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Neurological Sciences

, Volume 39, Issue 11, pp 1965–1969 | Cite as

Morvan’s syndrome—is a pathogen behind the curtain?

  • Rohit Singh
  • Pritam Das
  • Upinder Kaur
  • Anamika Misra
  • Ashis Choudhury
  • Sukdev Manna
  • Rohit Gaude
  • Deepak Gautam
  • Indrajeet Singh Gambhir
  • Sankha Shubhra ChakrabartiEmail author
Brief Communication

Abstract

Morvan’s syndrome is a rare syndrome of likely autoimmune etiology characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium with prominent hallucinations. Since its first mention in 1890, less than 100 cases have been described in literature. The largest existing review includes details of 29 cases. This case series describes 4 cases (M = 4) of Morvan’s syndrome which presented between May and November 2017 to a single tertiary care referral teaching hospital in north India. All the four patients manifested behavioral abnormalities, sleep disturbances, hallucinations, autonomic dysfunction, and clinical signs of peripheral nerve hyperexcitability, mostly as myokymia. Two of the patients had Anti-CASPR2 (contactin-associated protein 2) antibodies. Three of them had electromyography features of peripheral nerve hyperexcitability and only one had elevated cerebrospinal fluid protein level. We hypothesize that Morvan’s syndrome and other less characterized autoimmune encephalitis/peripheral nervous system syndromes may have infectious triggers. A possible viral trigger may result in generation of autoantibodies which result in the typical manifestations. We base these hypotheses on the finding of four cases of an orphan disease within a short period of time in a limited geographical distribution.

Keywords

Morvan’s syndrome Neuromyotonia Myokymia Viral Pathogenesis VGKC (voltage-gated potassium channel) 

Introduction

The French physician Augustine Marie Morvan first used the term “la chorιe fibrillare” to describe a syndrome characterized by peripheral nerve hyperexcitability, dysautonomia, insomnia, and fluctuating delirium [1]. Morvan’s syndrome belongs to the broad category of antibody-associated neurological conditions like limbic encephalitis and Isaacs’ syndrome but has certain distinctive features such as its association with high-titer CASPR2 antibodies and also the typical clinical features [2]. The CASPR2 protein (contactin-associated protein 2) of VGKC complex was the first identified antibody target in patients with Morvan’s syndrome. Subsequently, LGI1 (leucine-rich glioma inactivated 1) was identified as an additional and a major target in limbic encephalitis (LE) and in a few cases with Morvan’s syndrome [3]. CASPR2 and LGI1 antibodies bind to multiple brain areas, which justifies the various clinical features of this disease [4]. CASPR2 antibodies have also been associated with other diverse conditions such as a syndrome of Parkinsonism/ataxia and a syndrome of dementia/ataxia/aphasia [5, 6]. The diagnosis of Morvan’s syndrome is made by the hallmark symptoms of myokymia or neuromyotonia, dysautonomic symptoms, severe sleep disturbance, and fluctuating encephalopathy, mostly with vivid hallucinations. For uncertain reasons, males are predominantly affected (M:F = 9:1). The median age of onset is in the late 50s. Electromyography typically shows spontaneous muscle fiber activity with fasciculations, multiplets, myokymia, and neuromyotonic discharges [7]. Brain imaging is usually normal and electroencephalography is either normal or shows diffuse slowing with absence of NREM (non-rapid eye movement sleep) phase, presence of atypical REM (rapid eye movement), and a 4–6 Hz theta wave activity [4, 7]. Several cases have been found to occur in patients with the background of thymoma [8], other malignancies, and neurological autoimmune syndromes such as myasthenia gravis [4, 8]. It is prudent to remember that neither the bland imaging features or presence of autoantibodies or typical electrophysiologic findings or an underlying tumor is an absolute essential for making a Morvan’s diagnosis, and diagnosis is predominantly clinical [4, 9]. Several features of Morvan’s syndrome are also shared with limbic encephalitis syndromes including viral and autoimmune encephalitis but a prominence of peripheral nerve hyperexcitability and insomnia and a relative absence of seizures characterize Morvan’s syndrome [10]. The treatment options for Morvan’s syndrome include steroids, plasmapheresis, and other immunosuppressants. Prognosis is variable [9].

