Basket to Purkinje Cell Inhibitory Ephaptic Coupling Is Abolished in Episodic Ataxia Type 1.

Dominantly inherited missense mutations of the KCNA1 gene, which encodes the KV1.1 potassium channel subunit, cause Episodic Ataxia type 1 (EA1). Although the cerebellar incoordination is thought to arise from abnormal Purkinje cell output, the underlying functional deficit remains unclear. Here we examine synaptic and non-synaptic inhibition of Purkinje cells by cerebellar basket cells in an adult mouse model of EA1. The synaptic function of basket cell terminals was unaffected, despite their intense enrichment for KV1.1-containing channels. In turn, the phase response curve quantifying the influence of basket cell input on Purkine cell output was maintained. However, ultra-fast non-synaptic ephaptic coupling, which occurs in the cerebellar 'pinceau' formation surrounding the axon initial segment of Purkinje cells, was profoundly reduced in EA1 mice in comparison with their wild type littermates. The altered temporal profile of basket cell inhibition of Purkinje cells underlines the importance of Kv1.1 channels for this form of signalling, and may contribute to the clinical phenotype of EA1.

Demystifying the spontaneous phenomena of motor hyperexcitability.

Possessing a discrete functional repertoire, the anterior horn cell can be in one of two electrophysiological states: on or off. Usually under tight regulatory control by the central nervous system, a hierarchical network of these specialist neurons ensures muscular strength is coordinated, gradated and adaptable. However, spontaneous activation of these cells and their axons can result in abnormal muscular twitching. The muscular twitch is the common building block of several distinct clinical patterns, namely fasciculation, myokymia and neuromyotonia. When attempting to distinguish these entities electromyographically, their unique temporal and morphological profiles must be appreciated. Detection and quantification of burst duration, firing frequency, multiplet patterns and amplitude are informative. A common feature is their persistence during sleep. In this review, we explain the accepted terminology used to describe the spontaneous phenomena of motor hyperexcitability, highlighting potential pitfalls amidst a bemusing and complex collection of overlapping terms. We outline the relevance of these findings within the context of disease, principally amyotrophic lateral sclerosis, Isaacs syndrome and Morvan syndrome. In addition, we highlight the use of high-density surface electromyography, suggesting that more widespread use of this non-invasive technique is likely to provide an enhanced understanding of these motor hyperexcitability syndromes.

Quantitative analysis of myokymic discharges in radiation versus nonradiation cases.

INTRODUCTION: Myokymic discharges are classically associated with nerve injury from prior radiation but may occur in other neuromuscular disorders. Using quantitative analysis we aimed to identify the spectrum of conditions in which myokymic discharges are present and determine if there are electrophysiological features that distinguish postradiation from nonradiation causes of myokymia. METHODS: We reviewed the clinical history of all patients examined in our electromyography labs with myokymic discharges recorded from June 2017 to February 2020. Quantitative analysis of each myokymic discharge was performed using a custom MATLAB script, assessing features such as burst frequency, spikes per burst, and burst regularity. RESULTS: Eighty-eight distinct myokymic discharges (70 patients) were analyzed: 51 postradiation recordings from 35 patients and 37 recordings from 35 nonradiation patients. The diagnostic spectrum of nonradiation cases was diverse, with common causes being median neuropathy (n = 8), cervical (n = 7), and lumbar (n = 5) radiculopathy, and motor neuron disease (n = 5). On quantitative analysis, postradiation myokymia had an increased burst-to-silence ratio (median, 0.29; nonradiation, 0.08) and greater peak number (median, 15; nonradiation, 7). Except for one patient with hereditary peripheral nerve hyperexcitability, all patients who had two or more muscles demonstrating myokymic discharges belonged to postradiation group. CONCLUSIONS: Myokymic discharges can be seen in diverse neuromuscular conditions; most common in our cohort was chronic median neuropathy. Postradiation myokymia appears to have distinguishing morphological features when quantitatively analyzed compared with nonradiation cases.

Utility of stimulus induced after discharges in the evaluation of peripheral nerve hyperexcitability: Old wine in a new bottle?

Limited literature is available on stimulus induced after discharges (SIAD) in patients with peripheral nerve hyperexcitability (PNH). The aim of the study was to examine the diagnostic utility of SIAD in the diagnosis and monitoring of primary PNH disorders. In this retrospective study, we studied 26 patients who were admitted with a diagnosis of primary PNH to the department of Neurology from January 2013 to April 2019. Their clinical profile, immunological characteristics were extracted from the database and nerve conduction studies were relooked for the presence of SIAD. 76% of patients in the primary PNH cohort had SIAD with 90% of them being voltage-gated potassium channel complex antibody positive; predominantly against contactin-associated protein-2 antigen and rest being paraneoplastic. There was also resolution of SIAD following treatment indicating reversible hyperexcitability. SIAD is a sensitive marker for Primary PNH syndrome with monitoring and diagnostic implications.

