www.neurologyindia.com Indian Perspective Progressive myoclonic epilepsy P. Satishchandra, S. Sinha Department of Neurology, National Institute of Mental Health & Neurosciences, Bangalore, India Abstract Progressive myoclonic epilepsy (PME) is a disease complex and is characterized by the development of relentlessly progressive myoclonus, cognitive impairment, ataxia, and other neurologic deficits. It encompasses different diagnostic entities and the common causes include Lafora body disease, neuronal ceroid lipofuscinoses, Unverricht–Lundborg disease, myoclonic epilepsy with ragged-red fiber (MERRF) syndrome, sialidoses, dentato-rubro-pallidal atrophy, storage diseases, and some of the inborn errors of metabolism, among others. Recent advances in this area have clarified molecular genetic basis, biological basis, and natural history, and also provided Address for correspondence: a rational approach to the diagnosis. Most of the large studies related to PME are from Dr. P. Satishchandra, south India from a single center, National Institute of Mental Health and Neurological National Institute of Mental Health Sciences (NIMHANS), Bangalore. However, there are a few case reports and small series & Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029, about Lafora body disease, neuronal ceroid lipofuscinoses and MERRF from India. We India. review the clinical and research experience of a cohort of PME patients evaluated at E-mail: drpsatishchandra@yahoo. NIMHANS over the last two decades, especially the phenotypic, electrophysiologic, com pathologic, and genetic aspects. Key words: Lafora body disease, myoclonic epilepsy with ragged-red fiber, PMID: *** neuronal ceroid lipofuscinoses, progressive myoclonic epilepsy, Unverricht–Lundborg DOI: 10.4103/0028-3886.68660 disease Introduction There are a few case reports and case series on various PMEs from India.[10-15] However, most of the larger Progressive myoclonic epilepsy (PME) is a syndrome studies are from a single center, National Institute of complex characterized by progressive myoclonus, Mental Health and Neurological Sciences (NIMHANS), [5-7,16] cognitive impairment, ataxia, and other neurologic Bangalore, in south India. The research interest in deficits.[1] It encompasses several diagnostic entities and one of the PMEs, LBD has started in early 1990s and the often causes diagnostic problems leading to nosological genetic analyses of patients with LBD have been carried [9,17] confusion. Over the last two decades, considerable out in collaboration with IIT, Kanpur. developments have occurred in the field of PMEs and A total of 147 patients with PME have been evaluated at they have been recognized as a group of syndromes NIMHANS, Bangalore, India, till date, they include: LBD: with specific etiologies.[2-4] Genetic tests had further 54; NCL: 65; ULD: 08; MERRF: 10; and Tay–Sachs disease enhanced the understanding of the disease process. (TSD): 10 [Table 1]. We have earlier described a cohort The most important causes of PME include:Unverricht– 97 histopathologically confirmed patients with PME Lundborg disease (ULD), myoclonic epilepsy with [Table 2]. This cohort included 63 males and 34 females; ragged-red fiber (MERRF) syndrome, Lafora body mean age at onset of illness 10.7 ± 8.2 years (median: disease (LBD), neuronal ceroid lipofuscinoses (NCL), 11 years, range: 6 months to 48 years); and duration and sialidoses.[2] Further, recent advances have clarified of illness at presentation 2.5 ± 2.2 years. History of the clinical features and facilitated a rational diagnostic consanguineous parentage was evident in 60 patients approach. [1- 3,5-9] Understanding of the molecular genetics (61.8%). Most of the patients presented with the classical may help in determining the biological basis and also the triad: myoclonus, cognitive decline, and neurologic natural history of these disorders. deficits. 514 Neurology India | Jul-Aug 2010 | Vol 58 | Issue 4 Satishchandra and Sinha: PME in India Lafora Body Disease and retinal degeneration has been documented but normal retina is usually noted. Ataxia is often missed The characteristics of LBD include: generalized tonic– because of severe myoclonus. The characteristic EEG clonic seizures (GTCS), resting and action myoclonus, pattern is slowing of background activity with recurrent ataxia, dementia, polyspike and wave discharges in the epileptiform discharges: spikes/polyspikes, with or [20] electroencephalogram (EEG) basophilic cytoplasmic without slow waves. LBD is caused by mutation in the inclusion bodies in portions of brain, liver, and skin, as PME 2 gene (EPM2A) on chromosome 6q and EPM2B [5] well as the duct cells of the sweat glands. The disease gene. has autosomal recessive inheritance with the age of onset between 5 and 20 years. Most often patients with LBD NIMHANS cohort Clinical characteristics present at 13 or 14 years of age with few exceptions.