Conventional and novel anti-seizure medications reveal a particular role for GABAA in a North Sea progressive myoclonus Epilepsy Drosophila model.

OBJECTIVE: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3-5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. METHOD: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. RESULTS: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. CONCLUSION: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.

[Efficacy of zonisamide in Lafora's disease case and brief review of its use in progressive myoclonic epilepsy]. / Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.

INTRODUCTION: Mioclonic progressive epilepsy (MPE) includes a clinical and genetical heterogeneous group of neuro-degenerative disorders that associate spontaneous and action-induced myoclonus as well as progressive cognitive impairment. Lafora`s disease is a subtype of MPE with autosomical recessive inheritance due to a mutation in EPM2A or EPM2B genes. Seizures, especially myoclonus, are often refractary to antiepileptic drugs (AD). CASE REPORT: In this article we report a patient with Lafora´s disease diagnosis, previously resistant to several AD tested with good and sustained response to zonisamide. Indeed, we describe a brief review about the efficacy of zonisamida in MPE. CONCLUSION: Zonisamide may be considered as a good therapeutic alternative in MPE.

TITLE: Eficacia de la zonisamida en un caso de enfermedad de Lafora y breve revisión en la epilepsia mioclónica progresiva.Introducción. La epilepsia mioclónica progresiva constituye un grupo complejo de enfermedades neurodegenerativas clínica y genéticamente heterogéneas que asocian mioclonías espontáneas o inducidas por la acción y el deterioro neurológico progresivo. Dentro de estas entidades se encuentra la enfermedad de Lafora, una patología autosómica recesiva causada por mutación en el gen responsable de la síntesis de una proteína llamada laforina (EPM2A) o el gen responsable de la síntesis de la proteína malina (EPM2B o NHLRC1). Son entidades cuyas crisis, en especial las mioclonías, son frecuentemente resistentes a los fármacos anticrisis epilépticas. Caso clínico. Presentamos el caso de una paciente con diagnóstico de enfermedad de Lafora que, tras varios regímenes terapéuticos ineficaces, presentó buena respuesta a la introducción de la zonisamida, con una respuesta favorable mantenida en el tiempo. Asimismo, hacemos una breve revisión de la eficacia de la zonisamida en cuadros de epilepsia mioclónica progresiva. Conclusión. La zonisamida puede ser una buena alternativa en el tratamiento de cuadros con epilepsia mioclónica progresiva.

A systematic review of the efficacy of perampanel as treatment for myoclonic seizures and symptomatic myoclonus

Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.

Higher order visual dysfunction and myoclonic-atonic seizure: an atypical presentation of CLN6 neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis is a rare childhood neurodegenerative disease, classified under the spectrum of progressive myoclonic epilepsy (PME). Cognitive decline, seizures including myoclonus, vision loss and ataxia are the commonly described manifestations of this illness. While visual failure in this disease is largely attributed to retinal, macular degeneration and optic atrophy, with this index case, we report an atypical presentation in the form of higher order visual dysfunction. The pattern of cognitive regression has further been explored here with higher order visual dysfunction and language regression being the predominant manifestations, stemming from an involvement of bilateral occipitoparietal/occipitotemporal networks. Yet another unique feature of this case also lies in the occurrence of myoclonic-atonic seizure, a semiology rarely reported before in PME.

Long-term efficacy of low-dose perampanel for progressive myoclonus epilepsy in a patient with Gaucher disease type 3.

PURPOSE: We report the case of a patient with progressive myoclonus epilepsy due to Gaucher disease type 3 whose seizures and ability to perform activities of daily living were significantly improved after starting low-dose perampanel therapy. CASE: Our patient's generalized tonic-clonic seizures and myoclonus did not improve despite the administration of multiple antiseizure medications and enzyme replacement therapy. The myoclonus reduced following pharmacological chaperone therapy, but this effect was temporary, and the generalized tonic-clonic seizures continued to occur. However, the generalized tonic-clonic seizures disappeared following treatment with 2 mg/day of perampanel. In addition, the decrease in myoclonus dramatically improved motor function such as talking, eating, and walking and stabilized the patient's mental status. These effects have been sustained for more than 4 years. CONCLUSION: Perampanel is expected to be effective in the treatment of progressive myoclonus epilepsy associated with Gaucher disease type 3 and should be considered the drug of choice for this condition.

Zonisamide-responsive myoclonus in SEMA6B-associated progressive myoclonic epilepsy.

We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient's gait and thus mobility.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report.

BACKGROUND: A number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes. CASE PRESENTATION: We describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient's lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy. CONCLUSIONS: Metreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

Drug Treatment of Progressive Myoclonic Epilepsy.

