Headaches
Occurring During Sleep
Secondary
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.
Obstructive
Sleep Apnea
Snoring
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
with OSA.
Sleep
Bruxism
Bruxism
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,
diazepam.
Sleep
Deprivation and Sleeping In
Lack
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.
Sleep
to Relieve Migraine
Many
migraineurs obtain relief from acute attacks by sleeping.
In one study, 28% could terminate a migraine with sleep.
Parasomnias
and Migraine
Somnambulism
occurs in 28% of children with migraine and 5% of controls.
Children with migraine also have a greater incidence
of night terrors.
Exploding
Head Syndrome
Episodes
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.
Gene
Therapies for Parkinson's Disease
BACK
INTRODUCTION
Neurodegeneration
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
even reversed.
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
molecules.
PARKINSON'S
DISEASES
Parkinson's
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.
The
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.
ANIMAL
MODELS OF PARKINSON'S DISEASE
Several
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
transport chain.
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.
NEUROTRANSMITTER
REPLACEMENT GENE THERAPIES
As
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.
Ex
Vivo Enzyme Replacement Gene Therapy
A
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.
Table
1 : Gene Therapy in Animal Models of Parkinson's Disease
Paradigm
Biological effect Refs
| Paradigm |
|
Biological
effect |
Refs |
I.
Ex vivo Gene Therapy Approaches
Neurotransmitter Systems
|
|
|
6-OHDA
6-OHDA
6-OHDA
6-OHDA |
Fibroblast-TH
Fibroblast-TH
Neural cell-TH
Astrocyte-TH |
?
Apomorphine rotation
Apomorphine rotation
Apomorphine rotation
Apomorphine rotation |
18
20
25
23 |
| Neurotrophic
Factors |
|
|
MPP
+
MPP +
6-ODHA,
partial
6-ODHA,
striatal
6-ODHA,
MFB
Unlesioned |
Rat
I - BDNF
Fibroblast-BDNF
BHK-GDNF
Astrocyte-BDNF
Fibroblast-BDNF |
Protection
of soma
SN DA levels
Sprouting of fibers
Improvement in rotation
Protection of soma, fibers
Protection of soma
No effect
DA turnover, sprouting |
63
64
68
67
66 |
Chromaffin/NGF-
Chromaffin/NGF-cografts
PC12cells+NGF |
astrocyte
cografts
fibroblast |
Protective/stimulatory
Survival/differentiation
Protective ( survival) |
71.72
73.74
76.77 |
II.In
vivo Gene Therapy Approaches
Neurotransmitter Systems
|
|
|
| 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 |
| |
|
|
|
| Neurotrophic
Factors |
|
|
|
| 6-OHDA |
Ad-GDNF |
Protection of soma |
81,82,
86
|
| 6-OHDA |
AAV-GDNF |
DA,
improved behavior, DA transporters |
85 |
| 6-OHDA |
AAV-GDNF |
Protection
of soma |
87 |
I.
Ex vivo Gene Therapy Approaches
Neurotransmitter
Systems
| 6-OHDA
Fibroblast-TH ? Apomorphine rotation |
18 |
| 6-OHDA
Fibroblast-TH ? Apomorphine rotation |
20 |
| 6-OHDA
Neural cell-TH ? Apomorphine rotation |
25 |
| 6-OHDA
Astrocyte-TH ? Apomorphine rotation |
23 |
Neurotrophic
Factors
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
striatal
6-ODHA, Fibroblast-GDNF Protection of soma 69
MFB Fibroblast-BDNF No effect 65
Unlesioned Fibroblast-BDNF ? DA turnover, sprouting
65
Chromaffin/NGF-astrocyte cografts Protective/stimulatory
71.72
Chromaffin/NGF-fibroblast cografts ? Survival/differentiation
73.74
PC12cells+NGF Protective ( survival) 76.77
II.In vivo Gene Therapy Approaches
Neurotransmitter Systems
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
Neurotrophic Factors
6-OHDA Ad-GDNF Protection of soma 81,82,
86
6-OHDA AAV-GDNF ? DA, improved behavior, 85
? DA transporters
6-OHDA AAV-GDNF Protection of soma 87
Ex
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.
In
vivo Enzyme Replacement Gene Therapy
An
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]-
spiperone ligand.
GENE
THERAPIES WITH NEUROTROPHIC FACTORS
DA
Neurotrophic Factors
Early
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.
| Table
2 : Dopaminergic Neurotrophic Factors |
|
| TGF
- Superfamily members |
Refs |
| GDNF
|
35 |
| GDF-5
|
97 |
| TGF-
- 1 |
98 |
| TGF-
, 3 |
98,99 |
| Activin
A |
98 |
| |
|
| Neurotrophins |
|
| BDNF |
34 |
| NT-3 |
100 |
| NT-4/5
|
100 |
| |
|
| Cardiotrophin-1
|
101 |
| CNTF |
102 |
| I1-1b
|
103 |
| I1-6 |
104 |
| I1-6,7
- modest effects |
105 |
Although
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.
Exo
Vivo Neurotrophic Factor Gene Therapy
The
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
metallothionein promoter.
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.
In
Vivo Neurotrophic Factor Gene Therapy
In
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.
CONCLUSIONS
Gene
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
brain.
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
BACK
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
pressure (ICP).
The
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
to ischemia.
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.
BASIC
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.
HYPERTENSIVE
THERAPY
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"
(43).
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
aneurysm surgery.
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
be defined.
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.
HYPERVOLEMIA
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
viscosity.
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.
VASODILATATION
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).
HEMODILUTION
Viscosity
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.
HYPEROSMOLARITY
Mannitol
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.
PERSPECTIVE
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
ischemic challenge.
References
1.
Amea A, Wright RL, Kowada MD, et al., Cerebral ischemia.
II. The no-reflow phenomenon. Am J Pathol 52:437-453,
1968.
2. Astrup J, Siesjo BK, Symon L: Thresholds in cerebral
ischemia - the ischemic penumbra. Stroke 12:723-725,
1981.
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BACK
Drug
Therapy In Epilepsy A Resume
Anti-epileptic
medication
Indications for treatment
-
Recurrent
unprovoked epileptic seizures that are not separated
by years.
-
Single
seizure in patients with:
- A relevant underlying brain lesion or neurologic
abnormality, or
- A specific epileptic syndrome and an unprovoked
seizure that will eventually
need treatment, such a juvenile myoclonic epilepsy.
-
The
risks and benefits of both treatment and no treatment
have been discussed extensively with the patient.
-
The
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
other factors.
Principles
of anti-epileptic drug therapy
- Aim
to control seizures with the lowest effective dose
that causes no adverse effects.
- The
goal is not to achieve the quoted 'therapeutic drug
level':
-
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.
- Start
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
comes first.
- Judge
the response primarily on clinical grounds.
Choice
of anti-epileptic drug:
- Select
the single most appropriate drug for the seizure type
and patient
(Tables 9,10).
§ Carbamazepine and v
- proate
are the first line treatments for focal epliepsies.
- Valproate
is the first line treatment for generalized epliepsies.
- Lamotrigine
is also very effective for generalized epliepsies.
- Phenytoin
and clonazepam still have a place, but barbiturates
are now used less.
- Vigabatrin,
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.
- Ethosuximide
is only used for juvenile abscence epilepsy.
- The
cost of newer anti-epileptic drugs (e.g. lamotrigine,
topirmate, gabapentin, tiagabine, vigabatrin) is about
10 times greater than older drugs (phenobarb, phenytoin).
Sodium
valproate (Epilim)
- Uncertain
mechanism of action. Increases synthesis and slows
the breakdown of GABA.
- Effective
for the primary generalized epilepsies, particularly
tonic-clonic seizures, abscences and myoclonus.
- As
effective as carbamazepine and phenytoin for partial
seizuers, especially is secondary generalization.
- Available
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.
- Plasma
half-life: 6-9 hours, so may be administered as two
or three divided doses daily.
- Starting
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.
- Dose
can be increased slowly to I g three times daily (tds)
if necessary and tolerated.
