Clinical course and variability of non-Rasmussen, nonstroke motor and sensory epilepsia partialis continua: a European survey and analysis of 65 cases

Purpose: To gain new insights into the clinical presentation, causes, treatment and prognosis of epilepsia partialis continua (EPC), and to develop hypotheses to be tested in a prospective investigation. Methods: In this retrospective multicenter study, all cases were included that fulfilled these criteria: constantly repeated fragments of epileptic seizures, with preserved consciousness, lasting ≥1 h and representing locally restricted motor or sensory epileptic activity. Single episodes were included when they lasted for a minimum of 1 day. EPC with Rasmussen syndrome and acute stroke were excluded. Key Findings: Three time courses with two subtypes each were distinguished, that is, EPC as a solitary event (de novo or in preexistent epilepsy); chronic repetitive nonprogressive EPC (with frequent or rare episodes); and chronic persistent nonprogressive EPC (primarily or evolving out of an episodic course). These were unrelated to etiologies (morphologic lesions 34%, inflammatory 29%, systemic disorders 9%, idiopathic 5%, unknown 23%). Precipitation and inhibition of seizures is a frequent feature of EPC. Levetiracetam and topiramate have improved the possibilities for pharmacotherapy. Topiramate seems to be particularly effective with dysontogenetic etiologies. Significance: The existence of several clearly distinct courses of nonprogressive EPC is a new finding. These distinctions will be further investigated in a prospective study with precise protocols for electroencephalography (EEG), imaging, and other studies. This should better establish the relation of motor and somatosensory EPC; further clarify the relations, pathogenesis, and significance of the different types and their etiologies; and possibly identify more semiologic variants. It should also provide more precise knowledge about therapy and modification of ictogenesis by external stimuli.     

Chronic focal encephalitis (Rasmussen syndrome): six cases

Six of 81 (7.4%) patients with medically intractable epilepsy treated by selective cortical excision at The Hospital for Sick Children, Toronto, Canada, since 1974 were found to have inflammatory changes in the excised specimens of cerebral cortex. The clinical and histopathological findings in these cases resemble the chronic encephalitic syndrome described by Rasmussen. We confirm the unsatisfactory seizure control and the guarded neurological and intellectual prognosis that has been associated with Rasmussen syndrome.     

Palatal Tremor of Cortical Origin Presenting as Epilepsia Partialis Continua

Summary Palatal tremor (PT) is frequently caused by brainstem lesions. The inferior olive plays a major role in the pathophysiologic mechanisms involved. We report a case of PT of cortical origin presenting as epilepsia partialis continua. EEG showed continuous left frontocentral epileptiform discharges and both single photon emission computed tomography (SPECT) and positron emission tomography (PET) showed focal hypoperfusion and hypometabolism in the corresponding location.     

Abnormal local-circuit neurons in epilepsia partialis continua associated with focal cortical dysplasia

Summary A limited cortical resection including the rolandic fissure and the pre-and postcentral cortical regions was carried out in a patient suffering from epilepsia partialis continua resistant to antiepileptic drugs. The histological examination revealed several foci of very large neurons distributed with no laminar organization in the depth of the rolandic fissure and in the crown of the primary motor and primary somatosensory areas; these lesions were consistent with focal cortical dysplasia. In addition, decreased numbers of neurons, astrocytosis and proliferation of capillaries, compatible with chronic tissue necrosis, were found in the inferior regions of the banks of the rolandic fissure. Subpopulations of local-circuit neurons were examined with parvalbumin, calbindin D-28k and somatostatin immunocytochemistry. Focal areas of cortical dysplasia contained abnormal immunoreactive neurons. Huge parvalbumin-immunoreactive cells were distributed at random and resembled axo-axonic (chandelier) and basket neurons. Abnormal calbindin D-28k-immunoreactive cells were reminiscent of double-bouquet neurons and multipolar cells. Very large somatostatin-immunoreactive cells were seldom observed in the dysplastic foci. On the other hand, areas of tissue necrosis displayed massive reduction of immunoreactive cells and fibers. Abnormalities in the morphology and distribution of local-circuit (inhibitory) neurons observed here for the first time in focal cortical dysplasia may have a pivotal role in the appearance and prolongation of electrical discharges and continuous motor signs in human focal epilepsy.Supported in part by a grant FIS 90E1263     

