Chapter 21 Neurological disorders – epilepsy, Parkinson’s disease and multiple sclerosis
• This chapter focuses on several common neurological disorders, each of which has a wide range of therapeutic strategies available. These disorders are: epilepsy, Parkinson’s disease and multiple sclerosis. The treatments of other common neurological disorders are covered in other sections: namely: headaches (Pain section: Ch. 18), stroke (Ch. 24) and dementia (Ch. 20).
• It also touches on the pharmacological principles of other neurological disorders, including: movement disorders other than Parkinson’s disease; spasticity (that is a physical sign characteristic of certain diseases such as stroke or multiple sclerosis); peripheral neuropathy; motor neurone disease; tetanus.
Epilepsy
Definitions
A seizure is a clinical symptom or sign caused by abnormal electrical discharges within the cerebral cortex.1 For example, a tonic–clonic seizure refers to a pattern by which a patient loses consciousness, becomes generally stiff (tonic), and subsequently jerks all limbs (clonus); whereas a complex partial seizure refers to a constellation of impaired consciousness, déjà vu sensations, epigastric rising sensation, olfactory hallucinations and motor automatisms, e.g. lip smacking.2 By contrast, epilepsy refers to the clinical syndrome of recurrent seizures, and implies a pathological state that predisposes to further future seizures. Hence having one, or even a single cluster of seizures (i.e. over a few days) does not in itself qualify as epilepsy, since these seizures may have been due to a febrile illness or drug intoxication that themselves later resolve. By contrast, having at least two seizures, separated by at least a few weeks, is usually sufficient to signify epilepsy. Only one-third of people having seizures develop chronic epilepsy.
Pathology and seizure types
Epilepsy affects 0.5–1% of the general population, while the lifetime risk of having a seizure is 3–5 %. There are both multiple causes and multiple seizure types.3 Approximately half of adult epilepsy is believed to be due to genetic or early developmental causes, although the exact nature of these – e.g. sodium channel mutations or cerebral palsy – are determined in only a small minority. The other half of adult epilepsy is due to acquired causes, such as alcohol, stroke, traumatic head injury or brain tumours.
The cause of epilepsy determines the seizure type. Genetic causes (i.e. ‘primary’) predispose to generalised seizures4 characterised by tonic–clonic or absence seizures (lapses of consciousness lasting seconds), myoclonus (random limb jerk at other times), photosensitivity (seizures triggered by flashing lights), EEG showing a 3-Hz spike-and-wave pattern, and a normal MRI brain. Conversely, where focal brain injury has occurred, e.g. brain tumour or stroke, and the brain scan is abnormal, focal epileptic discharges occur within the brain leading to a partial seizure – i.e. when only a narrow set of brain functions are disturbed, e.g. causing single limb jerking (implying motor cortex involvement). Importantly, partial seizures can propagate very quickly to become a ‘secondary generalised seizure’. Another common cause of adult-onset partial epilepsy is maldevelopment of the medial temporal lobes (‘mesial temporal sclerosis’) believed to be due to injury, e.g. hypoxia or infection, during fetal or early childhood life, and sometimes apparent as atrophic hippocampi and amygdala on high-resolution MRI.
Principles of management
• Identification of underlying cause and treatment of this where possible, e.g. cerebral neoplasm or arteriovenous malformation.
• Educate the patient about the disease, duration of treatment and need for compliance.
• Counselling the patient about avoiding harm from seizures, e.g. driving regulations, swimming or bathing alone and climbing, as well as other dangerous pursuits, to be avoided.
• Avoid precipitating factors, e.g. alcohol, sleep deprivation, stroboscopic light.
• Anticipate natural variation, e.g. fits may occur particularly or exclusively around menstruation in women (catamenial5 epilepsy).
• For most cases with recurrent seizures, an antiepileptic drug is prescribed with subsequent monitoring and adjustment of dosage or drug type (see below).
• Consider surgical therapies in patients with refractory seizures, e.g. vagal nerve stimulation, temporal lobectomy. For childhood refractory epilepsy, a ketogenic diet – i.e. high fat:carbohydrate ratio – is useful, as ketone bodies are antiepileptogenic.