- Monitoring
of blood levels is often not necessary as three is
a poor relation between serum concentrations and anti-epileptic
efficacy or toxicity.
- Drug
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.
- Adverse
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
(idiosyncratic).
Carbamazepine
(Tegretol)
- First
used in 1964.
- Effective
for the prophylaxis of generalized tonic-clonic and
partial seizures but not for absence o myoclonic epilepsy
(which it may aggravate).
- Available
as 100 mg and 200 mg tablets, or 200 and 400 mg controlled-release
tablets that are helpful for avoiding peak-dose adverse
effects.
- Plasma
half-life: 24-45 hours initially but after continued
long term use it falls to about 9 (8-24) hours.
- The
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.
- Adverse
effects:
- Dose-related: neuroptoxicity (dizziness, double
vision, unsteadiness), nausea,
vomiting, cardiac arrhythmia and orofacial dyskinesia.
- Idiosyncratic: skin rash (5-8% of patients), agranulocytosis,
aplastic anemia,
syndrome of antidiuretic hormone secretion (leading
to fluid retention and
hyponatremia) hepatotoxicity, photosensitivity, Stevens-Johnson
syndrome,
lupus-like syndrome, thrombocytopenia and pseudolymphoma.
- A
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.
- Drug
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,
and verapamil.
Phenytoin
(Dilantin)
- First
used as an antiepileptic drug in 1938.
- Effective
for generalized tonic-clonic and partial seizures.
- No
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).
- Available
as a 6 mg/ml suspension, as chewable 50 mg tablets,
and as capsules of 30mg and 100 m.
- Plasma
half-life: about 24 (9-40) hours.
- One
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.
- Starting
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.)
- If
seizures continue, an increment of 30mg is appropriate
particularly if the serum concentration is above 12mg/1
(60 umol/1).
- Adverse
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.
- Idiosyncratic
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.
- Drug
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.
Barbiturates
Phenobarbitone (phenobarbital)
Has
been used an anti-epileptic drug since 1912.
- Inexpensive,
widely available and as good as carbamazepine and
phenytoin in controlling generalized tonic-clonic
and partial seizures.
- Main
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.
- Usual
dose varies from 90 to 300mg/day.
- Long
plasma half life of 3-4 days; can therefore be taken
as a single daily dose.
- In
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.
- Withdrawal
can lead to temporary increase in seizure frequency.
Methylphenobarbitone
(prominal) (mephobarbital)
Methylphenobarbitone (mephobarbital) is metabolized
to phenobarbitone (phenobarbital), and is given it twice
the dose of phenobarbitone but co gers no special advantage.
Primidone
(Mysoline)
Primidone is metabolized to phenobarbitone (phenobarbital)
and phenylethlmalonamide, both of which are pharmacologially
active. Efficacy is similar to that of phenobarbitone.
Clonazepam
(Rivotril)
- A
1,4 benzodiazepine (like diazepam).
- Effective
for generalized tonic-clonic and myoclonic seizures,
and generalized absence (petit mal) epilepsy and partial
seizures.
- Has
more sustained and effective anti-epileptic activity
than diazepam (Valium) but tolerance develops.
- Available
as 0.5mg and 2.0mg tablets.
- Dose
varies from 0.5-4.0mg three times daily.
- Long
plasma half life of 20-40 hours.
- Adverse
effects include sedation, irritability, and aggression.
- Few
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.
Clobazam
(Frisium)
- A
1,5 benzodiazepine.
- Less
sedative than clonazepam and diazepam but still commonly
cause tiredness as well as depression and iritability.
- Has
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
exacerbations.
- A
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.
- Visual
field defects are the most common serious adverse
effect, which limits the use of this drug.
Lamotrigine
(Lamictal)
- Inhibits
voltage-gated sodium channels and reduces the release
of glutamate, an excitatory amino acid neurotransmitter
implicate in the pathophysiology of epilepsy.
- Effective
in both partial and generalized tonic-clonic and absence
seizures in adults and children.
- A
weak inhibitor of dihydrofolate reductase, so long
term therapy may disturb folate metabolism.
- Does
not significantly induce or inhibit hepatic oxidative
drug-metabolizing enzymes, nor affect the plasma concentrations
of concomitant anti-epileptic drug.
- Metabolism
induced by anti-epileptic drugs that induce liver
enzymes such as carbamazepine, phenytoin and phenobarbiton
(phenobarbital) (half-life about 15 hours).
- Metabolism
inhibited by sodium valproate (half-life about 60
hours).
- Plasma
half-life: about 29 hours (mean).
- Eliminated
largely as an N-glucuronide conjugate.
- Available
as 5mg dispersible, 25mg, 50mg, 100mg, and 200mg standard
tablets.
- Starting
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.
- Starting
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.
- Adverse
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.
Gabapentin
(Neurontin)
- A
GABA-related amino acid.
- Mechanism
of action: uncertain; it may after L-type voltage-depandent
calcium channels.
- Effective
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
tonic-clonic seizures.
- Not
effective for absence seizures.
- Available
as 300mg and 400mg capsules.
- Usual
maintenance dose: 1200-2400 mg/day, but higher doses
may be more effective.
- Does
not seem to interact with other anti-epileptic drugs.
- Adverse
effects on cognitive function may arise with higher
doses.
Ethosuximide
- Used
only for absence seizures; not effective against generalized
tonic-clonic seizures.
- Infants
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
capsules daily.
- Adverse
effects include drowsiness and bone marrow depression.
Topiramate
(Topamax)
- A
sulfamate derivative structurally unique among anti-epileptic
drugs.
- Reversibly
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
granule cells.
- Reduces
elevated levels of excitatory amino acids, glutamate
and aspartate.
- Reversibly
enhances post-synaptic GABA receptor currents.
- Effective
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.
- Needs
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.
Tiagabine
- A
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.
- Effective
against partial and generalized convulsive seizures.
- May
be contraindicated in generalized absence epilepsy.
- Failed
monotherapy
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.
Withdrawal
of antiepileptic medication
- Anti-epileptic
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.
- Drug
withdrawal is not likely to be successful (i.e. seizures
recur) if:
- Late age to onset (>16 years of age).
- Mental retardation.
- Symptomatic epilepsy (i.e. underlying untreated
cause).
- Certain epileptic syndromes, such as juvenile myoclonic
epilepsy, when
unprovoked seizures have occurred.
- Family history of epilepsy.
- Slow wave activity or focal epileptiform activity
on EEG prior to medication
withdrawal.
- History of atypical febrile seizures.
- There
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.
- Withdrawal
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
seizures.
BACK
ANTIPHOSPHOLIPID
SYNDROME
AND OTHER PROTHROMBOTIC STATES
(THROMBOPHILIAS)
Disorders
of the blood that predispose to recurrent venous and
possibly arterial thrombosis.
ANTIPHOSPHOLIPID
SYNDORME
Definition
A
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.
Antiphospholipid
antibodies (APAs)
- APA
are a family of antibodies which are specific for
several plasma proteins, such as human prothrombin
and ß2 glycoproteins, which may bind to phospholipid
surfaces.
- LA
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.
- Las
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.
- ACAs
are detected by immunoassay, most commonly enzyme-linked
immunosorbent assay.
Epidemiology
- Prevalence
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.
- Age
: any age.
- Gender
: F>M.
Pathology
Thrombi
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
vascular wall.
Pathophysiology
of Thrombosis
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 :
- Perturbation
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.
- Alteration
of the antithrombin III heparin sulfate down regulation
of serine proteases : some APAs have specificity for
heparin sulfate found on the surface of endothelial
cells.
- Up-regulation
of tissue factor expression by endothelial cells.
In
some cases the APAs may represent an epiphenomenon.
Etiology
Primary
No evidence of other underlying disease.
Secondary
- Associated
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.
- Associated
with other conditions :
- Infections : viral ; bacterial ; parasitic.
- Drug exposure : chlorpromazine ; hydralazine ; quinidine;
quinine ; antibiotics ; phenytoin ; valproate ; procainamide.
- Lymphoproliferative diseases ; malignant lymphoma;
paraproteinemia.
