Voltage Gated Potassium Channel Antibody Presenting with S

Published online: 2019-09-26

Case Report

Morvan’s syndrome with anti contactin associated protein like 2 – voltage gated potassium channel antibody presenting with syndrome of inappropriate antidiuretic hormone secretion Anjani Kumar Sharma, Manminder Kaur, Madhuparna Paul Department of Neurology, Sawai ManSingh Medical College, Jaipur, Rajasthan, India

ABSTRACT Morvan’s syndrome is a rare autoimmune disorder characterized by triad of peripheral nerve hyperexcitability, autonomic dysfunction, and central nervous system symptoms. Antibodies against contactin‑associated protein‑like 2 (CASPR2), a subtype of voltage‑gated potassium channel (VGKC) complex, are found in a significant proportion of patients with Morvan’s syndrome and are thought to play a key role in peripheral as well as central clinical manifestations. We report a patient of Morvan’s syndrome with positive CASPR2–anti‑VGKC antibody having syndrome of inappropriate antidiuretic hormone as a cause of persistent hyponatremia. Key words: Anti‑voltage‑gated potassium channel antibodies, hyponatremia, myokymia, Morvan’s syndrome, syndrome of inappropriate antidiuretic hormone

Introduction Case Report

Morvan’s syndrome is a rare autoimmune disorder A 45‑year‑old male presented with 4‑month duration characterized by peripheral nerve hyperexcitability, of nonradiating mild back pain, followed a month later autonomic dysfunction, and central nervous system by burning sensation in palms and soles with nocturnal symptoms.[1] The syndrome of muscle twitching, exacerbations. He developed abnormal twitching of dysautonomia, insomnia, and delirium was first reported muscles in both upper and lower limbs. He became by Morvan by the name of la choree fibrillare in 1890.[2] aggressive, over‑talkative, and insomniac over 15 days We report a rare case of contactin‑associated protein‑like before presentation. He had significant weight loss 2 (CASPR2), a subtype of voltage‑gated potassium during the period. channel (VGKC) complex antibody positive Morvan’s syndrome, with syndrome of inappropriate antidiuretic On examination, he was anxious and restless, having hormone secretion (SIADH). resting tachycardia and excessive sweating. His higher mental function and cranial nerves examinations were normal. He had continuous undulating twitching in both Address for correspondence: upper and lower limbs and back muscles. His knee and Dr. Manminder Kaur, Department of Neurology, ankle jerks were sluggish and rest of the examination Sawai ManSingh Medical College, was normal. Jaipur, Rajasthan, India. E‑mail: [email protected] This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows Access this article online others to remix, tweak, and build upon the work non‑commercially, as long as the Quick Response Code: author is credited and the new creations are licensed under the identical terms. Website: www.ruralneuropractice.com For reprints contact: [email protected]

How to cite this article: Sharma AK, Kaur M, Paul M. Morvan's DOI: syndrome with anti contactin associated protein like 2 – voltage gated 10.4103/0976-3147.188638 potassium channel antibody presenting with syndrome of inappropriate antidiuretic hormone secretion. J Neurosci Rural Pract 2016;7:577-9.