• Acute treatment of generalised convulsive seizures consists of ensuring the patient lies on the floor away from danger, and is postictally manoeuvred into the recovery position. If a seizure continues for more than a few minutes, rectal or buccal diazepam or intranasal midazolam can be given. If convulsive seizures last for more than 5 min, patients should be transferred to hospital for consideration of intravenous benzodiazepine and phenytoin.
Practical guide to antiepilepsy drugs
1. When to initiate. Following a single seizure the chance of a further seizure is approximately 25% over the following 3 years. Furthermore, only 33% of single-seizure patients develop chronic epilepsy. Hence the majority of first seizures are provoked by a reversible, and often recognisable, factor, e.g. infection, drug toxicity, surgery. For these reasons, following a single seizure6 anticonvulsants are not generally prescribed, whereas after two or more distinct seizure episodes (i.e. with more than a few weeks apart between episodes), they generally are prescribed. Immediate treatment of single or infrequent seizures does not affect long-term remission but introduces the potential for adverse effects. Patients need to be made aware that anticonvulsant therapy reduces harm caused by generalised seizures, and may also reduce the risk of sudden death in epilepsy (SUDEP), that usually occurs during sleep.
2. Monotherapy. Although the choice of anticonvulsants is large (approximately 20), first–line therapy is generally restricted to one of only a few drugs that have a good track record and are relatively safe and well-tolerated. Initial therapy is confined to a single drug (i.e. monotherapy) that is usually effective in stopping seizures or at least significantly decreasing their frequency. The majority of epilepsy patients (70%) can remain on monotherapy for adequate control, although sometimes the choice of monotherapy may need to be switched to allow for tolerance or optimisation of seizure control. As the number of single anticonvulsants tried increases, the incremental likelihood that any new one will offer a significant reduction in seizures decreases: from 50% response to a first drug, to an additional 30% to a second drug, to an extra 10% to a third drug, and less than 5% for any subsequent drug tried.
3. What drug to initiate. For older types of anticonvulsants, knowing the seizure type – i.e. whether partial or primary generalised – mattered, because in certain cases the spectrum of seizure efficacy is limited, and, moreover, certain seizure types can be worsened by ill-chosen drugs. For example, carbamazepine is an effective first-line therapy for partial seizures but may worsen primary generalised, absence or myoclonic seizures; similarly phenytoin can worsen absence and myoclonic seizures. Ethosuximide, by contrast, is only effective in primary generalised, and not partial, seizures.
More modern anticonvulsants, by contrast, are in general effective over a much broader range of seizure types allowing for more confidence of use even when seizure type is uncertain. Thus sodium valproate, lamotrigine and levetiracetam are active against both primary and secondary generalised epilepsy, and being relatively well tolerated, account for most first-line prescriptions. In one head-to-head study comparing popular first-line therapies for generalised and partial seizures, lamotrigine was generally tolerated better than other drugs, while valproate was the most efficacious; carbamazepine and topiramate were more likely to cause unwanted effects.7
4. Women of reproductive age and children. These categories of patients prompt selection of particular drugs and avoidance of others (see below for more detail).
5. Polytherapy. If a trial of three or so successive anticonvulsants (i.e. taken as monotherapy at adequate dosage for at least several months) does not control a patient’s epilepsy, it may be worthwhile trying dual therapy. Polytherapy offers the theoretical advantage of controlling neuronal hyperexcitability by more than one mechanism, that can be synergistic. In reality, increasing polytherapy often adheres to the law of diminishing returns, viz. the proportion of uncontrolled patients who show a positive response decreases at each addition of drug number And at the same time, adverse effects become more likely.
6. Abrupt withdrawal. Effective therapy must never be stopped suddenly, as this is a well-recognised trigger for status epilepticus, which may be fatal. But if rapid withdrawal is required by the occurrence of toxicity, e.g. due to a severe rash or significant liver dysfunction, a new drug ought to be started simultaneously. The speed by which the dose of a new drug can be raised varies according to drug type and urgency.
7. Circumstantial seizures. In cases where fits are liable to occur at a particular time, e.g. the menstrual period, adjust the dose to achieve maximal drug effect at this time or confine drug treatment to this time. For example, in catamenial epilepsy, clobazam can be useful given only at period time.
