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When the solution makes the problem worse

MagazineAugust 2003 (Vol. 14 Issue 5)When the solution makes the problem worse

It is the second most common neurological disorder after stroke - affecting one in 2000 people

It is the second most common neurological disorder after stroke - affecting one in 2000 people. However, this is not a simple disorder, but a group of central nervous system (CNS) disorders sharing certain symptoms.

The most well known symptom is the seizure, which is a movable feast. It can range in intensity from momentary 'blanking out' (absence or petit mal) to loss of consciousness (atonic or 'drop attack') to uncontrollable convulsions (generalised tonic-clonic or grand mal).

Complex partial epilepsy is characterised by a blank stare, behavioural changes and a chewing motion often preceded by an 'aura', which can be a peculiar odour, 'butterflies' in the stomach or a distorted sound. Myoclonic seizures are brief, but massive, muscle jerks. Simple partial jacksonian seizures are sudden jolting movements while the sufferer is conscious whereas, in simple partial sensory seizures, things that don't exist are seen, heard or sensed. Finally, febrile convulsions occur when a child has very high fever due to an infection.

What causes seizures (and other neurological symptoms) are abnormal out-of-synch electrical discharges from the millions of nerve cells in the brain - literally a fault in the circuitry.

Given the right stimulus, any brain can short-circuit in this way. The amount of stimulation required to cause a seizure is known as the seizure 'threshold'. People with epilepsy are thought to have a low seizure threshold, and the usual treatment is with one or more of a variety of antiepileptic drugs (AEDs).

While AEDs may be effective in preventing some types of seizures, they can also lower a person's seizure threshold. Indeed, they may even cause seizures. This is especially true for children, who are even more prone to AED-induced seizures than adults. The elderly, who may be more sensitive to the effects of any medications than others, and those who are taking more than one drug to control seizures are also at higher than normal risk.

Intoxicated by medication
Nobody knows for sure how often AEDs induce seizures as no research is being done (Epilepsia, 1998; 39: 5-17). A major difficulty is that clinical trials of AEDs only examine if a particular drug can suppress seizures. They never ask whether symptoms get worse (Ann Saudi Med, 2000; 20: 316-8).

Nevertheless, new research is revealing the ways in which AEDs can cause seizures. Overdosing with virtually any AED can cause seizures, even in those without epilepsy. In epileptics, AED intoxication (when the dose is too high) can increase the frequency and severity of seizures, bring on new seizure types and even non-stop serial seizures, with or without convulsions (status epilepticus).

Most of the early reports of drugs making seizures worse involved phenytoin, though this may simply be because this was the drug of choice for epilepsy at the time many of these observations were made.

In one of the first-ever trials to assess the safety of AEDs in children, around 9 per cent of 167 epileptics aged 3-16 given phenobarbital or phenytoin had to come off it because of serious side-effects. In addition, 4 per cent of those given either sodium valproate (Epilim) or carbamazepine also had a worsening of seizures.

Interestingly, it was difficult to recruit enough children for this UK study as many doctors were opposed to them being given phenobarbital (despite its popularity for epilepsy in many countries) and others had concerns about the safety of sodium valproate. These ethical objections, however, did not stop the researchers from ultimately experimenting on the children they had (Lancet, 1996; 347: 709-13).

In other reports, phenobarbital aggravated absence seizures in children (Acta Scand, 1996; 94: 367-77), and induced tonic seizures (muscle tightening) in those with Lennox-Gastaut syndrome, a severe childhood epilepsy with multiple types of seizures (Epilepsia, 1972; 13: 421-35).

Most recently, other AEDs - carbamazepine, tiagabine and valproate - have been implicated in aggravating seizures because the prescriptions were too high. In the case of valproate, worsening seizures may also indicate the presence of severe liver or brain toxicity - even when the patient doesn't show high levels of the AED in the blood.

Drugs can also worsen seizures by 'selective aggravation', when the wrong AED is given for the type of epilepsy. So far, the vast majority of these cases involve carbamazepine and children with generalised seizures.

Carbamazepine can cause and aggravate a vast array of seizures, including absence, atonic, tonic and myoclonic seizures. A severe consequence is that the patient is thrown into a state of perpetual seizure.

The sheer range of individuals who do poorly with carbamazepine is frightening. In one study, 59 epileptic children were given this drug and followed-up with regular electroencephalograms (EEGs). Thirty-three of them did well and no one needed to be taken off the drug. But 26 of the children (46 per cent) began having seizures or their seizures got worse. Nearly half of them had to stop taking the drug, and most of those who continued taking it needed to use other AEDs as well (Epilepsia, 1994; 35: 1154-9).

In another study of 170 children with juvenile myoclonic epilepsy (JME), 40 received carbamazepine or phenytoin early in their treatment. Nearly 57 per cent of these children had their symptoms worsen with these drugs. JME usually responds best to valproic acid (from which valproate is derived) and is the drug of choice for this condition (Neurology, 2000; 55: 1115-21).

The latest 'wonder' drug
Adverse reactions are not limited to the older drugs. Most recently, lamotrigine has been hailed as a treatment with fewer adverse effects than other drugs and a good record of effectiveness. But it has now come to light that the drug may actually eliminate the 'warning signals' associated with seizures. Many people who have epileptic episodes get a warning feeling - an 'aura' - that a seizure is coming. This warning, lasting from a few seconds to minutes, that an epileptic seizure may kick off shortly, gives the sufferer time to avoid injury by moving out of the way of potential hazards such as objects they could collide with, stairs or motor vehicles.

