Peripheral Nerve Hyperexcitability Research Articles

Clinicopathological Features in Morvan’s Syndrome: An Autopsy Case Study

Morvan’s syndrome is a rare, complex autoimmune syndrome comprising peripheral nerve hyperexcitability, dysautonomia, insomnia, and encephalopathy. In this case report, we highlight the clinical and pathological findings of an elderly gentleman who presented to us with clinical features of Morvan’s syndrome associated with anti-contactin-associated protein 2 (CASPR-2) antibodies. Histopathology [Figure 3] revealed cortical atrophy with gliosis and mild microglial proliferation. Microglial activation and gliosis were observed in the hippocampus, hypothalamus, and thalamus. Brainstem showed multifocal inflammation. Mild inflammation was observed in the leptomeninges. Morvan’s syndrome is an autoimmune disease with antibodies targeted against CASPR within the voltage-gated potassium channel (VGKC) complex. Early diagnosis and treatment play a key role in the management of patients. Most patients show a good response when treated with plasmapheresis and steroids. This patient presented to us late into the illness and succumbed.

Autoimmune Parkinsonism: A Newer Manifestation of Contactin-Associated Protein-Like 2 Autoimmunity: A Case Report

Contactin-associated protein-like 2 (CASPR2) antibodies are part of an expanding spectrum of disorders. Although they were initially associated with Morvan’s syndrome and peripheral nerve hyperexcitability, their clinical manifestations are more varied than previously recognized. In this report, we present a rare case of a middle-aged woman who experienced gait disturbances, sleep disturbances, behavioral changes, and postural abnormalities over a period of five months. A thorough examination revealed a Parkinsonian phenotype. Considering the timeline and symptomatology, an autoimmune work-up was conducted, which detected CASPR2 antibodies in the patient’s serum. Treatment with high-dose intravenous Methylprednisolone followed by rituximab effectively reversed her clinical manifestations without residual neurological deficits.

Distinct phenotypes in a cohort of anti-CASPR2 associated neurological syndromes

IntroductionAnti-contactin-associated protein-like 2 (CASPR2) is classically associated with limbic encephalitis (LE), Morvan syndrome and peripheral nerve hyperexcitability (PNH). Additional clinical features have been previously recognized. ObjectiveTo describe a cohort of patients with anti-CASPR2-associated neurological syndromes from a tertiary referral centre. MethodsRetrospective analysis of patients with positive serum anti-CASPR2 antibodies in the period between 2014 and 2021. ResultsNineteen patients were identified, 11 (57.9%) male, with a median age at symptom onset of 49.0 (31.3–63.0) years and a median time to diagnosis of 1.0 (0.0–1.8) years. The most common clinical syndromes were LE (7 cases, 36.8%), Morvan syndrome (4, 21.1%) and PNH (2, 10.5%). Six patients presented with atypical phenotypes (31.6%), comprising dysautonomia (orthostatic hypotension and Adie’s Pupil), motor tics/stereotypies, obsessive-compulsive disorder, and brainstem involvement. The most common presenting symptoms were seizures (31.6%), PNH (21.1%) and cognitive dysfunction (15.8%). One LE patient had a disease duration of 2,5 years and was initially diagnosed with dementia. CSF was normal in most cases. Brain MRI showed temporal lobe hyperintensities in 4 LE cases (57.1%). All PNH cases had myokymic discharges of fasciculations in the electromyography. Two patients had associated thymoma and 1 had lung adenocarcinoma. Eight patients (42.1%) received treatment during the acute phase and 26.3% maintenance treatment. Approximately half of the treated cases improved or stabilised, with 4 (21.1%) deaths in the whole cohort. ConclusionAnti-CASPR2-associated neurological disorders may present with isolated atypical phenotypes, a slowly progressive clinical course, and with normal CSF or imaging findings.

