Continuing Education Activity

Morvan syndrome or Morvan fibrillary chorea (MFC) is a rare constellation of neurological symptoms, consisting of peripheral nerve hyperexcitability, autonomic instability, and encephalopathy often associated with autoantibodies to voltage-gated potassium channel complexes (VGKCs). This activity reviews the pathophysiology of Morvan syndrome and highlights the role of the interprofessional team in its management.

Objectives:

• Review the etiology of Morvan syndrome.
• Describe the presentation of Morvan syndrome.
• Summarize the treatment of Morvan syndrome.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by Morvan syndrome.

Introduction

Morvan syndrome or Morvan’s fibrillary chorea (MFC) is a rare constellation of neurological symptoms, consisting of peripheral nerve hyperexcitability, autonomic instability, and encephalopathy often associated with autoantibodies to voltage-gated potassium channel complexes (VGKCs).

On 12 April 1890, the French physician, Dr. Augustine Marie Morvan first published a novel description of this neurological syndrome in La Gazette Hebdomadaire de Medecine et de Chirurgie.  He called it “la choree fibrillaire,” which we now know as Morvan syndrome[1][2][1]. There have been approximately 60 cases published in the French and other literature but only a few in English literature since then. See table 1 in media section at the end of this script for a review and comparison of the varied clinical features and clinical outcomes in 20 such cases reported in English literature[3][4][5][6][7][8][9][1][10][11][12][13][14][15][16][17][18][4].                                                                                                                                    As per table 1, Morvan syndrome is predominantly a male-dominant entity with a male to female ratio of 19 to 1. The only female case was a rheumatoid arthritis patient on gold therapy who developed mild Morvan syndrome features, and whose condition reverted once treatment was discontinued. Insomnia, hyperhidrosis, dysautonomia, and myokymia were consistent findings noted in 100% (all 20) of the patients. Whereas, hallucinations were seen in 75% (15) of the patients and anti-voltage-gated potassium channel antibodies (VGKC) were observed in 45% (9) of the patients. Another very consistent finding was the conspicuous absence of seizures in 100% (all 20) of the cases and benign findings on MRI in 100% (all 20) in contrast to Limbic encephalitis where seizures and temporal lobe structural abnormalities on MRI are classic findings. Myokymia was seen in 100% (all 20) of the patients, and it was confirmed in most 80%(16) cases with EMG studies which showed spontaneous, either repetitive or continuous muscle activity in the form of fasciculations which were a combination doublet, triplet, multiplet, or neuromyotonic discharges. Other sporadic findings were elevated manganese levels in 5% (1), oligoclonal bands in cerebrospinal fluid (CSF) in 15% (3), thymoma in 40% (8), Acetylcholine receptor (AchR) antibodies in 30% (6) of patients. However, AchR antibodies in association with myasthenic features were seen in only 10% (2) of the patients. Twenty percent (4) of the patients had AchR antibodies without myasthenic features. Treatment modalities tried with varied effectiveness were thymectomy in 25% (5), anticonvulsant therapy in 45% (9), immunosuppression in 50% (10), and IVIG in 20% (4) of the patients. The most effective treatment was plasma exchange which was tried in 55% (11) of the patients, all of whom except one patient showed dramatic improvement. Treatment effectiveness was even more significant when immunosuppression and plasma exchange was tried together. Death was the outcome in only 20% (4) of the patients.

Etiology

Initially, the precise etiology of this syndrome was not completely understood. Occasional reports of heavy metal poisoning like gold[18], manganese[8], and mercury[19] were implicated in its etiology and pathogenesis. Association with elevated cerebrospinal fluid (CSF) IgG and oligoclonal bands[11][12], thyrotoxicosis[20] and autoimmune hypothyroidism[1], clinical or subclinical myasthenia, certain neoplasms like thymoma[6], small-cell lung cancer, teratoma, prostate adenoma, and carcinoma in situ of the colon[11][12][11], have also been implicated in its etiopathogenesis. Neuromyotonia alone occurring without any suggestion of central nervous system (CNS) or autonomic nervous system (ANS) involvement has been reported in association with Staphylococcus aureus infection in one case[21]. Another case following Legionnaire disease[4] and one associated with antibodies to N-type calcium channel has also been published[11]. Older reports have implicated lesions in the diencephalon, basal ganglia, and raphe nuclei in the brain and abnormalities in central serotonin metabolism[6][8].

However, presently, there is overwhelming evidence that strongly supports an autoimmune basis in its etiology where a strong association with autoantibodies to voltage-gated potassium channel complex (VGKCs)[4][5][1][11][12][11][1][5][22] are identified. It has become reasonably clear that VGKC antibodies are mainly directed against proteins that are an integral part of VGKC complexes in brain tissue. Proteins such as contactin-associated protein 2 (CASPR2) and leucine-rich glioma inactivated (1LGI1) were identified as primary targets for autoantibodies[23].

The first identified antibody target within the VGKC complex was CASPR2 in patients with Morvan syndrome. Subsequently, LGI1 was also recognized as an additional and significant target in a few cases with MoS and also limbic encephalitis (LE). In addition, a minority of patients have antibodies directed against the third identified antigenic component of the VGKC complex, namely contactin-2[6].

