Morvan Syndrome is a severe, acquired neurological disorder affecting the central, peripheral, and autonomic nervous systems. This rare, life-threatening condition is classified as an autoimmune disorder where the body’s immune system mistakenly attacks components of the nervous system. Its complex and multifaceted presentation, affecting fewer than one in a million people, creates significant diagnostic and management challenges for clinicians.
A Comprehensive Overview of Morvan Syndrome
Morvan Syndrome is fundamentally a disorder of nervous system hyperexcitability, meaning that nerve cells fire too easily and continuously. The syndrome is clinically defined by three major functional components that reflect its widespread impact across the nervous system. These components are neuromyotonia, autonomic dysfunction, and limbic encephalopathy, all of which often occur simultaneously.
Neuromyotonia involves the peripheral nerves that control muscle movement, causing continuous muscle fiber activity and stiffness. Autonomic dysfunction affects the involuntary nervous system, which controls essential body functions such as heart rate, blood pressure, and sweating. Limbic encephalopathy involves the brain, primarily the limbic system, leading to cognitive and psychiatric disturbances. The co-occurrence of these three distinct areas of dysfunction is what distinguishes Morvan Syndrome from related neurological disorders like Isaacs Syndrome, which typically only involves peripheral nerve hyperexcitability.
The Autoimmune Origin and Paraneoplastic Link
The immune system generates autoantibodies that target specific proteins in the nervous system. The primary targets are proteins associated with the voltage-gated potassium channel (VGKC) complex on the surface of nerve cells. These antibodies are most often directed against two proteins: contactin-associated protein-like 2 (CASPR2) and leucine-rich glioma-inactivated 1 (LGI1). When these antibodies bind to the VGKC complex, they disrupt the normal flow of ions across the nerve cell membrane, leading to the excessive excitability seen throughout the body. CASPR2 antibodies are more commonly associated with the full spectrum of Morvan Syndrome symptoms, including peripheral and central nervous system involvement.
The presence of these antibodies is often linked to a paraneoplastic origin, meaning the syndrome is triggered by an underlying cancer. A paraneoplastic syndrome occurs when cancer cells express nervous system proteins, causing the immune system to launch an attack that mistakenly targets both the tumor and the healthy nervous tissue. Morvan Syndrome is most frequently associated with a thymoma, a tumor of the thymus gland, found in approximately 38% to 56% of cases. Screening for an underlying tumor, which can also include small cell lung cancer, is a necessary step in the diagnosis and treatment of the syndrome.
Distinctive Symptoms and Clinical Presentation
A defining feature is the severe sleep disorder known as agrypnia excitata, where patients experience little to no true sleep, often reporting total insomnia. This profound sleep disturbance is often accompanied by delirium, confusion, memory loss, and vivid hallucinations, which are signs of the accompanying limbic encephalopathy.
Neuromyotonia, or peripheral nerve hyperexcitability, causes continuous muscle activity. This manifests as visible twitching, known as myokymia, and painful muscle cramps. Patients often experience muscle stiffness and a slowness in muscle relaxation, making simple movements difficult and exhausting.
The third major component is autonomic dysfunction, which results in poor regulation of involuntary bodily functions. Common symptoms include excessive sweating (hyperhidrosis), fluctuations in blood pressure and heart rate, and gastrointestinal issues like severe constipation. The combination of muscle hyperactivity, cognitive impairment, and autonomic instability can rapidly lead to a patient’s functional decline and necessitate intensive care.
Diagnostic Procedures and Treatment Strategies
Diagnosing Morvan Syndrome requires a combination of clinical assessment, laboratory, and imaging tests due to its overlapping symptoms with other neurological conditions. Initial clinical suspicion, based on the triad of neuromyotonia, autonomic dysfunction, and encephalopathy with severe insomnia, is supported by electromyography (EMG). An EMG study confirms the continuous, abnormal muscle fiber discharge characteristic of peripheral nerve hyperexcitability.
Confirmation is achieved through blood testing for the specific autoantibodies, primarily CASPR2 and LGI1, which are detectable in the serum of most patients. Once the diagnosis is confirmed, a comprehensive search for an underlying tumor is mandatory, usually involving computed tomography (CT) scans of the chest and abdomen, or a whole-body positron emission tomography (PET) scan. Identifying a tumor is important because treating the malignancy is often necessary for long-term recovery from the syndrome.
Treatment for Morvan Syndrome follows a two-pronged strategy: aggressive immunotherapy to remove the attacking antibodies and symptomatic management. First-line immunotherapy involves high-dose corticosteroids, plasma exchange (PLEX), and intravenous immunoglobulin (IVIg) therapy, which aim to rapidly reduce or neutralize the circulating autoantibodies. Subsequent long-term therapy often includes oral immunosuppressants, such as azathioprine or mycophenolate mofetil, to prevent relapse.
For patients with a detected thymoma, surgical removal (thymectomy) is often a necessary step and can lead to significant neurological improvement. Symptomatic treatment focuses on managing the most debilitating features, such as using anticonvulsant medications like carbamazepine or lacosamide to reduce muscle hyperexcitability and employing specific medications to address the severe insomnia. Early, aggressive treatment is associated with a better prognosis and a higher likelihood of clinical recovery.