Once treatment is stable, patients should keep to a particular proprietary brand as different brands of the same generic agent (e.g. carbamazepine) may exhibit varying pharmacokinetics.
Dosage and administration
The manner in which drug dosing is initiated depends on: (1) the drug type, and (2) the frequency and severity of the patient’s seizures (i.e. the relative urgency with which therapeutic levels are reached). Phenytoin and phenobarbital allow for a rapid loading (within 24 h); valproate, levetiracetam and oxcarbazepine allow for escalation over days or a few weeks, whilst lamotrigine and carbamazepine require gradual escalations over many weeks. If seizures are infrequent at the time of presentation, e.g. every few weeks, antiepileptics should generally be started at their lowest dose, with small increments made every 1–2 weeks. In this way, the risk of unwanted effects, especially dizziness or ‘feeling drunk’ are minimised. A slow introduction of lamotrigine is also essential to reduce the risk of rash or more severe hypersensitivity reactions, Most drugs have a generally recognised maintenance dose range; the lowest dose within this range that achieves a reasonable degree of seizure control should be established. Monitoring of blood concentrations is helpful in guiding dosage of carbamazepine, phenytoin and phenobarbital, but not other anticonvulsants.
Failure to respond
In patients who continue fitting in spite of the recommended maintenance dose range having been reached, there are numerous possible explanations:
• Non-compliance, diarrhoea and vomiting, patients instructed to be ‘nil by mouth’ (revealed by measuring blood concentrations of drug).
• Inadequate dosing, including the possibility of drug interaction, e.g. another drug reducing the effective dose of the anticonvulsant by hepatic enzyme induction.
• Pregnancy also causes hepatic induction, and reduces the effective dose of lamotrigine.
• Increase in the severity of an underlying disease, e.g. enlargement of a brain tumour, or new disease.
• Drug resistance, e.g. genetic polymorphisms in hepatic cytochromes (such as CYP 2 C9) that metabolise drugs, sodium channel subunit SCN1A, or the P glycoprotein drug transporter (ABCB1 gene) that expels drugs from neurones.
Drug withdrawal
If patients have remained seizure-free for more than a few years, it is reasonable to consider withdrawal of antiepilepsy drug therapy.8,9 The prognosis of a seizure disorder is determined by:
• Type of seizure disorder – benign rolandic epilepsy, solely petit mal or grand mal seizures confer a high chance of full remission, whereas juvenile myoclonic epilepsy, temporal or frontal lobe epilepsies often require lifelong treatment.
• Time to remission – early remission carries a better outlook.
• Number of drugs required to induce remission – rapid remission on a single drug is a favourable indicator for successful withdrawal.
• MRI brain scan findings – presence of an underlying lesion predicts difficult control.
• EEG findings – epileptogenic activity is a predictor of poor outcome for drug withdrawal.
• Associated neurological deficit or learning difficulty – control is often difficult.
• Length of time of seizure freedom on treatment – the longer the period, the better the outlook.
Discontinuing antiepilepsy medication is associated with about 20% relapse during withdrawal and a further 20% relapse over the following 5 years; after this period relapse is unusual. A general recommendation is to withdraw the antiepilepsy drug over a period of 6 months. If a fit occurs during this time, full therapy must recommence until the patient has been free from seizures for several years.
Driving regulations and epilepsy
Multiple driving regulations exist that relate epilepsy (and neurological conditions predisposing to epilepsy, e.g. brain surgery) to stipulations regarding driving (according to the UK Driving Vehicle Licensing Authority). These rules are based upon statistical data relating specific diagnoses or clinically described events (e.g. blackouts without warning) with the risk of future blackout and/or car accidents. Epileptic patients who wish to continue driving therefore need to contact their national driving licensing body so that each case can be judged on its merits; while waiting for a decision, patients must not drive.
In general in the UK, patients suffering seizures, or blackouts of undetermined cause, are not permitted to drive a car for 1 year from their last attack. Exceptions include: patients who have had exclusively nocturnal seizures for at least 3 years, or patients in whom a single seizure has occurred more than 6 months earlier, providing they have a normal brain scan and EEG; these groups are usually permitted to drive.