Epidemiology

The occurrence of Morvan syndrome is quite rare. Based on the published literature, Morvan syndrome is almost exclusively seen in males. This male preponderance is quite intriguing. One report has shown CASPR2 protein-coding mRNA in the prostate gland, which supports the possibility that the male reproductive system may also harbor these antigens besides brain tissue. This finding was consistent with the onset of Morvan syndrome in a few patients after scrotal drainage as reported by Irani et al.

Pathophysiology

As mentioned earlier antibodies against VGKC complex proteins, CASPR2, and LGI1 are now strongly implicated in the pathogenesis of Morvan syndrome[11][23]. There is experimental evidence that these antibodies can cause neuronal hyperexcitability by suppressing voltage-gated potassium outward currents needed for the repolarization of the motor nerve. Immunostaining of brain tissue showed that these antibodies target subtly different regions of the brain that is likely to be involved in the localization of the distinctive clinical features seen in Morvan syndrome.

CASPR2 antibodies are predominantly seen in Morvan syndrome and were often found in association with thymoma cases also. Furthermore, thymectomy and thymoma chemotherapy are likely to trigger the onset of Morvan syndrome which supports the possibility that thymic tumors shelter antigenic targets, particularly CASPR2, and become somehow exposed and potentially vulnerable to antibody attack following thymectomy or thymoma chemotherapy.

The various combinations of LGI1 and CASPR2 antibody binding in Morvan syndrome could contribute to the distinctive multifocal phenotype.

Monoaminergic diencephalic and brainstem nuclei are known to be involved in arousal, and autonomic homeostasis. A disturbance in this homeostasis can cause insomnia, dysautonomia, and less frequently hyponatremia.

Dysfunction in the neurons anywhere in the thalamus, hypothalamus, locus coeruleus, and raphe nuclei could produce insomnia.

The dysautonomia noted in Morvan syndrome is likely generated within the hypothalamus and raphe nuclei.

However, SIADH-related hyponatremia was sometimes found in patients with LGI1 antibodies. The LGI1 antibody binds to hypothalamic paraventricular neurons that produce ADH, which mediates water retention. This suggests that LGI1 antibody binding may increase ADH secretion which in turn causes hyponatremia, although some patients with CASPR2 antibodies do have low plasma sodium due to some unknown mechanism.

It was found that LGI1 or CASPR2 antibodies bind to all these regions and possibly have variable specificities at the subcellular level that may determine the relative functional significance of each antibody. Besides the target antigen distribution, other factors, including the accessibility to circulating antibodies and physiological properties of neuronal populations, may also determine the clinical manifestations.

As mentioned earlier in etiology some patients did also have anti-contactin-2 antibodies, which are only rarely found in LE; contactin-2 is expressed in cardiac conduction tissue and some reports that found anti-contactin-2 antibodies had had cardiovascular instability. Some other patients had reactivities to antigenic targets that were not consistent with LGI1, CASPR2, or contactin-2, leading to the suspicion that different antibody reactivities are present in, at least, some of these patients. Therefore, to facilitate further understanding, more research and data are needed.

History and Physical

Morvan syndrome is mainly a clinical diagnosis[8][1](see also table 1). It is characterized by features caused by central, autonomic, and peripheral nervous system hyperactivity[14].

1. The CNS features include encephalopathy, severe insomnia, vivid complex hallucinations, delirium, spatial and temporal disorientation, confusion, amnesia, agitation, and belligerence.
2. The ANS features, due to autonomic instability, are excessive sweating, fever, palmoplantar erythema, pruritus, drooling, severe constipation, excessive lacrimation, arrhythmias, hypertension, weight loss, skin and rarely hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion[1][24].
3. The peripheral nervous system (PNS) features are peripheral nerve hyperexcitability resulting in continuous muscle fiber activity, neuropathic pain, areflexia (loss of deep tendon reflexes), and a stocking-type sensory loss. Continuous muscle fiber activity is manifested as neuromyotonia which is clinically seen as myokymia[9] (a term coined by Schultze in 1895 to describe this unique, vividly visible muscular hyperactivity[7][9][25]).

These comprise most of the possible symptoms of Morvan syndrome. However, it is less likely for an individual patient to manifest all the above clinical features. The varied occurrence of the clinical features of the syndrome may depend on the type of antibody detected either anti-CASPR2 or anti-LGI1 or both or some other antibodies.

The presence of tumors (especially thymoma), weight loss, and additional antibodies directed toward the acetylcholine receptor are found in association with CASPR2 antibodies. Whereas, serum hyponatremia and delusions, as well as myoclonus, are more common in the presence of LGI1 antibodies.

