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Neuromyotonia is continuous peripheral nerve hyper-excitability manifesting in muscle twitching at rest (myokymia), inducible cramps and impaired muscle relaxation, and characterized by EMG findings of spontaneous single motor unit discharges (with doublet, triplet, or multiplet morphology). The disorder may be genetic, acquired, and often in the acquired cases autoimmune. This chapter focuses on autoimmune acquired causes. Autoimmune associations include mainly contactin-associated protein-like 2 (CASPR2) antibody-associated disease (previously termed as VGKC or voltage-gated potassium channel antibody-associated neuromyotonia) (van Sonderen et al., 2016, p. 2), leucine-rich glioma-inactivated 1 (LGI1) antibody disease, the Guillain-Barré syndrome, NMDAR encephalitis (Varley et al., 2019), and IgLON5 (Gaig et al., 2021) disease. Nonimmune associations include radiation-induced plexopathy. An association with myasthenia gravis and other autoimmune disorders, response to plasma exchange (Newsom-Davis and Mills, 1993) and physiologically induced changes in mice injected with patient-derived immunoglobulins led to the discovery of autoantibodies to juxtaparanodal proteins complexed with potassium channels (Shillito et al., 1995). The target of the antibodies is most commonly the CASPR2 protein. The disorder may be paraneoplastic, and a search for and treatment of an underlying tumor is a necessary step. In cases in which there is evidence for an immune cause, then immune suppression, with an emerging role for B cell-depleting therapies, is associated with a good clinical outcome. In parallel, sodium channel blocking drugs remain effective symptomatic therapies.

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Ocular neuromyotonia (ONM) is an infrequent disorder characterised by recurrent episodes of binocular diplopia caused by paroxysmal contraction of one or several extraocular muscles innervated by the same cranial nerve. It can be triggered spontaneously or caused by prolonged contraction of specific eye muscle(s) and is usually related to a local intracranial radiotherapy antecedent. We report the case of a 46-year-old woman who developed intermittent episodes of binocular diplopia eight years after radiotherapy for a nasopharyngeal carcinoma. After a complete neuro-ophthalmic assessment we diagnosed the case as an abducens nerve neuromyotonia. Although it is infrequent, radiotherapy to the nasopharynx is a possible cause of ONM, due to the proximity to the base of the skull and extraocular motor nerve pathways, especially that of the VI cranial nerve, as is the case presented in this article, about a patient whose history is a nasopharyngeal carcinoma treated with local radiotherapy.

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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.

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RATIONALE: Isaacs syndrome is peripheral nerve hyperexcitability characterized by spontaneous muscle twitching and rigidity and is often associated with antibodies to CASPR2 (contactin-associated protein-like 2) and LGI1 (leucine-rich glioma-inactivated 1). But it is a rare Isaacs syndrome with LGI1 and CASPR2 antibodies after human papilloma virus (HPV) vaccination. PATIENT CONCERNS: The patient presented with limb pain, muscle twitching, numbness in the extremities and around the mouth, and hand rash after the second dose of HPV vaccine. DIAGNOSES: Laboratory tests indicated positive for LGI1 antibodies, CASPR2 antibodies, anti-phosphatidylserine/prothrombin antibodies and anti-sulfatide antibodies, TPO and ATG, IgG E. The patient post-M-wave discharges were seen on F-wave examination of the posterior tibial nerve in both lower limbs. We diagnosis the patient with Isaacs syndrome. INTERVENTIONS: Treatment with the intravenous immunoglobulin (IVIG) treatment, after 5 days of IVIG therapy (0.4 mg/kg/day), the rash on the hand disappeared, the pain was relieved, the sleep improved. OUTCOMES: After 3 Courses of treatment, the clinical manifestations of the nervous system disappeared and negative responsibility antibodies profile. LESSONS: This case report suggests a possible adverse reaction to HPV vaccination, which could be treated by attempting several periods of IVIG therapy. The underlying immune mechanisms need to be studied with further extensive data.