The progressive myoclonic epilepsies (PMEs) represent a rare but devastating group of syndromes characterized by epileptic myoclonus, typically action-induced seizures, neurological regression, medically refractory epilepsy, and a variety of other signs and symptoms depending on the specific syndrome. Most of the PMEs begin in children who are developing as expected, with the onset of the disorder heralded by myoclonic and other seizure types. The conditions are considerably heterogenous, but medical intractability to epilepsy, particularly myoclonic seizures, is a core feature. With the increasing use of molecular genetic techniques, mutations and their abnormal protein products are being delineated, providing a basis for disease-based therapy. However, genetic and enzyme replacement or substrate removal are in the nascent stage, and the primary therapy is through antiepileptic drugs. Epilepsy in children with progressive myoclonic seizures is notoriously difficult to treat. The disorder is rare, so few double-blinded, placebo-controlled trials have been conducted in PME, and drugs are chosen based on small open-label trials or extrapolation of data from drug trials of other syndromes with myoclonic seizures. This review discusses the major PME syndromes and their neurogenetic basis, pathophysiological underpinning, electroencephalographic features, and currently available treatments.

An Italian multicentre study of perampanel in progressive myoclonus epilepsies.

Perampanel (PER) is a novel anti-seizure medication useful in different types of epilepsy. We intended to assess the effectiveness of PER on cortical myoclonus and seizure frequency in patients with progressive myoclonus epilepsy (PME), using quantitative validated scales. Forty-nine patients aged 36.6 ±â€¯15.6 years with PME of various aetiology (18 EPM1, 12 EPM2, five with sialidosis, one with Kufs disease, one with EPM7, and 12 undetermined) were enrolled between January 2017 and June 2018. PER at the dose of 2-12 mg (5.3 ±â€¯2.5) was added to existing therapy. Myoclonus severity was assessed using a minimal myoclonus scale (MMS) in all the patients before and after 4-6 months of steady PER dose, and by means of the Unified Myoclonus Rating Scale (UMRS) in 20 patients. Logistic regression analysis was used to identify the factors potentially predicting treatment efficacy. Four patients dropped out in the first two months due to psychiatric side effects. In the remaining patients, PER reduced myoclonus severity as assessed using MMS (Wilcoxon test: p < 0.001) and UMRS (p < 0.001), with the 'Action myoclonus' section of the UMRS showing the greatest improvement. The patients with EPM1 or EPM1-like phenotype were more likely to improve with PER (p = 0.011). Convulsive seizures which have recurred at least monthly in 17 patients were reduced by >50%. Side effects occurred in 22/49 (44.8%) patients, the most common being irritability followed by drowsiness. PER is effective in treating myoclonus and seizures in PME patients. The frequency of psychiatric side effects suggests the need for careful patient monitoring.

Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex.

OBJECTIVE: To elucidate the effects of perampanel (PER) on refractory cortical myoclonus for dose, etiology and somatosensory-evoked potential (SEP) findings. METHODS: We examined 18 epilepsy patients with seizure and cortical myoclonus. Based on data accumulated before and after PER treatment, correlations among clinical scores in myoclonus and activities of daily life (ADL); early cortical components of SEP; and PER blood concentration, were analyzed. RESULTS: PER (mean dose: 3.2 ±â€¯2.1 mg/day) significantly improved seizures, myoclonus and ADL and significantly decreased the amplitude of and prolonged latency of giant SEP components. The degree of P25 and N33 prolongations (23.8 ±â€¯1.6 to 24.7 ±â€¯1.7 ms and 32.1 ±â€¯4.0 to 33.7 ±â€¯3.4 ms) were significantly correlated with improved ADL score (p = 0.019 and p = 0.025) and blood PER concentration (p = 0.011 and p = 0.025), respectively. CONCLUSIONS: Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. Our results suggest that SEP, particularly P25 latency, can be used as a potential biomarker for assessing the objective effects of PER on intractable cortical myoclonus. SIGNIFICANCE: In this study, PER lessened the degree of synchronized discharges in the postsynaptic neurons in the primary motor cortex.

Pharmacological rescue of mutated Kv3.1 ion-channel linked to progressive myoclonus epilepsies.

Progressive myoclonus epilepsies (PMEs) constitute a cluster of inherent, genetically diverse, rare seizure disorders characterized by ataxia, tonic-clonic seizures, and action myoclonus. Recently, a mutation in the KCNC1 gene (Arg320His) was described in a group of PME patients. The KCNC1 gene encodes the Kv3.1 potassium ion channel responsible for the rapid repolarization of the membrane potential following action potential firing in fast spiking GABAergic interneurons (FSI), thereby enabling high firing frequency. In the present study, we demonstrate that the Arg320His mutation cause a reduction in the Kv3.1 current amplitude and acts in a dominantly negative fashion. The mutation profoundly affects channel activation and deactivation kinetics, and we further find that it impairs recruitment of the Kv3.1 channel to the plasma membrane. The Kv3 activating compound, RE01, partly rescues the electrophysiological deficit, suggesting that pharmacological activation of Kv3.1 activity might be a feasible approach for treatment of this cohort of PME patients.