Without such a warning, people with epilepsy could suddenly and unexpectedly fall and injure themselves. Indeed, several patients who'd lost their auras once they'd switched to lamotrigine suffered injuries during seizures - some serious (Lancet, 1997; 350: 1751-2).

In addition to removing a vital warning signal, lamotrigine also aggravates seizures. Although some children with myoclonic epilepsy appear to benefit from this treatment, the drug may fail to control, or may even aggravate, this type of seizure (Neurology, 2000; 55: 1758). Lamotrigine can also worsen seizures when used as an add-on drug (Epilepsia, 1995; 36 [Suppl 3]: S65).

For babies with severe myoclonic epilepsy of infancy, in which spasms may occur in one or more groups of muscles separately or synchronously about the body, lamotrigine has simply served to make their epilepsy worse. In a study of 21 infants with this rare disorder, the vast majority showed worsening of at least one type of seizure after add-on therapy with lamotrigine. Eventually, all but two of these infants discontinued the drug - and all but one of them improved on stopping the drug. Because lamotrigine's dose needs to be increased in steps, deterioration of the patient's condition developed insidiously, so much so that, in some cases, it was not recognised by the treating physicians (Epilepsia, 1998; 39: 508-12).

Stopping AED treatment
Most researchers and physicians are loathe to remove an epileptic from medication once the regime has begun. Yet, new evidence shows that those with well-controlled epilepsy are far less likely to experience adverse effects if taken off their AEDs than was once thought.

Those patients most at risk of seizures after AED withdrawal are those whose seizures were poorly controlled by the drug treatment. Also, although there is an initial risk of recurring seizures - usually within the first two years - after that, the risk is the same for those who've stopped compared with those who continue to take AEDs (Epilepsia, 1996; 37: 1043-50).

Some physicians believe that the answer to AED-induced seizures is a simple change of medication. But the evidence shows that this may be a false hope. A recent meta-analysis of all randomised placebo-controlled studies, involving six AEDs - gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and zonisamide - concluded that none was more effective than any other as a second-line therapy in those with recurring seizures (BMJ, 1996; 313: 1169-74).

In some instances, the better solution might be to investigate the possibility of stopping antiepileptic drug therapy altogether. In adults, several factors can help to determine whether drugs can be successfully withdrawn. If your neurological examination, EEG readings following treatment and neuroimaging are all normal, and if you are of normal intelligence and have suffered from only one type of seizure, you may be a good candidate for successful drug withdrawal (Neurology, 1996; 46: 600-2). Indeed, for these patients, seizures only recur in 25 per cent. But the rate of relapse will double for those who have abnormal test readings or more than one type of seizure (Lancet, 1991; 337: 1175-80).

Certainly, it's vital that you thoroughly discuss with your doctor the risk of relapse and the benefits of discontinuing AEDs. But, according to a review update looking into the current management of epilepsy, AED treatment can be discontinued if the patient has been seizure-free for two to three years (N Engl J Med, 1994; 330: 1407-10; Hong Kong Pract, 2001; 23: 246-250).

This information is particularly important for parents whose children have been diagnosed with epilepsy. In these cases, the decision to medicate or not is often agonising. Nevertheless, the evidence shows that children who suffer their first-ever epileptic seizure are no worse off for delaying treatment until they've had another episode.

In a study that followed the progress of 479 children who'd had two or more seizures, those who were treated immediately after the first seizure suffered a second one nearly 15 months later whereas those whose treatment was delayed had their second seizure after just over four months (Neurology, 1996; 46: 41-4).

Although immediate treatment might stave off the second seizure for a few months, the researchers finally concluded that a treatment delay will not adversely affect the chances of controlling the seizures later on or affect the chances of possible remission as the child grows older. Doctors and parents who insist on drug treatment immediately after the very first attack will never truly know what the outcome would have been without the drugs. Given the emerging evidence that drug therapy itself can produce seizures, a watch-and-wait policy may be a preferable route.

Another way to avoid AED-induced seizures is to obtain a correct diagnosis. Epilepsy should not be diagnosed on the basis of a solitary seizure. The evidence suggests only about one-quarter of people who suffer a single seizure are likely to have a recurrence within three years (Schroeder SA et al. Current Medical Diagnosis & Treatment, Norwalk, CN: Appleton & Lange, 1989: 611-5).

In those with repeated seizures, it is vital for the doctor to be as clear as possible about their origin and type before prescribing drugs. This will minimise drug use and the risk of AED-induced seizures.

Certain types of seizures may be the result of tumours in the brain. However, the majority of cases are likely to have less easily definable origins. Indeed, some seizures may have nothing to do with the brain at all. For instance, in one Italian study, laboratory analysis showed that 77 per cent of epileptics showed the characteristics of coeliac disease (Lancet, 1992; 340: 439-43).

New evidence is emerging all the time of a deep connection between the brain and the 'second' brain (the complex nervous system located in the gut that mirrors the function of the central nervous system). Allergic reactions can occur in any 'weak spot' in the body.

The ability of AEDs to cause a worsening of seizures is not something most physicians are aware of. When a patient comes to them with a worsening of symptoms, the physician may be reluctant to remove the one thing - the drug - which may be causing the problem.

Epilepsy remains a baffling condition, but what is becoming increasingly clear is that drug treatment, while invaluable for a few, may be risky for a great many more. Like all drug treatments, it may make the problem much worse over the long run. Patients and their loved ones need to think very carefully about all their options once a diagnosis of epilepsy is made, and perhaps be more vocal over the need for proper diagnostic procedures to be carried out to determine what type of epilepsy is involved. Only then should the pros and cons of different treatment options be weighed up.
Pat Thomas


Seroxat

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