Lowe Syndrome Association

Antiepileptic Drugs and the Lowe Syndrome

by Lawrence Charnas, M.D., Ph.D.
Human Genetics Branch, National Institute of Child Health and Human Development
National Institutes of Health

Antiepileptic drugs or AED's are medications in common use in medical practice. Most AED's were specifically developed for the treatment of seizures, and the bulk of their usefulness in clinical practice is in the treatment of seizures. However, other medical uses for anticonvulsants have been defined and are widely recognized as being effective. These include psychiatric disorders, particularly Manic-Depressive Illness, movement disorders, such as ties or dystonia, and neuralgias, or nerve pain. These medicines, like all medicines, are synthetic chemicals with the risk of toxicity; that is, all medicines can be a poison if used incorrectly or if a person is unusually sensitive to the medicine.

The toxic effects of medicines are usually broken down into two types, acute and chronic. Acute effects occur very shortly after a medication is given, or after the amount of medicine goes too high, usually measured in hours to days. Chronic effects develop after long term administration, and are usually thought of in the course of months to years. Toxic side effects from these medicines can involve the nervous system, affecting intelligence, behavior, and awareness, but may also involve organs other than the brain.

AED's in common use include Dilantin (Phenytoin), Tegretol (Carbamazepine), Luminal (Phenobarbital), Mysoline (Primidone), Depakene, Valproic Acid, Klonopin (Clonazepam), Valium (Diazepam), Zaronitin (Ethosuximide), and AdrenocortictrophicHormone (ACTH).

These medications are used for a variety of different seizure disorders. Seizures occur in approximately one third of patients with the Lowe syndrome. The most common seizure type in the Lowe syndrome is generalized tonic clonic or grand mal seizures. Dilantin, Tegretol, Phenobarbital, and Depakote have all been used in this seizure type with good success. Staring spells, either in isolation or with grand mal seizures, occur almost as commonly as isolated grand mal seizures, and have been treated effectively with Dilantin, Phenobarbital, Mysoline, and Tegretol. Classic petit mal seizures are not known to occur in the Lowe syndrome.. Zarontin is a particularly effective AED in petit mal seizures, but is rarely effective in other seizure types, and, to my knowledge; has not been used in the Lowe syndrome. A particularly severe form; of infantile seizure disorder, called Infantile Spasms, occurs rarely in the Lowe syndrome and is treated with ACTH. Valium is used primarily in grand mal status epilepticus given as an IV drug; it is a poor AED given by mouth chronically, while Klonopin may be a useful adjunct in severe seizure disorders.

Dilantin has neurotoxic effects which; are ·usually dose related and include slowing of motor iasks, intellectual dulling, decreased alertness, memory disturbance, and rarely, a hyperactive behavioral syndrome. Other effects include nystagmus (jerking eye movements which are already usually present in Lowe syndrome), atsutia (unsteady gait), dysarthria (slurred speech), and abnormal movements. Major nonneurologic side effects of Dilantin include cosmetic changes (enlarged gums which may require frequent surgery, increased body hair and skin rashes), and swelling of the lymph glands in the body. Dilantin is widely used in Lowe syndrome and is quite effective in controlling seizures and is modestly priced.

Tegretol probably has the least adverse effect of the AED's on intellectual function and no recognized behavioral disturbance. It can be associated with temporary nausea, drowsiness, vertigo, ataxia, and blurred and double vision, all of which are usually due to taking too much medicine. Chronic side effects reported include tremor, headache, and movement disorders, although I personally have:not seen these in patients I have treated with Tegretol. Other side effects can include stomach upset, a low white blood cell count, which usually is of no medical consequence, and rarely, an aplastic anemia or shutdown of the bone marrow. Most physicians will routinely check blood counts at regular intervals with patients taking Tegretol: Tegretol is more expensive than Dilantin, and is used less frequently than Dilantin in patients with the Lowe syndrome, but has been very effective in controlling seizures when used in patients with the Lowe syndrome.

Phenobarbital may produce the most severe behavioral disturbances of any of the AED's which can include hyperactivity, irritability, drowsiness, and depression with long term use. The behavioral disturbance may mask effects on intelligence, although in normal volunteers no intellectual dulling can be detected that cannot be explained by the behavioral effects alone. It is physically addictive and cannot be stopped suddenly without running the risk of producing a seizure from the withdrawal. Other side effects from Phenobarbital are quite rare, however, and the medicine itself is extremely inexpensive and effective in theLowe syndrome. Mysoline is very similar to Phenobarbital in its chemical structure and side effects, except that its behavioral side effects are said to be worse than Phenobarbital. 1 personally have not observed this to be a problem.

Depakote has no recognized bad side effects on intellectual function or behavior at therapeutic doses. It has been associated with weight gain due to increased appetite, fine tremor or shaking of the hands, at~uria, and p8resthesias or unusualsensations. It is perhaps the most powerful AED on the market today, and would be a wonder drug except for several problems.:Depakote can be quite upsetting to the stomach, and may need to be increased slowly. It is associated with a mild, clinically insignificant liver dysfunction in virtually all patients taking the medicine, but can produce severe liver involvement. In children under 2 years of age, particularly those on multiple medications, the liver disease can be fatal. It can also suppress the bone marrow, producing low platelet counts and leading to easy bruisability. The experience is patients with Lowe syndrome is small. It was stopped in 3 of the 5 patients in whom it was used either because it was ineffective in controlling the seizures, or because of significant side effects. Finally, the medicine is very expensive.

ACTH is associated with extreme irritability, poor sleep, and crying, as well as extreme weight gain and muscle weakness. It is useful only in the most severe forms of infantile seizures, where it is really the only effective drug.

Klonopin and Valium are chemicals very similar to one another. Both impair intellectual functioning and can produce severe behavioral disturbances with sedation (sleepiness), depression, hyperactivity, aggressiveness, and irritability. Valium may cause respiratory depression when given IV, and both AED's produce a mild physical addition. However, they are otherwise remarkably safe in terms of non-neurologic complications unless they are mixed with other drugs, most notably alcohol. To my knowledge, no patient with the Lowe syndrome has received Klonopin chronically. A few patients have received Valium for treatment of status epilepticus with good success.

The choice of an AED can only be made after a full medical evaluation and complete discussion with the family about the particular risks and benefits involved for each patient. Several pieces of information can guide understanding the decision of AED choice. These include the seizure type, patient age, specific drug side effects, the doctor's age and experience. The diagnosis of a seizure disorder and the decision to treat and stop treating a seizure disorder are beyond the scope of this article, but should be viewed as a mutual decision between the physician and the family, and a balance between the benefits of stopping the seizures versus the risk, expense, and inconvenience of taking medicine. In general, effective seizure management is optimized by working with a physician with whom you have easy communication. If a communication "gap" is present, it may be appropriate to seek a second opinion, or, in extreme cases, consider transferring care to another doctor.

On The Beam Winter/Spring, 1990 (9:1)