Cortical Myoclonus Research Articles

Episodic tremors representing cortical myoclonus are characteristic in Angelman syndrome due to UBE3A mutations.

Neurological manifestations including psychomotor developmental delay and epilepsy in patients with Angelman syndrome caused by ubiquitin protein ligase E3A (UBE3A) mutations has been considered similar but is relatively milder than that in patients with deletion-type Angelman syndrome. This makes the diagnosis of the former subgroup often difficult. We here characterized epilepsy, specifically the types of tremulous movement, in 4 patients (age, 3-38years) with Angelman syndrome caused by UBE3A mutations. Ictal electroencephalography was used to record episodic tremors in all study patients. Jerk-locked averaging was performed using digital electroencephalography and surface electromyogram data from patients who were monitored for 24h. All patients had tremors in the limbs, head, and trunk, which resulted in 2 patients falling backward. These tremors lasted several seconds, and could emerge in clusters for hours in older patients. In addition, the tremors coincided with 7-8Hz rhythmic activity with a frontocentral predominance, diffuse spike-wave bursts, or no apparent change on electroencephalography. In 2 patients, these tremors were confirmed as cortical myoclonus using jerk-locked averaging. The other seizure types were isolated generalized myoclonus and tonic seizures. None of the patients experienced atypical absence seizures. Levetiracetam therapy was effective in controlling the myoclonic events in 2 of the 3 patients. Semirhythmic myoclonus is common in patients with Angelman syndrome caused by UBE3A mutations, and such myoclonic events are often life disabling. The preserved expression of gamma-aminobutyric acid type A receptor subunit genes located proximal to UBE3A might explain the low prevalence of absence seizures in this population.

The role of the cerebellum in the pathogenesis of cortical myoclonus

The putative involvement of the cerebellum in the pathogenesis of cortical myoclonic syndromes has been long hypothesized, as neuropathological changes in patients with cortical myoclonus have most commonly been found in the cerebellum rather than in the suspected culprit, the primary somatosensory cortex. A model of increased cortical excitability due to loss of cerebellar inhibitory control via cerebello-thalamo-cortical connections has been proposed, but evidence remains equivocal. Here, we explore this hypothesis by examining syndromes that present with cortical myoclonus and ataxia. We first describe common clinical characteristics and underlying neuropathology. We critically view information on cerebellar physiology with regard to motorcortical output and compare findings between hypothesized and reported neurophysiological changes in conditions with cortical myoclonus and ataxia. We synthesize knowledge and focus on neurochemical changes in these conditions. Finally, we propose that the combination of alterations in inhibitory neurotransmission and the presence of cerebellar pathology are important elements in the pathogenesis of cortical myoclonus.

EEG–EMG information flow in movement-activated myoclonus in patients with Unverricht–Lundborg disease

ObjectiveWe aimed the present study at estimating the appropriateness of generalised partial directed coherence (GPDC) in detecting myoclonus-related EEG–EMG connectivity pattern and the information flow between sensorimotor cortex and muscles in patients with typical cortical myoclonus due to Unverricht–Lundborg disease. MethodsIn 13 patients with cortical myoclonus, we analysed the EEG and EMG signals recorded during simple voluntary motor activities using GPDC, a frequency domain linear index of connectivity estimated from a multivariate autoregressive model. The results were compared with those obtained in 12 healthy controls. ResultsThe GPDC revealed a peculiar pattern characterising patients with cortical myoclonus with respect to healthy subjects. Patients consistently had significant more robust outflow toward activated muscle originating from cortical areas exceeding the motor one. Moreover, they also had a more robust EMG outflow directed toward a wider cortical area contralateral to activated hand and sometimes also toward the ipsilateral central region. ConclusionsOur results clearly indicate the recruitment of extensive cortical network in afferent and efferent EEG–EMG relationships. SignificanceGiven that robust cortical outflow can be considered as the pathogenic mechanism sustaining myoclonus, the perturbation from the EMG outflow could lead to the involvement of large cortical area implied in sensorimotor integration and became capable of generating and maintaining the jerk recurrence.

Cortical myoclonus during IV thrombolysis for ischemic stroke.