Hemogram, renal, liver, and thyroid functions were 1 mg/kg for 3 months and later tapered gradually over normal. Electromyography showed spontaneous activity next 2 months. including myokymic discharges [Figure 1], doublets, and triplets in both upper and lower limb muscles. Magnetic resonance imaging of the brain and lumbosacral spine Discussion was normal. The patient had positive serum anti‑CASPR2 Morvan’s syndrome is characterized by myokymia antibody, a subtype of VGKC complex detected by associated with muscle pain, excessive sweating, weight immunofluorescence method. His cerebrospinal fluid loss, hallucinations, sleep disorders, and behavioral examination showed raised proteins 76 mg/dl (normal: abnormality.[1,3] This is considered as a form of 20–40 mg/dl), with normal cell count (cells: 3/mm3, neuromyotonia having prominent central features. There all lymphocytes). Computed tomography (CT) of the was considerable overlap between central and peripheral chest showed no evidence of thymoma. The patient features in our patient. The basic mechanism for both was diagnosed as Morvan’s syndrome with positive presentations is same, that is anti‑VGKC antibody, anti‑CASPR2 – VGKC antibody. acts at different levels of neuraxis, both at central and peripheral level.[4] Association of SIADH is uncommon in There was persistent low serum sodium in the range VGKC–CASPR2 antibodies positive cases but common in of 125–130 mEq/L, for which patient was evaluated. anti‑leucine‑rich glioma inactivated‑1 (LGI‑1) antibodies His urinary osmolarity was raised (216.36 mOsm/kg, positive cases.[5] normal <100 mOsm/kg) and random urinary sodium was increased (42 mmol/L, normal <30 mmol/L). The VGKC‑complex antibodies include both CASPR2 serum osmolarity was decreased (271.5 mOsm/kg) and LGI‑1antibodies. LGI‑1 antibodies are usually and urinary specific gravity was 1.010. These findings associated with hyponatremia, and CASPR2 antibodies showed SIADH secretion as a cause of his persistent are usually associated with thymomas which carry poor hyponatremia. The patient was treated with intravenous prognosis. CASPR2 antibodies mostly bind the neuropil, immunoglobulin (IV Ig) 2 g/kg in 5 divided doses. He whereas antibodies to LGI‑1 bound to neuronal cell was given phenytoin at dose of 100 mg three times a bodies including the antidiuretic hormone‑secreting day for symptomatic relief for twitching, which acts as and orexin‑secreting hypothalamic neurons present membrane stabilizer. The patient was started on oral in hypothalamus, raphe nucleus, and locus coeruleus. prednisone (1 mg/kg) and fluid restriction was advised. Hyponatremia is not commonly reported in Morvan’s syndrome although it is present in half of the patient in He had marked improvement in muscle twitching LGI‑1 antibodies positive limbic encephalitis.[5] and was able to sleep properly with immunotherapy. Electromyography done 2 weeks after the course of IV Ig The classical electromyographic finding is the myokymic showed decrease in spontaneous activity; occasional and neuromyotonic discharges. In addition, fasciculation, fasciculations were seen. His hyponatremia was also doublets, triplets, multiplets, and positive sharp waves corrected. On follow‑up, after 3 months, the patient are also present. Management includes antiepileptic was completely normal and electromyography showed drugs and immunotherapy which improve the clinical no spontaneous activity. Oral prednisone was given and electrophysiologic manifestations.[6]

This is a rare case report of Morvan’s syndrome with SIADH having anti‑CASPR2–VGKC antibodies that responded to immunosuppression.

Financial support and sponsorship Nil.

Conflicts of interest There are no conflicts of interest.

References

1. Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Figure 1: Spontaneous activity in right tibialis anterior showing Neurophysiologic studies in Morvan syndrome. J Clin Neurophysiol. myokymic discharges (sweep speed: 0.1 ms and sensitivity: 50 µV) 2004;21:440-5.

578 Journal of Neurosciences in Rural Practice | October - December 2016 | Vol 7 | Issue 4 Sharma, et al.: SIADH in Morran's syndrome: A rare association

2. Löscher WN, Wanschitz J, Reiners K, Quasthoff S. Morvan’s syndrome: profile of twenty cases from northwest India. Neurol India 2006;54:382‑6. Clinical, laboratory, and in vitro electrophysiological studies. Muscle Nerve 5. Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, et al. 2004;30:157‑63. Morvan syndrome: Clinical and serological observations in 29 cases. Ann 3. Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Neurol 2012;72:241‑55. Neurophysiologic studies in Morvan syndrome. J Clin Neurophysiol 6. Rana SS, Ramanathan RS, Small G, Adamovich B. Paraneoplastic Isaacs’ 2004;21:440‑5. syndrome: A case series and review of the literature. J Clin Neuromuscul 4. Panagariya A, Kumar H, Mathew V, Sharma B. Neuromyotonia: Clinical Dis 2012;13:228‑33. Commentary