Progressive myoclonic epilepsy and horizontal gaze palsy: a rare aetiology.

Gaucher's disease is a rare autosomal recessive, potentially fatal disorder but most common type among lysosomal storage disorders. The disease's incidence is around 1/40 000 to 1/60 000 births in the general population. A 32-year-old man, born out of non-consanguineous union, presented with generalised tonic-clonic seizures and myoclonus since 17 years of age. Seizures were noted to be resistant to multiple epileptic drugs. He developed gait imbalance, intentional tremor and dysarthria. Detailed examination revealed hepatosplenomegaly, bilateral pancerebellar signs with normal power, reflexes and sensory system. He had major cognitive impairment with impaired frontal and temporal lobar functions. Bone marrow evaluation revealed Gaucher cells, confirming the diagnosis.

Update on Pharmacological Treatment of Progressive Myoclonus Epilepsies.

BACKGROUND: Progressive myoclonus epilepsies (PMEs) are a group of rare inherited diseases featuring a combination of myoclonus, seizures and variable degree of cognitive impairment. Despite extensive investigations, a large number of PMEs remain undiagnosed. In this review, we focus on the current pharmacological approach to PMEs. METHODS: References were mainly identified through PubMed search until February 2017 and backtracking of references in pertinent studies. RESULTS: The majority of available data on the efficacy of antiepileptic medications in PMEs are primarily anecdotal or observational, based on individual responses in small series. Valproic acid is the drug of choice, except for PMEs due to mitochondrial diseases. Levetiracetam and clonazepam should be considered as the first add-on treatment. Zonisamide and perampanel represent promising alternatives. Phenobarbital and primidone should be reserved to patients with resistant disabling myoclonus or seizures. Lamotrigine should be used with caution due to its unpredictable effect on myoclonus. Avoidance of drugs known to aggravate myoclonus and seizures, such as carbamazepine and phenytoin, is paramount. Psychiatric (in particular depression) and other comorbidities need to be adequately managed. Although a 3- to 4-drug regimen is often necessary to control seizures and myoclonus, particular care should be paid to avoid excessive pharmacological load and neurotoxic side effects. Target therapy is possible only for a minority of PMEs. CONCLUSIONS: Overall, the treatment of PMEs remains symptomatic (i.e. pharmacological treatment of seizures and myoclonus). Further dissection of the genetic background of the different PMEs might hopefully help in the future with individualised treatment options.

Myoclonus and seizures in progressive myoclonus epilepsies: pharmacology and therapeutic trials.

Generalized motor seizures, usually tonic-clonic, tonic-vibratory, myoclonic or clonic, and stimulus-sensitive/action myoclonus are typical features of progressive myoclonus epilepsies (PMEs). Despite the introduction of many anticonvulsants, the treatment of these symptoms, particularly myoclonus, remains challenging, due to the incomplete and often transitory effects of most drugs. Moreover, treatment is only symptomatic, since therapy targeting the underlying aetiology for these genetic conditions is in its infancy. Traditional antiepileptic drugs for the treatment of PMEs are valproate, clonazepam, and phenobarbital (or primidone). These drugs may improve the overall performance of PME patients by decreasing their generalized seizures and, to a lesser extent, their myoclonic jerks. Newer drugs which have been shown to be effective include piracetam, levetiracetam, topiramate, zonisamide, and possibly perampanel for Lafora disease. The potential of other drugs (such as L-triptophan and N-acetylcysteine) and procedures (such as vagal and deep brain stimulation) has also been discussed. The available data on the efficacy of drugs are mainly based on small series or anecdotal reports. Two prospective, randomized, double blind studies investigating the novel SV2A ligand, brivaracetam, in genetically confirmed Unverricht-Lundborg patients have been performed with disappointing results. When treating PMEs, particular care should be paid to avoid drugs known to aggravate myoclonus or myoclonic seizures, such as phenytoin, carbamazepine, oxcarbazepine, lamotrigine, vigabatrin, tiagabine, gabapentin, and pregabalin. The emergency treatment of motor status, which often complicates the course of PMEs, consists of intravenous administration of benzodiazepines, valproate, or levetiracetam.

Post-modern therapeutic approaches for progressive myoclonus epilepsy.