Adult-Onset Rasmussen's Encephalitis: Anatomical-Electrographic-Clinical Features of 7 Italian Cases

Summary:  Purpose: A limited number of cases of adult-onset Rasmussen's encephalitis (A-RE) have been reported, but the features of the syndrome are still unclear. The aim of this study was to verify the clinical features of A-RE, and outline a noninvasive approach that may allow its early diagnosis and treatment.
Methods: Retrospective evaluation of extensive noninvasive work-up of seven patients with A-RE, including repeat clinical, neurophysiological, and neuroimaging investigations.
Results: The study identified two distinct patterns of disease presentation, one characterized by focal motor epilepsy (the "epileptic" phenotype), and the other by focal cortical myoclonus (the "myoclonic" phenotype). Unilateral neurological deficits and brain atrophy were progressive in both phenotypes, but they were more prominent and were detected earlier in the "epileptic" phenotype.
Conclusions: The anatomo-electroclinical features of these patients allowed a noninvasive diagnosis of A-RE and identification of two distinct disease phenotypes. Early noninvasive diagnosis can allow faster initiation of treatment.     

GOSR2: a progressive myoclonus epilepsy gene

GOSR2‐associated PME is associated with a homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene. The functional effect of this mutation is a loss of function that results in failure of the GOSR2 protein to localize to the cis‐Golgi. The main clinical features of the GOSR2‐associated PME are early‐onset ataxia, areflexia, action myoclonus and seizures, scoliosis, elevated creatine kinase levels, relative preservation of cognitive function until the late stages of the disease, and relentless disease course. Severe photosensitive myoclonus is a common feature. GOSR2‐associated PME is a rare disease with very few cases reported so far and it can be expected that the identification of further patients will contribute to expanding the phenotype and genotype of this condition.     

Clinical stages of progressive myoclonus epilepsy in adult patients

Nineteen hospitalized adult patients with progressive myoclonus epilepsy were studied. According to their clinical status they were divided into three groups of severity. The ages and durations of the disease did not differ significantly between the groups. The groups showed significant differences in ability of daily living, amount of spontaneous myoclonus, IQ and psychomotor reaction time. In EEG the groups differed in respect to the dominant occipital rhythm and amount of myoclonic spikes but not in respect to universal paroxysms. Myoclonic spikes and paroxysms in EEG were only loosely related. The results yield a conclusion that the deterioration caused by the disease is individual and the progression may even cease. In this respect progressive myoclonus epilepsy differs clearly from many hereditary neurometabolic and storage diseases.     

Spinal muscular atrophy associated with progressive myoclonus epilepsy

A rare syndrome characterized by lower motor neuron disease associated with progressive myoclonic epilepsy, referred to as “spinal muscular atrophy associated with progressive myoclonic epilepsy” (SMA‐PME), has been described in childhood and is inherited as an autosomal recessive trait. SMA‐PME is caused by mutation in the ASAH1 gene encoding acid ceramidase. Ceramide and the metabolites participate in various cellular events as lipid mediators. The catabolism of ceramide in mammals occurs in lysosomes through the activity of ceramidase. Three different ceramidases (acid, neutral and alkaline) have been identified and appear to play distinct roles in sphingolipid metabolism. The enzymatic activity of acid ceramidase is deficient in two rare inherited disorders; Farber disease and SMA‐PME. Farber disease is a very rare and severe autosomal recessive condition with a distinct clinical phenotype. The marked difference in disease manifestations may explain why Farber and SMA‐PME diseases were not previously suspected to be allelic conditions. The precise molecular mechanism underlying the phenotypic differences remains to be clarified. Recently, a condition with mutation in CERS1, the gene encoding ceramide synthase 1, has been identified as a novel form of PME. This finding underlies the essential role of enzymes regulating either the synthesis (CERS1) or degradation (ASAH1) of ceramide, and the link between defects in ceramide metabolism and PME.     