One Bite, Two Patients: Disparate Clinical Courses Following Simultaneous Crotalus oreganus abyssus Envenomation.

A number of crotaline species have been associated with neurotoxic envenomation in North America. One clinical sign that can occur is myokymia: fine, involuntary, wave-like muscle movements occurring at regular intervals. We report an unusual scenario in which a single snakebite resulted in simultaneous envenomation of 2 patients. Both developed myokymia, with 1 having respiratory compromise. One patient also developed a hypersensitivity reaction to antivenom. Envenomation by the Grand Canyon rattlesnake, Crotalus oreganus abyssus, can produce significant neurotoxicity and resultant respiratory compromise. Antivenom may be helpful but can produce hypersensitivity reactions.

Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features.

OBJECTIVE: Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms. METHODS: A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied. RESULTS: Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/-; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/-; 11/56, 19.6%). LE/- and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10-10). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p<0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%). INTERPRETATION: Symptoms' distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.

Neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous Kv1.1 N255D mutation with normal serum magnesium levels.

Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the KCNA1 gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in KCNA1, previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.

Superior oblique myokymia.

Superior oblique myokymia (SOM) is a rare condition of unclear etiology. We discuss the history, etiology, clinical features, differential diagnoses, management, and prognosis of SOM. We conducted a meta-analysis of all 116 cases published since SOM was first described in 1906. The age at examination was 17-72 years (mean: 42 years.) There was a right-sided preponderance in 61% of cases (P < 0.02) that was statistically significant in females (63%, P < 0.04) but not in males (59%, P = 0.18). The pathophysiology of SOM may be neurovascular compression and/or ephaptic transmission. Although various pharmacological and surgical approaches to SOM treatment have been proposed, the rarity of the condition has made it impossible to conduct clinical trials evaluating the safety and efficacy of these approaches. Recently, topical beta blockers have managed SOM symptoms in a number of cases, including the first case treated with levobunolol. Systemic medications, strabismus surgery, and neurosurgery have been used to control symptoms, with strabismus surgery carrying a moderate risk of postoperative diplopia in downgaze. Although there is no established treatment for SOM, we encourage clinicians to attempt topical levobunolol therapy before considering systemic therapy or surgery.

Clinical and Oculographic Analysis of Inferior Oblique Myokymia.

A 63-year-old man experienced transient vertical oscillopsia lasting several seconds for 2 months. Examination disclosed paroxysmal excyclotorsion of the right eye, spontaneously or triggered by adduction. Eye movements using 3D video-oculography showed intermittent, monocular phasic movements which consisted of excyclotorsion of the right eye mixed with a small amount of supraduction and abduction, and a tonic movement with excyclotorsion and slight elevation. Orbital and brain MRI was unremarkable. Administration of oxcarbazepine markedly decreased the severity and frequency of the episodes. The oculographic characteristics in our patient may indicate that inferior oblique myokymia may be attributed to aberrant, spontaneous discharges in the inferior oblique motor unit.

Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.

BACKGROUND: Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients. METHODS: A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function. RESULTS: Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation. CONCLUSIONS: Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society.

Action potential broadening in a presynaptic channelopathy.

Brain development and interictal function are unaffected in many paroxysmal neurological channelopathies, possibly explained by homoeostatic plasticity of synaptic transmission. Episodic ataxia type 1 is caused by missense mutations of the potassium channel Kv1.1, which is abundantly expressed in the terminals of cerebellar basket cells. Presynaptic action potentials of small inhibitory terminals have not been characterized, and it is not known whether developmental plasticity compensates for the effects of Kv1.1 dysfunction. Here we use visually targeted patch-clamp recordings from basket cell terminals of mice harbouring an ataxia-associated mutation and their wild-type littermates. Presynaptic spikes are followed by a pronounced afterdepolarization, and are broadened by pharmacological blockade of Kv1.1 or by a dominant ataxia-associated mutation. Somatic recordings fail to detect such changes. Spike broadening leads to increased Ca(2+) influx and GABA release, and decreased spontaneous Purkinje cell firing. We find no evidence for developmental compensation for inherited Kv1.1 dysfunction.

Distinctive role of KV1.1 subunit in the biology and functions of low threshold K(+) channels with implications for neurological disease.