Clinical and neuroelectrophysiological characteristics of primary peripheral nerve hyperexcitability syndrome

Objective: To investigate the clinical and neuroelectrophysiological characteristics of patients with primary peripheral nerve hyperexcitability syndrome (PNHS). Methods: The clinical data of 20 patients who were diagnosed with PNHS in Beijing Tiantan Hospital from April 2016 to January 2023 were retrospectively collected. All patients underwent neuroelectrophysiological examinations. Clinical and electrophysiological characteristics were compared between the antibody positive and antibody negative groups, according to serum and cerebrospinal fluid anti-contactin-associated protein-like 2 (CASPR2) and/or anti-leucine-rich glioma-inactivated protein 1 (LGI-1) antibodies. Results: There were 12 males and 8 females, with a mean age of (44.0±17.2) years and the disease course of [M (Q1, Q3)] 2.3 (1.1, 11.5) months. Motor symptoms included fasciculations, myokymia, muscle pain, cramps, and stiffness. These symptoms were commonly seen in the lower limbs (17 patients), followed by upper limbs (11 patients), face (11 patients) and trunk (9 patients). Nineteen (19/20) patients had sensory abnormalities and/or autonomic dysfunction, 13 patients had central nervous system involvement, and 5 patients had concomitant lung cancer or thymic lesions. The characteristic spontaneous potentials on needle electromyography (EMG) were myokymia potential (19 patients), fasciculation potential (12 patients), spastic potential (3 patients), neuromyotonic potential (1 patients), etc, which were commonly seen in the lower limb muscles, especially the gastrocnemius muscle(12 patients). After-discharge potential was found in 8 patients, and 7 were in the tibial nerve. Seven patients had positive serum anti-CASPR2 antibodies, and 3 of them had concomitant anti-LGI1 antibodies. And 1 patient had positive serum anti-LGI1 antibody alone. Compared with patients in the antibody negative group (n=12), the patients who had anti-VGKC complex antibodies (n=8) had a shorter course of disease [M (Q1, Q3): 1.8 (1, 2) months vs 9.5 (3.3, 20.3) months, P=0.012], higher incidence of after-discharge potential (6/8 vs 2/12, P=0.019). The immunotherapy regimen (multi-dru, single-drug, no immunotherapy: 6, 2, 0 patients) in antibody-positive patients was different from the antibody-negative group (3, 6, 3 patients, U=21.00, P=0.023). Conclusions: The symptoms of motor nerve hyperexcitation, characteristic EMG spontaneous potentials and after-discharge potentials in PNHS patients are most commonly seen in the lower limbs. Attention should be paid to concomitant sensory and autonomic nerve hyperexcitation. PNHS patients with positive serum anti-CASPR2 antibodies may require immunotherapy with multiple drugs.

LGI1 and CASPR2-related Morvan syndrome - diagnostic challenges in a pediatric case

Morvan syndrome is a rare immune-mediated pathology involving the central, peripheral and autonomic nervous systems. Although it was described in adults, mostly as a paraneoplastic syndrome, it is rarely seen in pediatric patients. In this report, we present the case of a 15-year-old male patient who experienced insomnia, peripheral nerve hyperexcitability and autonomic signs, highly suggestive for Morvan syndrome, but prone to diagnostic dilemmas as well. The diagnosis was confirmed by the presence of antibodies against voltage-gated potassium channels (VGKC). This article aims to highlight the unique clinical picture of a rare syndrome, diagnostic pitfalls and treatment options in pediatric patients.

Voltage-Gated Potassium Channels (VGKC) Complex-Associated Disorders: Anti-LGI1 Encephalitis and Anti-Caspr2 Encephalitis

Autoantibodies against LGI1 and Caspr2 complexed with voltage-gated potassium channels (VGKC) cause limbic encephalitis. Anti-LGI1 encephalitis progresses in a subacute course with memory impairment, disorientation, and focal epileptic seizures. Anti-LGI1 encephalitis is preceded by faciobrachial dystonic seizures (FBDS), which are specific involuntary movements and frequently complicated by hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Neutralization of LGI1 by anti-LGI1 antibodies reduces AMPA receptors and induces epileptic seizures and memory impairment. Anti-Caspr2 encephalitis (Morvan's syndrome) is associated with limbic symptoms, severe autonomic disorders, muscle cramps and burning extremity pain due to peripheral nerve hyperexcitability. Thymomas and other malignant tumors may be complicated, and search for them is necessary. Anti-Caspr2 antibodies bind to Caspr2 on the surface of afferent cells in the dorsal root ganglion, and internalization of VGKCs causes a decrease in the K+ current, resulting in neuronal hyperexcitation and severe pain. Early immunotherapeutic intervention may improve the prognosis of these diseases, and measuring these autoantibodies should be performed in the presence of specific clinical signs, even with normal cerebrospinal fluid findings.

