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.

Initially, a 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][11], 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 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].

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.

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 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.