A novel variant of dehydrodolichol diphosphate synthase (DHDDS) mutation with adult-onset progressive myoclonus ataxia

We report a novel variant of DHDDS mutation in a patient with progressive adult-onset myoclonus ataxia. The mutation in our patient was different from previous reports of denovo mutations in DHDDS in 6 patients who showed tremor-like myoclonus and generalized epilepsy.     

79例成人连续部分性癫痫患者临床分析

目的探讨成人连续部分性癫痫(EPC)的临床特征。方法回顾性分析79例成人EPC患者的临床特征,评价治疗结果。结果所有患者均表现为不伴意识障碍的运动性部分性癫痫持续状态。EPC平均持续时间6.3d(1~28d),最常累及部位为面臂部(33例,41.8%)。最常见病因为高血糖(35例,44.3%)。预后良好54例(68.4%),预后不良25例(31.6%)。所有病因为高血糖的患者预后良好,无需长期抗癫痫治疗。预后良好的相关因素为代谢性疾病或高血糖导致的EPC、单药治疗和EPC持续时间。结论 EPC最常见病因为高血糖,预后依赖于病因、使用的抗癫痫药物种类和EPC持续时间。     

Long-term follow-up for patients with nonprogressive epilepsia partialis continua in a single center in China

Epilepsia partialis continua (EPC) is a rare variant of epilepsy. Cases from China are rare. We present a case series of seven patients to analyze its clinical features, imagining findings, etiology, drug use, and long-term outcome in a single epilepsy center. We made assessments of drug effects twice (Stage I – when they left our hospital; Stage II in March 2017 – by telephone interviews to rate their long-term outcome). The mean duration of the second follow-up was 4.8 years. Of the seven patients, four patients characterized motor and sensory EPC and three motor EPC. Local distributions of EPC were: the left face (2 patients), right face (1 patient), left leg (3 patients), right leg and arm (1 patient). CT/MR was abnormal in four, normal in two, and not available in one patient. EEG abnormalities commonly consisted of spike-waves, sharp-waves (or) slow wave activity, and periodic lateralized epileptiform discharges. They were all nonprogressive EPC (encephalitis: 2; tumor: 2; head trauma: 1; and not found in 2 cases). In our observations, topiramate might be effective in patients with facial muscles continuous jerking, while carbamazepine in cases of limbs continuous myotonia. Our cases had favorable long-term outcome. Thus, our cases’ etiology differentiated from other regions. Some drugs used by referring to EPC distributions might help to control EPC and their outcome were usually favorable.     

Leucoencephalopathy with vanishing white matter may cause progressive myoclonus epilepsy

Leucoencephalopathy with vanishing white matter (VWM) is caused by mutations in the genes encoding for one of the five subunits that constitute the eukaryotic initiation factor 2B (eIF2B), and is characterized by a highly suggestive MRI pattern indicating vanishing of the cerebral white matter. Seizures are well known to occur in VWM disease, but usually do not represent a prominent feature. We report a 40-year-old man who was diagnosed with progressive myoclonus epilepsy in his twenties. All major causes of progressive myoclonus epilepsy (PME) were excluded. Brain MRI showed extensive white matter involvement. Mutation analysis of the EIF2B5 gene revealed a homozygous c.338G>A (p.Arg113His) mutation.     

Report of progressive myoclonus ataxia (PMA) in two Chinese pedigrees

Objective: To describe the clinical characteristics of patients diagnosed with progressive myoclonus ataxia (PMA) from two Chinese pedigrees.

