A Case Report: Morvan’s Syndrome

 

S Sreeni, Nafiya Muhammed Zackariah, Lakshmi R^*

Dept of Pharmacy Practice, Amrita School of Pharmacy, Kochi, Amrita Vishwa Vidyapeetham,

Amrita University, India

 

ABSTRACT:

Morvan’s syndrome is a rare autoimmune disorder showing peripheral nervous system hyperexcitability accompanied by autonomic and central nervous system (CNS) hyperactivity. Peripheral hyperactivity includes clinical and electrophysiological evidence of painful cramps, myokymia and neuromyotonia. Acquired neuromyotonia manifests clinically in cramps, stiffness and fasciculation. Autonomic symptoms include hyperhidrosis, fluctuations in blood pressure, tachycardia. CNS hyperactivity include insomnia, agitation, hallucination, confusion, anxiety. We present a case of 48 year old female with morvan’s syndrome with central, peripheral and autonomic hyperexcitability. Admitted with alleged history of seizure and was having memory disturbances, paraesthesia and perfused perspiration with palpitation. She tested strongly positive for CASPR2 antibodies and LHI1 antibodies. On the basis of symptoms like neuromyotonia, hyperhidrosis and insomnia with features of encephalopathy and indirect immunofluorescence the patient was diagnosed to have morvan’s syndrome. Treatment was started Inj. Methylprednisolone 1gm IV, during this treatment the patient restarted dysautonomia features then intravenous immunoglobulin (IVIG) and T. Cellcept (mycophenolate mofetil) 1mg BD was given. She was managed symptomatically over time.

 

 

 

INTRODUCTION:

Morvan’s syndrome is an eponymous disease also known as “La choreefibrillaire” in the late 19^th century is a very rare autoimmune disorder which affects the central, autonomic and peripheral activity characterized by a slow insidious onset of action¹. There are only limited number of reported cases of morvan’s syndrome in Indian subcontinent. The reported cases reflect the fact that majority of the patients were male². Some of the cases were thought to involve industrial and chemical workers.

 

The exact cause of the syndrome remains unknown. Pathogenesis involve the production of voltage gated potassium antibodies that target either contactin associated protein-2 (Caspr2, hippocampic and paranodal protein) or leucine rich, glioma inactivated 1 (Lgi1) protein and commonly presence of both³. Therefore is also known as an autoimmune synaptic syndrome. The involvement of only Caspr-2 protein is usually associated with thymoma. CNS activities are disrupted functionally rather than structurally.

 

Striking clinical features are myokymia (muscle twitching), insomnia (2-4hrs) confusion, memory problem, fluctuating delirium, agitation, hallucination, excessive sweating and dissociation of sensation⁴. Some other symptoms like painful fasciculations, rigid forms and pseudomyotonic cases are variable. Hyperhidrosis, constipation, blood pressure fluctuation and tachycardia are some of inter-related manifestations associated with autonomic neuropathy. There are also increased risk of thymoma in these patients.

 

Insomnia, a constant feature of morvan’s syndrome is also common in Isaac syndrome and limbic encephalitis. So polysomnography (neurophysiologic study) can give confusing diagnosis. Radioimmunoprecipitation screening assay detects the presence of specific VGKC complex auto antibody. Sometimes abnormal CSF level can also be taken as a hint to detect Morvan’s syndrome. Suspected thymoma can be confirmed by testing for Ach receptor antibodies. Disease can be further diagnosed by comprehensive autonomic testing, position emission tomography, EEG, Single proton emission CT and other imaging techniques like MRI⁵.

 

This disease is found to have poor prognosis. The treatment helped to achieve remission in 90% of cases. Plasmapheresis is one of the most commonly used first line treatment option⁶. IVIG, immunomodulatory therapy is preferred in case of urgent situation. Patients receiving IVIG should be reviewed regularly to ensure that the treatment remains appropriate⁷. Dose should be in such a way that the lowest dose produces appropriate clinical outcome for each patient. The treatment helps to slow or modulate the unwanted response of the body and disease progression.

 

Use of immunosuppressive agents like Cyclophosphamide helped clinically. Oral corticosteroids like Prednisolone and other agents like carbamazepine, propranolol are also related with symptomatic improvement⁸. Oxycodone, a synthetic opioid is sometimes preferred for sleep maintenance. Thymoma associated Morvan’s syndrome is treated with neoadjuvant chemotherapy (cisplatin, doxorubicin, cyclophosphamide). Often thymectomy is carried out.

