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

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.

Afterdischarges following M waves in patients with voltage-gated potassium channels antibodies

Objective To explore the clinical features, auxiliary examinations, therapies and prognoses of patients with antibodies against contactin-associated protein-like 2 (CASPR2). Methods The clinical data of 11 anti-CASPR2 encephalitis patients who were admited to the People′s Hospital of Zhengzhou University from March 2015 to April 2018 were retrospectively analyzed. Results The age of these 11 cases was (35.6±19.4) years (ranged 20-74 years), and eight cases were females. There were seven cases with limbic encephalitis which included six cases of epilepsy, four cases of memory impairment, two cases of mental and behavioral abnormalities. Four cases had peripheral nerve hyperexcitability. Four cases had neuropathic pain. There were six cases with autonomic dysfunction including five cases of constipation, three cases of tachycardia, two cases of hyperhidrosis, two cases of urinary disorder. Seven cases had sleep disorder. Four cases had weight loss. Two cases showed cerebellar symptoms and two cases had hyponatremia. Magnetic resonance imaging scan of the brain showed abnormal signal in two cases, mainly involved medial temporal lobe and the hippocampus. Six cases underwent 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) examination, and three cases showed abnormalities, including two with temporal hypermetabolism and one with cortical hypermetabolism. Chest enhanced CT and PET-CT showed thymoma in one case. All cases received immunotherapy, and after treatment their symptoms were improved. Long-term follow-up was performed in nine cases, and three cases relapsed. Conclusions The major clinical manifestations of anti-CASPR2 encephalitis were limbic encephalitis, peripheral nerve hyperexcitability, neuropathic pain, autonomic dysfunction, insomnia and so on. Immunotherapy was effective and some patients may have recurrence. Key words: Autoantibodies; Encephalitis; Autoimmune encephalitis; Contactin associated protein-like 2

Contactin-associated protein-like 2 (CASPR2) is a transmembrane protein of the neurexin superfamily, essential for clustering voltage-gated potassium channels, particularly Kv1, at the juxtaparanodal regions of myelinated axons. This precise localisation is essential for maintaining normal axonal excitability and preventing aberrant signal propagation. Autoantibodies targeting CASPR2 have been associated with various neurological syndromes, notably peripheral nerve hyperexcitability (PNH), which presents clinically with neuromyotonia and myokymia. PNH is characterised by distinctive electrophysiological findings, including neuromyotonic discharges, myokymic discharges, and afterdischarges, which provide diagnostic value and insight into underlying pathophysiology. This review explores the mechanisms of anti-CASPR2-associated PNH, focusing on how antibody-mediated disruption of Kv1 channel clustering leads to altered axonal excitability. Current evidence suggests that both the distal and proximal segments of the axon are sites of pathological activity, where impairments in action potential termination and re-entry prevention result in spontaneous, repetitive discharges. While afterdischarges likely originate within the axon, the precise location-whether in the alpha-motoneuron soma or axon-is uncertain. The involvement of spinal inhibitory circuits has also been proposed, though it remains speculative. Understanding the neurophysiological features of anti-CASPR2-associated PNH is essential for improving diagnostic accuracy and guiding treatment strategies. Further research is needed to clarify the mechanisms of CASPR2-related hyperexcitability.

Contactin-associated protein-like 2 (CASPR2) autoantibody disease has a variable clinical phenotype. We present a case report and performed a systematic review of the literature to summarize: (1) the clinical phenotype of patients with CASPR2 antibodies, (2) the findings in neurological investigations, and (3) the associated neuroimaging findings. A chart review was performed for the case report. A systematic review of the medical literature was performed from first available to June 13, 2018. Abstracts were screened, and full-text peer-reviewed publications for novel patients with CASPR2 positivity in serum or cerebrospinal fluid (CSF) were included. Selected publications were reviewed, and relevant information was collated. Data were analyzed to determine overall frequency for demographic information, clinical presentations, and investigation findings. Our patient was a previously healthy 61-year-old male with both serum and CSF CASPR2 antibodies who presented with limbic encephalitis and refractory epilepsy. He was successfully treated with immunosuppression. For our systematic review, we identified 667 patients from 106 studies. Sixty-nine percent were male. Median age was 54years (IQR 39-65.5). Median disease duration was 12months (IQR 5.6-20). Reported overall clinical syndromes were: autoimmune encephalitis [69/134 (51.5%)], limbic encephalitis [106/274 (38.7%)], peripheral nerve hyperexcitability [72/191 (37.7%)], Morvan syndrome [57/251 (22.7%)], and cerebellar syndrome [24/163 (14.7%)]. Patients had positive serum [642/642 (100%)] and CSF [87/173 (50.3%)] CASPR2 antibodies. MRI was reported as abnormal in 159/299 patients (53.1%), and the most common abnormalities were encephalitis or T2 hyperintensities in the medial temporal lobes, or hippocampal atrophy, mesial temporal sclerosis, or hippocampal sclerosis. FDG-PET was abnormal in 30/35 patients (85.7%), and the most common abnormality was temporomesial hypometabolism. The most commonly associated condition was myasthenia gravis (38 cases). Thymoma occurred in 76/348 patients (21.8%). Non-thymoma malignancies were uncommon [42/397 (10.6%)]. Most patients have autoimmune or limbic encephalitis and corresponding abnormalities on neuroimaging. Other presentations include peripheral nerve hyperexcitability or Morvan syndromes, cerebellar syndromes, behavioral and cognitive changes, and more rarely movement disorders. The most commonly associated malignancy was thymoma and suggests a role for thymoma screening in CASPR2-related diseases.

Autoimmune encephalitis with CASPR2 antibody: A case series and updated literature review.

Neuropathic pain in CASPR2 antibody disease spectrum: A systematic review.

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Pseudophakic cystoid macular edema treated with high-dose intravenous methylprednisolone

P-AD003. Autonomic dysfunction in CASPR2 antibody associated neurological disease

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.

Chapter 14 Peripheral nerve hyperexcitability and the neuromuscular junction

BackgroundTo investigate visual recovery after treatment of acute optic neuritis (ON) with either oral or intravenous high-dose methylprednisolone, in order to establish the best route of administration.MethodsRetrospective analysis of patients treated with oral or intravenous high-dose (≥500 mg per day) methylprednisolone for acute ON of unknown or demyelinating etiology. Twenty-eight patients were included in each treatment group. Visual acuity was measured with the Snellen letter chart, color vision with Boström-Kugelberg pseudo-isochromatic plates, and visual field with a Humphrey Field Analyzer.ResultsThe treatment results were similar in the two groups at follow-up, with no significant difference in visual acuity (p = 0.54), color vision (p = 0.18), visual field mean deviation (p = 0.39) or the number of highly significantly depressed test points (p = 0.46).ConclusionsThe results show no clinical disadvantage of using oral high-dose corticosteroids compared to intravenous administration in the treatment of acute ON, which would facilitate the clinical management of these patients.

<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.

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.