Methods: An analysis of clinical data is presented and inferences drawn. Results: The propositus from pedigree-I (9-year-old female) could not walk stably and had a history of frequent falls. The symptoms aggravated over time until she lost the ability to take care of herself. Her physical and mental development (including cognitive ability) was normal. She had an ataxic gait, ataxic dysarthria, bilateral horizontal nystagmus and visible limb myoclonus. She failed the bilateral finger-to-nose and heel-knee-tibia tests and could not walk in a straight line. Babinski signs were not observed. EEG tracing during sleep showed low-amplitude spikes and spike-and-slow waves in the bilateral frontal and mid-frontal areas. Her magnetic resonance imaging scan was normal. In pedigree-II, the propositus (a 54-year-old male) could not walk stably and had a history of occasional falls for the past 34 years. The symptoms aggravated gradually until he lost the ability to perform routine daily activities. There was no history of convulsions. His physical and mental faculties, as well as the neurological findings were similar to those of the pedigree-I. Both proposituses did not respond well to symptomatic treatment. A novel mutation has been identified in SGCE gene (NM_003919:exon3:c.360delT:p.A120fs) using exome sequencing.

Conclusion: PMA patients from the two pedigrees had autosomal dominant mode of inheritance, with variability in the age of onset and disease severity. The cardinal symptoms were myoclonic seizures and ataxia without mental retardation.     

Prolonged cortical somatosensory evoked potential latencies in progressive myoclonus epilepsy

In 9 mildly affected and 7 severely affected patients with progressive myoclonus epilepsy, we observed a distinct slowing in the short-latency median nerve SEP components N 19 (5.2% and 24.7%), P 22 (14.6% and 37.1%) and N 30 (4.8% and 17.1%, respectively). The P 22-N 30 amplitude increased in mild but decreased again in severe disease. These findings are indicative of mild affection of the peripheral and spinal sensory connections, and more severe involvement of the thalamocortical pathways. In controls, a clear correlation between the height and the latency of the N 19 and P 22 components was observed. We also often observed a small additional negative SEP component adjoining the P 22 component.     

Electrophysiological signs of peripheral nerve dysfunction in progressive myoclonus epilepsy

Electrophysiological findings were analysed in a group of 24 patients with progressive myoclonus epilepsy (PME) without Lafora bodies. Denervation activity in needle EMG and diminution of motor and sensory responses pointed out a mild axonal degeneration. We observed a significant slowing of motor and sensory conduction velocities in all the limb nerves examined, but distal motor latencies were not significantly increased. H-reflex latency of the posterior tibial nerve was prolonged. These results yielded the suggestion that there is a systemic peripheral nerve membrane dysfunction in PME.     

KCTD7‐related progressive myoclonus epilepsy

Progressive myoclonic epilepsy associated with KCTD7 mutations has been reported in 19 patients from 12 families. Patients show homozygous mutations in the coding regions of the KCTD7 gene. The disease starts in infancy. Patients typically show an initial severe epileptic disorder, with abundant epileptiform discharges on EEG and myoclonic seizures in the foreground, associated with cognitive regression and ataxia. Continuous multifocal myoclonus aggravated by action is observed in more than half of the cases. After a few years, the disease tends to stabilize and long survival can be expected. Some patients remain able to walk independently. The severity of the disease is variable from one patient to another, even within the same family. It is hypothesized that the epileptic disorder may influence the neurological regression observed in patients.     

Electroneuromyographical and morphological findings in progressive myoclonus epilepsy (PME)

The purpose of this study was to assess the function of peripheral nerves and muscles and to describe morphological changes in muscle biopsies of patients with progressive myoclonus epilepsy. Electroneuromyographic studies were performed on 24 adult patients whose mental and motor skills were either little, moderately or severely impaired by the disease. In 5 patients a specimen of tibial anterior muscle was morphologically and histochemically investigated. The electrophysiological functions of the peripheral nerves and muscles showed gradual increasing abnormalities parallel to the severity of clinical deterioration. The muscle biopsies of 2 patients showed signs compatible with peripheral neuropathy. These findings suggested that progressive myoclonus epilepsy may be related to a systemic membrane disorder.