 

CASE REPORT

A 48 year old female with comorbidities of Type 2 diabetes mellitus on treatment was presented to casualty at 9. 30pm with alleged history of seizure at 8. 00pm and was loaded with Inj. Levetiracetam 500mg and observed under ICU care. Patient had background history of memory disturbances since 3 weeks, paraesthesia over the hands since 2 weeks involving right hand. Initially she had involvement of fingers of right hand, followed by involvement of both hands within 2 days and profuse episodic perspiration with palpitations. She had history of intermittent flickering of muscles, non painful mainly over arms and chest. She consulted Neurology OP and considering the possibility of brainstem stroke, she underwent MRI stroke protocol which was within normal limit and with probability of neuropathy and was advised Tab. Nootropil (piracetam) 800mg BD.

 

Routine blood workup showed low level of serum Na (Table 1, Table 2) and related work up showed SIADH as cause and she was started on Inj. 3% NaCl iv infusion with strict monitoring of serum sodium level.

 

Table 1: Serum sodium level

 

 

Table 2: Serum sodium level

 

*Normal range -Sodium serum (Na): 135 -145mEq/L

 

Then after 2 days correction the infusion was discontinued. MRI Brain showed no significant abnormality and portable half hour EEG did not show any epileptiform of abnormality. CSF study was considered which was within normal range including CSF cytology, smear and culture sensitivity. Her blood culture and urine culture were also negative. Neuroimmunology workup was performed inview of her waxing and waning consciousness level and she tested strongly positive for CASPR2 antibodies and mildly positive for LGI1 antibodies by indirect immunofluorescence. On the basis of history and workup done the possibility of Morvan’s syndrome was considered as patient was having neuromyotonia, hyperhidrosis and insomnia with features of encephalopathy. Patient’s relatives were explained in detail for the further management including need of immunotherapy, pulse steroid therapy followed by oral form of steroid to which they agreed. Started her on Inj. Methylprednisolone 1gm for 5 days with antibiotic coverage, rest, supportive management and also strict monitoring of her blood sugar levels. Improvement was noted on her sensorium and perspiration episodes with palpitation which gradually subsided. However at the same time her dyselectrolytemia was corrected with strict monitoring and was shifted to ward care.

 

During the corticosteroid course she restarted dysautonomic features. Proper explanation was given to the relatives and was given options for IVIG or Plasma exchange, to which they agreed toIVI G. Inj. IVIG 2g/kg body weight was given for 5 days and improvement was noted in her sensorium and gradually subsidence of dysautonaomia. She was managed symptomatically over the time. Following IVIG Tab. Cellcept (mycophenolate mofetil) 500mg BD was started with serial monitoring of required routine parameters.

Table. 3: Neurophysiological findings

TEST DONE	COMMENTS
Electroencephalogram (EEG)	Recording showed mild degree of generalized nonspecific disturbance of electrical function. Presence of triphasic waves.
Blood Smear Peripheral	Normocytic normochromic blood picture with neutrophilia.
Indirect immunofluorescence on transfected cells	Sample tested strongly positive for Caspr2 antibodies and positive for Lgi1 antibody.Caspr2 antibodies are associated with neuromyotonia and autoimmune encephalopathy, Lgi1 antibody associated with limbic encephalitis and fasciobrachial dystonic seizures.
Indirect immunofluorescence confirmed by immune dot plot	Serum sample was negative for Antineuronal Nuclear antibodies (ANNA-1, 2, 3), Purkinje Cell cytoplasmic antibodies(PCA-1, 2.Tr), Antiglial nuclear antibody (AGNA-1), Amphiphysin, Collapsin response mediator protein-5 (CRMP-5), Ma/Ta. Nervous system specific autoimmunity noted in the form of an unclassified antibody, clinical significance of which is uncertain.
Nerve Conduction Velocity (NCV)	Moderate degree of bilateral carpel tunnel syndrome (CTS)
Autonomic function Test (AFT)	Sympathetic dysfunction
9q m Rs score	Pretreatment: 03 Post treatment:02

 

Dermatologist’s opinion was sought for skin lesions over abdomen and trunk and advised topical applicants[ Aloe Vera Gel L/A BD for 1 week, Clindamycin phosphate 1% L/A BD for 1 week] in view of Milaria rubra and pustulosis. Endocrinologist’s option was considered for her fluctuating blood sugar level and their advice of dose modification of insulin [Inj. Lantus Insulin 20 Us. c 0-0-1, Inj. H. Actrapid Insulin 28-24-29; half an hour before meal] and oral hypoglycemic agents [Tab. Glyvomet (metformin) 500mg PO 1/2-1/2-0, T. Januvia (sitagliptin) 100mg 1-0-0 ] followed with strict blood sugar level monitoring. Patient had constipation and is managed with Syp. Looz (lactulose) 15ml PO HS andSOS.

