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Purpose: The purpose of this study was to describe the clinical features, management, outcomes, and diagnostic pitfalls in a large series of patients with ocular neuromyotonia., Design: Retrospective cohort., Methods: Patients diagnosed with ocular neuromyotonia from January 1, 2004, through January 1, 2023, seen at one of the 3 Mayo Clinic sites in Rochester, MN, Scottsdale, AZ, and Jacksonville, FL, comprised the study population. We ascertained patients with ocular neuromyotonia through a search using the medical records database. Only patients with an observed episode of ocular neuromyotonia were included and the medical records were reviewed. The main outcome measures were clinical features and outcomes of patients with ocular neuromyotonia., Results: Forty-two patients who were diagnosed with ocular neuromyotonia were included. The median age was 58 years (range, 16-80 years). A history of cranial radiation therapy was present in 39 patients (93%). The sixth cranial nerve was involved in 31 patients (74%). Bilateral disease was found in 2 patients (5%). The median time from onset of diplopia to diagnosis was 8 months (range, 1 month-25 years), with a high rate of initial misdiagnosis in 52%. Twenty of 42 patients (48%) were treated with oral medication, of whom 95% had significant improvement or resolution of symptoms., Conclusion: Prior cranial irradiation is the most common cause for ocular neuromyotonia, affecting the sixth cranial nerve most often. Although delayed and initial misdiagnosis is common, most patients show improved symptoms on medical treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: The current review will cover the clinical presentation, causes, epidemiology, differential diagnoses, workup, and treatment of ocular neuromyotonia (ONM) in detail., Recent Findings: While ONM largely remains a unilateral eye movement disease affecting adults with a history of sellar radiation, recent case reports highlight an expansion of this presentation to include bilateral, pediatric, and congenital cases., Summary: ONM is a rare but recognizable ocular motility disorder involving sustained contraction of the extraocular muscle, commonly resulting in intermittent diplopia. Diagnosis of ONM relies upon a thorough history and clinical exam, with particular attention to history of radiotherapy and eccentric gaze testing. Treatment with carbamazepine remains first-line therapy, although other membrane stabilizing agents and surgical interventions can be effective., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare disease entity linked to mutations in the histidine triad nucleotide binding protein 1 (HINT1) gene. The diagnosis and treatment of ARAN-NM are challenging. There have been few reports of ARAN-NM in East Asia., Methods: A 15-year-old Chinese ARAN-NM patient developed muscle weakness, cramps and atrophy in the lower limbs at the age of 12. Electromyography (EMG) showed motor axonal degeneration and neuromyotonic discharges. Whole exome sequencing was performed. Bioinformatic methods and computational 3D structure modeling were used to analyze the identified variant. According to literature review, carbamazepine was prescribed to the patient., Results: Genetic tests identified a homozygous mutation c.356G > T (p.R119L) in the HINT1 gene, which has never been reported before according to HGMD database. Several bioinformatic approaches predicted the variant was damaging. Computational 3D modeling indicated the variant changed the structure of HINT1 protein. Notably, we demonstrated the positive effects of carbamazepine in treating muscle stiffness and cramps of ARAN-NM., Discussion: 22 variants have been reported in the HINT1 gene, and we identified a novel c.356G > T (p.R119L) variant. Our study expands the genetic spectrum of ARAN-NM. Moreover, large clinical trials are required to further demonstrate the role of carbamazepine in ARAN-NM., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: HINT1 mutations cause an autosomal recessive axonal neuropathy with neuromyotonia. This is a first case report of coexistence of myasthenia gravis (MG) and HINT1-related motor axonal neuropathy without neuromyotonia., Case Presentation: A 32-year-old woman presented with recurrent ptosis for 8 years, diplopia for 2 years and limb weakness for 1 year and a half. Neostigmine test, elevated AChR antibody level and positive repetitive nerve stimulation supported the diagnosis of MG. Electroneurography (ENG) and electromyography (EMG) examinations revealed a motor axonal neuropathy without neuromyotonic or myokymic discharges. Next-generation sequencing and Sanger sequencing were performed to identify the gene responsible for suspected hereditary neuropathy. Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at c.278G>T (p. G93V). The patient was treated with pyridostigmine, oral prednisolone and azathioprine. Her ptosis and diplopia have significantly improved at 6-month follow-up., Conclusions: Concurrence of MG and hereditary motor axonal neuropathy without neuromyotonia is quite rare. Detection of ptosis with or without ophthalmoplegia, distribution of limb weakness, and reflex can help in recognizing the combination of MG and peripheral neuropathy. Early diagnosis is important for initial treatment and prognosis. The novel homozygous variant c.278G>T(p.G93V) contributes to the pathogenic variants spectrum of the HINT1 gene., (© 2022. The Author(s).)

