Pharmacotherapy 22(11):1504-1507, 2002.
Beth M. Dubisar, Pharm.D., Steven C. Stoner, Pharm.D., Rintu Khan, M.D., Cynthia D. Farrar, M.D.
From the Northwest Missouri Psychiatric Rehabilitation Center, St. Joseph, Missouri (all authors); and the University of Missouri-Kansas City School of Pharmacy, Kansas City, Missouri (Dr. Stoner).
Abstract and Introduction
Seizure activity is a known complication associated with multiple sclerosis; however, it may also result from side effects of the treatments for the disease. A 21-year-old man with Tourette's syndrome, pedophilia, Asperger's syndrome, and multiple sclerosis experienced seizures after receiving therapy with interferon b-1a. Adjustments in his drug regimen led to the discovery of pseudoparkinsonism and other extrapyramidal symptoms. This case report illustrates how pharmacodynamic properties of drugs can complicate the treatment of neurologic disorders. Clinicians must be aware of the delicate balance between the signs and symptoms of disease states and the effects of drugs.
Multiple sclerosis is a chronic neurologic disease that can affect people of any age. Patients with the disease are at greater risk for development of seizures than age-matched controls. Seizures can be physically as well as psychosocially disabling and can further impair quality of life. In a review of medical records of patients with multiple sclerosis seen at the Mayo Clinic in Rochester, Minnesota, 51 (0.89%) of 5715 patients experienced seizures. The most common (68.6%) ictal behavior was generalized tonic-clonic seizure activity. A placebo-controlled study found that four (3%) of 158 patients receiving interferon b-1a experienced seizures, whereas none were reported in the placebo group. Three of the four patients had no history of seizures.
The development of extrapyramidal symptoms -- pseudoparkinsonism, dystonia, akathisia, and tardive dyskinesia -- during treatment with psychotropic drugs in a patient with multiple sclerosis can impair the clinician's ability to identify the progression of the neurologic disease. Extrapyramidal symptoms can be treated with anticholinergic or dopaminergic agents. Drugs such as tricyclic antidepressants possess anticholinergic properties that may mask these symptoms. Therefore, when agents with anticholinergic properties are removed from a patient's drug regimen, extrapyramidal symptoms may be revealed.
We conducted a MEDLINE search of the literature (January 1966-July 2002) using the key search terms interferon b-1a, seizures, clomipramine, pseudoparkinsonism, and extrapyramidal symptoms. We found no published reports of seizures occurring during treatment with interferon b-1a or pseudo-parkinsonism and other extrapyramidal symptoms exposed after discontinuation of clomipramine.
We describe the case of a patient whose physical and mental disease states contributed to the development of two unusual drug-related adverse events on two separate occasions.
A 21-year-old Caucasian man at the Northwest Missouri Psychiatric Rehabilitation Center was being treated for Tourette's syndrome, pedophilia, Asperger's syndrome, and multiple sclerosis. The patient had been admitted to the center 3 years earlier after a court order for inpatient evaluation and treatment was issued. His medical history was significant for a head injury when he was 3 years old and spinal meningitis at age 5. He was first treated for mental illness at age 9, when he was diagnosed with attention-deficit-hyperactivity disorder. Numerous hospital stays occurred in subsequent years. His medical record indicated that he typically came to psychiatric facilities because of intrusiveness, inappropriate sexual behaviors, lack of awareness of his environment, and failure to develop appropriate peer relationships. During his latest admission, treatment focused on improving his social skills, addressing his inability to learn from mistakes, and gaining control of his continuing impulsivity and aggression.
The patient's history of pharmacologic management consisted of guanfacine, methylphenidate, clonidine, pemoline, and fluoxetine. On admission to the center, he had been taking guanfacine 1 mg 3 times/day for behavioral and motor tic control, risperidone 1 mg twice/day for tic control, and clomipramine 25 mg at bedtime for enuresis. During his first year at the center, the dosage of clomipramine was increased to 300 mg at bedtime in an effort to better control obsessive-compulsive symptoms associated with his ongoing pedophilia (sexual arousal by children). In addition, his risperidone was increased to 3 mg at bedtime to control motor tics and aggression. The patient also was receiving long-acting propranolol 60 mg every morning for symptoms of aggression and impulsivity.
Even with this drug regimen, the patient's aggression and motor tics continued to progress, leading to an increase in the dosage of risperidone to 2 mg twice/day. Over the next 4 months, the long-acting propranolol was increased to 120 mg every morning and 180 mg every evening. During that time the patient was diagnosed with multiple sclerosis. Results of magnetic resonance imaging showed a number of white matter lesions consistent with a demyelinating disease and thinning of the corpus callosum. Ophthalmologic examination indicated bilateral optic atrophy. After consent was obtained from the patient's parents, treatment with intramuscular interferon b-1a 30 µg/week was begun in an effort to delay progression of the multiple sclerosis (Table 1).
After 3 weeks of treatment with interferon b-1a, the patient experienced a generalized tonic-clonic seizure. He fell backward, with arms and legs initially straight and rigid, progressing to a total body shake, with subsequent tonic-clonic movements of his arms. After a 2-day stay for treatment at the local community hospital, he was readmitted to the center. On readmission, his drug therapy consisted of risperidone 2 mg twice/day, clomipramine 300 mg at bedtime, long-acting propranolol 120 mg every morning and 180 mg every evening, and interferon b-1a 30 µg/week. Oxcarbazepine 150 mg twice/day was added by a neurologist to prevent further seizure activity.
