Neurophysiological Disorders: Epilepsy
Definition and
classification of epilepsy
Epilepsy represents a transitory disturbance
of the functions of the brain that develops suddenly, ceases spontaneously and
can be induced by a number of different provocations. It is the most prevalent
serious neurological conditions, with a peak incidence in early childhood and
in the elderly.
Patients may be
classified according to whether:
· the fit is generalized or
partial (focal), i.e. remains within one small CNS site, e.g.
temporal lobe;
· there is an impairment of
consciousness (if there is then it is termed complex);
· the partial seizure causes secondary
generalization.
Overall, 60–70% of all
epileptics have no obvious cause for their seizures, and abouttwo-thirds of all
patients stop having seizures within 2–5 years of their onset, usually in the
context of taking medication.
Pathogenesis of
epilepsy
The aetiology of
epilepsy is largely unknown, but much of the therapy used to treat this condition
works by modifying either the balance between the inhibitory γ-aminobutyric
acid (GABA) and excitatory glutamatergic networks within the brain or the
repetitive firing potential of neurones.
The recording of the
electroencephalograph (EEG; see Chapters 43 and 52) reveals that epileptic
fits (ictal events) are associated with either generalized synchronous or
focal spike and wave dis- charges, although abnormalities can be seen
transiently at other times without overt evidence of a seizure (interictal
activity).
A generalized epileptic
fit can take several forms but classically consists of a tonic (muscles go
stiff) – clonic (jerking of limbs and body) phase followed by a period of
unconsciousness. This used to be termed a grand mal seizure, but is now
classified as a generalized tonic–clonic seizure. Petit mal epilepsy is now
reclassified as a form of primary generalized epilepsy.
A model for the
generation of an epileptic discharge is that:
1. the interictal activity corresponds
to a depolarizing shift with superimposed action potentials from an assembly of
neurones;
2. there follows a period of
hyperpolarization as these same neurones activate local inhibitory
interneurones while becoming inactivated themselves;
3. with repeated interictal spikes the
period of hyperpolarization shortens and this activates a range of normally
quiescent ion channels in the neurone as well as raising extracellular K+
concentrations, all of which further depolarizes the neurones;
4. if sufficient neurones are activated
(and the inhibition of local GABA interneurones overcome) then synchronous
discharges are produced across populations of neurones which leads to a
seizure;
5. the seizure or synchronous discharge
is then terminated by active processes of inhibition both within the neurone
(through ion channels) and within the neuronal network by GABAergic
interneuronal activity.
Although this model is
useful, it is clear that different forms of epilepsy have different underlying
abnormalities.
• Primary generalized epilepsy, which is associated with diffuse EEG changes,
is thought to result from abnormalities in specific calcium channels in the
thalamus.
• Patients
with complex partial seizures of temporal lobe origin may have a
small scar in the mesial temporal lobe corresponding to neuronal loss and
gliosis within the hippocampus, secondary to hypoxic or ischaemic insults early
in life.
Treatment of epilepsy
For most patients the
treatment of epilepsy involves antiepileptic drugs. A small proportion of
refractory patients benefit from a surgical approach, especially if an
underlying structural lesion is identified. The most common operation is
temporal lobe resection, which has a 60–70% chance of making the patient
seizure free.
Tonic–clonic and partial
seizures are treated mainly with oral carbamazepine, valproate, lamotrigine
or topiramate. These drugs are of similar effectiveness and a single
drug will control the fits in 70–80% of patients with tonic–clonic seizures,
but only 30–40% of patients with partial seizures. In these poorly controlled
patients, combinations of the above drugs or the addition of a second-line
drug, e.g. clobazam, levetiracetam, may reduce the incidence of
seizures.
Absence seizures are
treated with ethosuximide, valproate or lamotrigine.
Absence epilepsy occasionally continues into adult life. Status epilepticus is
defined as continuous seizures lasting at least 30 minutes or a state in which
fits follow each other without consciousness being fully regained. Urgent
treatment with intravenous agents is necessary, which, if unchecked,
result in exhaustion and cerebral damage. Lorazepam or diazepam is used
initially followed by phenytoin if necessary. If the fits are not
controlled, the patient is anaesthetized with propofol or
thiopental.
Mechanisms of action
of anticonvulsants
Antiepileptic drugs
control seizures by mechanisms that usually involve one of the following:
• enhancement of GABA-mediated inhibition (benzodiazepines, vigabatrin, phenobarbital,
tiagabine)
• use-dependent blockade of sodium channels (phenytoin, carbamazepine, valproate,
lamotrigine);
• inhibition of a spike generating Ca2+ current in thalamic neurones (ethosuximide,
valproate and lamotrigine).
• Valproate also
seems to increase GABAergic central inhibition by mechanisms that may involve
stimulation of glutamic acid decarboxylase activity and/or inhibition of
GABAT activity.
• Vigabatrin is
an irreversible inhibitor of GABAT, which increases brain GABA
levels and central GABA release.
• Tiagabine inhibits
the reuptake of synaptically released GABA and therefore increases central
inhibition.
• The
benzodiazepines (e.g. clonazepam) and phenobarbital also increase
central inhibition, but by enhancing the action of synaptically released GABA
at the GABAA receptor–Cl− channel complex (see Chapter
59).
• Absence
seizures involve oscillatory neuronal activity between the thalamus and
cerebral cortex. This oscillation involves (T-type) Ca2+ channels in
the thalamic neurones, which produce low threshold spikes and allow the cells
to fire in bursts. Drugs that control absences (ethosuximide, valproate and
lamotrigine) reduce this Ca2+ current.
Carbamazepine, valproate
and lamotrigine are widely used because of their efficacy and well-documented
but largely tolerable side effects. The advantages of sodium valproate are
its relative lack of sedative effects, its wide spectrum of activity and the
mild nature of its adverse effects (nausea, weight gain, bleeding tendencies,
tremor and transient hair loss). The main disadvantage is that occasional
idiosyncratic responses cause severe or fatal hepatic toxicity and
teratogenicity. For this reason, carbamazepine or lamotrigine is often
preferred.
• Lamotrigine is
a relatively new drug with a broad range of efficacy and seems to be relatively
safe in pregnancy.
• Phenytoin is
a difficult drug to use because of its complex metabolism, such that it may
take up to 20 days for the serum level to stabilize after changing the dosage.
Therefore, the dosage must be increased gradually until fits are prevented, or
until signs of cerebellar disturbance occur (nystagmus, ataxia,
dysarthria). Other unpleasant side effects, including gum hypertrophy, acne,
greasy skin, coarsening of the facial features and hirsutism.
• Phenobarbital is
effective in tonic–clonic and partial seizures but is very sedative. Tolerance
occurs and sudden withdrawal may precipitate status epilepticus.
• Vigabatrin, gabapentin,
topiramate and levetiracetam are newer agents introduced as
‘add-on’ drugs in patients where epilepsy is not satisfactorily controlled by
other antiepileptics.
• Pregabalin is
a prodrug of gabapentin with greater potency.
• Ethosuximide is
only effective in the treatment of absences and myoclonic seizures (brief jerky
movements without loss of consciousness).
• Clonazepam is
a potent benzodiazepine anticonvulsant that is effective in absence,
tonic–clonic and myoclonic seizures. It is very sedative and tolerance occurs
with prolonged oral administration.
Anticonvulsant therapy
in pregnancy requires care because of the teratogenic potential of many of
these drugs, especially valproate and phenytoin. In addition, there is concern
that in utero exposure to valproate may damage neuropsychological developent
even in the absence of physical malformation.