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OBJECTIVES: Isaac syndrome (IS) is a condition characterized by peripheral nerve hyperexcitability caused by voltage-gated potassium channel (VGKC)-complex antibodies. Muscle twitching, stiffness, hypertrophy, and dysautonomic characteristics, such as hyperhidrosis, are common manifestations. The syndrome can be autoimmune or paraneoplastic, with thymoma being a common cause of paraneoplastic IS. Furthermore, this condition could be handed down from one generation to another. However, there is limited information regarding outcomes, relapses, associated syndromes, associated malignancies (other than thymoma), and treatment options. Despite its rarity, there remains a need for effective management strategies for patients with IS. To address this gap, we conducted a systematic review to summarize the most common and effective treatments of IS in immunomodulatory agents and symptomatic medications, as well as to describe outcomes, relapses, and associated malignancies. Altogether, this review serves to guide clinical practice recommendations for IS and highlight areas for further research. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol to conduct a systematic review of cases reposted through the PubMed and Google Scholar databases. The terms "Isaac Syndrome" and "Acquired Neuromyotonia" were used. The Joanna Briggs Institute's critical appraisal tool was used to evaluate the quality of the included studies. RESULTS: We identified 61 case reports and 4 case series, comprising a total of 70 patients with IS (mean age at onset: 42.5 ± 18 years, and 69% were males). Fourteen cases reported relapses. Thymoma was the most common malignancy associated with IS, followed by lymphoma. Among various serum antibodies, voltage-gated potassium channel-complex antibodies were the most reported antibodies elevated in IS (reported in 38 patients and elevated in 21 patients [55.2%]), followed by acetylcholine ganglionic receptor antibodies, which were reported in 30% of patients (n = 21) and were elevated in 5 cases. The most common electromyography findings were myokymic discharges (n = 22), followed by fasciculations (n = 21) and neuromyotonia (n = 19). For treatment, combining anticonvulsants such as carbamazepine with immunotherapy therapy showed the best results in controlling the symptoms. Among immunotherapy therapies, the combination of plasma exchange plus intravenous high-dose steroids achieved the best results in the acute treatment of IS ([n = 6], with improvement noted in 83.3% [n = 5] of cases). Among the symptomatic treatments with anticonvulsants, carbamazepine was the most efficacious anticonvulsant in treatment of IS, with an average effective dosing of 480 mg/day (carbamazepine was used in 32.3% of acute treatment strategies [n = 23], with improvement noted in 73.9% [n = 17] of cases). CONCLUSIONS: IS a rare neuromuscular syndrome that tends to affect middle-aged men. These patients should be screened for thymoma and other malignancies such as lymphomas. The management of IS symptoms can be challenging, but based on our review, the combination of multiple immunosuppressives such as IV steroids and plasmapheresis with anticonvulsants such as carbamazepine seems to achieve the best results.

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Neuromyotonia and cramp-fasciculation syndrome diagnosis currently relies on neurophysiological examination. In this study we investigated the clinical features and neural antibody profile of patients with neuromyotonia and cramp-fasciculation syndrome to assess the diagnostic value of serological testing. Available sera from adult patients with electromyography-defined neuromyotonia and cramp-fasciculation syndrome were tested for neural antibodies by indirect immunofluorescence on mouse brain sections and live cell-based assays. Forty patients were included, 14 with neuromyotonia and 26 with cramp-fasciculation syndrome. Neural antibodies were detected in 10/10 neuromyotonia sera, most commonly against contactin-associated protein 2 (7/10, 70%), and in 1/20 (5%) cramp-fasciculation syndrome sera. Clinical myokymia, hyperhidrosis, and paresthesia or neuropathic pain were more common in neuromyotonia and mostly associated with contactin-associated protein 2 antibodies. Central nervous system involvement was present in 4/14 (29%) neuromyotonia patients. A tumor was detected in 13/14 (93%) neuromyotonia patients (thymoma, 13), and in 4/26 (15%) with cramp-fasciculation syndrome (thymoma, 1; other neoplasms, 3). Twenty-one/27 (78%) patients achieved a significant improvement or complete remission. Our findings highlight clinical, neurophysiological and serological clues that can be useful in the diagnosis of neuromyotonia and cramp-fasciculation syndrome. Antibody testing is valuable for neuromyotonia diagnosis, while its usefulness in cramp-fasciculation syndrome confirmation is limited.