While the PME are arguably the severest epilepsies and neurological disorders, the vast majority are monogenic. Additionally, many affect straightforward biochemical pathways. Finally, by definition, they occur in previously healthy and well-developed brains. As such, their therapies should be easier than in complex, albeit often less severe, neurological developmental disorders where the complex, poorly understood, and extremely difficult-to-correct, neural network of the brain is affected. This last article reviews the latest cutting edge technologies in monogenic disease therapy, with some examples provided applicable to a number of disease. It aims to give a sense of where we are and how much closer we are, to the goal of making an actual organic difference.

Blink reflex in progressive myoclonic epilepsies.

PURPOSE: Progressive myoclonic epilepsies (PME) include a heterogeneous group of disorders. The brainstem is involved in these disorders, as demonstrated by neuroimaging and autopsy studies. The blink reflex (BR) is characteristically elicited after supraorbital electrical stimulation. The BR has two components, an ipsilateral R1 and bilateral R2 (R2 and R2c). The central generator of the BR is the brainstem. In this study, we aimed to investigate the functional status of the brainstem using the BR in PME cases with different etiological factors. METHODS: We prospectively included 17 patients with a diagnosis of PME (8 male, 47.1%) who were examined between June 2009 and June 2012. For comparison, we included 41 healthy volunteers (18 male 43.9%) who did not have any neurological or systemic diseases. We recorded responses bilaterally over the orbicularis oculi muscles after supraorbital stimulation in all participants. RESULTS: The R1 and R2 components of the BR were obtained in all healthy subjects with normal latencies, whereas abnormalities in the R2 and R2c components were observed at significantly higher rates in the PME patients. The mean latencies of the bilateral R2 and R2c components were significantly prolonged, and the amplitudes were diminished in the PME patients. Disease duration and the use of multiple antiepileptic drugs were related to abnormal R2s. CONCLUSION: The abnormalities of the R2 and R2c components of the BR confirmed the inhibition of the reticular formation. The findings are probably related to disease processes and partially due to the use of multiple antiepileptic drugs.

Role of LIMP-2 in the intracellular trafficking of ß-glucosidase in different human cellular models.

Acid ß-glucosidase (GCase), the enzyme deficient in Gaucher disease (GD), is transported to lysosomes by the lysosomal integral membrane protein (LIMP)-2. In humans, LIMP-2 deficiency leads to action myoclonus-renal failure (AMRF) syndrome. GD and AMRF syndrome share some clinical features. However, they are different from clinical and biochemical points of view, suggesting that the role of LIMP-2 in the targeting of GCase would be different in different tissues. Besides, the role of LIMP-2 in the uptake and trafficking of the human recombinant (hr)GCase used in the treatment of GD is unknown. Thus, we compared GCase activity and intracellular localization in immortalized lymphocytes, fibroblasts, and a neuronal model derived from multipotent adult stem cells, from a patient with AMRF syndrome, patients with GD, and control subjects. In fibroblasts and neuronlike cells, GCase targeting to the lysosomes is completely dependent on LIMP-2, whereas in blood cells, GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism. Although hrGCase cellular uptake is independent of LIMP-2, its trafficking to the lysosomes is mediated by this receptor. These data provide new insights into the mechanisms involved in the intracellular trafficking of GCase and in the pathogeneses of GD and AMRF syndrome.

Severe 5,10-methylenetetrahydrofolate reductase deficiency and two MTHFR variants in an adolescent with progressive myoclonic epilepsy.

BACKGROUND: 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is an inborn error of the folate-recycling pathway that affects the remethylation of homocysteine to methionine. The clinical presentation of MTHFR deficiency is highly variable ranging from early neurological deterioration and death in infancy to a mild thrombophilia in adults. PATIENT AND METHODS: We describe an adolescent girl with a history of mild learning disabilities who presented at age 14 years with an epilepsy syndrome initially thought to be juvenile myoclonic epilepsy. She later developed intractable epilepsy with myoclonus, leg weakness, cognitive decline, and ataxia consistent with the syndrome of progressive myoclonic epilepsy. This prompted further evaluation that revealed elevated plasma homocysteine and decreased plasma methionine. The diagnosis of MTHFR deficiency was confirmed based on extremely reduced fibroblast MTHFR activity (0.3 nmol CHO/mg prot/hr) as well as mutation analysis that revealed two variants in the MTHFR gene, a splice site mutation p (IVS5-1G>A), as well as a missense mutation (c.155 G>A; p. Arg52Gln). Therapy with folinic acid, betaine, and methionine has produced significant clinical improvement, including improved strength, less severe ataxia, and decreased seizure frequency, as well as improvements in her electroencephalography and electromyography. CONCLUSION: This patient demonstrates the importance of considering MTHFR deficiency in the differential diagnosis of progressive myoclonic epilepsy because it is one of the few causes for which specific treatment is available.