N°128 – Needle EMG – An essential tool in the diagnosis of peripheral nerve hyperexcitability disorders

N°128 – Needle EMG – An essential tool in the diagnosis of peripheral nerve hyperexcitability disorders

Seronegative Isaac Syndrome Presenting as Focal Limb Stiffness Responsive to Plasma Exchange Therapy (P8-8.015)

<h3>Objective:</h3> N/A <h3>Background:</h3> Isaac syndrome is an autoimmune disorder of peripheral nerve hyperexcitability characterized by neuromyotonia, myokymia, muscles stiffness, pseudomyotonia, and pseudotetany frequently accompanied by dysautonomia and neuropathic pain. Approximately 50% of cases are associated with antibodies against contactin-associated protein-like 2 (CASPR2) or less commonly leucine-rich glioma inactivated protein 1 (LGI1), both components of the voltage-gated potassium channel (VGKC) complex. Paraneoplastic, genetic, and toxic etiologies must be considered. Management includes membrane-stabilizing drugs as well as immunotherapy in more severe cases. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 50-year-old woman presented with one year of left neck, shoulder, and upper extremity pain and stiffness that began one month after an upper respiratory illness. Her exam was notable for anterocollis, left shoulder elevation, impaired left shoulder abduction beyond 35–40 degrees, tonically contracted left biceps, and marked tenderness to palpation of the affected muscles. Symptomatic management with diazepam, lorazepam, baclofen, mexiletine, and trihexyphenidyl was ineffective. EMG demonstrated widespread neuromyotonic discharges throughout the proximal greater than distal left upper extremity, cervical and thoracic paraspinals, and right deltoid. Laboratory studies including CASPR2, LGI1, VGKC, GAD-65, and amphiphysin antibodies were unremarkable. Comprehensive screening for occult malignancy was unrevealing. She received partial benefit from carbamazepine, levetiracetam, cyclobenzaprine, and onabotulinumtoxinA injections, but symptoms remained debilitating. She was treated with IVIg 1g/kg Q2 weeks for three months with symptom progression to the jaw and lower extremities. She was started on plasmapheresis QOD for ten days every four weeks with rapid improvement in symptoms. <h3>Conclusions:</h3> We report a case of seronegative Isaac syndrome initially presenting with focal limb stiffness and dystonic posturing that was exquisitely responsive to plasmapheresis. This case highlights the need to consider peripheral nerve hyperexcitability syndromes in patients presenting with focal limb stiffness or painful dystonia and provides additional support for plasmapheresis as an effective treatment option for patients with debilitating symptoms. <b>Disclosure:</b> Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a Resident and Fellow Council Member with American Association of Neuromuscular &amp; Electrodiagnostic Medicine. Dr. Khalil has received personal compensation in the range of $0-$499 for serving as a MS Mentorship Forum Participant with Foundation of the Consortium of Multiple Sclerosis Centers. Dr. Bradshaw has nothing to disclose.

Teaching Video NeuroImages: Acquired focal neuromyotonia in LGI-1 autoimmunity

An 81-year-old woman was diagnosed with corticobasal degeneration (cognitive decline and left hand posturing). Hyponatremia and bilateral faciobrachial dystonic seizures (FBDS) ensued. Neurologic examination (figure, A; video) revealed persistent involuntary continuous left 3rd and 4th finger flexor activation and delayed relaxation. EMG revealed high-frequency spontaneous discharges, including neuromyotonia and fast myokymia of the left flexor digitorum superficialis and pronator teres (figure, B). LGI1 immunoglobulin G (IgG)1 was detected, but not CASPR2-IgG (figure, C–E). Oncologic evaluation revealed breast ductal carcinoma in situ. Encephalopathy and FBDS resolved after IV immunoglobulin. Encephalopathy coexisting with peripheral nerve hyperexcitability can mimic neurodegeneration, and should prompt exclusion of LGI1/CASPR2 autoimmunity.2

Contactin-Associated Protein-Like 2-Related Peripheral Nerve Hyperexcitability Associated With Charcot-Marie-Tooth Type 4F.