We describe a patient with an acute middle cerebral artery ischemic stroke developing subtle involuntary movements of the paretic upper limb with cortical origin during rt-PA perfusion. Despite the multiple potential pathophysiological mechanisms for the relationship between thrombolysis and epileptic activity, seizures during this procedure are scarcely reported. Our hypothesis is that subtle and transient clinical seizures, like those described in our patient, may not be detected or are misdiagnosed as nonepileptic involuntary movements. We aimed to draw attention to the recognition challenge of this paroxysmal motor behavior, highlighting this clinical and neurophysiological identification using video recording and back-average analysis of the EEG.

The α2B-adrenergic receptor is mutant in cortical myoclonus and epilepsy.

Autosomal dominant cortical myoclonus and epilepsy (ADCME) is characterized by distal, fairly rhythmic myoclonus and epilepsy with variable severity. We have previously mapped the disease locus on chromosome 2p11.1-q12.2 by genome-wide linkage analysis. Additional pedigrees affected by similar forms of epilepsy have been associated with chromosomes 8q, 5p, and 3q, but none of the causing genes has been identified. We aim to identify the mutant gene responsible for this form of epilepsy. Genes included in the ADCME critical region were directly sequenced. Coimmunoprecipitation, immunofluorescent, and electrophysiologic approaches to transfected human cells have been utilized for testing the functional significance of the identified mutation. Here we show that mutation in the α2 -adrenergic receptor subtype B (α2B -AR) is associated with ADCME by identifying a novel in-frame insertion/deletion in 2 Italian families. The mutation alters several conserved residues of the third intracellular loop, hampering neither the α2B -AR plasma membrane localization nor the arrestin-mediated internalization capacity, but altering the binding with the scaffolding protein spinophilin upon neurotransmitter activation. Spinophilin, in turn, regulates interaction of G protein coupled receptors with regulator of G protein signaling proteins. Accordingly, the mutant α2B -AR increases the epinephrine-stimulated calcium signaling. The identified mutation is responsible for ADCME, as the loss of α2B -AR/spinophilin interaction causes a gain of function effect. This work implicates for the first time the α-adrenergic system in human epilepsy and opens new ways of understanding the molecular pathway of epileptogenesis, widening the spectrum of possible therapeutic targets.

Ramsay hunt syndrome: Clinical characterization of progressive myoclonus ataxia caused by GOSR2 mutation

Ramsay Hunt syndrome (progressive myoclonus ataxia) is a descriptive diagnosis characterized by myoclonus, ataxia, and infrequent seizures. Often the etiology cannot be determined. Recently, a mutation in the GOSR2 gene (c.430G>T, p.Gly144Trp) was reported in 6 patients with childhood-onset progressive ataxia and myoclonus. We evaluated 5 patients with cortical myoclonus, ataxia, and areflexia. All 5 patients had the same homozygous mutation in GOSR2. Here we present their clinical and neurophysiological data. Our patients (aged 7-26 years) all originated from the northern Netherlands and showed a remarkably homogeneous phenotype. Myoclonus and ataxia were relentlessly progressive over the years. Electromyography revealed signs of sensory neuronopathy or anterior horn cell involvement, or both, in all patients with absent reflexes. Based on the presented phenotype, we would advise movement disorder specialists to consider mutation analysis of GOSR2 in patients with Ramsay Hunt syndrome, especially when they also have areflexia.

HYPEREXCITABLE BRAIN AND REFRACTORY COELIAC DISEASE: A NEW SYNDROME

Hyperexcitable brain and refractory coeliac disease: a new syndrome Gluten related disorders (GRD) is the newly proposed term to encompass a spectrum of immune mediated diseases triggered by gluten ingestion....