Pregnancy and epilepsy
Pregnancy worsens epilepsy in about a third of patients, but also improves epilepsy in another third. One of the main concerns in this patient group is that all anticonvulsants increase the chance of teratogenicity slightly, with valproate, phenytoin and phenobarbital carrying most risk. The toxicological hazard must be weighed against the risk of seizures which themselves can be harmful to mother and unborn baby, and are likely to worsen if anticonvulsants are discontinued. For instance, the risk of major congenital anomalies in the fetus is 1% for healthy mothers, 2% in untreated epileptic mothers (in observational studies, so generally not severe epileptics), and 2–3% in mothers on epilepsy monotherapy. Valproate, by contrast, has been associated with a malformation rate of approximately 10%,10 while 20–30% of children are subsequently found to have mild learning disabilities or require ‘special needs’ education. The UK maintains a national drug monitoring register of all pregnant women taking antiepileptic drugs.
• neural tube defects are related to deficiencies in folic acid stores before pregnancy, so that antiepileptic drugs that affect stores, e.g. valproate, can be avoided, and folic acid 5 mg per day given for several months in advance, and
• adjustments in dose and type of drug can be avoided in the early stages of pregnancy as there is a higher risk of toxicity and seizure breakthrough during this critical phase of fetal development. In general, patients having seizures with blackouts should be on an effective dose of an anticonvulsant, because of the risks of anoxia, lactic acidosis and trauma.
During pregnancy, liver enzymes become induced, which has implications in epilepsy. Firstly, patients on lamotrigine before conception require a gradually increased dose during the pregnancy, to cope with enhanced catabolism (lowering lamotrigine plasma concentration). Secondly, enzyme-inducing drugs often aggravate a relative deficiency of vitamin K that occurs in final trimester women, predisposing to postpartum haemorrhage; vitamin K is therefore given by mouth during the last 2 weeks of pregnancy.
Breast feeding
Antiepilepsy drugs pass into breast milk: phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but provided there is awareness of these effects, the balance of advantage favours breast feeding while taking antiepilepsy drugs.
Epilepsy and oral contraceptives
Many antiepileptic drugs induce steroid-metabolising enzymes and so can cause hormonal contraception to fail. This applies to: carbamazepine, oxcarbazepine, phenytoin, barbiturates, and topiramate. Patients receiving any of these drugs and wishing to remain on the combined contraceptive pill need a higher dose of oestrogen (at least 50 micrograms/day), which they should take back-to-back for three cycles (‘tri-cycling’), before stopping for 3 days, and then repeating the pattern. Even this method offers a suboptimal level of contraception, and a non-oestrogenic form of contraception is preferred. Lamotrigine is not an enzyme inducer but can decrease levonorgestrel plasma concentration through other mechanisms.
Epilepsy in children
Seizures in children tend to arise from different sets of causes (usually genetic or cerebral palsy) from those arising in adults, and can carry either very good long-term outcomes, e.g. spontaneous resolution, or, less commonly, bad outcomes, e.g. gradual deterioration. Treatments are similar to those used in adults, but certain seizure types necessitate drugs that are rarely used in adults, e.g. ethosuximide for absence seizures, or vigabatrin for refractory partial seizures (partly because children may become irritable or more cognitively impaired with drugs such as valproate and phenobarbital).
Febrile convulsions. Seizures triggered by fever due to any cause (typically viral infection) are common in young children (3 months – 5 years old). Two-thirds of such children will have only one attack, and in total only 2% will progress to adult epilepsy. For this reason, continuous prophylaxis is seldom given, except for those cases where atypical febrile seizures occur, e.g. lasting for more than 15 min, have focal features or recur within the same febrile illness. Long-term antiepileptic therapy is avoided where possible in children due to recognised adverse effects of most such drugs on learning and social development. Febrile convulsions may be treated on an ad hoc basis by issuing parents with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) that allow for easy and early administration. Febrile convulsions may be prevented by treating febrile children with paracetamol and cooling with sponge soaks.