- Miscellaneous conditions : autoimmune thrombocytopenia;
autoimmune hemolytic anemia ; sickle-cell disease;
intravenous drug abuse; livedo reticularis; Guillian
- Barre syndrome.
Clinical
Features
Any
vascular site can be affected so there is a wide range
of clinical manifestation :
Dermatologic
- Sneddon's
syndrome : livedo reticularis, stroke-like episodes
and hypertension.
- Non-healing
ulceration of the ankles and skin necrosis.
Neurologic
- TIA,
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.
- Migraine
- like headaches.
Obstetric
- Recurrent
spontaneous miscarriage/fetal loss due to intrauterine
death in the latter part of the first trimester or
early second trimester.
- Intrauterine
foetal growth retardation.
- Early
- onset pre - eclampsia.
- Prematurity
Pediatric
Post - infectious thromboembolic events.
Investigations
for Antiphospholipid Syndrome or any other
Suspected Procoagulant state (Thrombophilia)
Indications
- Young
(<50 years) and no other cause found for TIA or
ischemic stroke.
- Past
history or family history of premature arterial or
venous thrombosis, especially if unusual sites (cerebral,
mesenteric, hepatic veins).
- Past
history of recurrent miscarriages.
- Abnormal
full blood picture or blood film (e.g., thrombocytopenia).
- VDRL/RPR
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.
Thrombophilia
diagnostic tests
- Full
blood count and film.
- ESR.
- Prothrombin
time.
Coagulation
assays for lupus anticoagulant (LA)
- Activated
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
LA.
- Dilute
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.
- Kaolin
clotting time test : also detects LA, but it is not
as sensitive as the dRVVT, and sensitivity is highly
reagent dependent.
- Tissue
thromboplastin inhibition test.
These
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.
Immunologic
assays
- Anticardiolipin
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.
- Other
phospholipids, e.g., phosphatidyl serine.
- Antibodies
to ß2 GPI.
Other
thrombophilia diagnostic blood tests
- Antithrombin
activity
- Protein
C activity.
- Protein
S antigen level.
- Factor
V Leiden genetic analysis or activated protein C resistance
functional analysis.
- Prothrombin
G202 10A mutation.
- Antinuclear
antibodies.
- Serum
protein levels, serum protein electrophoresis and
plasma viscosity : indicated in patients with elevated
ESR or suspected hyperviscosity syndrome.
- Hemoglobin
electrophoresis/sickle test : indicated in appropriate
racial groups to detect sickle cell trait or disease.
- Fibrinogen.
- Platelet
aggregation.
- Fasting
plasma homocysteine.
Diagnosis
Thrombophilia
The
diagnosis is usually established from routine first
line investigation and standard thrombophilia screening
and diagnostic tests.
Antiphospholipid
antibody syndrome
Cannot
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.
Lupus
anticoagulant (LA)
Four
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
inhibitor
3. Establishing the PL-dependence of the inhibitor.
4. Ruling out other coagulopathies.
Ischemic
stroke due to a procoagulant state
It
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
the stroke.
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.
Treatment
Uncertain
; no controlled trials of aspirin, anticoagulants, or
immunosuppressive therapy have been undertaken.
Thromboembolic
events
Long
term anticoagulant therapy, INR : 2.5, if risks considered
to be outweighed by benefits. Otherwise antiplatelet
therapy.
Pregnancy
Heparin
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.
Prognosis
Uncertain,
but limited studies suggest a high rate of recurrent
stroke and other vascular events in patients with ischemic
stroke and the antiphospholipid syndrome.
Other
Procoagulant states
Quantitive abnormalities of formed blood
Elements
Erythrocytes
- Polucythemia
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.
- Anemia
(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.
Leukocytes
- Leukemia
:
- 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.
- Malignant
angioendotheliosis :
- can present like a stroke but the neurologic involvement
soon becomes diffuse and progressive.
Platelets
- Essential
thrombocythemia
- 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
to bleeding.
- 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.
Qualitative
abnormalities of formed blood elements
- Erythrocytes
- Sickle
cell (SC) disease :
- Tschemic stroke is common in homozygotic children
and young adults ; intracranial hemorrhage may also
occur sometimes.
- Stroke is rare in heterozygotic adults, and usually
in the context of a hypoxia - provoked sickle-cell
crisis.
- 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.
- Hemoglobin
SC disease
- may also be complicated by stroke.
- Paroxysmal
nocturnal hemoglobinuria :
- very rare :
- intracranial venous thrombosis is more common than
arterial thrombosis.
- Anemia, abdominal pain, recurrent deep venous thrombosis,
dark urine, hemolysis and a low platelet and granulocyte
count are recognized features.
Hyperviscosity
Paraproteinemias
- Waldenstrom's
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
proteins.
- Intracranial hemorrhage also occurs due to reduced
number and
Impaired reactivity of platelets, perhaps as a result
of uremia.
Coagulation
disorders
Antithrombin
III
- Inactivates
thrombin and activated factors, X, IX, XI, and XII
(but not VII).
- An
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.
- Deficiency
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.
Protein
C
- A
vitamin K-dependent plasma protein that is synthesized
in the liver in an inactive form.
- When
activated by thrombin in the presence of calcium,
it inhibits the procoagulant activity of factor Va
and factor VIIIa and inactivates plaminogen activator
inhibitor 1.
- Deficiency
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.
- Resistance
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
venous thrombosis.
Protein
S
- A
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
protein C.
- Deficiency
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.
Herediatry
deficiency of coagulation inhibitors, activated protein
C resistance, and hereditary abnormalities of fibrinolysis
: plasminogen deficiency and / or abnormality
- Conditions
in which spontaneous and recurrent venous thrombosis
and rarely, arterial thrombosis are presenting or
complicating features.
- The
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.
- Difficulties
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
if possible.
- 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
occasions.
- 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.
Factor
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.
Immunologic
disorders
Antiphospholipid syndrome
Prothrombotic
States of Uncertain cause
Thrombotic
thrombocytopenic purpura (TTP)
- Rare.
- Microangiopathic
hemolytic anemia, thrombocytopenia, fever, and renal
failure are characteristic.
- Platelet
microthrombi cause infarcts in many organs, including
the brain
- Neurologic
symptoms in 90% of cases, and are the presenting symptoms
in 60%.
- Fluctuating
encephalopathy, rather than a stroke syndrome, is
the usual presentation.
- The
patient is unwell with malaise, fever, skin purpura,
renal failure, proteinuria, hematuria, thrombocytopenia,
hemolytic anemia and fragmented red blood cells.
- Brain
CT may be normal, or show infarcts, or occasionally
intracerebral hemorrhage, more commonly due to heparin
treatment than the disease itself.
- Non-convulsive
status epilepticus is another treatable cause of altered
mental status in these patients.
Cancer
Laboratory
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.
Possible
causes of ischemic stroke or TIA include :
- A
coagulopathy mediated by intravascular mucinosis,
low-grade disseminated intravascular coagulation,
or the patient's chemotherapy.
- Embolism
of non-infected heart valve vegetations.
- Tumor
or septic emboli, sometimes with aneurysm formation.
- Sepsis.
- Hemostatic
failure
- Hyperviscosity
syndrome
- Neoplastic
compression or invasion of neck arteries.
- Irradiation
of neck arteries.
Disseminated
intravascular coagulation
- Manifests
as an acute or subacute global encephalopathy, rather
than stroke-like episodes, in a very sick patient.
- CT
brain scan reveals widespread hemorrhagic infarcts
and hemorrhages.
- Low
platelet count, low plasma fibrinogen, raised fibrin
degradation products and raised D-dimer point to the
diagnosis.
Pregnancy
and the puerperium
The
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 :
- Paradoxical
embolism from the venous system of the pelvis of legs.
- Valvular
heart disease.
- Cardiomyopathy
of pregnancy.
- Arterial
dissection during labor.
- Hematologic
disorders.
Less
commonly :
- Amniotic
fluid embolism
- Air
or fat embolism
- Metastatic
choriocarcinoma.