Contactin-associated protein-like 2 autoimmunity is an uncommon disorder resulting in peripheral nerve hyperexcitability or encephalitis. In a fifth of cases, onset may be provoked by thymoma, but other associations are largely unknown. We report a patient with anti-contactin-associated protein-like 2-related peripheral nerve hyperexcitability arising in the setting of Charcot-Marie-Tooth type 4F and discuss potential mechanisms underlying the association.

Chapter 14 - Motor symptoms in nonparaneoplastic CNS disorders associated with neural antibodies

Motor symptoms are common, and sometimes predominant, in almost all nonparaneoplastic CNS disorders associated with neural antibodies. These CNS disorders can be classified into five groups: (1) Autoimmune encephalitis with antibodies against synaptic receptors, (2) cerebellar ataxias associated with neuronal antibodies that mostly target intracellular antigens. (3) Stiff-person syndrome and progressive encephalomyelitis with rigidity and myoclonus which have antibodies against glutamic acid decarboxylase and glycine receptor, respectively. Both diseases have in common the presence of predominant muscle stiffness and rigidity. (4) Three diseases associated with glial antibodies. Two present motor symptoms mainly due to the involvement of the spinal cord: neuromyelitis optica spectrum disorders with aquaporin-4 antibodies and myelin oligodendrocyte glycoprotein antibody-associated disease. The third disorder is the meningoencephalitis associated with glial fibrillar acidic protein antibodies which frequently also presents a myelopathy. (5) Two antibody-related diseases which are characterized by prominent sleep dysfunction: anti-IgLON5 disease, a disorder that frequently presents a variety of movement disorders, and Morvan syndrome associated with contactin-associated protein-like 2 antibodies and clinical manifestations of peripheral nerve hyperexcitability. In this chapter, we describe the main clinical features of these five groups with particular emphasis on the presence, frequency, and types of motor symptoms.

A CASE OF MORVANS SYNDROME ASSOCIATED WITH HEAVY METAL POISONING AFTER SIDDHA DRUG INTAKE

Morvan syndrome (MoS) or Morvan's fibrillary chorea (MFC) is an autoimmune-mediated syndrome that is frequently associated with autoantibodies targeting contactin-associated protein-like 2 (CASPR2-Abs). It is often associated with peripheral nerve hyperexcitability, autonomic instability and neuropathic pain. Here we report a case who presented with Morvans syndrome after 4 months siddha drug intake.This case highlights the association of Morvans syndrome with heavy metal poisoning and its incidental occurrence after siddha drug intake.

Early-Stage Contactin-Associated Protein-like 2 Limbic Encephalitis: Clues for Diagnosis.