Background: Hemifacial spasm is diagnosed on a clinical base, with certain atypical features alerting the physician for mimics., Phenomenology Shown: Hemifacial neuromyotonia/myokymia characterized by tonic hemifacial contraction followed by multifocal undulating hemifacial twitches., Educational Value: These features are a red flag for (post-irradiation) facial neuromyotonia/myokymia which generally responds well to low dose carbamazepine., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

Objective: To analyze the clinical characteristics and outcomes of patients diagnosed with acquired neuromyotonia and who were treated with tacrolimus., Methods: A single center, retrospective study was performed on patients with acquired meuromyotonia whose treatment included tacrolimus. The clinical information, antibody tests, and electromyography results were reviewed. The Numeric Rating Scale for pain and modified Rankin scale were used to quantify outcomes., Results: This study included four patients who presented with fasciculation or myokymia in their limbs. Electromyography suggested peripheral nerve hyperexcitability. Autoantibodies including contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated protein 1 (LGl1) or IgLON5 antibody were detected in three patients, and another patient had Sjogren's syndrome. Initial treatment included membrane-stabilizing drugs and/or corticosteroids. Tacrolimus was administered at a dose of 3 mg once daily to all patients. All patients showed clinical improvement after the treatment. No recurrence was observed after gradual tapering or discontinuation of therapy during follow-up., Conclusions: Tacrolimus may be a therapeutic option for acquired neuromyotonia. Further studies on tacrolimus in larger patient cohort should be performed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Autoantibodies to leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein like-2 (CASPR2) are associated with clinically distinctive syndromes that are highly immunotherapy responsive, such as limbic encephalitis, faciobrachial dystonic seizures, Morvan's syndrome and neuromyotonia. These autoantibodies target surface-exposed domains of LGI1 or CASPR2, and appear to be directly pathogenic. In contrast, voltage-gated potassium channel (VGKC) antibodies that lack LGI1 or CASPR2 reactivities ('double-negative') are common in healthy controls and have no consistent associations with distinct syndromes. These antibodies target intracellular epitopes and lack pathogenic potential. Moreover, the clinically important LGI1 and CASPR2 antibodies comprise only ~15% of VGKC-positive results, meaning that most VGKC-antibody positive results mislead rather than help. Further, initial VGKC testing misses some cases that have LGI1 and CASPR2 antibodies. These collective observations confirm that laboratories should stop testing for VGKC antibodies and instead, test only for LGI1 and CASPR2 antibodies. This change in practice will lead to significant patient benefit., Competing Interests: Competing interests: SRI and PW are coinventors on ‘A Diagnostic Strategy to improve specificity of CASPR2 antibody detection.’ Ref. JA94536P. SRI is a co-applicant and receives royalties on patent application WO/2010/046716 (U.K. patent no. PCT/GB2009/051441) entitled ‘Neurological Autoimmune Disorders’. The patent has been licensed for the development of assays for LGI1 and other VGKC-complex antibodies. He has received honoraria from UCB, MedImmune, ADC Therapeutics and MedLink Neurology, and research funding from UCB, ONO and CSL Pharmaceuticals. PW is a named inventor on patents for antibody assays and has received royalties. He has received honoraria from Biogen Idec, Mereo BioPharma, Retrogenix and UBC; travel grants from the Guthy-Jackson Charitable Foundation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Ocular neuromyotonia is a rare disorder of the oculomotor nerves caused by chronic damage to the nerve, usually secondary to previous irradiation or longstanding compression. We present the case of a 40-year-old man who had received proton beam therapy for a right cavernous sinus chondrosarcoma 15 years earlier. He developed intermittent episodes of self-limited horizontal diplopia, which occurred over the course of 1 year. At its peak, the deviation reached 20 Δ in primary gaze and 25 Δ in right gaze. Signs included right upper lid retraction and right medial rectus muscle absence of relaxation after sustained left gaze, with mild deficit of elevation and depression but no pupillary involvement. Full recovery occurred after he closed his eyes. Ocular neuromyotonia of the right oculomotor nerve was diagnosed after recurrence of primary disease relapse was ruled out. Symptoms remitted completely under oxcarbazepine., (Copyright © 2020 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Introduction: Isaacs's syndrome (IS), is a rare neurological disorder, characterized by sustained muscular activity, fasciculations, cramps, myokymia, excessive sweating, and occasional elevation of creatine phosphokinase (CPK) enzyme., Aim: To report our experience in patients with IS and urinary manifestations, describing clinical findings, test's results, and response to treatment. Methods An observational, retrospective analysis of patients with IS and urinary manifestations treated at German Hospital of Buenos Aires between 2001 and 2011 was done. Diagnosis was performed with clinical examination and electromyography (EMG) of external sphincter of the anus and/or urethra. Demographic, clinical, and treatment variables were analyzed. International Prognostic Scoring System (IPSS) at diagnosis and follow up was made., Results: Eleven IS patients were recruited, of whom 8 (72.72%) were females with a mean age 47.87 years (DS ± 13.95) and presented associated lower tract urinary symptoms (LUTS). Six of them (75%) had voiding and 2 (25%) filling symptoms. Urodynamic and electromyographic findings reproduced symptomatology in all patients. Patients with voiding symptomatology were treated with combination of alpha-blockers with benzodiazepines; membrane stabilizings agents; antiepileptics; neurotropic; corticoids; posterior tibial nerve stimulation and botulinum toxin, achieving improvement in 4/6. The two patients with storage symptoms were treated in first instance with anticholinergic drugs, one of which did not respond completely was added oral pentosansulfate and electrical stimulation, reversing the symptomatology. Four patients had associated pathologies: Hashimoto's thyroiditis; Sjögren's syndrome; dysautonomia, and myasthenia gravis., Conclusions: In our experience, IS urinary manifestations are common and usually has a good evolution with adequate treatment for each patient., (© 2017 Wiley Periodicals, Inc.)

