21 (2012) 810–812

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Seizure

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Case report Clinical utility of vagus nerve stimulation for progressive myoclonic

Ayataka Fujimoto *, Tomohiro Yamazoe, Takuya Yokota, Hideo Enoki, Yuki Sasaki, Mitsuyo Nishimura, Takamichi Yamamoto

Seirei Hamamatsu General Hospital, Comprehensive Epilepsy Center, 2-12-12 Sumiyoshi, Naka-ku, Hamamatsu, Shizuoka 430-8558, Japan

ARTICLE INFO 2.1. Patient1 Article history: Received 9 July 2012 A 16-year-old, right hand-dominant man visited our hospital Received in revised form 23 August 2012 with bilateral hand , epileptic , cerebellar Accepted 27 August 2012 symptoms, and mild mental impairment. He had exhibited myoclonus and epileptic seizures since 12 years of age. These symptoms gradually worsened. The seizure frequency and 1. Introduction intensity also deteriorated and occasionally progressed to . This condition was diagnosed as PME based on the Progressive (PME) is a group of disorders in presence of EEG abnormalities, myoclonus, and mental retarda- which myoclonus is a major component. Patients with PME tion. Muscle biopsy and genetic studies showed mitochondrial typically have generalized tonic–clonic or clonic seizures, mental encephalomyelopathy with ragged-red fibers (MERRF). He used to retardation culminating in dementia, and a neurologic syndrome be on , clonazepam, and topiramate, but he developed that almost always includes cerebellar dysfunction. It comprises a valproate-induced acute pancreatitis. Currently, he had been on heterogeneous group of inherited disorders.1,2 Conditions in which levetiracetam 3000 mg/day, clonazepam 1.5 mg/day, and topir- PME is seen include Unverricht–Lundborg disease, sialidosis, amate 300 mg/day. The seizure frequency was weekly. Status Gaucher’s disease, mitochondrial encephalomyelopathy with epilepticus occurred once to twice a year. He was basically ragged-red fibers (MERRF), Lafora’s disease, neuronal ceroid wheelchair bound, walking occasionally with assists. He had lipofuscinosis, and Dentato-Rubro-Pallido Luysian Atrophy intentional and resting tremor and truncal ataxia. (DRPLA). The intensity of the various clinical features varies EEG showed diffuse 6–7 Hz theta activities. There were depending on the etiology. Although valproate, benzodiazepines, frequent generalized poly-spike-waves. Photic stimulation in- piracetam, zonisamide, topiramate, and levetiracetam have had a duced bilateral hand and eyelid myoclonus with generalized poly- positive impact on the control of the epilepsy, the prognosis of this spike-wave activities. MRI showed an atrophic brain stem and syndrome is poor.3 PME is also not responsive to open surgical cerebellum. resection. Among complimentary treatment options for epilepsy VNS (VNS therapy system, Cyberonics, Inc., Houston, TX, USA) resistant to medical and open surgical treatments, most patients so was performed for this patient. far have been treated by vagus nerve stimulation (VNS).4,5 VNS is a widely used neurostimulation for treatment-resistant epilepsy. Its 2.2. Patient 2 components are a pulse generator and a bipolar vagus nerve lead. The generator is designed to be implanted in the patient’s chest on A 20-year-old woman was referred from a nearby hospital. She the upper left side. This pulse generator produces charge-balanced was diagnosed as having Gaucher’s disease type III based on waveforms at a constant current. genetic and other studies. Gaucher cells were found in her bone The effectiveness of VNS for PME has rarely been reported.6 The marrow. Blood sampling showed deficient glucosylceramidase purpose of this study was to evaluate the efficacy of VNS for PME. enzyme activity. Her sibling was also diagnosed as having the same disease. She started exhibiting myoclonus involving her hands and 2. Patients and methods generalized seizures at the age of 13 years. Her seizure frequency and intensity had deteriorated gradually, becoming daily by 18 All the investigations and treatments were evaluated and years of age. She also suffered from status epilepticus monthly. approved by the ethics committee at Seirei Hamamatsu General Although she had cerebellar symptoms, she was able to walk by Hospital. herself with spasticity. She was on valproate 600 mg/day, clonazepam 1.5 mg/day, and topiramate 400 mg/day. She was also on enzyme replacement therapy and chaperone therapy. * Corresponding author. Tel.: +81 53 474 2222; fax: +81 53 475 7596. EEG showed posterior dominant, 7–8 Hz alpha and theta E-mail address: [email protected] (A. Fujimoto). activities. There were frequent high-amplitude, generalized,