Background and ObjectivesPrevious studies suggested that autoimmune limbic encephalitis with antibodies against contactin-associated protein-like 2 (CASPR2-encephalitis) is clinically heterogeneous and progresses slowly, preventing its early recognition. We aimed to describe the onset and progression of CASPR2-encephalitis and to assess long-term outcomes.MethodsWe retrospectively analyzed the medical records of all patients whose CSF tested positive for anti-CASPR2 antibodies in our center between 2006 and 2020. Standardized telephone interviews of all available patients and relatives were conducted, assessing long-term functional independence using the Functional Activity Questionnaire (FAQ) and quality of life using the 36-Item Short-Form Survey (SF36).ResultsForty-eight patients were included (98% males; median age 64 years), and 35 participated in telephone interviews (73%). At onset, 81% had at least 1 neurologic symptom among the following: limbic (54%), peripheral nerve hyperexcitability (PNH; 21%), and/or cerebellar symptoms (17%). Most of the patients (75%) had initially symptoms of only one of these categories. Limbic symptoms at onset included mostly seizures (33%), while memory disturbances were less frequent (10%). PNH signs were mostly neuropathic pain (9/10 patients). Other symptoms seen at onset included asthenia (33%), mood disorders (25%), and insomnia (21%); 19% of patients did not show any limbic, peripheral, or cerebellar symptom at onset but only asthenia (15%), mood disorders (6%), weight loss (8%), dysautonomia (4%), and/or insomnia (2%). The peak of the disease was attained in median 16.7 months after onset. Over the study period (median follow-up, 58.8 months, range 10.6–189.1), 77% of patients developed ≥3 core CASPR2 symptoms and 42% fulfilled the diagnostic criteria for autoimmune limbic encephalitis, although all patients ultimately developed limbic symptoms. At the last visit, most interviewed patients (28/35 patients, 80%; median, 5 years after onset) had recovered functional independence (FAQ <9) while only the vitality subscore of the SF36 was lower than normative data (mean 49.9 vs 58.0, p = 0.0369).DiscussionCASPR2-encephalitis has a progressive course and is highly heterogeneous at the early stage. In men older than 50 years, otherwise unexplained seizures, cerebellar ataxia, and/or neuropathic pain are suggestive of early-stage CASPR2-encephalitis, especially if they coincide with recent asthenia, mood disorders, or insomnia.

Autoimmune neuromyotonia.

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. 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. 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.

A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode

The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes, LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations of LGI1 and LGI4 are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with either LGI2 or LGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants in LGI3 and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generated Lgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants in LGI3. Deep phenotypic characterization showed LGI3 LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability. Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants in LGI3 cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.

Isaacs\u2019 syndrome as the initial presentation of malignant thymoma and associated with double-positive voltage-gated potassium channel complex antibodies, a case report

BackgroundIsaacs’ 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 presentationA 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.ConclusionsOur 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.

Efficacy and Safety of Pregabalin for Muscle Cramps in Liver Cirrhosis: A Double-Blind Randomized Controlled Trial.

BackgroundMuscle cramp is possibly related to peripheral nerve hyperexcitability (PNH), and one of the most debilitating symptoms frequently encountered in patients with liver cirrhosis. We investigated whether pregabalin, a gamma-aminobutyric acid analogue, can suppress neuronal excitability and reduce muscle cramps in cirrhotic patients.MethodsWe conducted a randomized, double-blind, placebo-controlled trial in which study participants with cirrhosis from a single tertiary center were enrolled. Primary endpoint was the relative change in cramp frequency from the run-in to standard dose treatment phase (4 weeks per each). Secondary endpoints included the responder rate, and the changes in cramp frequency during sleep, pain intensity, health-related quality of life (Liver Disease Quality of Life Instrument, Short Form-36) and electrophysiological measures of PNH.ResultsThis study was terminated early because of insufficient accrual. 80% (n = 56) of the target number of participants (n = 70) were randomized to pregabalin (n = 29) or placebo (n = 27). Median baseline frequency of muscle cramps (interquartile range) was 5.8 (3.5–10) per week in the pregabalin group and 6.5 (4.0–10) in the placebo group (P = 0.970). The primary analysis showed a significant reduction in cramp frequency with pregabalin compared to placebo (−36% vs. 4.5% for the percentage change, P = 0.010). Secondary outcomes did not differ significantly between the two groups. Adverse effects with pregabalin were mainly dizziness and lethargy.ConclusionWith multiple problems emerging from premature termination in mind, the results suggested an acceptable safety profile and favorable effect of pregabalin in reducing muscle cramps compared to placebo in cirrhotic patients.Trial RegistrationClinicalTrials.gov Identifier: NCT01271660

Adult-onset hypothyroidism causes mechanical hypersensitivity due to peripheral nerve hyperexcitability based on voltage-gated potassium channel downregulation in male mice.