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PURPOSE OF REVIEW: Autoimmune neuromyotonia encompasses a group of rare immune-mediated neurological disorders frequently associated with anti-contactin-associated protein-like 2 (CASPR2) antibodies and featuring clinical and electrical signs of peripheral nerve hyperexcitability (PNH). We aim to summarize the current knowledge on immune-mediated neuromyotonia, focusing on clinical presentations, pathophysiology, and management. RECENT FINDINGS: Neuromyotonia is a major feature of several autoimmune neurological syndromes characterized by PNH with or without central neurological system involvement. Experimental and clinical evidence suggest that anti-CASPR2 antibodies are directly pathogenic in autoimmune neuromyotonia patients. SUMMARY: Neuromyotonia, a form of PNH, is a major feature in several syndromes associated with anti-CASPR2 antibodies, including cramp-fasciculation syndrome, Isaacs syndrome, Morvan syndrome, and autoimmune limbic encephalitis. Diagnosis relies on the identification of motor, sensory, and autonomic signs of PNH along with other neurological symptoms, anti-CASPR2 antibody-positivity, and of characteristic electroneuromyographic abnormalities. Paraneoplastic associations with thymoma are possible, especially in Morvan syndrome. Patients usually respond to immune-active treatments, including steroids, intravenous immunoglobulins, plasma exchanges, and rituximab.

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The term "la chorιe fibrillare" was used by the French physician Augustine Marie Morvan to describe a syndrome showing hyperactivity features involving the central, autonomic, and peripheral nervous system. The central hyperactivity symptoms are confusion, behavioral problems, hallucinations, myoclonus, and insomnia; the autonomic hyperactivity symptoms are hyperhidrosis and variations in blood pressure; and peripheral hyperexcitability is characterized by painful cramps, myokymia, and neuromyotonia. Here, we present a case that has typical features of Morvan's syndrome and provides a brief description based on available literature.

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INTRODUCTION: The first report of oculomotor neuromyotonia (ONM) in a child induced by thyroid peroxidase antibodies (anti-TPO) in the absence of thyroid eye disease (TED). CASE: 14-year-old girl complained of left eye (LE) paroxysmal upper lid fluttering and ptosis precipitated by hyperventilation or sustained left gaze. On sustained left gaze, right eye (RE) upper lid retraction and LE upper lid fluttering with ptosis ensued. RESULTS: Diagnostic work-up revealed markedly elevated anti-TPO (> 600 IU/ml) and no TED. Brain MRI was normal with no signs of tortuous vessels presenting focal demyelination. We hypothesized that anti-TPO directly induced demyelination and set the ground for right ONM with ephaptic transmission between neurons supplying right medial rectus and levator muscle. CONCLUSIONS: Plethora of theories try to decode the ONM. TED associated ONM is not reported in children but is the second most common cause of ONM in adults, advocated to be of compressive origin. Conversely, this case holds true for cross talk hypothesis. All extraocular muscles must be tested to determine the triggering one. ONM should not be overlooked due to its positive response to carbamazepine.

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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.