Morvan’s syndrome is a constellation of clinical VGKC antibodies negative for both the LGI 1 and CASPR presentations including encephalitis, peripheral nerve 2 have been recognized. VGKC antibodies are detected hyperexcitability and dysautonomia manifesting with with radioimmunoassay that labels Kv1.1 and Kv1.2 fluctuating delirium, insomnia, muscle twitching, subunits. Immunofluorescence tests and cell‑based assay and autonomic symptoms. The syndrome was first are used to further characterize VGKCs. Anti‑LGI 1 described by the name of “la chorée fibrillare” in antibodies are associated with limbic encephalitis, and the late 19th century by Augustin Marie Morvan. anti‑CASRR 2 antibodies are observed in neurological Various European and subsequently, Asian authors syndromes presenting with encephalitis, peripheral have reported individual case reports or case series nerve hyperexcitability, or a combination of both of Morvan’s syndrome.[1,2] The pathogenesis of known as Morvan’s syndrome. The alteration in the Morvan’s syndrome was earlier speculated to be two proteins, LGI 1 and CASPR 2, provides basis for due to exposure to toxins, particularly heavy metals the pathophysiological mechanisms for the clinical and/or presence of autoantibodies. The association symptoms of each type of autoimmune response. of the syndrome with malignancies mostly thymoma Associated hyponatremia has been found in up to 60%

as a paraneoplastic manifestation was subsequently of patients with LGI 1 antibodies. The target proteins recognized. The observation of autoimmune disorders and sites for these LGI 1 and CASPR2 negative VGKC such as myasthenia gravis and thyroiditis, detection antibodies are continuously being further characterized of autoantibodies to voltage‑gated potassium with each passing year. In this issue, the authors describe channels (VGKCs), and improvement on treatment a case with VGKC antibodies positive for CASPR2 with immunosuppressive/immunomodulatory presenting with Morvan’s syndrome and syndrome therapies established Morvan’s syndrome as an of inappropriate antidiuretic hormone (SIADH).[5] The autoimmune disorder affecting both the central and authors report that SIADH is known to be associated the peripheral nervous system. Antibodies to VGKC with LGI 1 antibodies and this observed association with have been identified in several other neurological CASPR2 antibodies has not been reported. LGI 1 is a disorders including neuropsychiatric syndromes, neuronal protein secreted at the synapses and interacts epilepsies, Creutzfeldt–Jakob disease mimickers, and with presynaptic ADAM 23 and postsynaptic ADAM 22 frontotemporal dementia.[3] VGKC complex antibodies to organize a trans‑synaptic protein complex. This has have been reported in hitherto unsuspected situations been linked to epilepsy in humans. Presynaptic Kv1.1 and such as patients with neuropathic pain syndromes, Kv1.2 subunits of potassium channels and postsynaptic children with status epilepticus, and chronic epilepsies. alpha amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic This has greatly expanded the clinical spectrum of acid (AMPA) receptor form the other components of anti‑VGKC complex protein antibody associated this protein complex. LGI1 gene mutations have been autoimmune neurological disorders. associated with autosomal dominant lateral temporal lobe epilepsy and autosomal dominant partial epilepsy VGKC protein complex is a group of proteins that are with auditory features. In animal models, the mutation intensely associated in situ and even after extraction has been linked with increased neuronal excitability in mild detergent. The antibodies to VGKC were possibly resulting from decreased AMPA receptor initially thought to be against the epitopes of VGKC. activity in inhibitory neurons and increased glutamate Subsequent research revealed that the most of these release. antibodies are directed against leucine‑rich glioma inactivated protein‑1(LGI1) and contactin‑associated CASPR 2 belongs to neurexin superfamily that binds protein‑like 2 (CASPR2).[3,4] Recently, patients with to contactin 2. This is axonal transmembrane protein

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