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.