Case series

Between May 2017 and November 2017, our center had multiple patients with complaints of insomnia with abnormal sleep behavior and hallucinations, continuous twitching of muscles of all four limbs (myokymia) in variable combinations, along with few of them also manifesting hyperhydrosis, palpitations, urinary symptoms, burning sensation in hands and feet, and intense itching, for weeks to months. The case summaries of four patients are provided in Table 1. The salient findings supporting the diagnosis of Morvan’s syndrome in respect to past literature are summarized in Table 2. Routine hematological and biochemical investigations including thyroid profiles were within normal limits for all patients except the fourth patient where elevated liver enzymes, deranged creatinine, and anemia were noted. No history of toxin or occupational exposure could be elicited. The course of treatment and outcome is detailed in Table 3. Patient-1 did not give consent to publish video footage. The videos of peripheral nerve hyperexcitability features of patients-2, 3, and 4, collected after taking written informed consent are presented as Videos 1, 2, and 3. The geographical distribution of the four cases is depicted in Fig. 1. During the same period, another 65-year-old man presented to the geriatric service with peripheral nerve hyperexcitability features. He had been taking oral prednisolone from his general practitioner for an exacerbation of chronic obstructive pulmonary disease. Myokymia was observed in this patient twice and he also complained of sleep disturbance but he did not consent to videography or further advanced investigations and obtained a discharge from the ward after improving with standard antibiotic therapy for community-acquired pneumonia. The patient has been lost to follow-up since. The authors feel that the early initiation of oral steroids in this patient for an unrelated illness may have prevented his Morvan’s syndrome-like symptoms from aggravating. No further cases of Morvan’s sydrome-like illness could be traced in the absence of a centralized data reservoir in our setup, for the said period. There have been no published case series of Morvan’s syndrome cases from nearby regions or any other part of India during the same period, as evident from a thorough search of existing medical literature.
Table 1

Clinical details of the four patients in brief

Case

Age/gender

History

1

35 years, male

Patient had fever for 10 days, around 2 months back; treated locally empirically for malaria. Then he gradually developed generalized muscular twitching, decreased sleep, intermittent irrelevant talking, and generalized pruritus. These had lasted for almost 45 days, at the time of presentation. On admission; myokymia, pruritus, hyperhidrosis, severe insomnia and intermittent irrelevant talking, and violent behavior were noted. Orthostatic hypotension was recorded on multiple occasions.

2

55 years, male

Patient presented with low backache, more in morning without any aggravating or relieving factors, for 45 days. He also had fever with burning micturition and increased urinary frequency. He had generalized myokymia and polyminimyoclonus for the past 15 days and also complained of insomnia, hyperhidrosis, and generalized pruritus.

3

65 years, male

Patient presented with altered behavior in the form of irritability for 1 month, severely decreased sleep for 20 days such that he used to get up and run away during sleep. There was also positive history of generalized pruritus since 10 days back and visual hallucinations for 7 days. At presentation, the patient was in delirium. Orthostatic hypotension was documented on multiple occasions. Myokymia was present in the thighs and legs predominantly.

4

80 years, male

Patient presented with bilateral lower limb myokymia since 1 month back and altered behavior for 15 days, visual hallucinations for 10 days and decreased sleep since last 7 days. The patient also had three episodes of generalized tonic clonic seizures in the 3 days before presentation and presented in delirium. Orthostatic hypotension was recorded on several instances throughout hospital stay. Myokymia was present in the thighs and legs predominantly.

Table 2

Salient findings in the four patients supporting a diagnosis of Morvan’s syndrome

Case no.

Seizure

Hallucination

Altered behavior/confusion

Autonomic dysfunction

Sleep disorder

Itching/neuropathic pain

MRI done

Anti-CASPR2 Abs

Clinical Pnh

EMG Pnh

Thymoma on CECT thorax/neck

1

+

+

+

+

+

+a

+

+

+

2

+

+

+

+

+

+

+

+

+

3

+

+

+

+

+

b

+

+

Not donec

4

+

+

+

+

+

+

+

+

Not doned

Not doned

Cases-2, 3, and 4 did not have supportive findings on neuroimaging

Pnh- features suggestive of peripheral nerve hyperexcitability [clinical features observed included myokymia and polyminimyoclonus; EMG features included doublet, triplet, or multiplet motor unit discharges in patients-1 and 2; multiple fasciculations in patient-3]

aIncreased T2/FLAIR signal involving bilateral medial temporal lobes and hippocampi. Features suggestive of limbic encephalitis

bContrast-enhanced CT scan done

cPatient wanted referral to other center

dPatient succumbed and investigations could not be done

Cerebrospinal fluid analysis: only patient-3 had elevated protein level of 80 mg/dL. All other reports were normal

