Clinical manifestations

Presentation and course

	• Agrypnia excitata corresponds to the combination of severe insomnia with a vigil oneiric state manifesting as confusion, delusions, visual hallucinations, and dream-enacting behavior.
	• Peripheral nerve hyperexcitability in Morvan syndrome combines motor symptoms (fasciculations, myokymia), dysautonomia with profuse hypersudation and sinusal tachycardia, and neuropathic pain.
	• Neurologic relapses of Morvan syndrome often herald malignant thymoma recurrences.

Some publications use the term “Morvan syndrome” to depict patients with CASPR2-Abs who present with any type of combination of peripheral and central neurologic symptoms (35). Yet, progress in the characterization of CASPR2-Abs patients suggests this definition is not accurate (21). According to a stricter definition, Morvan syndrome consists of the association of agrypnia excitata with peripheral nerve hyperexcitability symptoms (11). In general, the symptoms install progressively over weeks or months. In most cases, peripheral nerve hyperexcitability symptoms predate agrypnia excitata. Because of the diversity of the symptoms and the difficulty of making precise clinical-anatomical correlations in patients, the diagnosis is often delayed. Most patients are seen in tertiary centers months after disease onset, when they have already developed severe symptoms. The course is often monophasic; however, relapses may occur indicating malignant thymoma recurrence, which should prompt oncological reassessment (15).

Agrypnia excitata. Agrypnia excitata refers to a type of insomnia combined with motor and autonomic hyperactivity (18). It was described in 3 unrelated disorders: fatal familial insomnia (a hereditary prion disease), alcohol-withdrawal syndrome, and Morvan syndrome (25). Patients with Morvan syndrome have severe insomnia, reporting only rare, short periods of sleep that are full of vivid dreams. Besides insomnia, they frequently develop nonspecific neuropsychiatric symptoms such as anxiety, mood disorders, and confusion (10). The patients become irritable and restless; some develop dark ideas of despair or incurability. In most cases, patients progressively develop an oneiric state in which they alternate between stupor and agitation, with loss of space and time orientation, and they characteristically present with complex dream-enacting behavior (17). Complex visual hallucinations are frequent (03). Some patients develop delusions, often with paranoid ideas, with marked fluctuations (05). In contrast, seizures are not considered part of Morvan syndrome, although generalized seizures have been reported in some cases (10). The severity of the insomnia and the accompanying neuropsychiatric symptoms vary from one patient to another and usually increase over disease progression (30).

Peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability is the second major feature of Morvan syndrome. It includes motor, autonomic, and pain symptoms (10). These features are similar to those of acquired neuromyotonia (Isaacs syndrome), although in the authors' experience, they are more severe in Morvan syndrome. Motor symptoms include cramps, fasciculations, and generalized myokymia (30). Fasciculations are small involuntary contractions of the skeletal muscles and are seen as twitching of single bundles, best observed under grazing light. Myokymia refers to the spontaneous rippling and twitching of muscles, which involves groups of muscle fibers, yet they are insufficient to move a joint. They appear as wormlike undulations under the skin, whereas in lower extremities, myokymia characteristically manifests as spontaneously moving toes, along with an incessant quivering of the calves. Abnormal postures of the limb, similar to carpal or pedal spasms, and pseudomyotonia (difficulty of relaxing, without the EMG features of myotonia) may be seen.

Besides motor manifestations, signs of dysautonomia are especially prominent, including profuse sweating, hyperlacrimation, excessive salivation, constipation, urinary and erectile dysfunction, and cardiovascular abnormalities (orthostatic hypotension, sinus tachycardia). Some cases of sudden death in patients with Morvan syndrome have been attributed to dysautonomia-related cardiac dysrhythmia (16). Acrodynia, which is painful swelling, discoloration, and desquamation of the fingers and/or toes, has been described in historical series (27). Other skin symptoms include skin miliaria and pruritus, which are likely related to the profuse hypersudation (30).

