Ocular Neuromyotonia: Clinical Features, Diagnosis, and Outcomes.

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.

Ocular neuromyotonia: a review of diagnosis and treatment.

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.

A novel mutation in HINT1 gene causes autosomal recessive axonal neuropathy with neuromyotonia, effective treatment with carbamazepine and review of the literature.

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.

Myasthenia gravis coexisting with HINT1-related motor axonal neuropathy without neuromyotonia: a case report.

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.

Post-Irradiation Facial Neuromyotonia/Myokymia: A Hemifacial Spasm Mimic.

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.

An Unusual Case of Muscle Twitching: Its LGI1.

A 50-year-old male, presented with a two-months history of ascending paresthesias, with continuous twitchings over the body, associated with insomnia. His electromyography (EMG) revealed neuromyotonia and was diagnosed as a case of peripheral nerve hyperexcitability (PNH) syndrome due to Leucin-rich glioma-inactivated 1 (LGI1) antibody. He showed significant improvement with intravenous immunoglobulin and carbamazepine.

Tacrolimus as a therapeutic option in patients with acquired neuromyotonia.

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.

Ocular neuromyotonia of the right third cranial nerve.

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 20Δ in primary gaze and 25Δ 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.

Stop testing for autoantibodies to the VGKC-complex: only request LGI1 and CASPR2.

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.

Urinary manifestations in Isaacs's syndrome. Our experience in 8 cases.

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.

Isaacs syndrome with CASPR2 antibody: A series of three cases.

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.

Isaacs' syndrome in a patient with dermatomyositis: case report and review of the literature.

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.

Characterization of a Subtype of Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures.

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.

Use of botulinum toxin type A for the treatment of radiation therapy-induced myokymia and neuromyotonia in a dog.

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.

Neuromyotonia with polyneuropathy, prominent psychoorganic syndrome, insomnia, and suicidal behavior without antibodies: a case report.

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.