Morvan syndrome and related disorders associated with CASPR2 antibodies

Bastien Joubert MD

Sleep Disorders

Updated 09.22.2025
Released 12.14.2020
Expires For CME 09.22.2028

Morvan syndrome and related disorders associated with CASPR2 antibodies

Author: Bastien Joubert MD

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Editor: Francesc Graus MD PhD

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Morvan syndrome and related disorders associated with CASPR2 antibodies

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Introduction

Overview

Morvan syndrome is a rare, life-threatening autoimmune disorder associated with anti- autoantibodies targeting CASPR2 (CASPR2-IgG) (02). Morvan syndrome is characterized by the combination of severe peripheral nerve hyperexcitability with agrypnia excitata, a sleep disorder characterized by insomnia, behavioral disturbances, and visual hallucinations. There is a clinical overlap with the other autoimmune disorders associated with CASPR2-IgG, such as autoimmune limbic encephalitis, which may also feature behavioral disturbances and insomnia, and Isaacs syndrome (a peripheral nerve hyperexcitability syndrome) (12). However, sleep, motor, and autonomic manifestations are prominent in Morvan syndrome, which also appears to have distinctive immunological features (25).

Key points

	• Morvan syndrome is a life-threatening disease characterized by severe peripheral nerve hyperexcitability, severe insomnia, encephalopathy and hallucinations (agrypnia excitata), and association with CASPR2-IgGs.
	• Morvan syndrome frequently associates with a thymoma.
	• Autoimmune accompaniments such as myasthenia gravis or autoimmune cytopenias are frequent.
	• Rituximab seems highly efficient.
	• Relapses may occur and generally herald thymoma recurrence.

Historical note and terminology

The term “Morvan syndrome” derives from a publication in the late 19th century by French physician Augustin Morvan describing six patients with generalized "fibrillar contractions of the muscles," accompanied in one case by anxiety, sudation, and pain (24). In the mid-20th century, Roger and colleagues reported a series of 70 patients with a combination of confusion, visual hallucinations, insomnia, and severe peripheral nerve hyperexcitability symptoms, which they referred to as "syndrome de Morvan" (32). A specific sleep disorder, agrypnia excitata, was later linked to this syndrome (22). Finally, Irani and colleagues described CASPR2-Abs in Morvan syndrome, Isaacs syndrome, and autoimmune limbic encephalitis (12).

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.

Morvan syndrome consists of the association of agrypnia excitata with peripheral nerve hyperexcitability symptoms and, in most cases, develops progressively over weeks or months (14). Due to the complex phenotype, 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 and should prompt oncological reassessment (19).

Agrypnia excitata. Agrypnia excitata has been described in three unrelated disorders: fatal familial insomnia (a hereditary prion disease), alcohol-withdrawal syndrome, and Morvan syndrome (30). It combines severe insomnia, in which patients typically recall little to no sleep, and recurrent and stereotypic gestures that mimic daily life tasks, such as combing, dressing, eating, and drinking (26). Electroencephalographic sleep recordings show a progressive loss of delta/spindle activity, eventually leaving only stage 1 non-REM sleep, interrupted by brief bursts of REM sleep activity (with or without atonia). During wakefulness, the patients often exhibit irritability and restlessness; some develop delusions (06), with the severity of the insomnia paralleling that of the psychiatric and behavioral symptoms (35). Complex visual hallucinations are frequent (04) and are considered a hallmark of the syndrome (26). Seizures have been rarely reported, occasionally in relation to metabolic disorders, such as hypoglycemia. Over time, most patients progress towards an oneiric state, oscillating between wakefulness and dreamlike confusion (21).

Peripheral nerve hyperexcitability. Peripheral nerve hyperexcitability is the second major feature of Morvan syndrome. It includes motor, autonomic, and pain symptoms (13). These features are similar to those of Isaacs syndrome, even though the motor and autonomic symptoms are especially prominent and severe in Morvan syndrome.

Motor symptoms include cramps, fasciculations, and generalized myokymia (35). 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.

The autonomic symptoms in patients with Morvan syndrome include profuse sweating, hyperlacrimation, excessive salivation, and cardiovascular abnormalities, such as orthostatic hypotension and sinus tachycardia, along with constipation, and urinary and erectile dysfunction. Collectively, these symptoms suggest an overactive sympathetic autonomic nervous system, consistent with elevated levels of noradrenalin reported in two cases (20; 36). Some cases of sudden death in patients with Morvan syndrome have been attributed to dysautonomia-related cardiac dysrhythmia (20). Acrodynia, characterized by painful swelling, discoloration, and desquamation of the fingers or toes, have been described in historical series (32). Other skin symptoms include skin miliaria and pruritus, which are likely related to the profuse hyperhydrosis (35).

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 (18).

Other symptoms.

General status. Extreme fatigue and weight loss (up to 10 kg or more in some cases) are common (06; 25).

Myoclonus. Most patients present with myoclonus (09), which is in general asymmetrical, has a proximal predominance, and can be triggered by stimulation and orthostatism (11). Walking may be impaired due to inferior limb myoclonus and limb stiffness (40).

Ion disturbances. Hyponatremia is common; it is unclear if it is related to an inappropriate secretion of antidiuretic hormone or to other mechanisms (13).