Lastly, most patients report neuropathic pain, described as burning, electrical discharges, or stabbing sensations. Neuropathic pain is more frequently observed in lower, rather than upper, limbs and is usually symmetrical. Its severity varies among patients, with some reporting severe pain with allodynia and others only describing paresthesia. There is usually no sensory deficit, and deep tendon reflexes are preserved. Interestingly, skin biopsies have normal epidermal nerve fiber density, whereas functional small fiber nerve tests are usually altered (14).

Other symptoms.

General status. Extreme fatigue and weight loss (up to 10 kg in some cases) are common (05; 21).

Myoclonus. Most patients present with myoclonus (34), which is in general asymmetrical, has a proximal predominance, and can be triggered by stimulation and orthostatism (08). Walking may be impaired due to inferior limb myoclonus and limb stiffness (34).

Ion disturbances. Hyponatremia is common; it is unclear if it is related to an inappropriate secretion of antidiuretic hormone or to other mechanisms (10).

Respiratory functions. Breathing difficulty, including cases of acute respiratory failure requiring mechanical ventilation, has been reported (05). It is unclear if it is imputable to severe bronchial congestion, laryngeal spasm, phrenic nerve section during thymoma resection, or a combination of these causes (10).

Prognosis and complications

Morvan syndrome is a life-threatening disease, and several cases of sudden-onset deaths have been reported. The cause of death in these cases is not clear, with possible involvement of cardiac dysrhythmia, ionic disorders, central hypoventilation, co-occurring myasthenic crisis, and laryngeal spasm. The intense dysautonomia may be a cause of sustained hypermetabolism, as reflected by the major weight loss seen in many patients, and can be a participating factor in the poor outcome. Otherwise, Morvan syndrome has been described as a highly treatable disorder, with some patients returning to baseline. The apparition of other autoimmune conditions (myasthenia gravis, autoimmune cytopenia) during the progression of Morvan syndrome or after remission is frequent and should be monitored. Relapsing and remitting progressions have been described, often paralleling thymoma recurrences.

Biological basis

	• Morvan syndrome is usually associated with CASPR2-Abs, but other co-occurring antibodies (eg, LGI1-Abs, DCC-Abs, AchR-Abs) are common.
	• The differences in genetic characteristics as well as oncological and autoimmune comorbidities compared to other CASPR2 phenotypes suggest a distinct pathogenesis.

Etiology and pathogenesis

The etiology and pathogenesis of Morvan syndrome are far from being elucidated. Despite some advances in understanding the potential effects of CASPR2-Abs, the underlying mechanisms of the central and peripheral features of Morvan syndrome are still obscure. In fact, studies suggest distinct pathogenic mechanisms for CASPR2-antibody-associated limbic encephalitis, neuromyotonia, and Morvan syndrome (21). In particular, Morvan syndrome patients frequently harbor autoantibodies other than CASPR2-Abs, and it remains unclear whether CASPR2-Abs play a major pathogenic role in Morvan syndrome or only represent useful biomarkers.

Immunology. More than 20 years ago, Morvan syndrome was associated with antibodies against the voltage-gated potassium channel complex (15). However, we currently know that these antibodies actually recognize 2 different proteins associated with the voltage-gated potassium channel: leucine-rich glioma inactivated 1 (LGI1) and CASPR2, the latter being the most commonly found in Morvan syndrome (09; 13). Nevertheless, the co-occurrence of CASPR2-Abs and LGI1-Abs in the sera of patients with Morvan syndrome is frequent (nearly 60%) and is especially associated with an underlying malignant thymoma (10; 35; 21). Similarly, antibodies against netrin-1 receptors have been described as paraneoplastic markers of malignant thymoma in patients with CASPR2-Abs, including Morvan syndrome (33; 21). Finally, despite being very rare, isolated positivity for LGI1-Abs has also been reported (10; 35).