This is a case report of Isaacs' syndrome in dermatomyositis. The patient presented with proximal muscle weakness, rash, elevated muscle enzyme, myopathic electromyograph and typical muscle biopsy. Ultimately he developed typical symptoms of Isaacs' syndrome which is an autoimmune channelopathy from voltage gated potassium channel antibody (anti-VGKC) leading to dysfunction of axonal discharge at neuromuscular junctions. It shares some similar characteristics with dermatomyositis such as autoimmunity, its association with malignancy and the response to treatment., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Isaacs syndrome is a form of peripheral nerve hyperexcitability, characterized by spontaneous muscle twitching and stiffness. Some patients are reported to be positive for CASPR2 antibody that may be one of the pathogenic autoantibodies in Isaacs syndrome. We reported a series of three patients with Isaacs syndrome, including their clinical features, electrophysiologic findings, laboratory parameters and therapeutic responses. All the three patients were positive for CASPR2 antibodies examined on transfected human embryonic kidney 293 cells by indirect immunofluorescence method. One patient had invasive thymoma. Symptomatic treatment was not sufficient for them, while immunotherapies including corticosteroids, double filtration plasmapheresis and rituximab provided favorable outcomes. The titers of CASPR2 antibody decreased after immune modulating therapy in parallel to clinical improvements in two patients., (Copyright © 2017. Published by Elsevier Ltd.)

Importance: Autoantibodies against contactin-associated protein-like 2 (CASPR2) are observed in several neurological syndromes, including neuromyotonia (NMT), Morvan syndrome (MoS), and limbic encephalitis., Objective: To characterize the clinical and biological presentations of patients with anti-CASPR2 antibodies in the cerebrospinal fluid (CSF)., Design, Setting, and Participants: We conducted a retrospective cohort analysis of 18 patients who had anti-CASPR2 antibodies in their CSF between March 2009 and November 2015 at the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques in Lyon, France. Additionally, we analyzed 15 patients who were diagnosed as having NMT or MoS as a comparative group., Main Outcomes and Measures: Clinical presentations, anti-CASPR2 antibodies specificities, brain magnetic resonance imaging, and CSF analyses, cancer prevalence, and evolution., Results: In this cohort of 18 patients with anti-CASPR2 antibodies in their CSF, 17 (94.4%) were male and had a median (range) age of 64.5 (53-75) years; in the second group, 9 of 15 patients (60.0%) with NMT or MoS were male and had a median (range) age of 51 years (1 month to 75 years). Only 3 patients (16.7%) in this cohort had a previous or concomitant history of cancer (prostate, hematological, or thyroid), whereas 9 patients (60.0%) in the second group had a malignant thymoma. Symptoms of limbic encephalitis were observed in all patients, including temporal lobe seizures in 16 patients (88.9%) and memory disorders in 17 patients (94.4%) from the cohort. Extralimbic signs were also evident in 12 of 18 patients (66.7%), including cerebellar ataxia in 6 patients (33.3%). Only 2 patients (11.1%) from the cohort were diagnosed as having NMT. Brain magnetic resonance imaging displayed T2-weighted temporolimbic abnormalities in 14 of 15 patients (93.3%) in the second group. Cerebrospinal fluid analysis was abnormal in 9 of 12 patients (75.0%). For 16 of 18 patients (88.9%), follow-up was performed for at least a 6-month period (median [range], 34 [11-114] months). Of these, 15 (93.8%) improved and 6 (37.5%) relapsed. In all patients in this cohort, IgG4 autoantibodies were detected in the CSF. Anti-CASPR2 antibodies in the CSF targeted the laminin G1 and discoidin domains of CASPR2 in all patients. Importantly, anti-CASPR2 antibodies were detected in the serum but not in the CSF of all patients with NMT or MoS., Conclusions and Relevance: In this cohort study, anti-CASPR2 antibodies in the CSF are associated with a subtype of autoimmune encephalitis with prominent limbic involvement and seizures that is rarely associated with cancer. Conversely, patients with NMT and MoS have anti-CASPR2 antibodies only in the serum but not in the CSF and frequently present with a malignant thymoma. The anti-CASPR2 antibodies found in these patients targeted the discoidin and laminin G1 domains of CASPR2 and always included IgG4 autoantibodies.