Estrogens/oral
contraceptives
- High
estrogen dose oral contraceptive use is associated
with a threefold increased risk of TIAs and stroke.
But the absolute risk is very small.
- The
risk is greater in women who are older, who smoke
and who have other vascular risk factors such as hypertension.
- Exogenous
high doses of estrogen given to elderly men for treatment
of prostatic cancer and male survivors of MI increase
their risk of vascular death.
Heparin-induced
thrombocytopenia
Heparin
may paradoxically lead to thrombus formation and thrombocytopenia
by two mechanisms :
- Type
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.
- Type
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.
Nephrotic syndrome
Can
be complicated by ischemic stroke, perhaps due to 'hypercoagulability'
: loss of antithrombotic proteins in the urine.
Desmopressin
and intravenous immunoglobulin
May
cause hypercoagulability and ischemic stroke, perhaps
by altering blood viscosity, hemorrheology, platelet
aggregability or clotting factor levels.
Snake
bite
May
cause ischemic stroke but is more likely to cause defibrination
and bleeding.
BACK
CARDIOEMBOLIC
STROKE
Definition
Embolism
of material from the heart to the brain causing ischemia
or infarction of a part of the brain or eye, with or
without hemorrhagic transformation of the infarct.
Epidemiology
Embolism
from the heart probably accounts for about 20% of ischemic
stroke and TIAs.
Etiology
and Pathophysiology
Cardiac
Sources of embolism in anatomic sequence
Right to left shunt (paradoxical emboli from the venous
system) via
- Patent
foramen ovale.
- Atrial
septal defect.
- Ventricular
septal defect.
- Pulmonary
arteriovenous malformation.
Left
atrium
- Thrombus
: AF* ; sinoatrial disease (sick sinus syndrome) ;
atrial septal aneurysm.
- Myxoma
and other tumors*.
*Substantial
risk of embolism.
Mitral
valve
- Rheumatic
endocarditis (stenosis* or regurgitation).
- Infective
endocarditis*.
- Mitral
valve prolapse
- Non-bacterial
thrombotic (marantic) endocarditis.
- Antiphospholipid
antibody syndrome.
- Prosthetic
heart valve*.
- Papillary
finroclastoma.
Left
Ventricle
- Mural
thrombus :
- Acute myocardial infraction
- Left ventricular aneurysm or akinetic segment.
- Dilated cardiomyopathy*.
- Mechanical 'artificial' heart*.
- Blunt chest injury (myocardial contusion).
- Myxoma
and other tumors*.
- Hydatid
cyst.
- Primary
oxalosis.
Aortic
Valve
- Rheumatic
endocarditis (stenosis or regurgitation).
- Infective
endocarditis*.
- Syphilis.
- Non-infective
thrombotic (marantic) endocarditis.
- Libman
- Sacks endocarditis.
- Antiphospholipid
antibody syndrome.
- Prosthetic
heart valve*.
- Calcific
stenosis / sclerosis/ classification.
Congenital
heart disease (particularly with right to left shunt)
Cardiac
manipulation / surgery / catheterization / valvuloplasty
/ angioplasty
*Substantial
risk of embolism.
Prevalence
of potential cardiac sources of embolism in patients
with first-ever ischemic stroke*
- Any
AF : 13%.
- Without rheumatic heart disease : 12%
- With rheumatic heart disease : 1%.
- Mitral
regurgitation : 6%.
- Recent
(<6 weeks) myocardial infarction : 5%.
- Prosthetic
valve : 1%.
- Mitral
stenosis : 1%.
- Paradoxical
embolism : 1%.
- Any
of the above : 20%.
- Other
sources of uncertain significance : aortic stenosis/
sclerosis ; mitral annulus calcification, mitral valve
prolapse and son on : 11%.
*Sandercock
PAG, Warlow CP, Jones LN, Starkey IR (1989) Predisposing
factors for cerebral infarction : The Oxford Community
Stroke Project. BMJ, 298 : 75 - 80.
Note
:
- Not
all cardiac sources of embolism pose equal threats.
- Not
all emboli are of the same size of the same material.
Atrial
fibrillation
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 :
- Other
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.
- Some
AF patient have lacunar syndromes.
- 'Only'
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.
- In
a few case the AF is caused by the stroke.
The
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.
Risk
factors for embolization in AF patients
Low
risk : no other detectable heart disease.
High
risk :
- Rheumatic
mitral valve disease.
- Previous
cerebral or systemic embolic event.
- Increasing
age.
- Hypertension
- Diabetes.
- Left
ventricular systolic dysfunction.
- Enlarged
left atrium defined by echocardiography.
- Spontaneous
echo contrast in the left atrium, probably a consequence
of blood stasis.
- Left
atrial thrombi, left atrial appendage size and dysfunction,
and various hemostatic variables are perhaps adverse
risk factors also.
Uncertain
risk :
- Recent
onset AF.
- Paroxysmal
AF : probably depends on frequency and duration of
episodes of AF
- Thyrotoxic
AF.
Coronary
heart disease
Coronary
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 :
- Embolism
of left ventricular mural thrombus.
- Systemic
hypotension.
- Intracerebral
hemorrhage secondary or thrombolysis, anticoagulants
of aspirin.
- Embolism
of catheter thrombus during coronary angioplasty /
stenting.
- Concurrent
non-cardiac cause of stroke.
After
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.
Prosthetic
heart valves
- The
risk of embolism is above 2% per annum for all prosthetic
valves, provided patients with mechanical valves are
on anticoagulants.
- Mechanical
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.
- Some
Bjork - Shiley tilting disc valves have disintegrated
and embolized pieces to the brain.
- Prosthetic
mitral valves are more prone to thrombosis than arotic
valves.
- Infective
enodcarditis is a potential risk for any type of prosthetic
valve.
Rheumatic
Valvular disease
- Rheumatic
mitral stenosis / regurgitation is a well recognized
cause of left atrial dilation causing thrombus formation
and embolism to the brain.
- The
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.
- Stroke
may also occur as a result of infective endocarditis
and intracerebral hemorrhage due to anticoagulation
in these patients.
Non-rheumatic
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.
Mitral
valve (or leaflet) prolapse
Uncomplicated
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.
Non-bacterial
thrombotic endocarditis
Primary
cardiomyopathies are well recognized causes of intracardiac
thrombus, particularly the dilated type rather than
hypertrophic subaortic stenosis. Many are familial.
Sinoatrial
disease
- May
be associated with intracardiac thrombus and embolism,
particularly if bradycardia alternates with tachycardia,
or the patient is in AF.
- May
be familial.
Atrial
septal aneurysm
- Uncommon
- May
be complicated by thrombus and embolism to the brain.
- Often
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
stroke.
Paradoxical
embolism from the venous system, or right atrium
Patent
foramen ovale
- Common
; present in about 10% of normal people.
- An
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.
- A
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.
Atrial
septal defect
Ventriculoseptal
defect(rarely)
Pulmonary
arterial venous malformation
- Occurs
in isolation or as part of hereditary hemorrhagic
telangiectasis
- Clues
are clubbing, cyanosis, hemoptysis, bruit over the
chest and a 'coin lesion' on the chest x-ray.
Intracardiac
tumors
- Rare.
- Myxomas
are the most common heart tumor and most occur in
the left atrium.
- Some
are familial.
- Myxomas
may cause :
- Constitutional upset : malaise, weight loss, anemia,
raised ESR and hypergammaglobulinemia.
- TIA or ischemic stroke : embolism of tumor or complicating
thrombus.
- 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.
- Myocardial
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.
Myocardial
contusion
- Blunt
chest injury :
- May
be associated with left ventricular thrombus and embolization.
Clinical
Features
- Major
stroke occurs when large emboli impact permanently
in the internal carotid artery or trunk of the MCA.
- Partial
anterior circulation infarction occurs when smaller
emboli impact in a distal branch of the anterior of
MCA.
- Posterior
circulation infarction occurs when moderate or small
sized emboli impact in the tip of the basilar artery
or one of its branches.
- TIA
of the brain or eye.
- Asymptomatic
: Some emboli do not occlude arteries completely or,
if they do, there is sufficient collateral circulation
to maintain tissue integrity.