Several studies investigated the effects of CASPR2-Abs on neuronal function, but the samples were obtained from patients with limbic encephalitis or acquired neuromyotonia. In addition, the obtained results were not consistent across studies, particularly with regards to the effects on CASPR2 internalization and Kv1 channel expression. Nevertheless, 2 independent groups found that CASPR2-Abs are able to block the interaction between CASPR2 and contactin-2/TAG-1, its best-known interactor within voltage-gated potassium channel complexes (24; 29). Moreover, purified immunoglobulin from CASPR2 patients intraperitoneally injected in mice decreased Kv1 and CASPR2 expression at the juxtaparanodes and at dorsal root ganglia, which might explain peripheral nerve hyperexcitability manifestations (04). A mouse model also using intraperitoneal infusion of CASPR2-Abs led to some behavioral changes, including social interactions and working-memory deficit (06), resembling some of the clinical features of CASPR2 limbic encephalitis. However, further research is needed to fully understand the pathogenic role of CASPR2-Abs.

Although the in vitro and in vivo effects of CASPR2-Abs from patients with Morvan syndrome is still unknown, the epitopes recognized by these antibodies have been shown not to differ from those of CASPR2-Abs from limbic encephalitis and acquired neuromyotonia (23; 12); therefore, it could be expected that they provoke the same effects. However, the difference in IgG subclasses (IgG4 being more common in the serum from limbic encephalitis patients) and CSF positivity is noteworthy as it has been reported that patients with Morvan syndrome lack CSF CASPR2-Abs (12; 21). It remains obscure whether the CNS signs and symptoms of Morvan syndrome are really caused by CASPR2-Abs or, to the contrary, other additional and still undiscovered antibodies are truly responsible for CNS involvement in this disorder.

Genetics. Initially, an overrepresentation of the human leukocyte antigen allele DRB1*11:01 was described in a cohort of patients presenting with different clinical phenotypes associated with CASPR2-Abs, including some cases of Morvan syndrome (01). However, this human leukocyte antigen association prominently involved patients with limbic encephalitis (more than 90% of carriers), whereas the carrier frequency in patients with Morvan syndrome was similar to that of controls (21). So far, no consistent genetic predisposition has been described in Morvan syndrome; its development seems to depend on thymoma-related processes rather than on a genetic predisposition towards CASPR2 autoimmunity. Further work is needed to clarify the immunobiology of Morvan syndrome.

Pathology. Only 2 necropsies from patients with Morvan syndrome have been reported, and consequently, our knowledge of the histopathological changes underlying this disorder is very limited. Some relevant findings include immunoglobulin deposition in the thalamus and striatum, absence of T-cell infiltration, and marked neuronal loss in cerebellar and brainstem nuclei (16; 31). Interestingly, the location of some of the aforementioned histopathological findings, such as the thalamus or the olivary nuclei, is similar to that observed in fatal familial insomnia, another disorder presenting with agrypnia excitata. Indeed, agrypnia excitata is thought to be caused by dysfunction or damage to the thalamolimbic circuit (25).

Epidemiology

The exact incidence of Morvan syndrome is unknown. Around a hundred cases have been reported in the English literature. Overall, it seems extremely rare. In addition, it is probably underrecognized as the medical community is relatively unfamiliar with it. The disease affects mostly adult males, but has been reported in women and children (22).

Differential diagnosis

Confusing conditions

Morvan syndrome may be confused with several disorders due to its wide and diverse clinical presentation, including other conditions associated with CASPR2-Abs. Peripheral nerve hyperexcitability is also the major feature of acquired neuromyotonia or Isaac syndrome, which can be distinguished from Morvan syndrome by the absence of CNS involvement and the usually milder signs and symptoms of peripheral nerve hyperexcitability. Limbic encephalitis with CASPR2-Abs may appear in combination with peripheral nerve hyperexcitability, and these cases may be particularly difficult to differentiate from Morvan syndrome. However, typical limbic features, such as memory impairment or temporal lobe epilepsy, are not part of the clinical spectrum of Morvan syndrome. Severe insomnia, as well as the oncological and autoimmune comorbidities typical of Morvan syndrome, are very unusual in limbic encephalitis patients (21).