1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.08.009 A. Fujimoto et al. / Seizure 21 (2012) 810–812 811

Table 1 Four PME patients who underwent VNS therapy.

Author Age Sex Syndrome Generalized Sz SE Myclonus Cerebellar Follow-up period

Vesper 31 M Undetermined Improved N/A Deteriorated N/A 8 years, followed by DBS Smith 34 F ULS Improved N/A Improved Improved 1 year follow-up (f/u) Our Case1 16 M MERRF Improved Improved Not deteriorated Not deteriorated 1 year 6 months f/u Our Case2 20 F Gaucher III Improved Improved Deteriorated Not deteriorated 1 year 4 months f/u

Sz: seizure; DBS: Deep Brain Stimulation; ULS: Unverricht–Lundborg Syndrome; MERRF: mitochondria encephalomyelopathy with ragged-red fibers; SE: Status Epilept icus.

poly-spike-waves, especially with photic stimulation. This EEG PME is a progressive disorder, the efficacy of VNS might decrease was suggestive of encephalopathy and . MRI over time. Two of the four patients showed deterioration in showed a diffuse atrophic brain for her age. myoclonus. We regard this as part of the progressive disease, and VNS was performed for this patient. not a result of VNS. Wille11 reported five patients with PME who underwent subthalamic deep brain stimulation (DBS) system 3. Results implantation. DBS has been effective in myoclonus. One patient12 has been seizure-free with VNS and myoclonus reduction with Patient 1: Postoperatively, the patient did not show any DBS. However, an increase in stimulation amplitudes provoked complications, including hoarseness, infection, or cardiac issues. worsening of epileptic activity or considerable side effects in all but The VNS initial dosing 2 weeks after the VNS implant was: output one of five patients. VNS seems to show efficacy for ULS, MERFF, current, 0.25 mA; on time, 30 s/off time, 5 min; signal frequency, and Gaucher’s disease. The effect of VNS might not differ by PME 30 Hz; and pulse width, 500 ms. The patient visited our outpatient etiology. VNS reduced generalized seizures and status epilepticus office every 4–5 weeks until visit 5. The dosing increment was in patients with PME. However, the efficacy of VNS for myoclonus, 0.25–1.25 mA. He became free of seizures 4 months after the VNS mental retardation, and cerebellar symptoms remains unclear. implant. During 1 year and 8 months of follow-up, he has not exhibited epileptic seizures and status epilepticus. His mental 5. Conclusion retardation, myoclonus, and cerebellar symptoms have shown no marked changes after the VNS; VNS improved only the epileptic VNS is useful for epileptic seizures and status epilepticus in seizures (Table 1). patients with PMEs. However, VNS might not control myoclonus, Patient 2: Postoperatively, the patient did not show any cerebellar symptoms, and mental retardation in some patients. complications, including hoarseness, infection, or cardiac issues. Epileptic seizures and status epilepticus reduce PME patients’ The VNS initial dosing 2 weeks after the VNS implant was: output quality of life. VNS can be a treatment option for medically current, 0.25 mA; on time, 30 s/off time, 5 min; signal frequency, intractable epilepsy in PME patients. Further studies with a larger 30 Hz; and pulse width, 500 ms. The patient visited our outpatient number of patients and longer follow-up periods are needed. office every 4–5 weeks. The dosing increment was 0.25–1.5 mA. Her seizure frequency Conflict of interest reduced gradually. She had status epilepticus 4 months after the VNS implant, after which she has not showed status epilepticus. The authors report no conflict of interest concerning the During 1 year and 6 months of follow-up, she has been free from patients or methods used in this study or findings specified in this epileptic seizures. Her mental retardation and cerebellar symp- paper. toms have shown no marked changes after VNS. She continues to have severe hand myoclonus even after VNS. (Table 1) Contributions