Myoclonus

Myoclonus remains a challenging movement phenotype to characterize, evaluate, and treat. A systematic assessment of the temporal sequence, phenomenology, and distribution of movements can assist in the rational approach to diagnosis and management. Cortical forms of myoclonus are increasingly recognized as primarily cerebellar disorders. A syndrome of orthostatic myoclonus has been recognized by electrophysiology in patients with neurodegenerative disorders, mainly in Alzheimer disease, accounting for impairments in gait and balance previously mischaracterized as normal pressure hydrocephalus or orthostatic tremor. Tyrosine hydroxylase deficiency and Silver-Russell syndrome (uniparental disomy of chromosome 7) have been established as two novel causes of the myoclonus-dystonia syndrome. Mutations in the glycine receptor (GlyR) α1-subunit gene (GLRA1) explain the major expression of hyperekplexia, an inherited excessive startle disorder, butnewly identified mutations in GlyR β-subunit (GLRB) and glycine transporter 2 (GlyT2) genes (SLC6A5) account for "minor" forms of this disorder manifested as excessive startle and hypnic jerks. The entity previously known as palatal myoclonus has been reclassified as palatal tremor in recognition of its clinical and electromyographic features and no longer enters the differential diagnosis of myoclonic disorders. Increasing documentation of psychogenic features in patients previously characterized as having propriospinal myoclonus has cast doubts on the existence of this distinctive disorder. Myoclonus can be a prominent manifestation of a wide range of disorders. Electrophysiologic testing aids in distinguishing myoclonus from other mimics and classifying them according to cortical, subcortical, or spinal origin, which assists the choice of treatment. Despite the lack of randomized clinical trials, levetiracetam appears most effective in patients with cortical myoclonus, whereas clonazepam remains the only first-line therapeutic option in subcortical and spinal myoclonus.

Cortical action myoclonus due to cortical laminar necrosis

Cortical action myoclonus due to cortical laminar necrosis

Treatment of myoclonus.

Myoclonus creates significant disability for patients. This symptom or sign can have many different etiologies, presentations, and pathophysiological mechanisms. A thorough evaluation for the myoclonus etiology is critical for developing a treatment strategy. The best etiological classification scheme is a modified version from that proposed by Marsden et al. in 1982. Clinical neurophysiology, as assessed by electromyography and electroencephalography, can be used to classify the pathophysiology of the myoclonus using a neurophysiology classification scheme. If the etiology of the myoclonus cannot be reversed or treated, then symptomatic treatment of the myoclonus itself may be warranted. Unfortunately, there are few controlled studies for myoclonus treatments. The treatment strategy for the myoclonus is best derived from the neurophysiology classification scheme categories: 1) cortical, 2) cortical-subcortical, 3) subcortical-nonsegmental, 4) segmental, and 5) peripheral. A cortical physiology classification is most common. Levetiracetam is suggested as first-line treatment for cortical myoclonus, but valproic acid and clonazepam are commonly used. Cortical-subcortical myoclonus is the physiology demonstrated by myoclonic seizures, such as in primary epileptic myoclonus (e.g., juvenile myoclonic epilepsy). Valproic acid has demonstrated efficacy in such epileptic syndromes with other medications providing an adjunctive role. Clonazepam is used for subcortical-nonsegmental myoclonus, but other treatments, depending on the syndrome, have been used for this physiological type of myoclonus. Segmental myoclonus is difficult to treat, but clonazepam and botulinum toxin are used. Botulinum toxin is used for focal examples of peripheral myoclonus. Myoclonus treatment is commonly not effective and/or limited by side effects.

Clinical neurophysiology of psychogenic movement disorders: How to diagnose psychogenic tremor and myoclonus

Tremor and myoclonus are very common manifestations of psychogenic movement disorders (PMD). In this context, recording of movement disorders aims to provide objective criteria for a positive diagnosis of PMD, independently of the psychological situation. Neurophysiological observations are therefore considered to have a huge impact both on diagnosis and on therapeutic approaches. A specific recording strategy should be employed whenever the medical history or clinical clues raise the eventuality of a PMD. Polymyography coupled to accelerometry is used to demonstrate the major electrophysiological criteria of psychogenic tremor, namely spontaneous variability of tremor frequency and frequency entrainment induced by contralateral rhythmic tasks. Other features, such as paradoxical increase of tremor amplitude with mass loading, co-activation preceding tremor onset and alteration of voluntary contralateral motor performances when tremor is present, are also of interest. The clinical presentation of psychogenic myoclonus is extremely rich and polymorphous and can mimic virtually all forms of cortical, subcortical or spinal myoclonus. Focal, multifocal, axial or generalized jerks can occur. Psychogenic jerks can be sporadic or repetitive, rhythmic or arrhythmic, spontaneous or stimulus-induced. All of these parameters are crucial to determine an individualized neurophysiological strategy. Polymyography is critical to identify a ballistic pattern or a discordant or non-reproducible temporo-spatial organisation of the jerks, but has usually to be completed by other potentially decisive approaches. Reflex psychogenic myoclonus for example displays stimulus-response delays that are too long and variable. Spontaneous psychogenic jerks may be also preceded by a pre-movement potential, detectable by jerk-locked-back-averaging methods.