Status epilepticus
Status epilepticus refers to continuous or repeated epileptic seizures for more than 30 min. It often arises in patients already known to have epilepsy, in whom antiepileptic drug therapy has been inappropriately withdrawn or not taken. It can be the first presentation of epilepsy, due to an acquired brain insult, e.g. viral encephalitis.
Status epilepticus is a medical emergency. In the first instance, general resuscitation (airway control, oxygen, intravenous saline, etc.) is required. Treatment of seizures is initially with the intravenous benzodiazepine lorazepam (0.5–4 mg). Lorazepam is preferred to diazepam because it has a longer effective t½ and is less lipophilic and so accumulates less in fat, causing less delayed toxicity (hypotension and respiratory depression). The speed of action of lorazepam and diazepam are both rapid. Phenytoin i.v. may be started simultaneously to suppress further seizures, given as a loading dose (15–20 mg/kg body-weight) over 1 h, while monitoring ECG and blood pressure for arrhythmias and hypotension. Subsequently a maintenance dose of approximately 300 mg/day is given and adjusted according to plasma levels (corrected for albumin). Phenobarbital may be given i.v. as a third-line drug when seizures continue. At this point, the level of sedation (due both to seizures and drugs) is usually sufficiently great to warrant general anaesthesia, e.g. with propofol or thiopental, combined with intubation, mechanical ventilation and intensive care management. Pharmacologically induced sedation is removed periodically to allow for assessment of seizure activity (both from clinical observations and using EEG).
If resuscitation facilities are not immediately available, diazepam by rectal solution is a useful option. In some cases, midazolam (nasally) may be preferred, e.g. in children or those with severe learning disability. Intravenous benzodiazepines should not be used if resuscitation facilities are unavailable as there is risk of respiratory arrest.
Always investigate and treat the cause of a generalised seizure. Give aciclovir i.v. if viral encephalitis is suspected or, if status is triggered by removing an antiepileptic drug, it must be re-instituted. Magnesium sulphate is the treatment of choice for seizures related to eclampsia (see also p. 125).11
Details of further management appear in Table 21.1.
Table 21.1 Treatment of status epilepticus in adults
| Status | Treatment |
|---|---|
| Early | Lorazepam 4 mg i.v., repeat once after 10 min if necessary, or clonazepam 1 mg i.v. over 30 s, repeat if necessary, or diazepam 10–20 mg over 2–4 min, repeat once after 30 min if necessary |
| Established | Phenytoin 15–18 mg/kg i.v. at a rate of 50 mg/min, and/or phenobarbital 10–20 mg/kg i.v. at a rate of 100 mg/min |
| Refractory | Thiopental or propofol or midazolam with full intensive care support |
Pharmacology of individual drugs
Modes of action
Antiepilepsy (anticonvulsant) drugs aim to inhibit epileptogenic neuronal discharges and their propagation, while not interfering significantly with physiological neural activity. They act by one of five different mechanisms given below. It is generally recommended that when more than one drug is needed to control seizures, then drugs chosen should be selected from different classes of action, both to target epileptogenesis at more than one control point (resulting in synergistic effects) and to reduce unwanted effects.
Decreases electrical excitability
Examples: phenytoin, carbamazepine, lamotrigine, lacosamide. These drugs reduce cell membrane permeability to ions, particularly fast, voltage-dependent sodium channels which are responsible for the inward current that generates an action potential. Receptor blockage is typically use-dependent, meaning that only cells firing repetitively at high frequency are blocked, which permits discrimination between epileptic and physiological activity. A further potential avenue for reducing neuronal depolarisation is to use a potassium channel opener, e.g. retigabine.
Decreases synaptic vesicle release
Examples: calcium channel blockers: e.g. gabapentin; levetiracetam. Calcium channel activation is required for synaptic vesicle release and so calcium channel blockers may act by decreasing synaptic transmission, and therefore activity propagation, especially during periods of high burst activity. Calcium channel blockade may also reduce excitoxicity – a pathological process by which repetitive neuronal depolarisation leads to calcium entry into neurones, with resultant cell death. Gabapentin and pregabalin are specific for high-voltage-gated P/Q type calcium channels, whereas ethosuximide is specific for low-voltage-gated T-type calcium channels. Other drugs such as lamotrigine, valproate and topiramate block calcium channels as just one of many cellular actions.