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A 45-year-old woman was evaluated for right-sided hemicorporal scar-like skin lesions on her arm and thoracic and inguinal areas that appeared shortly after reduction mammoplasty. Five years later, she developed spontaneous cramps and involuntary abnormal, painful, twitching movements in the same areas. With time, the cramps worsened and disabled the patient. The use of her right arm triggered contractures of muscles and abnormal movements. A diagnosis of neuromyotonia (NMT) was established on the basis of clinical findings and on electromyographic findings of a burst of high-frequency motor unit potentials recorded in the right triceps in the area of skin lesions. The results of medullary, encephalic MRI as well as a comprehensive metabolic panel were normal. She was positive for antinuclear antibodies without specificity. Neither antineural antibodies nor antivoltage-gated potassium channel complex antibodies (specifically, leucine-rich glioma inactivated protein 1 and contactin-associated protein-like-2) were detected. Her skin lesions were diagnosed as morphea. Two combined strategies of treatment were initiated: antiepileptic drugs for NMT and corticosteroids and methotrexate for morphea. NMT is a rare, debilitating neurological complication of morphea.

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BACKGROUND: Isaacs' syndrome is a peripheral nerve hyperexcitability (PNH) syndrome due to peripheral motor nerve instability. Acquired Isaacs' syndrome is recognized as a paraneoplastic autoimmune disease with possible pathogenic voltage-gated potassium channel (VGKC) complex antibodies. However, the longitudinal correlation between clinical symptoms, VGKC antibodies level, and drug response is still unclear. CASE PRESENTATION: A 45-year-old man had progressive four limbs soreness, muscle twitching, cramps, and pain 4 months before admission. Electromyography (EMG) studies showed myokymic discharges, neuromyotonia, and an incremental response in the high-rate (50 Hz) repetitive nerve stimulation (RNS) test. Isaacs' syndrome was diagnosed based on clinical presentations and EMG reports. Serum studies showed positive VGKC complex antibodies, including leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies. The acetylcholine receptor antibody was negative. Whole-body computed tomography (CT) and positron emission tomography revealed a mediastinal tumor with the great vessels encasement, right pleura, and diaphragm seeding. Biopsy confirmed a World Health Organization type B2 thymoma, with Masaoka stage IVa. His symptoms gradually improved and both LGI1 and CASPR2 antibodies titer became undetectable after concurrent chemoradiotherapy (CCRT) and high dose steroid treatment. However, his Isaacs' syndrome recurred after the steroid was reduced 5 months later. Follow-up chest CT showed probable thymoma progression. LGI1 antibody turned positive again while CASPR2 antibody remained undetectable. CONCLUSIONS: Our patient demonstrates that Isaacs' syndrome could be the initial and only neuromuscular manifestation of malignant thymoma. His Isaacs' syndrome is correlated well with the LGI1 antibody level. With an unresectable thymoma, long-term immunosuppressant therapy may be necessary for the management of Isaacs' syndrome in addition to CCRT for thymoma.

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PURPOSE: To report five cases of ocular neuromyotonia in children and adolescents following radiation therapy for a variety of pediatric brain tumors. Notably, three cases occurred in children younger than 11 years. METHODS: Case series of five patients with ocular neuromyotonia following proton beam therapy or conventional radiation. RESULTS: Five cases of ocular neuromyotonia were identified following radiation treatment of various pediatric brain tumors. Onset ranged from 5 to 142 months after radiation treatment. The abducens nerve/lateral rectus muscle was affected in three patients, and the trochlear nerve/superior oblique muscle was affected in two patients. Ages at symptom presentation were 4 years (intermittent head tilt), 9 years (intermittent blurry vision and head tilt), 10 years (intermittent blurry vision progressing to intermittent diplopia), 15 years (intermittent diplopia), and 17 years (intermittent diplopia). One patient improved with gabapentin. Two patients experienced spontaneous resolution. One patient died due to meta-static disease, and one patient has planned follow-up. CONCLUSIONS: Ocular neuromyotonia occurs most commonly following radiation to the brain and skull base. Clinicians need to be aware that ocular neuromyotonia presents differently in children (who may not report diplopia) than in adults or adolescents (who typically report diplopia). Two children in this series never reported diplopia, only intermittent head tilt and blurry vision. Ocular neuromyotonia requires a high index of suspicion to diagnose, especially in children. Membrane stabilizers can be used effectively, but observation may be a valid option in children because spontaneous resolution was seen. [J Pediatr Ophthalmol Strabismus. 2022;59(5):338-343.].