Agrypnia excitata was described in only 2 diseases other than Morvan syndrome: fatal familial insomnia and delirium tremens (25). Fatal familial insomnia is a genetic prion disease caused by a missense mutation at codon 178 of the PRP gene. Age at onset varies from 30 to 60 years old, and median survival is approximately 18 months. Initial symptoms are often diurnal somnolence due to nocturnal insomnia, accompanied by psychiatric symptoms over several months until the development of dysautonomia, motor features, and cognitive decline. Contrary to other prion diseases, the ancillary tests (MRI, EEG, protein 14-3-3) are normal or unspecific.

Delirium tremens is an acute confusional state that appears 2 to 4 days after abrupt alcohol withdrawal. The usual clinical presentation includes severe psychomotor agitation with insomnia, tremor, fever, and sympathetic hyperactivity. Oneiric stupor, although also present in fatal familial insomnia and Morvan syndrome, is particularly prolonged and complex in delirium tremens. Anamnesis is crucial for the diagnosis of delirium tremens; moreover, the risk of delirium tremens is higher in alcoholics with heavy daily alcohol intake and prior episodes.

The combination of central and peripheral nervous system involvement observed in Morvan syndrome might also resemble that of other diseases, either of autoimmune origin, such as progressive encephalomyelitis with rigidity and myoclonus, or neurodegenerative origin, as amyotrophic lateral sclerosis.

Associated or underlying disorders

In contrast to other disorders associated with CASPR2-Abs, mainly limbic encephalitis, Morvan syndrome is very often a paraneoplastic condition. Malignant thymoma is the most common tumor found, with variable frequencies (40% to 80%) depending on the diagnostic criteria used for Morvan syndrome (10; 21). In addition, patients with Morvan syndrome and malignant thymoma often present with myasthenia gravis, which is usually generalized and seropositive for antibodies against acetylcholine receptor or other systemic autoimmune disorders (10; 35; 33; 21). Morvan syndrome and myasthenia gravis can occur independently; remarkably, in some patients, intervals of several years can be observed between the occurrences of the 2 disorders.

Other uncommonly reported tumor associations are lymphomas, prostate adenocarcinoma, and nonsmall cell lung cancer (10).

Diagnostic workup

	• Electromyography and polysomnography should be performed in every patient with clinical suspicion of Morvan syndrome.
	• Immunological investigations should include CASPR2-Abs and LGI1-Abs in serum and CSF.
	• MRI and cytobiochemical CSF analysis are usually uninformative.
	• Thoracic CT must be performed in order to exclude an underlying malignant thymoma.

Strategy to diagnosis. None of the signs and symptoms of Morvan syndrome are, in themselves, pathognomonic. The diagnostic workup aims at documenting the major defining features of Morvan syndrome (ie, peripheral nerve hyperexcitability and agrypnia excitata), detecting the associated antibodies, and, finally, excluding alternative diagnoses and potentially comorbid conditions.

Tests results.

Electromyography. A wide range of electromyographic findings characterize peripheral nerve hyperexcitability, including neuromyotonic and myokymic discharges, fasciculation and fibrillation potentials, and after discharges. Single motor unit discharges appear spontaneously as doublet, triplet, or multiplets. Those firing at the highest frequencies and showing an abrupt onset and end are labeled as neuromyotonic discharges, whereas the term “myokymic discharges” is often used for shorter, more regular discharges with lower firing frequencies. Conversely, “after discharges” refers to spontaneous activity that is enhanced or triggered by electrical nerve stimulation or voluntary muscle contraction. Characteristically, EMG findings of peripheral nerve hyperexcitability do not disappear during sleep (19). However, it is noteworthy that EMG abnormalities have a quantitative value in peripheral nerve hyperexcitability instead of a qualitative one; therefore, it’s possible that mild cases do not show the aforementioned features (07). Nevertheless, given the usual severity of peripheral nerve hyperexcitability in Morvan syndrome, EMG is almost always abnormal (21).

Polysomnography. Agrypnia excitata is defined by a very particular pattern on polysomnography consisting of a lack of cyclic sleep organization with a predominance of stage 1 non-REM sleep intermixed with general REM sleep without muscle atonia. Spindles, K-waves, and delta sleep are markedly reduced, indicating the suppression of deep non-REM sleep (02; 26; 25). Moreover, when video recordings are performed, stereotyped behaviors mimicking daily-life activities may be registered (26). Additionally, sleep obstructive apnea may also be observed in Morvan syndrome (02; 21).