Ten days later, the patient had a second generalized seizure, with tonic movements; he was confused in his postictal state. He was taken to the emergency department of the local hospital for evaluation but was not admitted. Instead, oxcarbazepine was increased to 300 mg twice/day, and both interferon b-1a and clomipramine were held due to concern about their possible contribution to lowering the patient's seizure threshold. During his treatment with interferon b-1a, no significant changes in laboratory values were observed. The next day, at the request of the patient's parents, interferon b-1a was discontinued. Oxcarbazepine was increased to 450 mg twice/day, and clomipramine 300 mg at bedtime was restarted.
Two weeks later, oxcarbazepine was tapered to discontinuation when no further seizure activity occurred after the interferon b-1a was discontinued. Five days after the oxcarbazepine taper was begun, seizure-like activity (tonic-clonic movements, clenched teeth) returned, and divalproex sodium 500 mg at noon and 1000 mg at bedtime was begun to control seizure activity and protect against mood lability. Three days later, clomipramine was tapered to discontinuation due to its potential to decrease the patient's seizure threshold further.
After clomipramine was discontinued, the patient's affect became flat, his movements were akinetic, and his concentration was poor. He could not participate in activities in which he was normally proficient, and he described himself as being in slow motion. Because his valproic acid level was 146 mg/L (therapeutic range 45-125 mg/L), the divalproex sodium dosage was decreased to 500 mg twice/day, which resulted in a level of 112 mg/L. Nevertheless, the patient continued to show significant cognitive impairment and had difficulty comprehending what others were saying to him.
Also of interest was that he began to have significant sialorrhea (excessive salivation). As he also developed depressive features, long-acting propranolol was discontinued, and divalproex sodium was decreased to 250 mg at noon and 500 mg every evening, which resulted in a blood level of 104 mg/L.
The patient continued to have slow verbal and motor responses. He stared blankly into space, continued to have sialorrhea, and his cognitive abilities declined further. Due to the complaints of intolerable drooling and the development of pseudoparkinsonism manifested by hand tremor, masked facies, and shuffled gait, risperidone was decreased to 1 mg twice/day. Part of the differential diagnosis at that time was to determine whether the patient's signs and symptoms were the result of rapidly progressing multiple sclerosis or were related to adverse effects from drug therapy. After his risperidone dosage was reduced, significant changes were observed. His reaction time and cognition improved, his sialorrhea decreased, and his affect brightened.
The patient then was treated with subcutaneous glatiramer acetate 20 mg/day to decrease the progression of his multiple sclerosis, extended-release divalproex sodium 1000 mg at bedtime to control seizures, risperidone 1 mg at noon and 2 mg at bedtime to control motor tics and symptoms of aggression, and desmopressin nasal spray at bedtime to control symptoms of enuresis. This combination prevented seizure activity and controlled his symptoms of Tourette's syndrome. However, the patient's magnetic resonance images showed intense signal intensity on the fluid-attenuated inversion recovery sequence in the corpus callosum, which appeared more dramatic than previously noted and extended into the white matter tracts of the frontal lobes. Also, high signal intensity was minimal in the medial temporal lobes and the parietal lobes around the ventricular system. These findings indicate a progression of multiple sclerosis.
Our patient's seizure activity may have resulted from treatment with interferon b-1a and clomipramine, which may have decreased his seizure threshold. However, seizure activity was still observed after discontinuation of interferon b-1a. Therefore, the progression of multiple sclerosis and associated seizures cannot be ruled out. In addition, the patient's cognitive slowing and akinesia may have resulted from the multiple sclerosis or the unmasking of extrapyramidal symptoms due to the discontinuation of clomipramine, which possesses significant anticholinergic properties.
Each drug administered to the patient was deemed appropriate and conformed to dosing parameters recognized by the Food and Drug Administration. Interferon b-1a is appropriate for first-line treatment of multiple sclerosis, and 30 µg/week is the recommended dosage. In addition, risperidone, up to 6 mg/day, is an effective treatment for Tourette's syndrome. The tricyclic antidepressant clomipramine is an accepted treatment for symptoms related to obsessive-compulsive disorder. Unfortunately, no drug is devoid of side effects. Hence, as a result of lowering the risperidone dosage after clomipramine was discontinued, the extrapyramidal symptoms (pseudoparkinsonism) resolved.
This case report illustrates the complex details encountered by clinicians who treat patients with neurologic disorders. The relationships between disease states, drugs, and their possible side effects are difficult to establish. The patient's rare physical and psychiatric conditions, combined with the occurrence of unusual drug-related adverse events, made it a particular challenge to identify cause-and-effect relationships and to measure patient response to drug therapy, both physically and mentally. At the same time, however, insight was gained into the management of patients whose complicated conditions make them especially difficult to treat.
Table 1. Timeline of Drug Therapy Interventions and Occurrences
of Adverse Events After Multiple Sclerosis Was Diagnosed and Interferon
Beta-1a Therapy Was Begun
|1||Multiple sclerosis diagnosed; interferon b-1a 30 µg/wk started.|
|22||Patient experienced generalized tonic-clonic seizure.|
|24||Oxcarbazepine 150 mg b.i.d added.|
|34||Patient had second generalized tonic-clonic seizure.|
|35||Interferon b-1a discontinued; oxcarbazepine increased to 450 mg b.i.d; clomipramine 300 mg at bedtime restarted.|
|49||Oxcarbazepine tapered to discontinuation.|
|53||Patient experienced seizure-like activity; divalproex sodium 500 mg at noon and 1000 mg at bedtime started.|
|56||Clomipramine tapered to discontinuation; divalproex sodium decreased to 500 mg b.i.d.|
|59||Patient experienced flat affect, akinetic body movements, and difficulty concentrating.|
|81||Risperidone decreased to 1 mg b.i.d.|
© 2002 Pharmacotherapy Publications