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Ocular neuromyotonia (ONM) is characterized by episodes of binocular diplopia usually triggered by an eye movement requiring contraction of the affected extraocular muscle. It consists of an involuntary, sometimes painful contraction of one or more extraocular muscles. It is most often secondary to radiotherapy of the para-sellar region, although other aetiologies have been reported. Some cases do not have a clearly identified aetiology and are classified as idiopathic. Most cases of ONMs are unilateral but bilateral ONMs have also been described.1-4 We report a case of left ONM in a 55-year-old female patient, several weeks after simultaneous surgical resection of two meningiomas, situated on the right side (Simpson II). The particularity of this case is linked to its puzzling presentation, its similarity with spasm of the near reflex and the putative mechanism through which surgery might have precipitated the symptoms.

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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.

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BACKGROUND: Recessive loss-of-function mutations in HINT1 are associated with predominantly motor axonal peripheral neuropathy with neuromyotonia. Twenty-four distinct pathogenic variants are reported all over the world, including four confirmed founder variations in Europe and Asia. The majority of patients carry the ancient Slavic founder variant c.110G>C (p.Arg37Pro) that shows a distribution gradient from east to west throughout Europe. METHODS: We report a case of HINT1 neuropathy in South America, identified by massive parallel sequencing of a neuropathy gene panel. To investigate the origin of the variant, we performed haplotyping analysis. RESULTS: A Brazilian adolescent presented with recessive axonal motor neuropathy with asymmetric onset and fasciculations. Neuromyotonia was found on needle electromyography. His parents were not consanguineous and had no European ancestry. The patient carried biallelic pathogenic p.Arg37Pro alterations in the first exon of HINT1. Both alleles were identical by descent and originated from the same ancestral founder allele as reported in Europe. CONCLUSION: Our findings expand the geographic distribution of HINT1 neuropathy to South America, where we describe a recognized founder variant in a Brazilian adolescent with no apparent European ancestry. We confirm the association of the hallmark sign of neuromyotonia with the disease.

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RATIONALE: Acquired neuromyotonia syndrome is a rare form of peripheral nerve hyperexcitability syndrome. It is characterized by spontaneous and continuous muscle contractions. Acquired neuromyotonia syndrome is mainly observed in patients with autoimmune diseases or tumors, but it is a rare neurological clinical manifestation in patients with mercury poisoning. PATIENT CONCERNS: A 56-year-old woman presented with continuous and involuntary muscle twitching in her legs for 2 months; it was accompanied by a burning sensation in the lower limbs, insomnia, fatigue, and night sweats. These symptoms did not disappear during sleep. DIAGNOSES: Toxicological blood analysis via atomic fluorescence spectrometry revealed that the level of mercury was 0.07 µmol/L (normal level: <0.05 µmol/L). Her urinary mercury level measured using the cold atomic absorption method was 217.50 µmol/mol creatinine, which was considerably higher than the reference range (0-2.25 µmol/mol creatinine for people not in contact with mercury, 0-20 µmol/mol creatinine following long-term exposure). Upon further testing, a high level of mercury (10,572 mg/kg) was detected in the patient's cream. Accordingly, this patient was diagnosed with mercury poisoning. INTERVENTIONS: Treatment with 2,3-dimercapto-1-propanesulfonic acid (DMPS) was initiated. Her urinary mercury level decreased to 9.67 µmol/mol creatinine, and her neuromyotonia syndrome and hyponatremia were relieved, with urine protein completely disappearing after 3 months of treatment. OUTCOMES: After DMPS treatment, the clinical manifestations of the nervous system disappeared and electrolyte parameters returned to normal levels. LESSONS: Acquired neuromyotonia syndrome is a rare disorder caused by the hyperexcitability of peripheral nerves, resulting in spontaneous and continuous muscle contraction. Mercury poisoning should be considered in patients with neuromyotonia syndrome. Early detection of mercury poisoning can prevent unnecessary examinations and treatments.

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