Evaluation

As mentioned earlier, Morvan syndrome is a clinical diagnosis. A high index of clinical suspicion is needed to diagnose Morvan syndrome when a patient presents with a combination of above mentioned diverse clinical features. Most of the investigations that are usually performed in such patients, such as CSF analysis, brain MRI, EEG, PET scan, are typically unyielding. EMG studies can confirm myokymia. However, the detection of VGKC-complex antibodies is quite diagnostic. Although these antibodies are directed against CASPR2, LGI1, or more commonly both, CASPR2 antibody's predominance is found in association with thymoma cases.

Treatment / Management

Clinicians have tried several treatment modalities with variable clinical responses (see also table 1). These include gold therapy, antiepileptic agents such as carbamazepine, valproate, phenobarbital, phenytoin, and procedures such as thymectomy.

However, plasma exchange appears to be the most effective treatment available for Morvan syndrome as seen in several cases, besides immunosuppression[1]. Immunosuppression is a patient response-based, and it is usually the initial treatment modality tried before plasma exchange. Due to unclear reasons, clinical response to plasma exchange and immunosuppression is also variable. It is probably related to the varied serum factors responsible for causing symptoms in mixed patient populations. Some authors postulate that with Morvan syndrome associated with other autoimmune conditions like myasthenia and autoimmune thyroid disorders, immunosuppression is more effective.

Differential Diagnosis

The first 2 close differentials of Morvan syndrome are limbic encephalitis (LE) and acquired neuromyotonia (Issac syndrome). A few others are also mentioned below.

1. Limbic encephalitis[24] has remarkably similar CNS features like Morvan syndrome. However, subtle differences do exist between these two conditions. Severe insomnia, hyperhidrosis, and myokymia are characteristics of Morvan syndrome. Whereas LE has amnesia, seizures, and temporal lobe structural abnormalities on imaging. LE differs from Morvan syndrome with the conspicuous absence of NMT, dysautonomia. There are other biochemical and radiological differences also. CASPR2 antibodies are more predominant in Morvan syndrome; LGI1 antibodies are more predominant in LE. Additional features that distinguish Morvan syndrome from classical LE are the presence of neuropathic lower limb pain, weight loss, male gender, and association with thymomas.
2. Acquired neuromyotonia or Isaac syndrome[13] is a disorder similar to Morvan syndrome with peripheral nerve hyperexcitability but without overt CNS or ANS dysfunction which is noted very vividly in Morvan syndrome.
3. Guillain-Barre syndrome (GBS)[14] is an immune system-mediated ascending neuropathy with, both, muscle weakness including loss of deep tendon reflexes and sensory deprivation resulting from the damage of the peripheral nervous system. A viral infection usually triggers GBS and less commonly it can present after surgery or vaccination. Diagnosis is generally through clinical exclusion and supported by tests such as nerve conduction studies and CSF analysis. In severe cases, prompt treatment with intravenous immunoglobulins or plasmapheresis, together with supportive care, will lead to functional recovery in the majority.
4. Clinical features such as severe insomnia, hallucinations, mental confusion, complex motor activity, dreamlike state, autonomic activation collectively called "agrypnia excitata," which is a clinic feature often encountered in familial fatal insomnia (FFI), was also described in one report of Morvan syndrome[12]. However, FFI is a prion disease, and structural brain abnormalities are quite clearly seen on imaging, unlike Morvan syndrome.

Prognosis

The natural history of Morvan syndrome is variable. Some cases have been reported to remit spontaneously, and some required extensive treatment, mainly in the form of immunotherapy including plasma exchange and long-term immunosuppression. Some cases were fatal. The overall prognosis of Morvan syndrome was particularly poor when associated with thymoma.

Consultations

Patients suspected to have Morvan syndrome, due to its extensive neurological symptomatology, would certainly benefit from a neurology consultation. Depending on other clinical complications such as cardiac arrhythmias, either cardiology or an EP consultation would be pertinent.

Pearls and Other Issues

The remarkable clinical improvement usually noted after plasma exchange strongly supports the idea that autoantibodies cause this condition. Although the combination of CASPR2 and LGI1 antibodies could explain many aspects of the clinical phenotype, the entire clinical picture is not wholly defined by antibodies against CASPR2 and LGI1 alone. It is possible that some antibodies directed against other VGKC-complex proteins exist which would help to explain the multifocal localization of the phenotype.

Further studies to precisely determine all such antibodies besides anti CASPR2, LGI1, and Contactin2, their triggers, their binding sites, and their molecular targets are needed. Whether serum antibodies affect CNS directly or indirectly via altering some neurohormones is also not clear and requires further investigation. Indeed it is an autoimmune phenomenon, however, what triggers the autoimmune phenomenon is unclear in most cases. The possibility of other serum factors besides autoantibodies or a primary occult malignancy manifesting its paraneoplastic features prematurely also are not eliminated.

Enhancing Healthcare Team Outcomes

In patients presenting with continuous muscle fiber activity syndromes, although rare, Morvan syndrome should always be kept in the differential. An exhaustive search for thymoma or other occult malignancies, anti-VGKC antibodies, and other autoantibodies should be done for early diagnosis and early treatment of this treatable, but possibly fatal, condition. If discovered, the best results will be achieved with an interprofessional team of specially trained nurses and clinicians providing patient care. [Level 5]