4. Discussion VNS operation: Fujimoto, Yamazoe and Yamamoto. Acquisition of date: Fujimoto, Sasaki and Nishimura. Analysis and interpreta- Current treatment for PME mostly relies on a combination of tion of date: Fujimoto, Yokota and Enoki. valproate and benzodiazepines, usually clonazepam.7 Zonisamide is considered a major antimyoclonic agent.8 Topiramate also seems References to have a specific antimyoclonic effect.9 Levetiracetam has proven efficacy for photo-sensitive seizures.10 However, the results for 1. Berkovic SF, Carpenter S, Andermann F, Andermann E, Wolfe LS. Kufs’ disease: a critical reappraisal. Brain 1988;111:27–62. PME have been disappointing. 2. Marseille Consensus Group. Classification of progressive myoclonus VNS was performed for two patients with PME. The VNS has and related disorders. Annals of Neurology 1990;28:113–6. achieved seizure freedom and been effective for status epilepticus 3. de Siqueira LF. Progressive myoclonic epilepsies: review of clinical, molecular and therapeutic aspects. Journal of Neurology 2010;257:1612–9. in these two patients throughout more than 1 year of follow-up. 4. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of There have been two previous reports on PME treated with VNS. chronic vagus nerve stimulation for treatment of medically intra table seizures. Thus, including the present cases, there have been four patients Neurology 1995;45:224–30. with PME who underwent VNS (Table 1), including one with 5. Arhan E, Serdaroglu A, Kurt G, Bilir E, Durdag˘ E, Erdem A, et al. The efficacy of vagal nerve stimulation in children with pharmacoresistant epilepsy: practical Unverricht–Lundborg disease (ULD), one with MERRF, one with experience at a Turkish tertiary referral center. European Journal of Paediatric Gaucher’s disease Type III, and one that remains unclassified. VNS Neurology 2010;14:334–9. improved generalized seizures in all four patients. Of these four 6. Smith B, Shatz R, Elisevich K, Bespalova IN, Burmeister M. Effects of vagus nerve stimulation on progressive myoclonus epilepsy of Unverricht–Lundborg type. patients, two had status epilepticus. Thus, VNS is effective for Epilepsia 2000;41:1046–8. status epilepticus. Although VNS improved myoclonus and 7. Iivanainen M, Himberg JJ. Valproate and clonazepam in the treatment of severe cerebellar dysfunction only in Smith’s patient, the present patients progressive myoclonus epilepsy. Archives of Neurology 1982;39:236–8. 8. Yoshimura I, Kaneko S, Yoshimura N, Murakami T. Long-term observations of and Vesper’s patient did not respond to VNS with respect to two siblings with treated with zonisamide. Epilepsy Research myoclonus, cerebellar symptoms, and mental retardation. Since 2001;46:283–7. 812 A. Fujimoto et al. / Seizure 21 (2012) 810–812

9. Montouris GD, Biton V, Rosenfeld WE. Nonfocal generalized tonic–clonic sei- 11. Wille C, Steinhoff BJ, Altenmu¨ ller DM, Staack AM, Bilic S, Nikkhah G. Chronic zures: response during long-term topiramate treatment. Topiramate YTC/YTCE high-frequency deep-brain stimulation in progressive myoclonic epilepsy in Study Group. Epilepsia 2000;41(Suppl. 1):S77–81. adulthood – report of five cases. Epilepsia 2011;52:489–96. 10. Kasteleijn-Nolst Trenite´ DG, Marescaux C, Stodieck S, Edelbroek PM, Oosting J. 12. Vesper J, Steinhoff B, Rona S, Wille C, Bilic S, Nikkhah G, et al. Chronic high- Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. frequency deep brain stimulation of the STN/SNr for progressive myoclonic Evaluation of the piracetam analogue, levetiracetam. Epilepsy Research epilepsy. Epilepsia 2007;48:1984–9. 1996;25:225–30.