CASE DESCRIPTION A 5-year-old castrated male Maltese was evaluated for intermittent clinical signs of muscle cramping and abnormal movements of the skin of the right pelvic limb at the site where an infiltrative lipoma had twice been resected. After the second surgery, the surgical field was treated with radiation therapy (RT). The clinical signs developed approximately 14 months after completion of RT. CLINICAL FINDINGS When clinical signs were present, the right biceps femoris and semitendinosus muscles in the area that received RT were firm and had frequently visible contractions, and the skin overlying those muscles had episodic vermiform movements. Electromyography of those muscles revealed abnormal spontaneous activity with characteristics consistent with myokymic discharges and neuromyotonia. Magnetic resonance imaging of the affected leg revealed no evidence of tumor regrowth. The myokymia and neuromyotonia were considered secondary to RT. TREATMENT AND OUTCOME 4 U of Clostridium botulinum toxin type A (BoNT-A) neurotoxin complex was injected into the affected muscles at each of 6 sites twice during a 24-hour period (ie, 48 U of BoNT-A were administered). The clinical signs were completely resolved 10 days after BoNT-A treatment and were controlled by repeated BoNT-A treatment every 3 to 4 months for > 1 year. CLINICAL RELEVANCE To our knowledge, this is the first report of myokymia and neuromyotonia secondary to RT in a dog. For the dog of this report, injection of BoNT-A into the affected muscles was safe, effective, and easy to perform.

Introduction: Peripheral nerve hyperexcitability disorders are characterized by constant muscle fiber activity. Acquired neuromyotonia manifests clinically in cramps, fasciculations, and stiffness. In Morvan's syndrome the signs of peripheral nerve hyperexcitability are accompanied by autonomic symptoms, sensory abnormalities, and brain disorders., Case Presentation: A 70-year-old Caucasian man developed, in the course of 3 months, polyneuropathy with unpleasant dysesthesia of lower extremities and gradually increasing fasciculations, muscle stiffness and fatigue. Subsequently, he developed a prominent insomnia with increasing psychological changes and then he attempted a suicide. Electromyography confirmed a sensory-motor polyneuropathy of a demyelinating type. The findings included fasciculations as well as myokymia, doublets and multiplets, high frequency discharges, and afterdischarges, following motor nerve stimulation. No auto-antibodies were found either in his blood or cerebrospinal fluid. Magnetic resonance imaging of his brain showed small, unspecific, probably postischemic changes. A diagnosis of Morvan's syndrome was confirmed; immunoglobulin (2g/kg body weight) was applied intravenously, and, subsequently, carbamazepine 2 × 200 mg, venlafaxine 150 mg, and mirtazapine each night were prescribed. His sleep improved, suicidal tendencies stopped, less fasciculations occurred, and muscle hypertonia also improved. Hyperexcitation also partially remitted including the electromyography finding., Conclusions: We described here the case of a patient with Morvan's syndrome; his case is rare because of severe psychical changes with a suicide attempt, short admission to a psychiatric ward, prominent electromyographic changes, and because antibodies were not detected. After therapy with immunoglobulins followed by corticosteroids with sodium channel blocker, his motor, autonomic, psychical signs and symptoms, and electromyography changes substantially improved.