Thyroid hormones play an important role in the central and peripheral nervous system functions. Approximately 50% of adult-onset hypothyroid patients have sensory symptoms including pain, possibly caused by peripheral neuropathy. However, the mechanism causing the pain has not been clarified. We generated an adult-onset hypothyroid model animal by administering 50ppm propylthiouracil (PTU) for 5weeks to male mice. Female mice were not tested in this study. Mechanical hypersensitivity, determined by the von Frey hair test, was observed during the PTU exposure and recovered after the exposure termination. The sciatic nerve compound action potential was also analyzed. Under single-pulse stimulation, no significant change in the threshold and conduction velocity was observed in the PTU-administered group. On the other hand, under train-pulse stimulation, the latency delay in the Aδ-fiber component was less in the PTU-administered group in Week 4 of PTU exposure, indicating relative hyperexcitability. Fluticasone, which is the anti-inflammatory agent with an ability to activate the voltage-gated potassium channel subfamily A (Kv1), restored the decrease in the latency change ratio by PTU exposure under the train-pulse stimulation supporting our hypothesis that Kv1 may be involved in the conductivity change. Kv1.1 protein level decreased significantly in the sciatic nerve of the PTU-administered group. These results indicate that adult-onset hypothyroidism causes mechanical hypersensitivity owing to hyperexcitability of the peripheral nerve and that reduction of Kv1.1 level may be involved in such alteration.

Contactin‐Associated Protein‐Like 2 (CASPR2)–Associated Movement Disorder in a Child

A 5-year-old boy with a 1-month history of seizures and abnormal twisting movements and posturing of the left upper and lower limbs presented to us with altered sensorium and involuntary jerks for the past 1 week. The child was born out of a nonconsanguineous marriage with full-term normal vaginal delivery. Antenatal, perinatal, and postnatal periods were uneventful. Developmental milestones including motor and language milestones were achieved appropriate to age. Immunization history was normal as per the schedule. Child's cognition was normal, and there were no other comorbidities before this illness. No history suggestive of autonomic involvement, sleep disturbances, mood/psychiatric issues, or peripheral nerve symptoms was found. Neurological examination revealed altered mental status with dystonic posturing of the bilateral upper limbs and left lower limb and myoclonic jerks noted over the left upper limb and left lower limb (Video 1 ). His routine blood counts, biochemical profile, serum ceruloplasmin, systemic autoimmune markers, cerebrospinal fluid (CSF) immunoglobulin G index for measles, nerve conduction studies (NCS), electromyography, electroencephalogram, and cranial magnetic resonance imaging were normal. CSF analysis revealed 6 cells and 0.25 g/L protein and glucose of 2.6 mmol/L. Contactin-associated protein-like 2 (CASPR2) antibodies assessed by cell-based assay were found to be positive in the serum sample. The patient was initiated on intravenousimmunoglobulin (IVIG) at a dose of 2 g/kg for 5 days followed by oral steroids. The child's altered sensorium improved, and the myoclonic jerks were reduced. The patient was screened for underlying malignancy, which was negative. Autoimmune syndromes are an important cause of treatable movement disorders, and hence early recognition is of prime importance.1 They may mimic metabolic or neurodegenerative diseases. Chorea, dyskinesias, cerebellar ataxia, dystonia, myoclonus, parkinsonism, tics, tremors, and stiff person spectrum disorders are some of the movement disorders with associated autoantibodies.1 The occurrence of some of them gives a strong clue to the underlying antibody because of their high specificity. Anti-N-methyl-d-aspartate receptor-encephalitis, the most common form of autoimmune encephalitis predominantly involving young individuals, is characterized by neuropsychiatric manifestations, speech abnormalities, memory disturbances, autonomic dysfunction, and a wide variety of movement disorders. Antibodies directed to proteins such as Leucine-rich glioma-inactivated 1 (LGI1), CASPR2, and rarely to contactin-2 are most frequently encountered in patients with limbic encephalitis.2 CASPR2, a membrane protein expressed both in the central and peripheral nervous system, is essential for proper localization of voltage-gated potassium channels (VGKC).3 The clinical spectrum of CASPR2 antibodies is broader in comparison with antibodies to LGI1, which is mainly associated with limbic encephalitis and faciobrachial dystonic seizures. Neuromyotonia, neuropathic pain, insomnia, dysautonomia, and weight loss are more common in patients with CASPR2 antibodies compared with patients with LGI1antibody positivity.3 Movement disorders are rarely seen in association with CASPR2 antibodies. Chorea in association with behavioral changes, paroxysmal myoclonus, and parkinsonism are the movement disorders rarely reported in patients with CASPR2 antibodies.1, 3 More than 60% of the patients had 4 or more of the core symptoms: cerebral symptoms (cognition, epilepsy), cerebellar symptoms, weight loss, peripheral nerve hyperexcitability (PNH), autonomic dysfunction, neuropathic pain, and insomnia.3 Idiopathic chorea in an adult with CASPR2 antibodies3 and isolated chorea with and without limbic encephalitis in adults with LGI1 antibodies have been previously described in single case reports.4 A case of CASPR2-mediated autoimmune limbic encephalitis in a 19-month-old toddler in India has been recently described.5 In 1 of the recently reported case series, encephalopathy, seizures, and PNH were the commonly reported symptoms.6 Movement disorders associated with CASPR2 antibodies are rare and underreported. Our patient presented with encephalitis, dystonia, and myoclonus. He responded to immunotherapy thus emphasizing the need for early diagnosis and treatment. With the discovery of an array of antineuronal autoantibodies, there has been an expansion in the phenotypic spectrum of autoimmune movement disorders in children. As early diagnosis and treatment improve the outcomes, prompt recognition by the practicing clinician is of utmost importance. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. R.B.R.N.: 1A, 1B, 1C, 2A, 2B A.K.: 1A, 2B D.J.: 1A, 1B, 2B The authors confirm that the approval of an institutional review board was not required for this work. We also confirm that the written informed consent was obtained from the parents for the publication of the video. We confirm that we have read the Journal's position on issues involved in the ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