The ACMSD gene, involved in tryptophan metabolism, is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism

Familial cortical myoclonic tremor and epilepsy is a phenotypically and genetically heterogeneous autosomal dominant disorder characterized by the presence of cortical myoclonic tremor and epilepsy that is often accompanied by additional neurological features. Despite the numerous familial studies performed and the number of loci identified, there is no gene associated with this syndrome. It is expected that through the application of novel genomic technologies, such as whole exome sequencing and whole genome sequencing, a substantial number of novel genes will come to light in the coming years. In this study, we describe the identification of two disease-segregating mutations in a large family featuring cortical myoclonic tremor with epilepsy and parkinsonism. Due to the previous association of ACMSD deficiency with the development of epileptic seizures, we concluded that the identified nonsense mutation in the ACMSD gene, which encodes for a critical enzyme of the kynurenine pathway of the tryptophan metabolism, is the disease-segregating mutation most likely to be responsible for the phenotype described in our family. This finding not only reveals the identification of the first gene associated with familial cortical myoclonic tremor and epilepsy but also discloses the kynurenine pathway as a potential therapeutic target for the treatment of this devastating syndrome. ACMSD is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism. ACMSD mutation contributes to the development of FCMTE QA accumulation is likely to play an important role in the pathogenesis of FCMTE. The kynurenine pathway as a potential drug target for the treatment of epilepsy.

Reply: Autosomal recessive epilepsy associated with contactin 2 mutation is different from familial cortical tremor, myoclonus and epilepsy

Sir, We would like to thank Striano et al. (2013) for their remarks on our paper and would like to comment on some of the mentioned points. We agree that it is important to pay close attention to the correct classification of new syndromes such as familial cortical myoclonic tremor with epilepsy (FCMTE) as any inconsistencies will hamper the discovery of the underlying pathophysiology. Summing up, FCMTE is at present the recommended heading of a heterogeneous syndrome characterized by an autosomal dominant inheritance, cortical myoclonus and seizures. Different families exhibiting these symptoms to a various extent have previously been named FCMTE, ADCME, FAME or BAFME in the literature (Striano et al. , 2010). The …

Autosomal recessive epilepsy associated with contactin 2 mutation is different from familial cortical tremor, myoclonus and epilepsy

ARTICLE Sir, In a recent interesting paper, Stogmann et al. (2013) described a consanguineous Egyptian family with autosomal recessively inherited condition featuring focal epilepsy, neuropsychiatric features, borderline cognitive level, and myoclonus. Exome sequencing in this family revealed a homozygous deletion (c.503_503delG) leading to a frameshift in the coding region of CNTN2 and segregating in the five affected family members. The gene CNTN2 encodes for contactin 2, a glycosylphosphatidylinositol-anchored neuronal membrane protein, necessary to maintain voltage-gated potassium channels at the juxtaparanodal region. Given the severity of the mutation and the function of the protein, the authors considered this mutation as the most likely cause of the clinical phenotype in this family (Stogmann et al. , 2013). However, we would recommend caution when describing this family as affected by ‘familial …

Improvement in Cortical Myoclonus in a Patient with VIM Deep Brain Stimulation for Essential Tremor (P07.202)

Improvement in Cortical Myoclonus in a Patient with VIM Deep Brain Stimulation for Essential Tremor (P07.202)

ミオクローヌスの病態生理

Myoclonus is one of the common movement disorders in clinical practice, and its differential diagnosis is important. Usually, myoclonus can be classified into cortical, subcortical, brain stem, spinal and peripheral, based on its pathogenesis. Especially, cortical myoclonus is closely associated with epilepsy (myoclonic epilepsy) and has been studied extensively so far. Here, we will review the pathogenesis of cortical myoclonus from the viewpoint of clinical neurophysiology.

Functional neuroimages of cortical myoclonus altered by levetiracetam in a patient with sialidosis

Levetiracetam can suppress sialidosis-related myoclonus but its effects on cerebral metabolism warrant elucidation. In this report, fluorodeoxyglucose-positron emission tomography was conducted before and after levetiracetam in a sialidosis patient. By subtracting the drug “off” from “on” signals, regions of enhanced metabolism were shown to be allocated mostly in the bilateral fronto-temporal regions whereas regions of reduced metabolism were distributed mainly in the occipital areas. Imaging changes suggest that the effects of levetiracetam may be different in different brain regions. The drug may also elicit fronto-temporal inhibitory impulses to suppress the vigorous myoclonus in sialidosis.