 

After discharge Morvan’s syndrome was managed with Tab. Eptoin (phenytoin) 100mg PO, 1-1-1, Tab. Rivotril (clonazepam) 0. 5mg PO 0-0-1, Tab. Cellcept (mycophenolate mofetil) 500mg PO 1-0-1, Tab. Duloxetine 20mg PO 1-0-2, Tab. Lyrica (pregabalin) 75mg PO 1-0-1, Tab. Wysolone (prednisolone) 50mg 1-0-0. Planned to hike Tab. Cellcept (mycophenolate mofetil) to 1gm twice a day on follow up and considered tapering of steroid therapy by 6 weeks. Patient’s relatives were explained in detail about the need for further management and followup.

 

DISCUSSION

We present a case of morvan’s syndrome with central, peripheral and autonomic nervous system hyperexciatiblity associated with detectable serum Caspr2 antibodies and Lgi1 antibodies by indirect immunofluorescence. Antibodies are found in 30 to 50% of patients with neuromyotonia and in most of the patients with morvans syndrome ⁹. Our case tested strongly positive for Caspr2 and Lgi1. Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P et. al have studied 29 morvan’s syndrome cases, out of which 15 patients were positive for both Caspr2 and Lgi1, additional 3 patient had additional contactin-2 antibodies². Distinct phenotype of morvan’s syndrome can be contributed by different antibody.

 

Our patient had a history of paraesthesia over both hands (predominantly right hand) and intermittent muscle fasciculation over arms and chest. Case study done by Bajaj BK, Shrestha S on the same condition had shown symptoms of fasciculation in 24 year old male and this patient had palpitation same as in our case¹⁰. Study done by Abou-Zeid E, Boursoulian LJ, Metzer WS et. al shows morvan’s disease patient with memory problem similar to our case ¹¹. Morvan’s syndrome is characterized by autonomic (hyperhidrosis, obstipation and tachycardia), central (insomnia, confusion, memory problems and hallucination) and peripheral (painful cramps, neuromyotonia and myokymia) nervous system hyperexcitability¹. Our patient had CNS symptoms like insomnia, memory problems; ANS symptoms like hyperhidrosis, tachycardia; Peripheral nervous system symptoms include neuromyotonia.

 

 

Diagnosis is made on the basis of clinical presentation and neurophysiological findings. Various tests done for conforming morvan’s syndrome are Electroencephalogram (EEG), MRI brain, CSF cytology, Peripheral Blood Smear, Immunofluorescence test, ANA profile, PET CT imaging, Nerve Conduction Velocity (NCV) test and Autonomic function test (AFT). In our patient, immunofluorescence test was strongly positive for Caspr2 antibodies and mildly positive for Lgi1 antibodies¹². Caspr2 are responsible for neuromyotonia and autoimmune encephalopathy, Lgi1 antibody is associated with limbic encephalitis and fasciobrachial dystonic seizures. NCV test done showed moderate degree of carpel tunnel syndrome. AFT test suggestive of sympathetic dysfunction.

 

Morvan’s syndrome treatment aims on immunosupression, influencing ion channels and controlling neuropathic pain. The commonly used immunosuppression treatment is with plasmapheresis or intravenous IVIG. Patients tested positive for VGKC antibodies (Caspr2, Lgi1 and contactin 2) is recommended to start immunomodulatory therapy with concomitant oral immunosuppressive therapy applying corticosteroids or immunosuppressants^{13, 14}. In patients with VGKC antibodies plasmapheresis is not effective, and it is recommended to start with full dose of IVIG (2g/kg body weight) and continue the maintenance dose of corticoids¹⁵. Our patient tested positive for Caspr2 and Lgi1 antibodies, so IVIG 2g/kg body weight was preferred as the treatment along with Tab. Prednisolone 50mg 1-0-0. Tab. Mycophenolate mofetil 500mg 1-0-1 was added considering tapering of steroid therapy. Severe insomnia and sleep disturbances are commonly reported in Morvans syndrome as CNS manifestations. Disappearance of fasciculation and insomnia was achieved by Benzodiazepines, T ab. Rivotril (Clonazepam) 0. 5mg 0-0-1. Seizure was managed by adding Tab. Eptoin (Phenytoin) 100mg 1-1-1, and Tab. Lyrica (pregabalin) 75mg 1-0-1. Fibromyalgia wass reduced by including Tab. Duloxetine 20mg 1-0-2. Patient was also diagnosed to have milaria rubra and pustlosis, and was treated with Aloe Vera Gel L/A BD for 1 week, Clindamycin phosphate 1% L/A BD¹⁶. Tachycardia, impotence, constipation, urinary incontinence, sialorrhea and increased urinary and plasma catecholamine levels have been reported in different cases. In our case the patient had constipation and was managed by Syp. Looz (lactulose) 15ml HS and SOS. Dyselectrolemia was corrected by taking Inj. 3% NaCl infusion, Syp. Potklor 15ml TID and Tab. Neurobion forte 0-1-0. The patient having morvan’s syndrome gradually improved symptomatically in treatment with IVIG and corticosteroid.