A 44-year-old man with a bilateral hand tremor suffered from a decline in concentration and abnormal vision for several months. He also complained of easily falling down because of muscle stiffness and cramps in his lower limbs. On admission, he demonstrated lower limb stiffness, muscle cramps, diplopia, hyperhidrosis, left upper limb ataxia and dysesthesia in all limbs. Laboratory examination showed a marked elevation in his serum creatine kinase level (26,890 U/l), and needle electromyography demonstrated myokymic discharges in the muscles of his lower extremities. Isaacs' syndrome was diagnosed based on a positive voltage-gated potassium channel antibody titer of 1,007 pM. Administration of an anticonvulsant (phenytoin, 200 mg/day) did not resolve his symptoms; however, high-dose intravenous methylprednisolone therapy (1 g/day for 3 days) resulted in marked clinical improvement. This case suggests that high-dose intravenous methylprednisolone therapy for Isaacs' syndrome might be as effective as other immunosuppressive therapies such as plasma exchange or intravenous immunoglobulin.

Objective: Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) and acquired neuromyotonia (aNMT), the role of these antibodies in disease pathophysiology has not been elucidated. The present study investigated axonal function across the spectrum of VGKC-complex antibody associated disorders., Methods: Peripheral axonal excitability studies were undertaken in a cohort of patients with LE (N=6) and aNMT (N=11), compared to healthy controls (HC; N=20)., Results: Patients with LE demonstrated prominent abnormalities in peripheral axonal excitability during the acute phase, with reduced threshold change in threshold electrotonus (depolarizing 10-20 LE: 58.5±3.1%; HC: 67.4±0.9%; P<.005; S2 accommodation LE: 17.2±1.4%; HC: 22.2±0.6%; P≤.005) and in recovery cycle parameters (superexcitability LE: -16.0±0.9%; HC: -23.4±1.1%; P<.01; subexcitability LE: 8.5±1.2%; HC: 13.8±0.7%; P≤.005). The pattern of change in LE patients was dissimilar to the effects of antiepileptic medications, suggesting that these factors did not underlie excitability changes in LE. Normalization of excitability parameters was associated with recovery (TEd peak correlation coefficient=.868; P=.002), suggesting that peripheral excitability studies may provide a marker associated with clinical improvement. In contrast, patients with aNMT demonstrated no significant changes at the site of stimulation., Conclusions: The lack of prominent excitability abnormalities in patients with aNMT likely reflects a distal origin of hyperexcitability, expected to be at the motor nerve terminal, while the prominent changes observed in patients with LE likely represent a complex disturbance at the level of the axonal membrane, combined with electrolyte imbalance and adaptive change., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Isaacs' syndrome is a rare neuromuscular disorder of continuous muscle fibre activity resulting from peripheral nerve hyperexcitability. Symptoms commonly include myokymia (muscle twitching at rest), pseudomyotonia (delayed muscle relaxation), muscle cramps and stiffness. It is caused by voltage-gated potassium channel dysfunction and may be inherited or acquired. Treatment commonly includes anticonvulsants, immunosuppressive therapy and plasma exchange. To date only two cases of Isaacs' syndrome in pregnancy have been reported. We present a case of maternal Isaacs' along with a review of the literature. There are few reports of Isaacs' syndrome in pregnancy, but all are associated with favourable outcomes. Given the autosomal dominant inheritance pattern, genetic counselling of the gravida is recommended. Anticonvulsant may have to be used in pregnancy, and given the potential teratogenicity with several of these agents; preference should be given to newer drugs such as lamotrigine., (2014 BMJ Publishing Group Ltd.)

Ocular neuromyotonia (ONM) is a rare disorder of ocular mal-alignment in which painless, transient spontaneous or gaze-induced abnormal deviation of the eye manifests as episodic diplopia. With only a few cases reported in the literature, ONM mostly follows months to years after cranial irradiation for sellar or suprasellar lesions. Here we present two patients with this rare ocular condition, secondary to brainstem demyelination, the association of which is hitherto unreported in the literature. Both patients were 15-year-old girls who presented to us with episodic forced-eye deviation with diplopia. Examination during these attacks revealed ONM involving the superior rectus and medial rectus in the first and second patient, respectively. There was clinical evidence of intrinsic brainstem involvement with downbeat nystagmus and skew deviation in one patient without any other cerebellar or long tract signs. MRI showed evidence of demyelination involving the brainstem in both, with CSF showing positive immunological markers and with positive aquaporin-4 antibody in one patient. Both patients responded remarkably to immunomodulatory therapy and are asymptomatic at follow-up. That ONM can occur with brainstem demyelination has not been reported in the literature. This association may help in explaining the pathophysiology of ONM as secondary to segmental demyelination., (© The Author(s) 2014.)

Background: To report an unusual case of cyclic oculomotor nerve paresis and spasms, which developed 5 years following brain radiotherapy for cerebellar medulloblastoma., Methods: Observational case report., Results: The cyclic oculomotor nerve paresis and spasms resolved in our patient when treated with carbamazepine. However, because of severe photophobia and tearing, carbamazepine had to be discontinued leading to reappearance of the eye movement disorder., Conclusion: Cyclic oculomotor nerve paresis and spasms appear to be a delayed effect of radiotherapy and respond to carbamazepine therapy. It may be a rare form of ocular neuromyotonia.