The
following strongly suggest embolism from the heart
- Non-lacunar
infarcts
- AF.
- Recent
acute MI.
- Valvular
heart disease.
- Embolic,
particularly calcific emboli, visible in the retina.
- Embolic
infarction in other organs.
Investigations
CT brain Scan
- Single
or multiple wedge-shaped cortical /subcortical infarcts,
with or without hemorrhage transformation.
- High
density in the middle or basilar artery on the non-contrast
CT suggestive of blood clot or calcium.
- Infarction
in the territory of the tip of the basilar artery
or superior cerebellar artery.
EKG
(electrocardiograph) : AF, IHD
Chest
x-ray
Echocaardiography
Indications
- Multiple
cortical / subcortical cerebral infarcts in different
arterial territories.
- Wedge-shaped
cortical / subcortical infarct or hemorrhage infarct,
or striatocapsular infarct and no carotid lesion on
carotid ultrasound.
- Clinical,
EKG or CXR evidence of heart disease.
- Age
<45 years and no cause found for TIA or stroke.
Preferred
echocardiographic technique for detecting various cardiac
disorders
Transthoracic echocardiography
- Left
ventricular thrombus
- Left
ventricular dyskinesis.
- Mitral
stenosis.
- Mitral
annulus calcification.
- Aortic
stenosis.
Tansesophageal
echocardiography
- Atrial
thrombus
- Atrial
appendage thrombus
- Spontaneous
echo contrast
- Intracardiac
tumors
- Atrial
septal defect*
- Atrial
septal aneurysm
- Patent
foramen ovale*
- Mitral
and aortic valve vegetations.
- Prosthetic
heart valve malfunction.
- Aortic
arch atherothrombosis / dissection.
- Mitral
leaflet prolapse.
*
Transcranial doppler. Detection of intravenously injected
air bubbles is less invasive, more specific, but not
quite so sensitive ; galactose particle suspension increases
sensitivity.
Diagnosis
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
individual patient.
Embolism
from the heart to the brain or eye
More likely to be the cause of ischemic stroke or TIA
if
- An
identified cardiac source of embolism, particularly
one with a substantial embolic risk.
- Ischemic
events in more than one arterial territory, particularly
if more than one organ is involved.
- No
evidence clinically or by angiography of arterial
disease in the neck.
- Calcific
emboli in the retina.
- Calcific
emboli on brain CT
- No
vascular risk factors
- Age
<50 years.
- No
other explanation for the stroke.
Less
likely if
- Lacunar
syndrome
- Low
flow infarction / ischemia
Uncertain
if
- Hemorrhagic
transformation of the infarct.
- Past
TIA.
High
risk of embolism
- Non-rheumatic
or rheumatic AF.
- Infective
endocarditis.
- Prosthetic
heart valve.
- Recent
MI.
- Dilated
cardiomyopathy
- Intracardiac
tumors
- Rheumatic
mitral stenosis
Low
risk of embolism
- Mitral
valve prolapse
- Mitral
annulus calcification
- Patent
foramen ovale with no evidence of deep venous thrombosis.
- Atrial
septal aneurysm.
- Aortic
sclerosis.
Treatment
Of acute ischemic stroke of suspected cardioembolic
origin.
Immediate
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.
Best
time to start unclear
Non-disabling ischemic stroke, no hemorrhagic transformation
of the infarction, and AF.
Immediate
anticoagulants probably worthwhile
Best time to start anticoagulants unclear
- Acute
MI within past few weeks and confirmed ischemic stroke
of TIA.
- Disabling
ischemic stroke and AF.
Aspirin
or no antithrombotic therpay ; anticoagulants not worthwhile
or contraindicated
Law risk of recurrent cardioembolic stroke without anticoagulants
- Heart
disease with a low risk of embolism
- Other,
non-cardiac lesion more likely cause of cerebral infarct
: severe ipsilateral carotid stenosis ; likely disease
of intracranial small vessels.
Little
to gain from long term anticoagulation
- Suspected
cholesterol embolization syndrome
- Already
severely disabled before the stroke.
- Moribund
or predicted to be severely disabled in the long term.
High
risk of cererbal hemorrhage on anticoagulants
- Infective
endocarditis.
- Large
cerebral infarct with midline shift and / or evidence
of major hemorrhagic transformation on brain CT.
- Likely
to comply poorly with anticoagulation therapy and
its monitoring after discharge.
- Severe,
uncontrolled hypertension.
Contraindication
to anticoagulants
These
depend on individual circumstances and are seldom absolute.
- History
of bleeding disorder.
- Hemophilia.
- Uncorrected
major bleeding disorder :
- Thrombocytopenia.
- Hemophilia.
- Liver failure.
- Renal failure.
- Uncontrolled
severe hypertension :
- Systolic pressure over 26.7 kPa (200 mgHg).
- Diastolic pressure over 16 kPa (120 mgHg).
- Potential
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
thrombosis.
- If
warfarin planned :
- Homozygous protein C deficiency.
- History of warfarin - related skin necrosis.
- Uncooperative / or unreliable patients.
- Risk of falling.
- Unable to monitor INR.
Adverse
effects of heparin
Local minor complications of subcutaneous heparin at
injection site
Local
complications of intravenous heparin at cannula site
(or elsewhere)
- Pain
at cannula site.
- Infection
at cannula
- Reduced
patient mobility because of infusion lines and pump.
Major
systemic complications
- Intracranial
bleeding :
- Hemorrhagic transformation of cerebral infarct
- Intracerebral hematoma.
- Subarachnoid hemorrhage.
- Subdural hematoma
- Extracranial
hemorrhages :
- Subcutaneous
- Visceral
- Thrombocytopenia
:
- Type I : dose and duration related, reversible,
mild, usually asymptomatic, not serious and often
resolves spontaneously.
- Type II : idiosyncratic, allergic, severe. Affects
3 - 11% of patients treated with intravenous heparin
and less than 1% of patients treated with subcutaneous
heparin.
- Osteoporosis
- Skin
necrosis
- Alopecia.
BACK
ESSENTIAL
TREMOR (ET)
Definition
A
low frequency postural tremor which is absent at rest
and not associated with the clinical signs of parkinsonism
or other neurologic deficits.
Epidemiology
- Incidence
8 (95% CI : 4 - 14% 100 000/year.
- Prevalence
(lifetime) : 0.3 - 1.7%.
- Age
of onset : bimodal : young adults (median about 15
years) and elderly.
- Gender
: M = F.
Pathology
No characteristic pathological or biochemical findings.
Etiology
- Hereditary
: autosomal dominant inheritance (50% of patients)
via a penetrant autosomal dominant gene. The responsible
gene(s) remain unknown.
- Sporadic
: probably the same entity as hereditary ET.
Pathophysiology
- Unknown
- A
central source of oscillation that is influenced by
somatosensory reflex pathways.
- Enhanced
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
tremor.
- Ventrointermediate thalamotomy or microstimulation
reduce tremor.
- It
is thought that the cerebellum introduces an error
in the timing of muscle bursts during voluntary movement,
and repeated corrective movements lead to tremor.
Clinical
Features
Tremor
- Postural
or action tremor of the finer, hands, and forearms
when they are help outstretched against gravity, or
used for specific, usually visually-guided, manual
tasks.
- Variable
kinetic component
- 4
- 12 cycles per second.
- Bilateral,
but may be asymmetric.
- Other
body parts involved in about half of cases : the head,
tongue, lips, voice, face, and trunk; and postural
tremor of lower limbs.
- Visible.
- Persistent,
but the amplitude may fluctuate.
- Exacerbated
by emotional upset such as excitement and anger.
- Improved
temporarily by alcohol, in small quantities, in about
half of patients.
- Relatively
longstanding.
- Froment's
sign (a rhythmic resistance to passive movements of
a limb about a joint when there is a voluntary action
of another body part).
Differential
Diagnosis
Intention
of 'terminal' tremor due to cerebellar disease
- Slower
(3-5 cycles per second).
- Principally
in a horizontal plane.