Epileptic seizures, movement disorders, and breathing disturbances in Rett syndrome: Diagnostic relevance of video-polygraphy

Epileptic seizures, movement disorders and breathing disturbances may be observed in Rett syndrome, and correct diagnosis is mandatory for the management. We evaluated the usefulness of video-polygraphy in the differential diagnosis between epileptic and non-epileptic paroxysmal events in eight patients with Rett syndrome. Based on video analysis, myoclonic seizures were usually misdiagnosed as movement disorders and stereotypies; the events identified by parents as generalized tonic-clonic seizures included episodes of motor activity and breathing abnormality. Myoclonic seizures aggravated by inappropriate treatment were evident in four patients; hyperventilation and apnea during wakefulness were present in all patients, while central sleep apneas were present in one patient; sinus tachycardia and cardiac arrhythmias emerged in six patients; cortical myoclonus was disclosed in five patients. In Rett syndrome, video-polygraphy is essential in characterizing the clinical features of paroxysmal events, determining autonomic dysfunctions, documenting myoclonic motor phenomena, and evaluating the responses to the treatment of epilepsy.

Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Editorial

In 1990, Ikeda et al. described an action and postural tremor that originated from the cerebral cortex and was thus termed “cortical tremor.” Due to its peculiar electrophysiological features, this involuntary movement was considered to be a variant of cortical reflex myoclonus [1]. Cortical tremor was then recognized to occur in Japanese families often in association with tonic– clonic seizures, and this observation led to the definition of an autosomal dominant trait named Benign Adult Familial Myoclonic Epilepsy (BAFME), which was mapped on chromosome 8q [2, 3]. Over the past decade, several European kindreds with overlapping clinical features have been reported under different acronyms, such as autosomal dominant cortical myoclonus and epilepsy and familial cortical myoclonic tremor with epilepsy (FCMTE) [4–7]. The available literature now suggests a worldwide distribution (more than 60 families have been reported) and genetic heterogeneity, yet with evidence that 2p11.1-q12.2 is a major locus for the kindreds of European origin [8]. Most affected individuals experience tonic–clonic seizures, which begin later than “tremor.” Seizures are generally rare (about five to ten episodes during life) and are not preceded by any warning. However, in some cases, they may be heralded by progressively increasing myoclonic jerks. Precipitating factors such as sleep deprivation, emotional stress, pain, and photic stimulation are often reported [3, 7]. In some cases, severe myoclonus can alter the quality of life. Although the epilepsy is usually benign, in rare cases, patients may present with drug-resistant complex partial seizures and focal EEG abnormalities [4]. Patients usually have normal cognition; however, mildto-moderate mental retardation may be present in some cases, especially in a more advanced age [6, 9]. Both the severity of seizures and the use of antiepileptic drugs could contribute to cognitive impairment. Cerebellar symptoms are usually mild: postural ataxia, downbeat nystagmus, impaired smooth pursuit. MRI may demonstrate a cerebellar atrophy. A pseudo-parkinsonism has also been reported. FCTME is usually diagnosed between the ages of 20 and 45 years. Myoclonus and EEG abnormalities progressively worsen from early to late adulthood. Clonazepam and sodium valproate are usually effective therapies. Thus far, the pathophysiological and biochemical bases of this condition remain poorly understood. Mutations in genes encoding ion channels have been excluded by several authors [3–7]. Patients typically show giant somatosensory evoked potentials and strong corticoand intermuscular coherence in the 8to 30-Hz range, thus suggesting an underlying cortical hyperexcitability, which can be the result of a decreased cortical inhibition by the cerebellum via its cerebello-thalamocortical projections [6]. Indeed, rare post-mortem histological studies have shown evidence of cerebellar pathology reminiscent of SCA type 6 [3, 5], and although P. Striano (*) Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Largo Gaslini 5, Pediatric Neurology and Muscular Diseases Unit, Padiglione 16, IV Piano, 16147 Genoa, Italy e-mail: pstriano@email.it

Familial cortical myoclonus with a mutation in NOL3.

Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype. A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation. We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro. We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.