Table 3

Course of treatment of the four patients

Case

Course

1

The patient initially responded to intravenous (iv) methylprednisolone and was discharged on 1 mg/kg oral prednisolone and azathioprine. After one and a half months, the patient developed insomnia and altered behavior again. Option of plasmapheresis was given to caregivers but due to financial issues this was refused. The patient was started on 2 mg/kg oral prednisolone and again improved symptomatically but succumbed to skin infections and sepsis after one and a half months.

2

The patient had predominantly burning pain and polyminimyoclonus. He was started on iv methylprednisolone and then shifted to 1 mg/kg oral prednisolone. Abnormal movements improved but dysesthesias persisted. He was given option of plasmapheresis. Plasmapheresis was done 1 month later and maintenance azathioprine was started. The patient improved symptomatically and is on follow-up.

3

The patient was started on iv methylprednisolone. Insomnia improved, altered behavior improved. The patient had financial issues and sought referral to an alternate center where he had subsidized facility for further management. MRI brain could not be done due to a pacemaker implant.

4

During initial workup the patient suffered an NSTEMI. The patient was shifted to coronary care facility where conservative management was done. The patient had a second episode of NSTEMI after 3 days and died. In this case, steroid could not be given, and the spectrum of symptoms persisted during course of hospital stay.

Fig. 1

The four sites from which the cases presented. 1 Garhwa (Jharkhand state); 2 Saran (Bihar state); 3 Gazipur (Uttar Pradesh state); 4 Bhabua (Bihar state). The distance between points 1 and 2 which are the farthest from each other is approximately 260 km by road

Discussion

Since the condition was first described in 1890, there have been mostly isolated case reports of Morvan’s syndrome. The most extensive review of Morvan’s syndrome details the findings of 29 cases [4]. The geographical dispersion of these cases is wide with three cases reported from India at different times. The cases are uniform for neuromyotonia which was documented in all 29 patients at various times during disease course [4]. Apart from this, the other clinical features observed, namely, autonomic fluctuation, sleep disorders, and delirium with hallucinations, may be seen in viral encephalitides too [11, 12]. Likewise, the same review describes normal MRI findings in 27 of the 29 cases. One case had right frontal T2 hyperintensity, and another had bilateral hippocampal T2 high signal [4]. Cortical T2 hyperintensities may be seen in yet uncharacterized viral encephalitides [11]. Even in our current series, the first patient had similar MRI findings. Cerebrospinal fluid findings in the review of 29 cases were abnormal in nearly half of the patients (47.7%) with moderate lymphocytosis and increased protein levels being seen in 4/29 and 5/29 cases respectively [4]. Again, viral encephalitides are known to demonstrate such features [11]. Many autoimmune conditions have been hypothesized in the past to have viral or other infectious triggers. These include SLE incited by mycoplasma [13], Guillain–Barre syndrome following Campylobacter infection [14], autoimmune hemolytic anemia following Epstein–Barr virus infection [15], and most notably post-streptococcal rheumatic fever and glomerulonephritis [14]. Devastating neurological syndromes such as acute disseminated encephalomyelitis (ADEM) are also presumed to follow a viral prodrome [16].