- Not
present at rest.
- Increases
with action and progressively increases during a voluntary
movement.
- Unlike
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.
- The
head may be affected, but usually as titubation
- May
be incapacitating.
- Responds
to propranolol and diazepam.
Parkinosonian
tremor
- Typically
6 (3-7) cycles per second.
- Present
at rest.
- Not
increased with posture or action.
- Involves
the limbs and head.
- 'Pill
rolling' character.
- Exacerbated
by emotion.
- Responds
to levodopa and anticholinergic medications.
Alcohol withdrawal
- 6
-10 cycles per second
- Head
and limbs involved.
- Periodic
: appears 8 - 12 hours after last drink.
- Responds
to diazepam and chlordiazepoxide.
Metabolic
derangements, such as thyrotoxicosis
- 10
- 20 cycles per second.
- Head
and upper limbs involved
- Symptoms
and signs of metabolic disturbance.
- Responds
to correcting metabolic disturbance.
Enhanced
Physiologic Tremor (EPT)
A
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.
Causes
- Drugs
:
Adrenergic drugs. Amiodarone.
Amphetamines. Antipsychotic drugs.
Caffeine. Cimetidine.
Corticosteroids. Cyclosporine A.
Lithium. Oral hypoglycemics.
Serotonin reuptake inhibitors.
Sodium valproate. Theophylline.
Thyroxine. Tricyclin antidepressants.
- Drugs
withdrawal :
Alcohol. Barbiturates.
Benzodiazepines. Opiates.
- Metabolic
:
Hypoglucemia. Metabolic encephalopathies.
Pheochromocytoma. Thyrotoxicosis.
- Exaggerated
physiologic response :
Anxiety. Fatigue.
Fight. Strenuous excretion.
Management
is directed to correction of the underlying medical
illness
or cessation of any contributing drug. If idiopathic
EPT becomes inconvenient or socially embarrassing, propranol
may be helpful.
Primary
orthostatic tremor
- Isolated,
high frequency bilaterally synchronous tremor of legs
and trunk when standing still.
- May
not be detected easily without palpation of the leg
muscles.
- Patients
may only complain of unsteadiness when standing.
- Responds
to clonazepam and, in some cases, pramipexole ; ET
does not respond to clonazepam.
Isolated
position - specific or task-specific tremors (including
occupational tremors and primary writing tremor)
- Have
the appearance of localized ET but the task specificity
of dystonia.
- May
respond to anticholinergics.
Rubral
tremor
- A
several tremor with features of a parkinsonian rest
tremor and
marked exacerbation during movement.
- Not
always associated with lesions of the red nucleus
but may result from lesions of the ipsilateral cerebellar
dentate nucleus or superior cerebellar peduncle in
the midbrain.
- Most
commonly seen in multiple sclerosis.
Dystonia
- Highly
asymmetric postural tremor is probably a form of dystonia.
- Isolated
voice tremor may be due to laryngeal dystonia and
other dytonias of the vocal apparatus.
Psychogenic
- Unphysiologic
variations in tremor frequency.
- Unusual
and inconsistent behavioral characteristics.
- Spontaneous
remissions.
- Psychiatric
or social factors
Diagnosis
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)
Definite ET
- Characteristic
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.
- No
definite evidence of sudden onset.
- No
direct or indirect trauma to the brain, spinal cord
or relevant part of the peripheral nervous system
in the preceding 3 months.
- No
recent exposure to tremorgenic drugs.
- Not
in a state of drug withdrawal.
- Normal
neurologic examination other than tremor.
- No
history or clinical evidence suggestive of psychogenic
origins of tremor.
- No
evidence of stepwise deterioration.
Probable
ET
- Tremor
: same as above
- Duration
more than 3 years
- No
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.
Possible
ET
Type
1
Patients satisfy the criteria for definite or probable
tremor but exhibit other neurologic disorders or other
neurologic signs of uncertain significance.
Type
II
Monosymptomatic and isolated tremors of uncertain relation
to ET.
Task-specific
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
yet known.
Treatment
Not all patients require treatment ; only those severely
affected.
Medical
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
treatment.
- Propranolol
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.
- Primidone
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
250 mg.
- Clonidine
in doses of 0.1 - 0.9 mg daily.
- Patients
with alcohol responsive tremors may find judicious
use of alcohol to be helpful before social engagements.
- Others
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
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.
Surgical
treatment
- Stereotactic
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
tremor.
- Thalamic
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.
A
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.
Prognosis
- ET
is slowly progressive but seldom becomes severe.
- Other
neurologic impairment do not occur.
BACK
LOCKED
- IN - SYNDROME
By
K. Gireesh
Definition
A
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.
Pathogenesis
- A
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.
- A
widespread nuclear or infranuclear (lower motor neuon)
disease of motor nerves.
Etiology
Ventral brain stem lesion
- Infarction
or hemorrhage
- Tumor
- Demyelination
- Central
pontine myelinolysis, following profound hyponatremia
- Head
injury
Polyneuropathy
- Critical
illness polyneuropathy.
- Acute
onset post-infectious polyradiculoneuropathy
Clinical
Features
- Unable
to speak
- Unable
to move the limbs
- Awareness
and consciousness are preserved because the brainstem
tegmentum, including the reticular formation and oculomotor
nerves and pathways are spared.
- Able
to open the eyes and move them, and blink, in order
to try and communicate.
Investigations
:
- CT
or MRI brain scan : ventral pontine or midbrain lesion.
- Other
investigations, as appropriate, to ascertain the cause.
Diagnosis
Diagnosis
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.
Treatment
General
Patients
can see, hear and feel everything so are sensitive to
what staff are saying. They are also very frustrated
that they cannot move.
- Prevention
of complications of immobility : pneumonia, deep vein
thrombosis, contractures, urinary tract infection.
- Rehabilitation
: physiotherapy, swallowing and speech therapy, occupational
therapy, psychologic support and therapy.
Prognosis
Prognosis
is poor. Some patient recover, usually with residual
limb spasticity.
BACK
MIGRAINE
Definition
A symptoms complex, or syndrome, than manifests as discrete
episodes of headache associated with other features
of sensory sensitivity.
Epidemology
Prevalence
Lifetime
· Women : 33% (95% CI:31 - 37%).
· Men : 13% (95% CI : 12 - 16%).
1
year
· Women : 25% (95% CI : 23 - 29%).
· Men : 7.5% (CI : 7 - 9%).
· Higher in Caucasians than Africian Americans,
than Asians.
Age
· 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.
Gender
· Children : M- F
· Adolescents and adults : F>M = 2 - 3:1.
Etiology
Unknown
Migraine
without aura
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
twins.
Migraine
without aura
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.
Familial
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
calcium channelopathy'.
Pathophysiology
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.
Triggers
- Emotional
stress and tension.
- Relaxation
after stress.
- Fatigue.
- Hormonal
changes : fall in estradiol levels at menstruation
and midcycle.
- High
dose estrogen - containing contraceptives.
- Strong
sensory stimulation : bright or flickering light ;
loud noise ; strong smells ; occipital nerve compression.
- Head
trauma, such as heading the ball in soccer
- Food
idiosyncrasies / allergies : rich foods, red wines,
specific dietary amines.
- Missing
meals.
- Sleeping
late in the morning.
- Meterologic
changes.
- Vasodilators,
such as alcohol, monosodium glutamate, and anti-anginal
agents.
- Substance
misuse.
- Physical
activity.
Trigeminovascular
reflex
The
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.
Migraine
aura and headache
At
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
terminals.
Clinical Features
Precipitating factors
Phase
one : prodrome
- Occurs
in 25 - 50% of migraineurs.
- Gradual
onset and evolution over up to 24 hours.
- Lightheadedness,
dulled perception, irritability, withdrawal, cravings
for particular foods , frequent yawning, elation and
speech difficulties.
Phase
two : aura
- 15
- 25% of migraine attacks are associated with aura.
- Visual
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.
- Somatosenosry
: tingling or pins and needles, or less commonly numbness,
in the face, arm, hand or leg.