The diversity of pore-forming subunits of KV1 channels (KV1.1-KV1.8) affords their physiological versatility and predicts a range of functional impairments resulting from genetic aberrations. Curiously, identified so far human neurological conditions associated with dysfunctions of KV1 channels have been linked exclusively to mutations in the KCNA1 gene encoding for the KV1.1 subunit. The absence of phenotypes related to irregularities in other subunits, including the prevalent KV1.2 subunit of neurons is highly perplexing given that deletion of the corresponding kcna2 gene in mouse models precipitates symptoms reminiscent to those of KV1.1 knockouts. Herein, we critically evaluate the molecular and biophysical characteristics of the KV1.1 protein in comparison with others and discuss their role in the greater penetrance of KCNA1 mutations in humans leading to the neurological signs of episodic ataxia type 1 (EA1). Future research and interpretation of emerging data should afford new insights towards a better understanding of the role of KV1.1 in integrative mechanisms of neurons and synaptic functions under normal and disease conditions.

Morvan syndrome: after scrotal sac drainage and chemical instillation in hydrocele.

We have described the occurrence of Morvan syndrome (MoS) after scrotal tap and injection of sclerosing agent for the treatment of hydrocele in 5 male. The mean age was 43.2 years, and the gap between the procedure and development of clinical features suggestive of MoS was 1.5-3 months. The neurophysiology studies demonstrated hyper excitability of peripheral nerves. In addition, autonomic dysfunction, severe insomnia, and neuropsychiatric features were observed. Significant VGKC-complex/CASPR-2 antibodies titer were present in all cases. Symptoms resolved spontaneously within 6 months of onset.

Clinical, laboratory and electrophysiological features of Morvan's fibrillary chorea.

Morvan's Fibrillary Chorea (MFC) is a rare autoimmune disorder causally associated with auto-antibodies directed at the voltage-gated potassium channel (VGKC-Abs). It classically presents with sleep disturbances, neuromyotonia and dysautonomia. We aimed to systematically characterise the features of MFC by describing a patient and reviewing published literature. Case notes of 27 patients with MFC (one from our clinic and 26 from the literature) were reviewed and clinical data were extracted and analysed. We found that MFC mainly affects men (96%) and runs a subacute course over months. Neoplasia (56%), VGKC-Abs positivity (79%) and autoimmunity (41%) are frequent associations. Myokymia, insomnia and hyperhidrosis were almost universally described. Other autonomic features were present in 63% with the most common being cardiovascular and bowel disturbances. Clinical, radiological or electroencephalographical features of limbic encephalitis were present in 19% of patients. Outcome was fair with an overall recovery rate of 78%. All patients with malignancies underwent surgery. Immunotherapies including corticosteroids, intravenous immunoglobulins and plasma exchange were instituted in 22 patients and 19 (86%) responded. Of all symptomatic treatments tried, carbamazepine, phenytoin, sodium valproate, levetiracetam and niaprazine were found to be effective. The broad clinical spectrum of VGKC-Abs diseases can make early recognition of MFC difficult. Myokymia, insomnia and hyperhidrosis are invariably present. There may be abnormalities on cerebrospinal fluid testing and VGKC-Abs can occasionally be absent. Early initiation of immunotherapies and malignancy screening are important to prevent adverse outcomes in a condition that generally responds favourably to treatment.

Agrypnia excitata.

Agrypnia (from the Greek: to chase sleep) excitata (AE) is a syndrome characterized by loss of sleep and permanent motor and autonomic hyperactivation (excitata). Disruption of the sleep-wake rhythm consists in the disappearance of spindle-delta activities, and the persistence of stage 1 non-rapid eye movement (NREM) sleep. Rapid eye movement (REM) sleep persists but fails to stabilize, appearing in short recurrent episodes, isolated, or mixed with stage 1 NREM sleep. Diurnal and nocturnal motor, autonomic and hormonal overactivity is the second hallmark of AE. Of particular interest is the finding that norepinephrine secretion is extremely elevated at all hours of the day and night whereas the nocturnal melatonin peak is lacking. Oneiric stupor is probably an exclusive sign of AE and consists in the recurrence of stereotyped gestures mimicking simple daily life activities. Agrypnia excitata aptly defines 3 different clinical conditions, fatal familial insomnia (FFI), an autosomal dominant prion disease, Morvan syndrome (MS), an autoimmune encephalitis, and delirium tremens (DT), the alcohol withdrawal syndrome. Agrypnia excitata is due to an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from cortico-limbic inhibitory control. This pathogenetic mechanism is visceral thalamus degeneration in FI, whereas it may depend on autoantibodies blocking voltage-gated potassium (VGK) channels within the limbic system in MS, and in the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in DT.