 

 

CONCLUSION:

We presented here a case of 48 year old female with morvan, s syndrome, with antibodies to Caspr2 and Lgi1, which are detected only in 50% of the patients. The disease is characterized by autonomic dysfunction, peripheral symptoms, neuropathic pain and cerebral symptoms. Patient had seizure which is a rare symptom in morvan’s syndrome. The patient was treated with IVIG and subsequent oral steroid therapy, then added immunosuppressants with a plan to taper steroid treatment. Benzodiazepines, fibromyalgic agents and anticonvulsants along with the first line treatment helped in symptomatic improvement. After the treatment patients clinical and neurophysiological findings gradually improved.

 

ACKNOWLEDGEMENT:

We obtained permission from patient to publish this case report.

 

CONFLICT OF INTERESTS:

Declared None

 

REFERENCE:

1.        WalusinskiOHonnorat J. Augustin Morvan (1819–1897), a little-known rural physician and neurologist. Revue Neurologique. 2013; 169(1):2-8.

2.        Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, Zuliani L, Watanabe O, Lang B, Buckley C, Vincent A. Morvan syndrome: clinical and serological observations in 29 cases. Annals of neurology. 2012 Aug 1; 72(2):241-55.

3.        Barber PA, Anderson NE, Vincent A. Morvan’s syndrome associated with voltage-gated K channel antibodies. Neurology. 2000 Feb 8; 54(3):771.

4.        Loukaides P, Schiza N, Pettingill P, Palazis L, Vounou E, Vincent A et al. Morvan's syndrome associated with antibodies to multiple components of the voltage-gated potassium channel complex. Journal of the Neurological Sciences. 2012; 312(1-2):52-56.

5.        Josephs KA, Silber MH, Fealey RD, Nippoldt TB, Auger RG, Vernino S. Neurophysiologic studies in Morvan syndrome. Journal of clinical neurophysiology. 2004 Nov 1; 21(6):440-5.

6.        Löscher WN, Wanschitz J, Reiners K, Quasthoff S. Morvan's syndrome: clinical, laboratory, and in vitro electrophysiological studies. Muscle and nerve. 2004 Aug 1; 30(2):157-63.

7.        Díaz-Manera J, Rojas-García R, Gallardo E, Juárez C, Martínez-Domeño A, Martínez-Ramírez S, Dalmau J, Blesa R, Illa I. Antibodies to AChR, MuSK and VGKC in a patient with myasthenia gravis and Morvan's syndrome. Nature Clinical Practice Neurology. 2007 Jul 1; 3(7):405-10.

8.        Panzer J, Dalmau J. Movement disorders in paraneoplastic and autoimmune disease. Current opinion in neurology. 2011 Aug; 24(4):346.

9.        EhlerEMeleková A. Neuromyotonia with polyneuropathy, prominent psychoorganic syndrome, insomnia, and suicidal behavior without antibodies: a case report. J Med Case Reports. 2015; 9(1).

10.     Bajaj BK, Shrestha S. An intresting case report of Morvan’s syndrome from the Indian subcontinent. Neurology India. 2007 Jan 1; 55(1):67.

11.     Abou-Zeid E, Boursoulian LJ, Metzer WS, Gundogdu B. Morvan syndrome: a case report and review of the literature. Journal of clinical neuromuscular disease. 2012 Jun 1; 13(4):214-27.

12.     Tan KM, Lennon VA, Klein CJ, Boeve BF, Pittock SJ. Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology. 2008 May 13; 70(20):1883-90.

13.     Kim NH, Vincent A, Irani SR, Kim SE, Lee KW, Park KS. Long-term clinical course with voltage-gated potassium channel antibody in Morvan's syndrome. Journal of neurology. 2013 Sep 1; 260(9):2407.

14.     Merchut M. Management of Voltage-Gated Potassium Channel Antibody Disorders. Neurologic Clinics. 2010; 28(4):941-959.

15.     Rinaldi C, Russo C, Filla A, De Michele G, Marano E. Course and outcome of a voltage-gated potassium channel antibody negative Morvan’s syndrome. Neurological Sciences. 2009; 30(3):237-239.

16.     Dermatologic Manifestations of Miliaria Treatment and Management: Medical Care, Activity [Internet]. Emedicine. medscape. com. 2016 [cited 26 August 2016]. Available from: http://emedicine. medscape. com/article/1070840-treatment.

 

 

Accepted on 20.01.2017           © RJPT All right reserved