- Dysphagia
: difficulty understanding and expressing specch.
- Gradual
onset, symptoms 'build up' or progress over 5 - 10
minutes, then subside within 5 - 60 minutes.
- Followed
within 60 minutes by headache ; the aura may continue
to the headache phase.
Phase
three : headache
Present in most, but not all migraine attacks.
Site
- Unilateral
in two-thirds of patients, and bilateral in one-third.
- Frontotemporal
region commonly, spreading to occipital region.
Quality
- Throbbing
/ pulsatile.
- Moderate
to severe.
Aggravating
factors
- Physical
activity / movement.
- Bright
light
- Loud
noise
Associated
features
- Scalp
tenderness on the affected side.
- Nausea
(90% of patients).
- Vomiting
(60%)
- Diarrhea
(20%)
- Heightened
awareness of sensation such as smell and noise.
- Fluid
retention at onset, and polyuria as headache subsides.
Duration
- 4
- 72 hours.
- Commonly
2 - 6 hours in children, and 6 - 24 hours in adults.
Phase
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.
Periodicity
with recurrence
Migraine is paroxysmal ; clearly defined episodes recur
as often as 4 - 6 times each month.
Family
history
Family history of migraine is present in more than half
of patients.
Special
Forms
Migraine variants
Less than 5 % of migraineurs,
Retinal
migraine
Monocular, rather than binocular hemianopic visual disturbance.
Ophthalmoplegic
migraine :
- Paralysis
of > 1 of the ocular cranial nerves, usually the
IIIrd nerve, at the height of a migraine headache.
- The
paralysis usually resolves but may persist after recurrent
episodes.
- This
entity does not embrace a transient dilatation or
constriction of one pupil as this is quite commonly
seen during severe migraine attacks.
- The
cause of the cranial neuropathy in ophthalmoplegic
migraine is probably transient ischemia of the cranial
nerve.
Vertebrobasilar
migraine
Gradual onset and evolution over several minutes of
brainstem, cerebellar and visual disturbances, often
acompanied or followed by headache and syncope.
Hemiplegic
migraine
- Hemiparesis
preceding or occurring with a migraine headache.
- A
family history of hemiplegic migraine is often present
and the gene is located on chromosome 19 or 1.
Migrainous
infarction
- Permanent
focal neurologic symptoms persisting beyond 24 hours
after the cessation of migraine headache. Cranial
CT or MRI scan shows features consistent with cerebral
infarction.
- The
cause is probably arterial thrombosis, provoked by
arterial spasm and a procoagulant state.
Menstrual
migraine
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.
Migraine
in childhood
- Headache
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
abdominal pain.
- Fever
up to 38.5 C may be present so that the suspicion
of appendicitis or mesenteric adenitis often arises.
- Rather
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.
Differential
Diagnosis
Abrupt onset of headache ('thunderclap headache')
Primary
- Cluster
headache
- Benign
exertional or sex headache.
- Idiopathic
stabbing headache.
Secondary
- Subarachnoid
hemorrhage.
- 'Sentinel
headache'
- Intracranial
hemorrhage.
- A
precipitous rise in blood pressure : drug induced
headache.
- Head
injury.
- Acute
obstruction of the CSF pathways.
Uilateral
headache
- Cluster
headache.
- Temporal
arteritis.
- Glaucoma.
- Temperomandibular
joint disease.
- Internal
carotid or vertebral artery dissection.
- Structural
intracranial lesion.
Continuous
or daily headache
Primary
- Tension
headache : just headache, and sometimes mild photophobia
and phonophobia but no other features of sensory sensitivity.
- Mixed
migraine / tension headache.
Secondary
- Drug
- 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
contain caffeine.
- Systemic
infection
- Giant
cell arteritis.
- Raised
intracranial pressure : idiopathic intracranial hypertension,
brain tumor.
- Vertebrobasilar
migraine
Neurocardiogenic syncope
Migraine
aura without headache (acephalgic migraine)
- TIA.
- Epileptic
seizure.
- Arteriovenous
malformation
- Mitochondrial
DNA disorders.
- Cerebral
autosomal dominant arteriopathy with subcortical infarction
and leukoencephalopathy.
Investigations
- Should
only be necessary if headache is suspected to be secondary
to another disorder.
- 'Alarm
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.
- The
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
however.
Diagnosis
- At
least 5 attacks.
- Attacks
last 4-72 hours if untreated or unsuccessfully treated.
- At
least two of :
- Unilateral headache.
- Pulsating headache.
- Moderate or severe headache.
- Headache aggravated by routine physical activity.
- At
least one of :
- Nausea, with or without vomiting.
- Photophobia.
- Phonophobia.
- Treatment
Avoid precipitating / triggering factors
Identify these by keeping a dairy if necessary.
Treatment
of the acute migraine attack
Ancillary measures
- Rest
in a quiet dark room.
- Intravenous
fluids if severely dehydrated.
Non-specific
analgesics and antiemetic / prokinetic compounds
Treat
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.
Anti-emetic
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.
Simple
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-steroidal
anti-inflammatory drugs :
- Ibuprofen.
- Naproxen : oral, rectal.
- Diclofenac : oral, intramuscular.
- Ketorolac : intramuscular.
Other
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.
Specific
antimigraine agents
Ergot
alkaloids :
- Alpha
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
- Ergotamine
exists in several forms :
- 1 mg capsule of ergotamine tartrate, or combined
with caffeine.
- 2 mg tablet of ergotamine tartrate combined with
caffeine and an antiemetic.
- Dihydroergotamine
mesylate can also be given orally, or more effectively,
by suppository, inhalation, sublingual, intramuscular
and intravenous routes.
- Effective
in about half of cases.
- If
two doses at intervals of 2 - 6 hours are ineffective,
no more should be given for that attack.
- Limitations
include poor oral and rectal bioavailability ; frequent,
long-lasting adverse effects; and risk of headache
and ergotism with chronic recurrent use.
- The
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.
Triptans
:
Selective
and potent agonists of 5-HTIB, ID, IF, and to some extent
5-HTIA receptors. Antimigraine effects are mediated
by :
- Inhibition
of firing of cells in trigeminal nuclei.
- Inhibition
of dural neurogenic inflammation and plasma extravasation.
- Vasoconstriction
of meningeal, dural, cerebral or pial vessels.
First
- generation triptans : sumatriptan :
- A
specific and selective agonist of 5-HTID presynaptic
receptors on cranial blood vessels, inhibiting trigeminal
neuronal firing at the trigeminal nerve ending.
- Available
as subcutaneous injection, oral tablets, nasal spray,
and rectal preparations.
- Subcutaneous
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.
- Oral
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.
- Recurrence
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.
- Adverse
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
be acceptable.
Second
-generation triptans :
- Zolmitriptan
2.5 mg, 5 mg : similar to oral sumatriptan.
- Naratriptan
2.5 mg : slower action and perhaps fewer and less
severe adverse effects, but lower efficacy.
- Rizatriptan
10 mg, 40 mg : better efficacy and consistency, and
similar tolerability.
- Almotriptan
12.5 mg : similar efficacy, better consistency and
tolerability.
- Eletriptan
20 mg, 40 mg and 80 mg : 80 mg orally is more effective
than sumatriptan 100 mg orally with similar consistency
but lower tolerability.
- Frovatriptan
: possibly lower efficacy than oral sumatriptan.
Advantages
over oral sumatriptan :
- Higher
bioavailability : 45-75%.
- More
rapid therapeutic plasma levels : within 30 - 60 minutes.
- Greater
potency at 5-HTIB / D receptor sites.
- Increased
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
terminals).
- Cheaper
alternatives for patients who do not respond to oral
sumatriptan.
None
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.
PREVENTION
Non-Pharmacologic
- Avoid
precipitating factors
- Stress
reduction through relaxation exercises and tapes,
meditation, yoga, swimming and similar strategies
will reduce migraine frequency in many patients.
- Regular
exercise such as swimming.
- Acupuncture
in short courses by an experienced therapist can be
a useful adjunct to other strategies in some patients.
Pharmacologic
- The
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.