[18] Death usually occurs within 10 years of onset. Seizures, In our cohort, there was a slight male dominance (M:F:: myoclonus, or learning disability may be the first 24:14). History of consanguineous parentage was note in 73.7% of patients. The mean age at onset of illness was symptom in the majority.[5,7,19] Myoclonus is said to be 14.4 ± 3.9 years (range: 10–35 years, median: 14 years) and more often fragmentary, asymmetric, arrhythmic, and the mean duration of illness was 2.8 ± 2.1 years. GTCS was progressively disabling.[5-7,20] Presence of optic atrophy the presenting symptom in 71% of patients. Myoclonus with or without generalized seizures and progressive Table 1: PME cohort from NIMHANS, Bangalore cognitive decline were universally present in all the Type of PME No. of cases Mode of Number patients. Seizures are often refractory to antiepileptic n (%) diagnosis n=147 medications. Occipital seizures with visualization of LBD 54 (36.7) Brain 02 Muscle 02 flashes of light (ictal phenomena) were reported in a Skin 50 third of the patients, while behavioral changes were NCL 65 (44.2) Brain 11 evident in almost one-fourth of the patients. In our Skin and 05 cohort, progression from a presymptomatic stage to muscle 49 only electrophysiologic abnormalities (EEG changes or Skin giant somatosensory-evoked potential [SSEP] potential), ULD 08 (5.4) Exclusion 08 diagnosis and finally to a clinically obvious stage have been [5] Normal skin documented. and muscle biopsy Electrophysiology MERRF 10 (6.8) Muscle 10 Scalp EEG was done in 37 patients and the findings TSD 10 (6.8) Biochemical 10 included varying degrees of slowing of background assay activity in 97.4% of patients [Figure 1a]. Generalized PME - Progressive myoclonic epilepsy; MERRF - Myoclonic epilepsy with ragged-red fiber; NCL - Neuronal ceroid lipofuscinosis; ULD - Unverricht– epileptiform discharges in 84.2% of patients, while Lundborg disease; LBD - Lafora body disease; TSD - Tay–Sachs disease focal discharges were present in ten patients. One Table 2: Clinical and electrophysiologic profile of 97 patients of PME, cohort from NIMHANS, Bangalore[7] Parameters NCL (n=40) LBD (n=38) MERRF (n=10) ULD (n=9) Age at onset (years) 5.9 ± 9.1 14.4 ± 3.9 14.6 ± 5.8 13.8 ± 9.5 Duration of illness (years) 2.5 ± 1.4 14.4 ± 3.9 2.1 ± 5.2 4.1 ± 4.05 M:F 28:12 24:14 6:4 5:4 Positive family history (%) 12.5 7.9 10 Nil Consanguineous parentage (%) 62.5 73.7 30 44.4 Common manifestations Regression of milestones, Myoclonus, generalized Myoclonus, generalized Myoclonus and ataxia seizure, myoclonus, chorea, seizure, occipital seizures, seizures, cognitive visual loss, and ataxia and cognitive decline decline, and ataxia EEG: n=37: n=37: n=7: n=9: Slowing of BGA 94.6% 97.4% 71.4% 55.5% Epileptiform discharges 81.1% 84.2% 71.4% 88.8% SSEP: n=25: n=31: n=6: n=7: giant potentials (>10 μV) 28% 77.4% 16.6% 57.1% VEP n=2: absent - 2, n=31: absent- 8, n=6: absent- 1 n=7: Prolonged P100- 7 Prolonged P100- 4 Normal Nerve conduction studies n=19: axonal neuropathy- 3 n=21: axonal n=10: myopathy- 1; n=9: neuropathy- 1 neurogenic- 1 Normal EEG - Electroencephalogram; BGA - Background activity; LBD - Lafora body disease; MERRF - Myoclonic epilepsy with ragged-red fiber; NCL - Neuronal ceroid lipofuscinosis; PME - Progressive myoclonic epilepsy; ULD - Unverricht–Lundborg disease; SSEP - Somatosensory-evoked potential; VEP - Visual-evoked potential Neurology India | Jul-Aug 2010 | Vol 58 | Issue 4 515 Satishchandra and Sinha: PME in India of the patient had multifocal epileptiform activity. b Photosensitivity with fast frequency stimulus was observed in 25% of patients, significantly less as compared to the western series..[20] Presymptomatic EEG abnormalities were detected in 3 families.[5] Progressive worsening in the background activity was observed in 4 patients. Interestingly, even presymptomatic individuals were found to have EEG changes, first time documented b from our center.[6] a Giant SSEP (14–175 μV) was demonstrated in 24 of the 31 patients studied [Figure 1b], while visual-evoked potential (VEP) studies revealed a prolonged P100 in four of the 31 patients studied and absent waveform in eight. Giant VEP potentials have also been documented for the first time from our center[5,6] [Figure 1b]. Brainstem c d auditory-evoked potential studies did not reveal any Figure 1: Laboratory parameters showing characteristic features of LBD: abnormality. Electrophysiologic features of neuropathy (a) scalp EEG with diffuse slowing of BGA with frequent spike/polyspike [7] and waves from both the hemispheres; (b) SSEP: giant potential (35.6 were present