Ocular neuromyotonia is an episodic involuntary contraction of one or more of the extraocular muscles resulting from spontaneous neural discharges of the oculomotor nerve. It is characterized by symptomatic diplopia for the duration of the contraction and occurs either spontaneously or after a sustained eccentric gaze. Although the mechanism of ocular neuromyotonia is not fully understood, primary or secondary aberrant regeneration and consequent ephaptic transmission generally are held to be involved. We report the case of a patient with right oculomotor neuromyotonia accompanied by lid ptosis on abduction of the left eye who was successfully treated with oral carbamazepine., (Copyright © 2013 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

A 27-year-old woman noticed diplopia when gazing left and paresthesia of the left face and headache of the left side for 8 months. Abduction and supraduction of the left eye were moderately restricted. Hypoesthesia of the face innervated by the ophthalmic branch of the left trigeminal nerve was detected. Visual disturbance due to optic neuropathy developed 5 months later. MRI with gadolinium revealed a mass lesion extending from the left cavernous sinus to the orbital apex. Ocular neuromyotonia and corresponding diplopia were induced by sustained right gaze. Such episodes occurred almost every day on awaking in the morning. Prednisolone (60 mg/day) was given and the headache and visual disturbance ameliorated in two days. The diplopia disappeared in 4 days. The patient remains free from these symptoms after 6 months. This is the first report of ocular neuromyotonia associated with Tolosa-Hunt syndrome.

We describe a patient presenting with a combination of muscle fasciculations, paresthesias, hyperhidrosis, as well as insomnia, agitation and confusion. He went on to develop psychosis and respiratory failure requiring intensive care. Electromyography confirmed the presence of neuromyotonia and CSF showed mild pleocytosis. Routine testing for voltage-gated potassium channel complex (VGKC-complex) antibodies was highly positive, confirming the clinical diagnosis of Morvan's syndrome. The patient improved after treatment with intravenous immunoglobulin and methylprednisolone. Further investigation of the antigenic targets using immunohistochemistry and cell-based assays revealed that he had autoantibodies targeting Lgi1, Caspr2 and Contactin-2/Tag-1, all proteins known to be complexed with VGKC in peripheral nerves and CNS. This is the first case of Morvan's syndrome from Cyprus and illustrates the clinical features as well as the emerging complexity of antigenic targets involved in the pathogenesis., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The clinical and clinicopathological characteristics, treatment and outcome of vermicular muscle contractions (myokymia) and generalized muscle stiffness (neuromyotonia) in 37 Jack Russell terriers were evaluated retrospectively. Thirty dogs were affected by both disorders, whereas seven were presented with myokymia and never developed neuromyotonia. Clinical signs started at the mean age of 8 months. Except for signs of myokymia and neuromyotonia, clinical and neurological examination was normal in all dogs. Thirty dogs demonstrated typical signs of hereditary ataxia. Changes in serum chemistry included increased creatine kinase, aspartate aminotransferase and alanine aminotransferase concentrations. Electromyographic abnormalities, especially in muscles showing macroscopically visible myokymia, consisted of semirhythmic bursts of doublet, triplet, or multiplet discharges of a single motor unit. The amplitudes varied between 80 μV and 1 mV and occurred with an interburst frequency between 10 and 40 Hz and an intraburst frequency between 150 and 280 Hz. Most dogs were treated with a sodium channel blocker with variable results. Seven dogs died (most likely because of hyperthermia) or were euthanased during a neuromyotonic attack; 15 dogs were euthanased due to worsening of clinical signs, or lack of or no long-lasting effect of medication, and three were euthanased for unknown or unrelated reasons. Nine dogs were lost to follow-up and three were still alive 5-10.5 years after the start of clinical signs. In conclusion, young Jack Russell terriers with myokymia and neuromyotonia should undergo a complete blood and electrophysiological examination. Long-term prognosis is not favourable., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Thymoma-associated paraneoplastic diseases include myasthenia gravis (MG), neuromyotonia (NMT), Morvan's syndrome, and several non-neurological paraneoplastic manifestations, including glomerulonephritis. Paraneoplastic syndromes often precede the occurrence of thymoma, but cases occurring after thymomectomy, which sometimes herald the recurrence of thymoma, have also been described. We report on a patient who developed MG after thymomectomy for a malignant thymoma. After MG remission, NMT and Morvan's syndrome occurred, which heralded a mediastinic recurrence, as demonstrated only by autopsy findings.

Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

Background: Important progress has been made in our understanding of the autoimmune neuromuscular transmission (NMT) disorders; myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia (Isaacs' syndrome)., Methods: To prepare consensus guidelines for the treatment of the autoimmune NMT disorders, references retrieved from MEDLINE, EMBASE and the Cochrane Library were considered and statements prepared and agreed on by disease experts., Conclusions: Anticholinesterase drugs should be given first in the management of MG, but with some caution in patients with MuSK antibodies (good practice point). Plasma exchange is recommended in severe cases to induce remission and in preparation for surgery (recommendation level B). IvIg and plasma exchange are effective for the treatment of MG exacerbations (recommendation level A). For patients with non-thymomatous MG, thymectomy is recommended as an option to increase the probability of remission or improvement (recommendation level B). Once thymoma is diagnosed, thymectomy is indicated irrespective of MG severity (recommendation level A). Oral corticosteroids are first choice drugs when immunosuppressive drugs are necessary (good practice point). When long-term immunosuppression is necessary, azathioprine is recommended to allow tapering the steroids to the lowest possible dose whilst maintaining azathioprine (recommendation level A). 3,4-Diaminopyridine is recommended as symptomatic treatment and IvIG has a positive short-term effect in LEMS (good practice point). Neuromyotonia patients should be treated with an antiepileptic drug that reduces peripheral nerve hyperexcitability (good practice point). For paraneoplastic LEMS and neuromyotonia optimal treatment of the underlying tumour is essential (good practice point). Immunosuppressive treatment of LEMS and neuromyotonia should be similar to MG (good practice point).

A 52-year-old man presented with hyperhydrosis, painful pseudomyotonia and gait disturbance. The condition was diagnosed as Isaacs' syndrome on the basis of characteristic findings noted on an electromyogram. Carbamazepine treatment was only partially and transiently effective. Intravenous immunoglobulin therapy was effective. The basal metabolic rate (BMR) was serially monitored using an automatic integrated system for breath analysis. Serial monitoring of the BMR facilitates therapeutic evaluation in an Isaacs' syndrome patient with chronic fluctuating symptoms.

Ocular neuromyotonia (ONM) is a rare neurogenic disorder of ocular motility. The affected patients complain of recurrent transient diplopia secondary to a sudden, painless deviation of one eye. This deviation occurs in the direction of action of an extraocular muscle, which is being stimulated at high frequency. ONM is usually seen after radiation therapy, but may also be caused by compression of the affected cranial nerve. The pathophysiology of ONM is incompletely understood, potential mechanisms include 1) ephaptic transmission along the affected nerve, 2) disturbances of potassium channels in the neuronal cell membrane, and 3) central neural re-organisation. The diagnosis of ONM is made based on clinical findings and can be supported by electrophysiological characteristics. Neuroimaging with attention to the affected cranial nerve should be obtained in order to exclude a compressive cause. Therapy of ONM with carbamazepine is usually effective., ((c) Georg Thieme Verlag KG Stuttgart-New York.)

Acquired neuromyotonia, or Isaacs' syndrome, has been described in combination with a variety of other autoimmune disorders; however there has never been a report of seropositive Isaacs' syndrome in a patient with a history of Guillain-Barré syndrome (GBS). Both conditions involve antibody-mediated autoimmune effects on the peripheral nervous system, although the clinical manifestations are quite different. We present a man who experienced an episode of GBS at the age of 21 and subsequently developed Isaacs' syndrome at the age of 24 which was positive for anti-voltage-gated potassium channel (VGKC) antibodies. When treated with intravenous immunoglobulins (IVIg) he developed an eczematous rash that differed markedly in pattern and duration from the usual presentation for this IVIg reaction.

A 15-year-old girl, previously treated with radiation, chemotherapy, and surgery for a posterior fossa medulloblastoma and parasellar metastasis at age 8, presented with a 10-month history of episodic horizontal diplopia. She was diagnosed with ocular neuromyotonia and successfully treated with oral carbamazepine. Given the strong association between peripheral neuromyotonia and the presence of autoimmune antivoltage-gated potassium channels, the patient's blood was tested and found negative for these autoantibodies. This is the first time this has been verified in a person with ocular neuromyotonia.

Case Report: We describe a 58-year-old man, without history of radiation therapy, who presented with transient episodic diplopia following sustained lateral gaze lasting around 30-50 seconds. He developed a large angle exotropia of the left eye that gradually returned to normal after 50 seconds. Between episodes he was asymptomatic. Partial resolution of his symptoms was obtained after treatment with carbamazepine., Discussion: Neuromyotonia must be considered when evaluating a patient with intermittent diplopia.