Thymoma and Autoimmune Encephalitis: Clinical Manifestations and Antibodies.

ObjectiveTo report the clinical, neuroimaging, and antibody associations in patients with autoimmune encephalitis (AE) and thymoma.MethodsA retrospective cohort study of 43 patients was conducted. Antibody determination and immunoprecipitation to characterize novel antigens were performed using reported techniques.ResultsPatients' median age was 52 years (range: 23–88 years). Forty (93%) had neuronal surface antibodies: gamma-aminobutyric acid receptor A (GABAAR) (15), amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (13), contactin-associated protein-like 2 (CASPR2) (4), leucine-rich, glioma inactivated 1 (LGI1) (3), glycine receptor (GlyR) (3), and unknown antigens (2). Concurrent antibodies against intracellular antigens occurred in 13 (30%; 9 anti–collapsin response mediator protein 5 [CRMP5]) and were more frequent in anti-AMPAR encephalitis (54% vs 20%; p = 0.037). The most common clinical presentation was encephalitis with multiple T2/fluid-attenuated inversion recovery hyperintense lesions in 23 (53%) patients (15 GABAAR, 5 AMPAR, and 1 unknown neuropil antibody), followed by encephalitis with peripheral nerve hyperexcitability in 7 (16%; 4 CASPR2, 2 LGI1, and 1 unknown antibody), limbic encephalitis in 6 (14%; 4 AMPAR, 1 LGI1, and 1 antibody negative), progressive encephalomyelitis with rigidity and myoclonus in 4 (9%; 3 GlyR and 1 AMPAR antibodies), and encephalitis with normal MRI in 3 (7%; AMPAR antibodies). Anti-GABAAR encephalitis was more prevalent in Japanese patients compared with Caucasians and other ethnicities (61% vs 16%; p = 0.003). In anti-AMPAR encephalitis, 3/4 patients with poor and 0/6 with good outcome had concurrent CRMP5 antibodies (p = 0.033). Immunoprecipitation studies identified metabotropic glutamate receptor 3 antibodies that were additionally found in 5 patients (3 with and 2 without encephalitis).ConclusionsAE in patients with thymoma include several clinical-radiologic syndromes that vary according to the associated antibodies. Anti-GABAAR encephalitis was the most frequent AE and occurred more frequently in Japanese patients.