- Efficacy
is limited : at most about half of patients will have
a reduction in attack frequency of half or more.
- Adverse
effects occur commonly.
- The
choice of prophylactic agent is primarily determined
by the patient and which potential adverse effects
are most acceptable.
- Discuss
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.
- Establish
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
occur.
- Start
slowly, with dosage increments every 7 - 10 days to
minimize adverse effects.
- Encourage
patients to persist for at least 3 months to adequately
trial the drug and because most adverse effects become
less prominent with time.
- Follow
on with a drug free interval to reassess the frequency
and severity of migraine attacks.
Menstrual migraine
- Try
standard prophylactic therapy, as above, before hormone
manipulation.
- Continuous
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.
- Non-steroids
anti-inflammatory drug, such as diclofenac 50 mg bd
commencing 24 hours before anticipated menstruation
.
- Application
of a gel containing 1.5 mg estradiol to the skin 48
hours before the expected onset of menstruation.
- Subcutaneous
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.
- Tamoxifen
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.
Clinical
Course
- Migraine
is paroxysmal. Clearly defined episodes of migraine
recur as often as three or six times each month but
sufferers remain symptom-free between attacks.
- The
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
analgesics.
- Migraine
symptoms frequently change over time.
- The
severity of the attacks often diminish with time and
in some patients the attacks cease in latter years,
particularly after the menopause in women.
- In
some women however, attacks increase in frequency
at the menopause.
- Remission
occurs in 70% of pregnancies.
- For
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.
BACK
PERMANENT
VEGETATIVE STATE (PVS)
Definition
:
- A
condition of 'wakefulness without awareness'.
- The
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.
The
vegetative state
- A
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.
- May
be transient stage in the recovery from coma or it
may persist until death.
The
continuing or persistent vegetative state
- A
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.
- Avoiding
this state is one of the most important aspects of
attempting to assess prognosis early in coma.
Epidemology
Prevelance
: 10 000 to 25 000 adults and 400 - 1000 children in
the USA.
Pathophysiology
- Several
damage to part or all of the cerebral hemispheres,
with an intact brain stem.
- Can
occur with damage to the more rostral part of the
brainstem.
Pathology
Three
main patterns :
- Diffuse
axonal injury, typically as a sequel to severe closed
head trauma, giving rise to degeneration of the white
matter throughout the cerebral hemispheres.
- Extensive
laminar necrosis of the cerebral cortex, following
global cerebral hypoxia or ischemia.
- Thalamic
necrosis, occasionally.
Etiology
- Head
injury
- Hypoxic-ischemic
encephalopathy : cardiac arrest, carbon monoxide poisoning.
- Stroke
: ischemic or hemorrhagic.
- Hypoglycemia.
- Intracranial
infection.
- Brain
tumor.
- End
stage of degenerative brain disorders : Alzheimer's
disease.
Clinical
Features
- Inattentive
and aware of the surroundings but breathes spontaneously,
without mechanical support, and has stable circulation.
- At
times the eyes are closed and the patient appears
asleep, at other times the eyes are open and they
seem to be awake.
- May
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.
- When
the eyes are open the eyelids may blink in response
to any threat to the eye.
- A
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.
- Body
posture may be decorticate or decerebrate.
- Brainstem
reflexes, oculocephalic are usually preserved.
- Primitive
reflexes such as pouting and sucking reflexes, grasp
reflex, and withdrawal reflexes to pain may be present.
- Painful
stimuli may provoke an extensor or a flexor response.
- Plantar
responses are commonly extensor.
Diagnosis
Two
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.
Diagnostic
Criteria
Preconditions
- A
cause for the syndrome has been established
- Persisting
effects of sedative, anesthetic and neuromuscular
blocking drugs have been excluded by the passage or
time or by appropriate analysis of body fluids
- Reversible
metabolic causes have been corrected or excluded as
the cause.
Clinical
criteria
All
three of
- No
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.
- Cycles
of eye closure and eye opening which may stimulate
sleep and waking shall be present.
- Hypothalamic
and brain stem function is sufficiently preserved
to ensure the maintenance of respiration and circulation.
Other
clinical feature include :
- Spontaneous
blinking.
- Inconsistent,
non-purposeful reflex movements in response to external
stimuli :
- 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.
- Retained
pupillary and corneal responses
- Absence
of visual fixation and ability to track moving objects
with the eyes or show a 'menace' response.
- Roving
eye movements may be present.
- Conjugate
or dysconjugate tonic eye movement, without corrective
saccades in response to ice water caloric testing.
- Variable
deep tendon reflexes and plantar responses.
- Clonus
and other signs of spasticity may be present.
- Incontinence
of bladder and bowel.
Differential
Diagnosis
- Locked
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.
- Coma
: most patients who are in 'coma' for weeks, months
or years are in a continuing vegetative state.
- Brain
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.
- Akinetic
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.
- Psychogenic
unresponsiveness.
Investigations
- CT
or MRI head scan : may show non-specific focal or
diffuse abnormalities, brain atrophy, and hydrocephalus.
- Single
photon emission computed tomography (SPECT) and positron
emission tomography )PET) : show a reduction in cerebral
metabolism.
- Neurophysiology
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.
No
findings are diagnostic of the permanent vegetative
state.
Prognosis
- Determined
by the age of the patient, underlying cause and the
duration of the vegetative state.
- The
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.
- If
the cause is head injury, a longer time should elapse
before being confident that the chances of recovery
are extremely low.
Management
Establish
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.
Medical
care
- Appropriate
nursing or home care
- Maintain
oxygenation, circulation and nutrition.
- Correct
complicating factors such as infection and hypoglycemia.
- Sensitive
discussion with, education of, relatives and carers
about the cause, clinical state, 'hopeless' prognosis,
artificial means of administering food and fluid.
- Decisions
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.
- Decisions
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
not. \
- The
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'.
BACK
Ageing
and the Brain
Ageing
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.
Macroscopic
changes, brain weight and volume
At
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.
A
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.
The
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.
The
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.
An
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.
In
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.
In
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
normal subjects.
Further
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.
Microscopic
changes
On
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.
Changes
in neurones
It
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
nuclei.
NEURONAL
LOSS
Many
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.
Quantative
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.
In
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.
The
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.
ALTERED
DENDRITIC PATTERN
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.
CHANGES
IN PIGMENTATION
Lipofuscin
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.
Lipofuscin
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.
In
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.
A
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
the cytoskeleton.
ALZHEIMER'S
NEUROFIBRILLARY DEGENERATION
This
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.
By
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.
Electron
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.
Neurofibrillary
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.
Neurofibrillary
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.
The
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.
GRANULOVACUOLAR
DEGENERATION
This
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
the cytoplasm.
Immunocytochemical
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.
Quantitative
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.
HIRANO
BODIES
In
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
Alzheimer's disease.
Electron
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
are microfilaments.
Changes
in the neuropil
THREADS
Histologically,
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
tangles.
NEURITIC
PLAQUES
Known
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
The
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.
A
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.
Three
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.
Non
- 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
assessed clinically.
Of
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.
Changes
in glia
Both
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
cortex.
Microglia
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
advancing age.
Corpus
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.
Changes
in neurotransmitter activity
That
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'.
Neurochemical
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.
These
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.
Vascular
Changes
Vascular
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.
Atheroma
Quantitative
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.
Hyaline
arteriolosclerosis
Changes
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.
Lacunae
These
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
or emboli.
Microaneurysms
Micro
(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
by hypertension.
Infarction
and leukoaraiosis
In
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.
The
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.
Congophilic
angiopathy
Amyloid
- 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.
Amyloid
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.
Age
- matched control brain
There
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.
Additional
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
sex specific.
In
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.
Morphometric
methods
In
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.
BACK
Blood
- Brain Barrier
The
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.
Origin
and development of the concept of a barrier
The
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.
Anatomy
of the barrier
In
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.
While
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.
This
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
the body.
Development
of the blood-brain barrier
The
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
foot processes.
Substances
freely permeable to the blood-brain barrier
Of
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.
For
highly permeable substances which are almost completely
extracted from the blood in a single passag