A 71-year-old man had recurrent spells of transient diplopia for about four years. Vertical diplopia were induced by downward gaze, mostly to the lower-left, and lasted for about ten seconds. During the spells, limitation in elevation of the left eye was observed. Other neurological examinations were normal except for a minor paresis of the left trochlear nerve revealed only by detailed neuroophthalmological examination. The patient was treated with carbamazepine 200 mg daily, which abolished the spells. He was diagnosed to have idiopathic ocular neuromyotonia of the left third or fourth nerve. Ocular neuromyotonia is a rare disturbance of ocular motility, characterized by paroxysmal monocular involuntary spasms of one or more extraocular muscles supplied by the third, fourth or sixth cranial nerves. Past studies showed that most patients had radiation therapy to the parasellar or sellar regions. Slight injury to the peripheral nerves such as one caused by radiation may have an important role in the development of ocular neuromyotonia. Furthermore, patients with ocular neuromyotonia often benefit from the use of carbamazepine, a membrane-stabilizing agent. We report a case of idiopathic ocular neuromyotonia without history of damage to the cranial nerves. It is the first report in Japan.

We describe a patient with the diagnoses of acquired neuromyotonia, cutaneous lupus erythematosus and alopecia areata, occurring many years after a thymectomy for myasthenia gravis associated with a thymoma. We review the current literature on autoimmune conditions associated with myasthenia gravis and thymectomy. To our knowledge, this combination of multiple autoimmune conditions has not been reported previously.

A patient with Isaacs' syndrome had generalized muscle spasms, twitching, and progressive muscle stiffness for 21 years. Electrodiagnostic study showed continuous spontaneous motor-unit activity and the presence of M-wave afterdischarges. He responded dramatically to treatment with carbamazepine but developed a drug rash; his treatment was changed to gabapentin with continued improvement. Subsequent nerve conduction studies showed decreased amplitude and later an absence of M-wave afterdischarges. Gabapentin thus appears to be an effective treatment for Isaacs' syndrome.

Acquired neuromyotonia (Isaacs' syndrome) is a rare disorder characterized by hyperexcitability of peripheral motor nerves. The cardinal features consist of myokymia, pseudomyotonia and contracture of hands and feet. The diagnosis of Isaacs' syndrome is based on the clinical features and classic electromyographic findings. Serum antibodies against Voltage-Gated Potassium Channels (VGKCs) are detected in some cases. The authors report a 17 year-old man presented with difficulty in walking, writing and respiratory discomfort for 7 months. His body weight had decreased from 120 to 70 kilograms during that period. Physical examination was remarkable for profound sweating. Muscles were in a state of contraction, action myotonia without percussion myotonia, myokymia and carpopedal spasm. Electromyography showed classical neuromyotonic and myokymic discharges. The investigations for conditions associated with Isaacs' syndrome were unrevealing. VGKCs antibody were not performed. Treatment with carbamazepine resulted in substantial improvement of the symptoms within 7 days.

Background: Ocular neuromyotonia is a rare ocular motility disorder characterized by involuntary contractions of one or several ocular motor muscles. In this report a typical case is presented., Patient and Methods: A 61-year-old female patient was referred with persistent diplopia despite previous surgical treatment for right 6 (th) nerve palsy. The palsy was caused by a meningeoma of the petrous bone, which had been incompletely resected. Subsequently, the patient had received radiation therapy. Strabismological and neuroophthalmological examinations were performed. The results coincide with data collected in our department from three other patients with ocular neuromyotonia (2 cranial nerve VI, 1 cranial nerve IV), over the past three years., Results: The patient showed orthophoria at distance (5 m) and an exophoria of 6 degrees at near vision. The abduction and adduction of the right eye were restricted to 40 degrees and 35 degrees , respectively. After several seconds of eccentric gaze to the right, the right eye remained in an abducted position of approximately 25 degrees . The gaze to the left led to a retraction instead of an adduction of the right eye. The spasm of the lateral rectus muscle resolved after some seconds, returning to the aforementioned right eye motility. Under oral treatment with carbamazepine, initially 200 mg, later increasing to 400 mg per day, the symptoms improved significantly, did not resolve entirely, however., Conclusions: These typical findings permit the diagnosis of ocular neuromyotonia. The characteristic symptoms of ocular neuromyotonia and the typical history of a previous intracranial tumor, treated neurosurgically with adjuvant radiotherapy, lead to the hypothesis that ephaptic transmission in the cranial nerve is the underlying pathophysiological mechanism in the development of ocular neuromyotonia. Hereby, efferent impulses from non-twitch motoneurons could activate neighbouring axons, and spread both peripherally and centrally. Beside other mechanisms discussed, an involvement of proprioceptive elements and their reafference is also a possible cause for the prolonged muscle contraction.