Respiratory functions. Breathing difficulty, including cases of acute respiratory failure requiring mechanical ventilation, has been reported (06). 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 (13).

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 pathogenesis of Morvan syndrome remains unclear, but clinical and immunological findings suggest it likely differs from other CASPR2-associated neurologic disorders, such as CASPR2 antibody-associated limbic encephalitis and Isaacs syndrome (25). Although CASPR2-IgG appears to play a pathogenic role in CASPR2-associated limbic encephalitis (16) and Isaacs syndrome (05), it remains uncertain whether they significantly contribute to the pathogenesis of Morvan syndrome, aside from serving as useful biomarkers.

Immunology. More than 20 years ago, Morvan syndrome was linked to antibodies against the voltage-gated potassium channel complex (19). However, it has now been established that these antibodies actually recognize two distinct 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 (12; 17). 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 (13; 42; 25). Similarly, antibodies against netrin-1 receptors have been described as paraneoplastic markers of malignant thymoma in patients with CASPR2-Abs, including Morvan syndrome (39; 25). Finally, isolated positivity for LGI1-Abs has also been reported (13; 42).

In vitro and in vivo studies have shown that CASPR2-IgGs can internalize CASPR2, possibly via IgG-mediated cross-linking (07; 16); in addition, they can disrupt the interaction between CASPR2 and its partner protein TAG-1 (29; 33; 16). As CASPR2 is involved in regulating potassium channel and glutamatergic receptors as the neuronal surface, these disruptions lead to impaired neuron excitability in the neocortex, hippocampus, and dorsal root ganglia (05; 41). In mouse models, CASPR2-IgG induces memory deficits when injected near the hippocampus and pain when injected intraperitoneally (05; 08; 16). In all CASPR2-associated neurologic disorders, CASPR2-IgG targets the discoidin domain of CASPR2, which is important for protein-protein interactions (28; 15); therefore, a pathogenic role seems plausible regardless of the observed phenotype. In Morvan syndrome, however, CASPR2-IgG titers are typically lower than in patients with limbic encephalitis, they are more frequently of the IgG4 subclass (which is unable to cross-link the target antigen) than IgG1, and they are generally not detected in the patients' CSF (25). As a result, the role of these antibodies in the development of central nervous system symptoms of the patients, such as agrypnia excitata and dysautonomia, remains unclear. Other immune effectors, including T cells and autoantibodies targeting additional antigens, may also be involved.

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 (25). 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 three 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, microglial activation with absence of T-cell infiltration, and marked neuronal loss in cerebellar and brainstem nuclei (20; 37; 34). 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 (30).

Differential diagnosis

Confusing conditions

Due to its complex phenotype, Morvan syndrome may be confused with several disorders, including other neurologic conditions associated with CASPR2-Abs. Peripheral nerve hyperexcitability is also the major feature of 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 (25). However, typical limbic features, such as memory impairment or temporal lobe epilepsy, are not part of the clinical spectrum of Morvan syndrome. Conversely, severe insomnia with hallucinations and prominent dysautonomia with profuse sweating are two hallmarks of Morvan syndrome that are uncommon in limbic encephalitis (25; 26).

Agrypnia excitata was described in only two diseases other than Morvan syndrome: fatal familial insomnia and delirium tremens (30). 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 (13; 25). 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 (13; 42; 39; 25). Morvan syndrome and myasthenia gravis can occur independently; remarkably, in some patients, intervals of several years can be observed between the occurrences of the two disorders.

Other uncommonly reported tumor associations are lymphomas, prostate adenocarcinoma, and nonsmall cell lung cancer (13).

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 (23). 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 (10). Nevertheless, given the usual severity of peripheral nerve hyperexcitability in Morvan syndrome, EMG is almost always abnormal (25).

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 (03; 31; 30). Moreover, when video recordings are performed, stereotyped behaviors mimicking daily-life activities may be registered (31). Additionally, sleep obstructive apnea may be observed (03; 25).

Immunological investigations and routine work-up. Approximately 80% to 90% of patients with Morvan syndrome have serum antibodies against CASPR2 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 (13; 42; 25). 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 (15; 42; 25).

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 (13; 39; 25).

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 (14; 13; 25).

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 (25). 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.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Bastien Joubert MD

Dr. Joubert of Hospices Civils de Lyon in France received speaker fees from ASTELLAS Pharma.
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Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Sergio Muniz-Castrillo MD
Jerome Honnorat MD

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Morvan syndrome and related disorders associated with CASPR2 antibodies

Associated Disorders

malignant thymoma
myasthenia gravis

Differential Diagnosis

acquired neuromyotonia
Isaac syndrome
limbic encephalitis
fatal familial insomnia
delirium tremens
- progressive encephalomyelitis with rigidity and myoclonus
- amyotrophic lateral sclerosis

Also Relevant

Insomnia
Fatal familial insomnia
Neuromyotonia and myokymia
Parasomnia overlap disorder and status dissociatus

Morvan syndrome and related disorders associated with CASPR2 antibodies

Morvan syndrome and related disorders associated with CASPR2 antibodies

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

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Morvan syndrome and related disorders associated with CASPR2 antibodies

Cite this article

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

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