Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances.

The progressive myoclonus epilepsies (PME) are a diverse group of disorders that feature both myoclonus and seizures that worsen gradually over a variable timeframe. While each of the disorders is individually rare, they collectively make up a non-trivial portion of the complex epilepsy and myoclonus cases that are seen in tertiary care centers. The last decade has seen substantial progress in our understanding of the pathophysiology, diagnosis, prognosis, and, in select disorders, therapies of these diseases. In this scoping review, we examine English language publications from the past decade that address diagnostic, phenotypic, and therapeutic advances in all PMEs. We then highlight the major lessons that have been learned and point out avenues for future investigation that seem promising.

CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy.

EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children's normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease.

Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities.

Progressive myoclonus epilepsies (PMEs) are a group of genetic neurological disorders characterised by the occurrence of epileptic seizures, myoclonus and progressive neurological deterioration including cerebellar involvement and dementia. The primary cause of PMEs is variable and alterations in the corresponding mutated genes determine the progression and severity of the disease. In most cases, they lead to the death of the patient after a period of prolonged disability. PMEs also share poor information on the pathophysiological bases and the lack of a specific treatment. Recent reports suggest that neuroinflammation is a common trait under all these conditions. Here, we review similarities and differences in neuroinflammatory response in several PMEs and discuss the window of opportunity of using anti-inflammatory drugs in the treatment of several of these conditions.

Emerging treatments for progressive myoclonus epilepsies.

Introduction: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades. Nowadays, PMEs treatment remains challenging with a significant burden of disability for patients. Pharmacotherapy is primarily used to treat seizures, which impact patients' quality of life. However, new approaches have emerged in the last few years, which try to curb the neurological deterioration of PMEs through a better knowledge of the pathogenetic process. This is a review on the newest therapeutic options for the treatment of PMEs.Areas covered: Experimental and clinical results on novel therapeutic approaches for the different forms of PME are reviewed and discussed. Special attention is primarily focused on the efficacy and tolerability outcomes, trying to infer the role novel approaches may have in the future.Expert opinion: The large heterogeneity of disease-causing mechanisms prevents researchers from identifying a single approach to treat PMEs. Understanding of pathophysiologic processes is leading the way to targeted therapies, which, through enzyme replacement or underlying gene defect correction have already proved to potentially strike on neurodegeneration.

The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy.

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.

Berardinelli-Seip syndrome and progressive myoclonus epilepsy.

Berardinelli-Seip syndrome, or congenital generalized lipodystrophy type 2 (CGL2), is characterized by a lack of subcutaneous adipose tissue and precocious metabolic syndrome with insulin resistance, resulting in diabetes, dyslipidaemia, hepatic steatosis, cardiomyopathy, and acanthosis nigricans. Most reported mutations are associated with mild, non-progressive neurological impairment. We describe the clinical and EEG data of a patient with progressive myoclonus epilepsy (PME), CGL2, and progressive neurological impairment, carrying a homozygous BSCL2 nonsense mutation. The patient had epilepsy onset at the age of two, characterized by monthly generalized tonic-clonic seizures. By the age of three, he presented with drug-resistant ongoing myoclonic absence seizures, photosensitivity, progressive neurological degeneration, and moderate cognitive delay. Molecular analysis of the BSCL2 gene yielded a homozygous c.(1076dupC) p.(Glu360*) mutation. Application of a vagus nerve stimulator led to temporary improvement in seizure frequency, general neurological condition, and EEG background activity. Specific BSCL2 mutations may lead to a peculiar CGL2 phenotype characterized by PME and progressive neurodegeneration. Application of a vagus nerve stimulator, rarely used for PMEs, may prove beneficial, if only temporarily, for both seizure frequency and general neurological condition.

Acid ceramidase deficiency: Farber disease and SMA-PME.

Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.

New discoveries in progressive myoclonus epilepsies: a clinical outlook.

INTRODUCTION: Progressive myoclonus epilepsies (PMEs) constitute a rare and heterogeneous group of genetic disorders with a distinctive triad of myoclonus, seizures, and progressive neurological deterioration. PMEs, even though rare, are arguably the severest form of epilepsies accounting for <1% of all epilepsies with age at onset varying from infancy to adulthood, depending on the disease. A majority are inherited as autosomal recessive traits, however rare types following autosomal dominant and mitochondrial inheritance are also present. Areas covered: This review discusses the genetics, molecular pathogenesis, and diagnosis of six major forms of PMEs, the current pharmacological interventions under practice and alternative treatment strategies. It also provides an update on the contemporary attempts, such as gene therapy, for etiological treatment of PMEs. Finally, it comments on the autophagy and lysosomal dysfunction, which has emerged as a unifying mechanism underlying the neurodegeneration in PMEs. Expert commentary: Despite the tremendous progress made in identifying the defective genes and dissecting their functional pathways, no etiological treatment is currently available. Thus, an integrated approach to personalized medicine with new drugs, gene therapy, and enzyme replacement therapy hold the promise in pursuit of neurotherapeutic treatment of PMEs.