Immunological investigations and routine work-up. Approximately 80% to 90% of patients with Morvan syndrome have serum antibodies against CASPR2 and/or LGI1. Among them, more than 90% have CASPR2-Abs, which are accompanied by LGI1-Abs in 60% of the cases. Isolated serum LGI1-Abs are rare, but have been described (10; 35; 21). Additionally, CASPR2-Abs have also been reported at low titers in CSF, whereas others have described negative CSF in Morvan syndrome as a differential characteristic from CASPR2 limbic encephalitis (12; 35; 21).

Furthermore, several other antibodies may be detected in patients’ serum indicating oncological and autoimmune comorbidities. Among them, antibodies against the acetylcholine receptor are usually present in patients with co-occurring clinical myasthenia gravis, whereas those recognizing ryanodine receptor, titin, or netrin-1 receptors (DCC, deleted in colorectal carcinoma; UNC5A, uncoordinated-5A) are associated with malignant thymoma (10; 33; 21).

Routine CSF analyses are usually unremarkable, with normal cell count and protein content, and lacking oligoclonal bands. Brain MRI is normal in a vast majority of cases, whereas electroencephalography may show diffuse, unspecific slowing (11; 10; 21).

Tumor screening. Tumor screening should be performed in every patient with suspected or confirmed Morvan syndrome and should consist of CT chest with or without FDG-PET/CT, mainly in order to exclude a malignant thymoma or, alternatively, other uncommon malignancies. In patients presenting with Morvan syndrome after the diagnosis of malignant thymoma, or in those with a neurologic relapse, a tumor reassessment is warranted.

Diagnostic criteria. There are no widely accepted and well-established diagnostic criteria for Morvan syndrome. Above all, the diagnosis requires the demonstration of peripheral nerve hyperexcitability and the polysomnographic defining features of agrypnia excitata.

Importantly, patients with peripheral nerve hyperexcitability symptoms and evident features of autoimmune limbic encephalitis (ie, temporal lobe seizures, prominent episodic amnesia) should not be labeled as Morvan syndrome but as co-occurring neuromyotonia and limbic encephalitis. Indeed, the underlying pathophysiology is likely different from Morvan syndrome; the association with thymoma is much weaker and the risk of disease-related death is virtually absent (21). In concrete terms, Morvan syndrome can be defined as a clinical picture characterized by the following:

	• Severe peripheral nerve hyperexcitability, both clinically and demonstrated by EMG, including severe dysautonomia and neuropathic pain.
	• Agrypnia excitata (an encephalopathic state with severe insomnia, stupor, hallucinations, and dream-enacting behavior) supported by specific polysomnographic features (complete disruption of sleep structure, severe reduction of N2 non-REM sleep, loss of atonia during REM sleep).
	• Frequently associated constitutional symptoms such as weight loss, malignant thymoma, and myasthenia gravis.
	• Lack of temporal lobe epilepsy and amnesic features.

Management

Because Morvan syndrome is strongly associated with malignant thymoma, its treatment must be managed in close cooperation between surgeons, neurologists, and oncologists and primarily focus on control of the underlying tumor. Treating the cancer is generally insufficient to reverse the autoimmune process and control the neurologic symptoms; therefore, immunomodulation-based therapy is required. There are no evidence-based recommendations or guidelines owing to the lack of published cohorts. Steroids, intravenous immunoglobulin, and plasma exchanges have been used with uneven success. Remarkably, several case reports emphasized the excellent response to rituximab, which is likely the best treatment option to date (14). Symptomatic treatment consists of treating pain using drugs such as pregabalin or gabapentin, correcting ionic disorders, and preventing denutrition. One case report suggested the efficacy of lacosamide in correcting peripheral nerve hyperexcitability symptoms (32). The management of patients can be complex due to the intrication of severe dysautonomia, ionic disturbances, malignant thymoma, and other autoimmune disorders. Supportive care is very important, and because the condition is treatable, intensive care must be performed whenever it is deemed necessary, with no limitations.