Levetiracetam uniquely inhibits synaptic vesicle protein 2A (SV2A), thereby reducing synaptic vesicle recycling.
Enhancement of gamma-aminobutyric acid (GABA) transmission
Examples: benzodiazepines, phenobarbital, valproate, vigabatrin, tiagabine.12 By enhancing GABA, the principal inhibitory transmitter of the brain, neuronal membrane permeability to chloride ions is increased, which secondarily reduces cell excitability. Benzodiazepines and barbiturates activate the GABA receptor via specific benzodiazepine and barbiturate binding sites.
Inhibition of excitatory neurotransmitters, e.g. glutamate
Examples: topiramate, felbamate. Glutamate inhibition both stops neuronal excitation in the short term, and excitotoxicity and cell death in the long term.
Sodium channel blockers
Carbamazepine
Carbamazepine (Tegretol) acts predominantly as a voltage-dependent sodium channel blocker, thereby reducing membrane excitability.
Carbamazepine is metabolised to an epoxide; both compounds possess antiepileptic activity but the epoxide may cause more adverse effects. The t½ of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to autoinduction of hepatic enzymes. For this reason, the dose of carbamazepine is gradually increased, over many weeks, with the expectation that plasma levels will remain within a therapeutic range over this time. Other drugs relying on hepatic metabolism may also have their effective plasma level decreased due to induction secondary to carbamazepine, e.g. glucocorticosteroids, contraceptive pill, theophylline, warfarin, as well as other anticonvulsants, e.g. phenytoin. The metabolism of carbamazepine itself may be inhibited by valproate and to a lesser extent, by lamotrigine and levetiracetam (thereby raising carbamazepine plasma levels).
Carbamazepine is effective for partial seizures with or without secondary generalisation. It is also first-line treatment for trigeminal neuralgia. It is not recommended for primary generalised seizures (especially myoclonic epilepsy), which can be worsened by it.
follow from the fact that it depresses electrical excitability. In the central nervous system (CNS) this results in cerebellar and brainstem dysfunction (causing dizziness, diplopia, ataxia, nausea and reversible blurring of vision), as well as drowsiness; in the heart this can result in depression of cardiac atrioventricular (AV) conduction. Rashes, including serious reactions such as Stevens–Johnson syndrome, tend to be more of a problem for this drug than other anticonvulsants. A further set of issues arise from the hepatic induction property of carbamazepine: both osteomalacia and folic acid deficiency may occur due to enhanced metabolism of vitamin D and folic acid, respectively. Elderly patients receiving any enzyme-inducing drug should be screened for osteoporosis with bone-density scanning, and treated with bisphosphonates if necessary. Other unwanted effects can include gastrointestinal symptoms, headache, blood disorders, e.g. leucopenia, syndrome of inappropriate antidiuretic hormone (causing hyponatraemia), liver and thyroid dysfunction. Carbamazepine impairs cognitive function less than phenytoin.
Oxcarbazepine
Oxcarbazepine, like its analogue carbamazepine, acts by blocking voltage-sensitive sodium channels. It is rapidly and extensively metabolised in the liver; the t½ of the parent drug is 2 h, but that of its principal metabolite (which also has therapeutic activity) is 11 h. Unlike carbamazepine, it does not form an epoxide, which may explain its lower frequency of unwanted effects; these include dizziness, headache and hyponatraemia, and selective cytochrome enzyme induction (potentially causing failure of oestrogen contraception). Monitoring of plasma sodium may be necessary in the elderly and patients on diuretics.
Oxcarbazepine is used either as monotherapy or as add-on therapy for partial seizures. The speed with which the dose can be escalated is generally quicker than that for carbamazepine.
Eslicarbazepine
This drug is an enantiomer of a hydroxyl derivative of oxcarbazepine, and has an efficacy spectrum similar to carbamazepine and oxcarbazepine, i.e. it is effective for partial epilepsy with or without secondary generalisation. It appears to have fewer of the unwanted effects of its parent drugs, and its dose can be raised to an effective range more quickly (within 1–2 weeks); only two dose are available.