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.

Deep brain stimulation in a dentatorubral-pallidoluyisian atrophy patient with myoclonic dystonia.

We describe a patient with myoclonic dystonia caused by dentatorubral-pallidoluyisian atrophy (DRPLA), which was successfully controlled with bilateral deep brain stimulation (DBS) of the globus pallidus internus (GPi). DRPLA is a rare disease which can progressively cause a loss or degeneration of neurons in the globus pallidus, dentate nucleus, subthalamic nucleus, and red nucleus. This observation is another example of secondary dystonia which can be controlled by GPi-DBS in carefully selected patients.

Polyglutamine (PolyQ) diseases: genetics to treatments.

The polyglutamine (polyQ) diseases are a group of neurodegenerative disorders caused by expanded cytosine-adenine-guanine (CAG) repeats encoding a long polyQ tract in the respective proteins. To date, a total of nine polyQ disorders have been described: six spinocerebellar ataxias (SCA) types 1, 2, 6, 7, 17; Machado-Joseph disease (MJD/SCA3); Huntington's disease (HD); dentatorubral pallidoluysian atrophy (DRPLA); and spinal and bulbar muscular atrophy, X-linked 1 (SMAX1/SBMA). PolyQ diseases are characterized by the pathological expansion of CAG trinucleotide repeat in the translated region of unrelated genes. The translated polyQ is aggregated in the degenerated neurons leading to the dysfunction and degeneration of specific neuronal subpopulations. Although animal models of polyQ disease for understanding human pathology and accessing disease-modifying therapies in neurodegenerative diseases are available, there is neither a cure nor prevention for these diseases, and only symptomatic treatments for polyQ diseases currently exist. Long-term pharmacological treatment is so far disappointing, probably due to unwanted complications and decreasing drug efficacy. Cellular transplantation of stem cells may provide promising therapeutic avenues for restoration of the functions of degenerative and/or damaged neurons in polyQ diseases.

Electroencephalographic criteria for nonconvulsive status epilepticus: synopsis and comprehensive survey.

There have been many attempts at defining the electroencephalography (EEG) characteristics of nonconvulsive status epilepticus (NCSE) without a universally accepted definition. This lack of consensus arises because the EEG expression of NCSE does not exist in isolation, but reflects status epilepticus under the variety of pathologic conditions that occur with age, cerebral development, encephalopathy, and epilepsy syndrome. Current NCSE definitions include "boundary conditions," in which electroencephalographic seizure activity occurs without apparent clinical seizures. Furthermore, what appears to one interpreter as status epilepticus, is not to another reader, reflecting the "art" of EEG interpretation. Seizures and epilepsy syndromes have undergone an evolution that has moved beyond a classification of focal or generalized conditions into a syndromic approach. It seems appropriate to make similar changes in the EEG analysis of the syndromes of NCSE. In effect, the literature on epilepsy classification has progressed to incorporate the different NCSE types with clinical descriptions, but the specific EEG evidence for these types is found largely in individual reports, and often by description only. NCSE classification of EEG patterns should derive from the aggregate of published EEG patterns in the respective clinical subtype, supported by an analysis of these EEG studies. The analysis that follows presents clinical descriptions and EEG patterns of NCSE in the neonatal period, infancy, childhood, adulthood, and late adulthood from a syndromic perspective based on age, encephalopathy, cerebral development, etiology, and syndrome. Proceeding from the proposed classification of status epilepticus syndromes in "Status epilepticus: its clinical features and treatment in children and adults" (published in 1994 by Cambridge University Press, New York), we have performed a systematic search for reports presenting EEG patterns of NCSE using the online medical search engine PubMed for 22 different search strategies. EEG patterns were reviewed by two board-certified epileptologists who reached consensus regarding presence of NCSE. From a total of 4,328 search results, 123 cases with corresponding EEG patterns could be allocated to underlying epilepsy syndromes. Typical characteristic, prominent electrographic patterns, and sequential arrangements are elucidated for the different NCSE syndromes. This compendium of patterns by NCSE syndrome classification with illustration of EEGs, and delineation of electroencephalographic features helps define the characteristics and semiologic borderlines among the types of NCSE.

