia. There are
two main reasons for this. Firstly, the kidney extracts
relatively little oxygen for metabolic processes and,
secondly, the medullary part of the kidney receives
only 6% of renal blood flow despite being responsible
for most of the energy requiring work of the kidney.
Oxygen delivery to the medulla is thus critical. If
it is reduced any means, renal function will be compromised
and this may occur even when total renal blood flow
appears to be adequate.
Mannitol increased both renal blood flow and glomerular
filtration and thus there is a greater solute and water
load to be resorbed by the tubules. This leads to energy
expenditure and a concomitant rise in oxygen demand,
so that mannitol may do more harm than good in situations
where there is impaired oxygen delivery. This increase
in solute load, however, needs to be balanced against
mannitol's ability to inhibit resorptive processes in
the loop of Henle by loss of medullary hypertonicity,
and thus, presumably, decrease the potential for increased
oxygen consumption. The relative importance of these
two opposing forces is unknown.
OF THE ROLE OF MANNITOL IN RENAL PROTECTION
theoretical promise of effective protection against
ischaemic injury of the kidney proves in practice as
illusory as its role in neuroportection after acute
brain injury. Clinical trials fail to adequately demonstrate
convincing advantages for mannitol except in the case
of cadaveric renal transplantation.
AS AN OXYGEN FREE RADICAL SCAVENGER
free radicals are extremely toxic molecules constantly
produced in all metabolically active cells during certain
stages of many different types of biological processes.
One common example is the formation of OFRs witht eh
electron reduction of oxygen by cytochrome oxidase.
Under normal circumstances, OFRs are inactivated immediately
by intracellular enzymes such as catalase, superoxide
dismutase and glutathione preoxidase; but, in certain
situations, such as tissue ischaemia, they are produced
in excess, which may overwhelm the normal limiting processes.
This can lead to oxidation of cellular components such
as mitochondrial and cellular membranes resulting in
cell damage or death. The most reactive OFR is the hydroxyl
radical but others include nitric oxide and superoxide
Mannitol has been proposed to act as an antioxidant
OFR scavenger, specifically targeting the OH raidcal
to cause its disproportionationor dimerization to non-toxic
metabolites. Much of the research on mannitol's OFR
scavenging capabilities has looked at reperfusion injury
following the restoration of oxygen supply to an ischaemic
organ. Models of this type are used because direct,
consistent measurement of OFRs are not possible in view
of their very short half-life of a few nanoseconds.
Cardiac surgery provides one of the easiest models for
study in this field. In spite of cardioplegia solutions
and cooling for myocardial protection, there is often
some postopeartive depression of myocardial function,
which is thought largely to be due to an excess of OFRs
produced after cardiopulmonary bypass. Cardioplegia
solutions also provide a relatively simple and convenient
method for introducing intervention therapies, such
One such study, for example, has demonstrated decreased
OFR production following CPB. Others, both animal and
human, have shown a slight decrease in the incidence
and duration of artrial and ventricular arrhythmia as
well as, evidence of histological preservation of the
myocardial cell architecture and improvement in ventricular
and renal function post CPB. However, given the problem
to detecting and measuring OFR production accurately,
it is difficult to know whether the results of these
studies are directly related to mannitol's OFR scavenging
capabilities or not and, as such, the results frequently
remain open to interpretation. Moreover, these positive
studies are increasingly being matched by others suggesting
mannitol has little effect on reperfusion injury. For
example, mannitol has equally been shown to have any
effect on the incidence and severity of reperfusion
atrial or ventricular arrhythmias, nor has it been shown
to improve ventricular function, renal function or haemodynamic
stability after CPB.
There are several valid explantations for mannitol's
ineffectiveness in protecting against reperfusion injury.
OFRs are produced intracellularly and need to be mopped
up instantaneously in order to prevent molecular damage.
Mannitol, on the other hand, tends to remain in the
extracellular compartment, with minimal amounts crossing
the cell membrane. It is thus unlikely that mannitol
plays a significantly intracellular role in preventing
any significant oxidative damage. Moreover, although
mannitol reacts rapidly with hydroxyl radicals it fails
to scavenge any other OFR to an extent that would offer
protection in a biological system.
Although the evidence for any direct OFR scavenging
effect of mannitol is poor, it may act indirectly to
reduce OFR production. It is an effective chelating
agent of ferric ions, which play a key role in converting
poorly reactive oxygen species into highly reactive
and damage OH-radicals. It may thus protect against
such damage by removing iron from the cellular molecules
and structures at risk of oxidative damage. This has
been seen both in vitro and in vivo and it has been
suggested that it may, under some conditions, be more
important than direct scavenging. Mannitol also forms
a stable compound with hydrogen peroxide, which is not
a free radical itself but can generate OH radicals in
the presence of ferric iron. This effect has been investigated
in patients undergoing CPB, where mannitol appears to
react directly with H2O2 to decrease its formation,
although it has yet to be determined how this significantly
improves clinical outcome.
Another potentially advantageous and indirect action
of mannitol may be through a modifying action on complement
formation. Complement fractions C3 and C5a are released
during CPB and bind to plymorphonuclear leukocytes which
are then stimulated to produce OFRs. Sequestered PMNL
and complement fragments have been found in the lung
after CPB and have been proposed to be responsible for
post bypass lung changes such as pulmonary oedema. One
beneficial effect of mannitol in CPB appears to be a
reduction in the incidence to postoperative pulmonary
oedema, and this may reflect an OFR scavenging reaction,
although its diuretic action cannot be excluded.
One final area where mannitol has been successfully
used is in the management of acute compartment syndrome.
It is uncertain, however, whether the reduction in the
perfusion oedema and injury are due to its hyperosmolar
or OFR scavenging effects or both. It appears that the
former is the more important, but that OFR scavenging
may contribute to a reduce severity of muscle necrosis.
Once again, the clinical evidence is inconclusive.
OF THE ROLE OF MANNITOL AS AN OXYGEN FREE RADICAL SCAVENGER
balance, inconclusiveness is a recurring theme in any
discussion of mannitol's role as an OFR scavenger. Nevertheless,
although the evidence for any significant effect is
scanty, it cannot be totally discounted are more conclusive
research is required.
mannitol is still widely used in many areas of medicine
and its worth in renal transplantation is unsurpassed,
the evidence for its continued use for the management
of head injuries and renal failure is limited, while
its value as an OFR scavenging agent has yet to be finally
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