Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type
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Epilepsia, 41(8): 1046-1048, 2000 Lippincott Williams h Wilkins, Inc., Baltimore 0 International Lcague Against Epilepsy Brief Communication Effects of Vagus Nerve Stimulation on Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type Brien Smith, Rhonna Shatz, *Kost Elisevich, j-Irina N. Bespalova, and -j-$MargitBurmeister Depurtment of Neurology and *Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan, U.S.A.; and ?Mental Health Research Institute, ?Department of Genetics, and $Department OJ' Psychiatry, University of Michigan, Ann Arbor, Michigan, U.S.A. Summary: Purpose: A 34-year-old woman with progressive demonstrated on neurological examination. The patient re- myoclonus epilepsy of Unverricht-Lundborg type was consid- ported improved quality of life based in part on her ability to ered for vagus nerve stimulation (VNS) therapy. perform activities of daily living. Methods: After demonstration of intractability to multiple Conclusions: VNS therapy may be considered a treatment antiepileptic regimens and progressive deterioration in cerebel- option for progressive myoclonus epilepsy. The effects of VNS lar function, the patient was implanted with a vagus nerve on seizure control and cerebellar dysfunction may provide stimulator and followed for 1 year. Neurological status, seizure clues to the underlying mechanism(s) of action. Key Words: frequency, and parameter changes were analyzed. Vagus nerve-Progressive myoclonus epilepsy-Electrical Results: VNS therapy resulted in reduction of seizures (more stimulation-Epilepsy-Seizure. than 90%) and a significant improvement in cerebellar function Progressive myoclonus epilepsy of Unverricht- duced symptomatic benefit, but phenytoin (PHT) has led Lundborg type (PME-UL) is a rare, autosomal recessive to progressive deterioration (4). Reduced seizure fre- disorder characterized by spontaneous, stimulus- quency and improved neurological function have also sensitive, and action myoclonus, tonic-clonic seizures, been reported in EPMl patients treated with piracetam and cerebellar dysfunction (ataxia, dysarthria, tremor). (5), zonisamide (ZNS) (6), baclofen (7), and Age of onset is usually in childhood, and the disease N-acetylcysteine, a sulfhydryl antioxidant (8). course is variable, ranging from limitations in perform- Vagus nerve stimulation (VNS) reduces seizure fre- ing activities of daily living to complete incapacitation. quency in some patients with intractable localization- Dementia is usually mild and occurs late in the course of related epilepsy (9). We report a case in which a patient the disease (1). with PME-UL had improved seizure control and reduced Using linkage analysis, Lehesjoki et al. (2) identified cerebellar dysfunction after implantation of a vagus the gene locus for PME-UL (EPM1) on chromosome 21, nerve stimulator. band q22.3. The EPMl gene has been associated with a gene encoding a cysteine protease inhibitor, cystatin B CASE REPORT (3). The specific mechanism whereby one gene abnor- mality allows development of typical clinical and neu- The patient was a 34-year-old woman of Finnish de- ropathological features has not been determined. Treat- scent who developed myoclonus at age 12 years. She had ment of PME-UL typically consists of antiepileptic her first generalized tonic-clonic seizure 2 years later. drugs, usually in polytherapy regimens. Valproic acid Her paternal great grandfather had a history of seizures, (VPA), clonazepam, and phenobarbital (PB) have pro- but the clinical semiology and nature of the illness were unknown. There were no other risk factors for seizures or epilepsy. Accepted May 24, 2000. The patient was initially diagnosed as having primary Address correspondence and reprint requests to Dr. Brien Smith, Department of Neurology, Henry Ford Hospital, 2799 West Grand generalized epilepsy. Electroencephalograms revealed Boulevard, Detroit, MI 48202-2689, U.S.A. bursts of bilaterally synchronous 2.5- to 4-Hz spike/ 1046 VNS AND PROGRESSIVE MYOCLONUS EPILEPSY 1047 slow-wave and polyspike/slow-wave discharges, which function with occasional secondary injury. Her most re- were activated by photic stimulation. She was treated cent regimen included clonazepam 8 mg/d, VPA 1,750 with various antiepileptic drugs (AEDs), including PHT, mg/d, PB 45 mg/d, and lamotrigine (LTG) 200 mg/d. PB, VPA, and clonazepam, either alone or in com- Attempts to obtain piracetam and ZNS were unsuccess- bination. Treatment with PHT worsened her myoclonus ful. Discussion of other potential treatment options, in- and tremor. Later, she developed impaired cognition, cluding VNS, surfaced at this time. It was explained to tremor, and dysarthria, and a diagnosis of progressive the patient