Pathological accumulation of atrophin-1 in dentatorubralpallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is caused by the expansion of polyglutamine (polyQ) in atrophin-1 (ATN1), also known as DRPLA protein. ATN1 is ubiquitously expressed in the central nervous system (CNS), although selective regions of CNS are degenerated in DRPLA, and this selective neuronal damage gives rise to the specific clinical features of DRPLA. Accumulation of mutant ATN1 that carries an expanded polyQ tract seems to be the primary cause of DRPLA neurodegeneration, but it is still unclear how the accumulation of ATN1 leads to neu-rodegeneration. Recently, cleaved fragments of ATN1 were shown to accumulate in the disease models and the brain tissues of patients with DRPLA. Furthermore, proteolytic processing of ATN1 may regulate the intracellular localization of ATN1 and its fragments. Therefore, proteolytic processing of ATN1 may provide clues to disease pathogenesis and hopefully aid in the determination of molecular targets for effective therapeutic approaches for DRPLA.

Impaired autophagy: a link between neurodegenerative diseases and progressive myoclonus epilepsies.

In recent years, research into the molecular bases of neurodegenerative diseases has progressed, and therapies have been developed to combat the causative agents. Based on the observation that progressive myoclonus epilepsies (PMEs) and neurodegenerative diseases share common features of neurodegeneration, we propose that the two pathologies share common underlying molecular characteristics. It is well documented that autophagy is overloaded or impaired in neurodegenerative conditions, and it is also impaired in some PMEs, the clearest example being EPM2 (Lafora disease). Although more research into this connection is warranted, we propose that existing therapies for PMEs could be augmented with similar drugs as those used for neurodegenerative diseases.

Progressive myoclonic epilepsies: review of clinical, molecular and therapeutic aspects.

The progressive myoclonic epilepsies (PME) are a rare group of inherited neurodegenerative diseases with debilitating evolution, resistance to treatment and poor prognosis. However, advances in molecular genetics have enabled better understanding of the pathogenesis of these diseases, bringing hope for improved treatment options in the future. This manuscript is an overview of the clinical and molecular findings in patients with PME. Furthermore, it describes therapeutic approaches that are currently recommended in the literature.

[Case report of dentatorubral pallidoluysian atrophy in a patient on a ketogenic diet].

We report a 16-year-old woman with dentatorubral pallidoluysian atrophy (DRPLA) on a ketogenic diet. She was scheduled for dental treatment under general anesthesia. She was diagnosed as having DRPLA at the age of 10. Medication included clonazepam, chlordiazepoxide, ethosuximide, sodium valproate and piracetam. She had been placed on a ketogenic diet at the age of 15, and seizures decreased. Preoperative laboratory data were normal except for serum cholesterol level (228 mg x dl(-1)) and blood ketones (1.8 mmol x l(-1)) with the use of Medisense Xtra. General anesthesia was induced using thiamylal, vecuronium, sevoflurane and maintained with sevoflurane and nitrous oxide-oxygen. Fluid infusion employed Solita T1 (glucose content of 2.6%: total 150 ml). Operation and general anesthesia presented no problems. We continued to infuse Solita T1 (total 350ml) for about 4 hours postoperatively. Ketogenic diet and additional medicine were started after 5 hours postoperatively. We measured perioperative and postoperative BS and blood ketones with the use of Medisense Xtra. She recovered from anesthesia without any significant complication.

Chronic high-frequency deep brain stimulation of the STN/SNr for progressive myoclonic epilepsy.

Chronic high-frequency deep brain stimulation (DBS) may also be effective in patients with refractory epilepsy. A possible benefit has been postulated because of the connections that exist between the subthalamic nucleus (STN) and the superior colliculus. Individual case reports and pilot studies of successful DBS in different types of epilepsy have already been presented. Here, the case of a 39-year-old male with progressive myoclonic epilepsy is reported who remained severely impaired despite VNS and combined antiepileptic drug therapy. Bilateral DBS electrodes were implanted into the STN, followed by implantation of a neurostimulation system under general anesthesia. Adjustment and testing of the remaining contacts was done over several months postoperatively. Bilateral monopolar DBS reduced the intensity and frequency of seizures by 50%. The patient has so far been followed for 12 months. This is the first report of positive effects of DBS in progressive myoclonic epilepsy in an adult patient. A subsequent prospective study will have to investigate whether the STN or other target nuclei are most suitable for DBS in these types of epilepsy and which long-term results can be obtained.