The peripheral nerve hyperexcitability–central nervous system syndromes such as Morvan’s syndrome share many common features with viral encephalitides and have been touted in recent times to have an autoimmune etiology. Many of the tentative antibodies have been demonstrated, most notably the anti-CASPR2 antibodies. We hypothesize that there may exist an infectious trigger for Morvan’s syndrome. We base this hypothesis on the finding of five cases of a historically rare condition at a single center over a short time span of 6 months and a restricted geographical dispersion of the cases. The four described cases had not much in common with respect to occupational exposures. The areas from whom the cases presented are in a similar subtropical geographical zone with a hot and humid summer merging into a dry winter [17]. The zone is endemic to many diseases, being a part of India with the highest poverty and illiteracy rates. Malaria, enteric fever, several pyogenic bacterial respiratory, and gastrointestinal infections are rampant. However, an intensive literature search did not reveal any disease epidemics in the concerned region out of the ordinary. Viral encephalitis cases also occur frequently but, in most cases, the etiological agent is undiagnosed. Japanese encephalitis is the most common diagnosed cause of viral encephalitis, but the symptom profile is completely different from that observed in this report [18]. The situation with regard to viral encephalitides is not entirely different in developed nations. For example, a study from a referral center in Italy stated nearly 66.3% cases of acute viral meningoencephalitis in adults to be of unknown etiology [19]. The authors hypothesize that the triggering pathogen in this case is most likely a virus. An initial viral trigger is more likely to be undetected due to the wide spectrum of viral illnesses and the high likelihood of an asymptomatic infection. Certain similarities between the clinical features and radiological manifestations of viral encephalitides and Morvan’s syndrome also provide reason to believe in such a trigger. A viral antigen may serve as a mimic for human neural antigens which may trigger an antibody response or cell-mediated toxicity towards the nervous system. Alternatively, a viral infection of human neural cells may result in the generation of novel epitopes or unmasking of hidden epitopes which may trigger an autoimmune response.

Incidentally, when the initial two cases presented at our center, we managed them as isolated cases of Morvan’s syndrome. In the presence of a normal cerebrospinal fluid analysis and absence of typical features of viral encephalitides, no attempt was made to identify a possible viral trigger. Only by the time the third and fourth cases were admitted in our ward, we suspected an infectious precursor inciting an autoimmune response like Morvan’s syndrome. Trying to detect the inciting agent posed new challenges. An autoimmune phenomenon is generally a delayed response to an infectious trigger and by the time the autoimmune process has set in, no evidence of the original infection may be found. Further, there are few epidemiological studies with respect to common viral pathogens causing encephalitis in the concerned part of north India. The etiology of most cases remains undetected apart from Japanese encephalitis whose symptom profile is completely different from that observed in our patients [18]. Hence, testing may not have yielded desired results considering huge cost constraints of testing for individual pathogens. Another important reason was that the authors were looking for a yet unreported viral association and the best technique to use would have been a next generation sequencing study performed on cerebrospinal fluid samples. Unfortunately, such facilities were absent at our center in the absence of a dedicated virology laboratory. The absence of testing for viral etiologies is a shortcoming of this report but the possibilities of false positives and cost-benefit analyses precluded such an attempt. We still believe that the finding of 5 cases of a historically rare condition within 6 months, only around 100+ cases of which have been described in more than hundred years of the entity being known suggests an infectious trigger.

Conclusion

We hypothesize an infectious trigger for the autoimmunity that plays a major role in the pathogenesis of Morvan’s syndrome. Further research may help in identifying the trigger pathogen. This would allow physicians to intervene at an early stage on the lines of penicillin therapy in rheumatic fever. Although, Morvan’s syndrome cases have been shown to respond to steroids, plasmapheresis, and other immunosuppressants; a quick look over previously reported cases show an unpredictable prognosis with deaths occurring even in those who responded early on [2, 4, 7, 9]. Early interventions may give some degree of control over prognosis.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10072_2018_3515_MOESM1_ESM.mp4 (3.8 mb)
Video S1 (MP4 3906 kb)
10072_2018_3515_MOESM2_ESM.mp4 (11.9 mb)
Video S2 (MP4 12179 kb)
10072_2018_3515_MOESM3_ESM.mp4 (9 mb)
Video S3 (MP4 9208 kb)