that the vagus nerve stimulator was approved myoclonus epilepsy was made 12 years after the first for use in partial epilepsy and that there was anecdotal symptoms appeared. evidence of benefit in primary and secondary generalized The patient had focal, regional, and generalized my- epilepsies, although there was no known experience with oclonus, which occurred on an almost daily basis. Pre- its use in PME-UL. cipitants included video games, stress, and laughter. A vagus nerve stimulator (Cyberonics; Houston, Clustering of seizures coincided with stress, alcohol use, Texas, U.S.A.) was implanted in December 1998, and use of oral contraceptives, and singing at parties. When indicators were set at minimal levels (Table l), as is attempts were made to simplify her AED regimen, dete- customary in our program. Within 3 weeks of implanta- rioration resulting from increased myoclonus led to dif- tion, the patient returned to the clinic and reported no ficulties performing activities of daily living, including appreciable change. Parameter changes were made, in- drinking from a cup and washing dishes. cluding maintenance of a narrow pulse bandwidth (130 Generalized tonic-clonic seizures usually lasting 2 to 3 microseconds), increasing the current (0.5 mA), and in- minutes occurred every 2 to 3 months. Secondary inju- creasing overall stimulation time (on time, 30 seconds; ries included a fractured nose (three times), periorbital off time, 10 minutes). We based these conservative trauma, and fractures of the teeth and ribs. changes on our previous experience with improved tol- erability at lower pulse bandwidths (130 to 250 micro- Physical examination revealed a pleasant young seconds) and lack of previous reported experience with woman with mild flattening of affect, monoprosody, vagal stimulation in this syndrome. The changes resulted bradyphrenia, and drowsiness. She had moderately se- in a dramatic improvement. The patient reported no sei- vere ataxic dysarthria characterized by explosive, hesi- zures, and physical examination demonstrated reduction tant, and staccato articulation with long pauses for word of tremor, dysarthria, and ataxia. Polyminimyoclonus finding and a slow speech rate. Extraocular movements with arms outstretched was barely perceptible, and over- were conjugately full but contaminated by square wave all tremulousness of limbs, eyelids, and mouth was simi- jerks. There was mild ptosis bilaterally as well as fine larly reduced. Although her affect remained restricted, eyelid and mouth tremors. her speech showed more prosodic variation, a higher rate Tremor involved most muscle groups and was aggra- of word production per minute without hesitation, less vated by postural input or action. Myoclonus appeared staccato and explosive articulation, and almost normal intermittently at rest. Both upper extremities exhibited overall understandability. Bradyphrenia decreased, and decreased tone with suspension. There was mild no drowsiness appeared during the interview. Her gait polyminimyoclonus of the fingers (ataxic type), more improved to a narrowly based walk, still with restricted prominent on the right. Moderate ataxia was present in arm and head swing and stooped posture, but overall she the arms and legs, and Romberg’s sign was present. Gait moved at a faster rate. She still turned en bloc. No my- was widely based, mildly stooped, and moderately oclonus appeared at rest. Limb ataxia on finger-to-nose slowed. There was loss of hand and arm swing, in- ability to perform tandem gait, and a tendency to turn en bloc. Reflexes were increased bilaterally in a symmet- TABLE 1. VNS parameter settings ric distribution. Operating Magnetic resonance imaging of the brain showed at- room First Second Third rophy of the brachium pontis and the inferior aspect of settings change change change the cerebellum. Muscle biopsy and evoked potential Output current (mA) 0.25 0.5 0.75 1.o studies were normal. Frequency (Hz) 15 15 30 30 Pulse bandwidth Genetic testing confirmed the diagnosis of PME-UL (microseconds) 130 130 250 250 by demonstrating the most common mutation, an expan- On time (seconds) 7 30 30 30 sion in the promoter of the cystatin B gene, by Southern Off time (minutes) 90 10 5 3 Magnet current (mA) 0.25 0.5 0.75 1 .o blot analysis (PstI) as well as low levels of cystatin B On time (seconds) 7 30 30 30 messenger RNA. Pulse bandwidth Despite the use of various AEDs, the patient continued (microseconds) 130 130 250 250 Postoperative interval 3 weeks 5 months 9 months to have frequent seizures and progressive cerebellar dys- Epilepsiu, Vol. 41, No. 8, 2000 1048 B. SMITH ET AL. testing was mild. She attended multiple parties and fam- control and sensorimotor function in a patient with PME- ily functions without exacerbation. No changes in her UL may help clarify