Phenytoin
Phenytoin (diphenylhydantoin, Epanutin, Dilantin) acts principally by blocking neuronal voltage-dependent sodium ion channels; this action is described as membrane stabilising, and discourages the spread (rather than the initiation) of seizure discharges.
Phenytoin provides a good example of the application of pharmacokinetics for successful prescribing.
Saturation kinetics. Phenytoin is hydroxylated extensively in the liver, a process that becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first-order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10–20 mg/L) is approached, i.e. dose increments of equal size produce a disproportional rise in steady-state plasma concentration. Thus dose increments should become smaller as the dose increases (which is why there is a 25 mg capsule), and plasma concentration monitoring is advisable. Phenytoin given orally is well absorbed, allowing for achievement of therapeutic range concentrations within 24 h (as may be required in patients with frequent seizures).
Enzyme induction and inhibition. Phenytoin is a potent inducer of hepatic enzymes that metabolise other drugs (carbamazepine, warfarin), dietary and endogenous substances (including vitamin D and folate), and phenytoin itself. This latter causes a slight fall in steady-state phenytoin concentration over the first few weeks of therapy, though this may not be noticeable with progressive dose increments. Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include sodium valproate, isoniazid and certain non-steroidal anti-inflammatory drugs.
The main role of phenytoin in modern practice is in the emergency control of seizures, including status epilepticus, because of its reliable antiepileptic effect, and because an effective treatment dose can be loaded rapidly. It may also be used to prevent partial seizures with or without secondary generalisation, but is not generally used first line in this regard because of its adverse effect profile (see below). It may worsen primary generalised epilepsies, such as absence or myoclonic seizures, and so is not used for these conditions unless status epilepticus occurs.
The membrane-stabilising effect of phenytoin finds use in cardiac arrhythmias, trigeminal neuralgia and myotonic dystrophy (an inherited disorder in which skeletal muscle becomes over-excitable).
of phenytoin are multitudinous, especially with years of therapy, which fact, together with its narrow therapeutic range, is why phenytoin is not favoured for long-term therapy. Unwanted effects related to the nervous system include cognitive impairment, cerebellar ataxia, dyskinesias, tremor and peripheral neuropathy. Cutaneous reactions include rashes (dose related), coarsening of facial features, hirsutism, lupus-like syndrome, gum hyperplasia (due to inhibition of collagen catabolism), and Dupuytren’s contracture (caused by free-radical formation). Haematological effects include: macrocytic anaemia due to increased folate metabolism (treatable with folate supplementation), IgA hypergammaglobulinaemia, lymphadenopathy and pseudolymphoma. Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy and calls for bone-density scanning.
Intravenous phenytoin is associated with cardiac depression, distal ischemia (‘purple-glove syndrome’) and, if drug extravasation occurs, local but severe ulceration.
causes cerebellar symptoms and signs, coma, apnoea or even paradoxically, seizures. The patient may remain unconscious for a long time because of saturation kinetics, but will recover with standard care.
Lamotrigine
Lamotrigine (Lamictal) stabilises pre-synaptic neuronal membranes by blocking voltage-dependent sodium and calcium channels, and reduces the release of excitatory amino acids, such as glutamate and aspartate. The t½ of 24 h allows for a single daily dose.
Lamotrigine is a favoured first-line drug for partial and generalised epilepsy, being both effective and well tolerated. It is also used in bipolar disorder as a mood stabiliser. It has few cognitive or sedating effects relative to other antiepileptic drugs.
It causes rash in about 10% of patients, including, rarely, serious reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (potentially fatal). The risk of rash lessens if treatment begins with a low dose and escalates slowly, whereas concomitant use of valproate, which inhibits lamotrigine metabolism, adds to the hazard. Carbamazepine, phenytoin and barbiturates accelerate the metabolic breakdown of lamotrigine, thereby prompting an increase in the prescribed lamotrigine dose. Other specific unwanted effects of lamotrigine include insomnia and headache, the latter effect distinguishing it from valproate and topiramate that are used for migraine prevention. Insomnia may respond to lamotrigine taken once daily in the morning.
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