References

  1. 1.
    Walusinski O, Honnorat J (2013) Augustin Morvan (1819–1897), a little-known rural physician and neurologist. Rev Neurol 169(1):2–8CrossRefGoogle Scholar
  2. 2.
    Lancaster E (2016) The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol 12(1):1–3CrossRefGoogle Scholar
  3. 3.
    Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133(9):2734–2748CrossRefGoogle Scholar
  4. 4.
    Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C, Zuliani L, Watanabe O, Lang B, Buckley C, Vincent A (2012) Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol 72:241–255CrossRefGoogle Scholar
  5. 5.
    Kannoth S, Nambiar V, Gopinath S, Anandakuttan A, Mathai A, Rajan PK (2018) Expanding spectrum of contactin-associated protein 2 (CASPR2) autoimmunity—syndrome of parkinsonism and ataxia. Neurol Sci 39:455–460CrossRefGoogle Scholar
  6. 6.
    Sousa S, Guerreiro R, Carmona C, Gouveia LO, Pita F (2017) Caspr2 antibodies in a patient with prostate cancer: a cognitive deterioration with recurrent and paroxysmal gait ataxia and aphasia. Neurol Sci 38:2217–2219CrossRefGoogle Scholar
  7. 7.
    Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P et al (2001) Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 124(12):2417–2426CrossRefGoogle Scholar
  8. 8.
    Evoli A, Lancaster E (2014) Paraneoplastic disorders in thymoma patients. J Thorac Oncol 9(9):S143–S147CrossRefGoogle Scholar
  9. 9.
    Maskery M, Chhetri SK, Dayanandan R, Gall C, Emsley HC (2016) Morvan syndrome: a case report with patient narrative and video. Neurohospitalist 6(1):32–35CrossRefGoogle Scholar
  10. 10.
    Misawa T, Mizusawa H (2010) Anti-VGKC antibody-associated limbic encephalitis/Morvan syndrome. Brain Nerve 62(4):339–345PubMedGoogle Scholar
  11. 11.
    Kennedy PG (2004) Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 75:i10–i15CrossRefGoogle Scholar
  12. 12.
    Venkatesan A, Geocadin RG (2014) Diagnosis and management of acute encephalitis: a practical approach. Neurol Clin Pract 4(3):206–215CrossRefGoogle Scholar
  13. 13.
    Ginsburg KS, Kundsin RB, Walter CW, Schur PH (1992) Ureaplasma urealyticum and mycoplasma hominis in women with systemic lupus erythematosus. Arthritis Rheum 35(4):429–433CrossRefGoogle Scholar
  14. 14.
    Ercolini AM, Miller SD (2009) The role of infections in autoimmune disease. Clin Exp Immunol 155(1):1–5CrossRefGoogle Scholar
  15. 15.
    Karunarathne S, Weerasinghe S, Govindapala D, Fernando H, Jayaratne B (2012) Cold autoimmune haemolytic anaemia secondary to Epstein Barr virus infection presenting with peripheral gangrene; case report. Thromb J 10(1):4CrossRefGoogle Scholar
  16. 16.
    Chaudhuri A, Kennedy P (2002) Diagnosis and treatment of viral encephalitis. Postgrad Med J 78(924):575–583CrossRefGoogle Scholar
  17. 17.
    Peel MC, Finlayson BL, McMahon TA (2007) Updated world map of the Köppen-Geiger climate classification. Hydrol Earth Syst Sci 11:1633–1644CrossRefGoogle Scholar
  18. 18.
    Narain JP, Dhariwal AC, MacIntyre CR (2017) Acute encephalitis in India: an unfolding tragedy. Indian J Med Res 145:584–587PubMedPubMedCentralGoogle Scholar
  19. 19.
    Monticelli J, Geremia N, D’Agaro P, Petix V, Luzzati R (2018) Aseptic central nervous system infections in adults: what predictor for unknown etiological diagnosis? Neurol Sci 39:863–870CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Rohit Singh
    • 1
  • Pritam Das
    • 1
  • Upinder Kaur
    • 2
  • Anamika Misra
    • 3
  • Ashis Choudhury
    • 1
  • Sukdev Manna
    • 1
  • Rohit Gaude
    • 1
  • Deepak Gautam
    • 1
  • Indrajeet Singh Gambhir
    • 4
  • Sankha Shubhra Chakrabarti
    • 4
    Email author
  1. 1.Department of General Medicine, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  2. 2.Department of Pharmacology (Previously Division of Geriatrics), Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  3. 3.Geriatric Research Lab, Department of Geriatric Medicine, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia
  4. 4.Department of Geriatric Medicine, Institute of Medical SciencesBanaras Hindu UniversityVaranasiIndia

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