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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UNASSIGNED: Peripheric nerve hyperexcitability (PNH) syndromes are a rare, heterogenous group of diseases characterized by continuous muscle overactivity due to spontaneous discharges of the lower motor neurons.
UNASSIGNED: Here we report four patients presented with painful cramps, generalized muscle twitches and lower extremity weakness. All patients had evidence of neuropathy and neuromyotonic discharges on electrodiagnostic studies. Screening for a broad panel of anti-neuronal antibodies proved uncharacterized neuropil antibodies in one patient. Despite extensive serologic and genetic investigations, no definitive etiology was found in our cohort. One out of three patients responded well to immunotherapy. No other diseases including malignancy appeared for 1.5-3 years follow-up duration.
UNASSIGNED: Our case series indicate a putatively high prevalence of neuropathy in PNH and emphasize anti-neuronal antibody positivity and early diagnosis as potential favorable prognostic factors.

Thymoma is often associated with paraneoplastic neurologic diseases. Neural autoantibody testing is an important tool aiding diagnosis of thymoma and its autoimmune neurologic complications. Autoantibodies specific for muscle striational antigens and ion channels of the ligand-gated nicotinic acetylcholine receptor superfamily are the most prevalent biomarkers. The autoimmune neurologic disorders associating most commonly with thymoma are myasthenia gravis (MG), peripheral nerve hyperexcitability (neuromyotonia and Morvan syndrome), dysautonomia, and encephalitis. Patients presenting with these neurologic disorders should be screened for thymoma at diagnosis. Although they can cause profound disability, they usually respond to immunotherapy and treatment of the thymoma. Worsening of the neurologic disorder following surgical removal of a thymoma may herald tumor recurrence. Prompt recognition of paraneoplastic neurologic disorders is critical for patient management. A multidisciplinary approach is required for optimal management of neurologic autoimmunity associated with thymoma.

Peripheral neuropathy is a common referral for patients to the neurologic clinics. Paraneoplastic neuropathies account for a small but high morbidity and mortality subgroup. Symptoms include weakness, sensory loss, sweating irregularity, blood pressure instability, severe constipation, and neuropathic pain. Neuropathy is the first presenting symptom of malignancy among many patients. The molecular and cellular oncogenic immune targets reside within cell bodies, axons, cytoplasms, or surface membranes of neural tissues. A more favorable immune treatment outcome occurs in those where the targets reside on the cell surface. Patients with antibodies binding cell surface antigens commonly have neural hyperexcitability with pain, cramps, fasciculations, and hyperhidrotic attacks (CASPR2, LGI1, and others). The antigenic targets are also commonly expressed in the central nervous system, with presenting symptoms being myelopathy, encephalopathy, and seizures with neuropathy, often masked. Pain and autonomic components typically relate to small nerve fiber involvement (nociceptive, adrenergic, enteric, and sudomotor), sometimes without nerve fiber loss but rather hyperexcitability. The specific antibodies discovered help direct cancer investigations. Among the primary axonal paraneoplastic neuropathies, pathognomonic clinical features do not exist, and testing for multiple antibodies simultaneously provides the best sensitivity in testing (AGNA1-SOX1; amphiphysin; ANNA-1-HU; ANNA-3-DACH1; CASPR2; CRMP5; LGI1; PCA2-MAP1B, and others). Performing confirmatory antibody testing using adjunct methods improves specificity. Antibody-mediated demyelinating paraneoplastic neuropathies are limited to MAG-IgM (IgM-MGUS, Waldenström\'s, and myeloma), with the others associated with cytokine elevations (VEGF, IL6) caused by osteosclerotic myeloma, plasmacytoma (POEMS), and rarely angiofollicular lymphoma (Castleman\'s). Paraneoplastic disorders have clinical overlap with other idiopathic antibody disorders, including IgG4 demyelinating nodopathies (NF155 and Contactin-1). This review summarizes the paraneoplastic neuropathies, including those with peripheral nerve hyperexcitability.

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.

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.
Retrospective cohort.
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.
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.
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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A man in his mid-60s presented with a 3-month history of progressive muscle twitching, agitation, cognitive impairment, insomnia, hyperhidrosis and lower limb pain. He had fasciculations, myokymia, myoclonus, exaggerated startle response and significant postural hypotension. Electrophysiological studies showed evidence of peripheral nerve hyperexcitability with neuromyotonia. Contactin-associated protein-like 2 antibodies (CASPR2) were strongly positive. A diagnosis of Morvan syndrome was made. CT of the chest, abdomen and pelvis was undertaken to identify any occult malignancy, and a large bowel carcinoma in situ was identified and resected. His central nervous system and autonomic symptoms significantly improved following surgery, but neuromyotonia persisted, and this was treated with intravenous immunoglobulins and steroids. Early detection of bowel cancer in this patient enabled curative treatment.

OBJECTIVE: 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.