Morvan Syndrome

What is Morvan Syndrome?

Morvan syndrome (MoS) is a rare and complicated disorder of the nervous system that makes it overly active. Originally, French physician Dr. Augustine Marie Morvan identified this condition back in April 1890. He initially referred to it as la chorée fibrillaire or fibrillary chorea, but it’s more commonly known today as Morvan syndrome.

This overactivity manifests in different ways throughout the body. It can cause mental effects such as confusion, behavior changes, twitching (myoclonus), and severe difficulty sleeping. Some people may also experience hallucinosis (a state of mind involving hallucinations) and encephalopathy (damage to the brain that alters its function or structure). Signs of overactivity in the body’s autonomic nervous system include excessive sweating (hyperhidrosis), constipation, unstable blood pressure, poor circulation (hemodynamic instability), and irregular heartbeat (cardiac arrhythmias). Overactivity in the peripheral nervous system, which controls body movements, typically includes muscle cramps, myokymia (continuous rippling movements, often seen as an eyelid twitch), and neuromyotonia (continuous involuntary muscle fiber activity). However, it’s important to note that individuals with Morvan syndrome may only show some of these symptoms and not all.

Historically, the causes of Morvan syndrome were believed to be infectious diseases or heavy metal toxicity. However, in 1999 a new type of abnormal protein, called anti-contactin-associated protein-like 2 (CASPR2), was identified as being associated with this syndrome. Since that discovery, multiple reports have been published on patients with CASPR2-related Morvan syndrome. The condition is also often linked to cancerous tumors, particularly those in the thymus gland.

Morvan syndrome needs to be differentiated from similar conditions known as acquired neuromyotonia and limbic encephalitis. The condition can be fatal in up to one-third of cases, but not all. It’s diagnosed by identifying elevated levels of certain proteins (CASPR2 and LGI1) in the blood. The preferred treatment often involves therapeutic plasma exchange and immunity-suppressing medication. Despite the potential for death, which occurred in 20% of patients in a 2012 case study, treatments can lead to full recovery for some patients.

Morvan syndrome is common in men, with male patients outnumbering female patients by a notable margin. However, the exact number of people with Morvan syndrome is not well known. The condition is often not recognized or reported. Some estimates suggest that Morvan syndrome affects less than one person per million.

What Causes Morvan Syndrome?

Morvan’s Syndrome (MoS) is a condition that affects the nervous system and is considered an autoimmune disorder, which is when your body’s immune system mistakenly attacks your body. This disorder has a close association with antibodies, which are proteins produced by your body to fight off bacteria and viruses, targeting a component in our cells called the voltage-gated potassium channel (VGKC). This VGKC is a passage for charged particles and plays a crucial role in how our nerves function. Antibodies reacting with it contributes to the occurrence of MoS and other related conditions including acquired neuromyotonia (Isaac’s syndrome), limbic encephalitis, and faciobrachial dystonic seizures.

Initially, scientists in the early 20th century thought that MoS was a consequence of a viral infection. Later on, people believed it might be connected to heavy metal exposure. More recently, there have been cases reported where MoS appeared after using traditional Siddha medicine in India.

Better understanding of the disease came about in the late 1990s. Researchers found that MoS is closely associated with Caspr2 autoantibodies, a type of antibodies that reacts with a protein found in nerves. In some instances, other antibodies, reacting with the LgI1 protein (involved in the working of our nerves), and the netrin-1 receptor (which has several roles in the body including new blood vessel formation and tissue repair) have been identified as additional factors contributing to the disease. Notably, antibodies toward netrin-1 receptor are associated with muscle stiffness in patients who had thymomas (tumors of the thymus gland). Some patients have antibodies against another component of the VGKC complex, contactin-2.

MoS is often found in individuals who have an underlying tumor, mainly the thymoma. Thus, it’s often thought of as a paraneoplastic syndrome, which are symptoms that occur due to cancer in the body but are not a result of the direct physical effects of the cancer mass itself. Other associated cancers include lung, colon, testicle cancers, and certain blood cancers like lymphoma. However, it’s important to know that MoS can happen without the presence of cancer. In these cases, the response to treatments aimed at modifying the immune system might be better compared to those cases linked to cancer.

One study found a specific type of protein (CASPR2) present in the prostate gland. This indicates that areas other than brain tissue, like the male reproductive system, might contain these antigens (foreign substances that provoke an immune response). This was consistent with MoS occurring in a few patients after a procedure to remove fluid from the scrotum. There are also isolated cases suggesting mRNA vaccinations against COVID-19 might be a cause of a specific type of limbic encephalitis, a condition which shares key characteristics with Morvan’s Syndrome.

Risk Factors and Frequency for Morvan Syndrome

MoS, or Morvan Syndrome, is a little-known disease, likely underreported because of it being often missed or unrecognized. According to a 2012 study, there were 29 known cases, and a later study in 2021 reported an additional 14 cases. These figures indicate that MoS is a rare disease, affecting less than one in a million people. It’s a serious neurological disorder, characterized by issues with muscle movements (neuromyotonia), problems with the automatic control of body functions (dysautonomia), mental clouding (encephalopathy), and severe insomnia.

MoS is significantly more common in males. A research using mice showed that when pregnant females were exposed to specific antibodies, only the male offspring exhibited abnormal brain development. Interestingly, there has been a recent case of a woman diagnosed with MoS, who tested positive for multiple antibodies, including one known as LGI1.

MoS is often linked to cancer, as it is frequently a paraneoplastic disorder. These kinds of disorders are associated with cancer but are often overlooked and underreported. However, about one in 300 individuals with cancer develop a paraneoplastic disease. The occurrence is between 1.6 and 8.9 cases per million people each year.

• In patients with MoS, 75% show positive reactions to Caspr2 antibodies, while about 60% show responses to LGI1 antibodies.
• There are lower percentages of patients who test positive for antibodies to netrin-1 or acetylcholine receptors.
• Thymoma, a type of tumor, is present in 50% to 90% of MoS cases.

Signs and Symptoms of Morvan Syndrome

Morvan Syndrome is a medical condition marked by overactive responses in the body’s central, autonomic, and peripheral nervous systems. The symptoms associated with this condition include several mental, physical, and nervous-related problems. However, it is essential to collect as much information as possible to diagnose this condition accurately as specific characteristics such as mental dysfunctions and sleep disorders are often overlooked.

The central nervous system features of Morvan Syndrome consist of:

• Encephalopathy (brain disease or damage)
• Severe insomnia (trouble sleeping)
• Experiencing vivid (often auditory) hallucinations
• Delirium (severe confusion)
• Spatial and temporal disorientation (loss of direction and sense of time)
• Confusion, amnesia (memory loss), agitation, and hostility

Autonomic dysfunction is mostly unstable and includes:

• Excessive sweating and fever
• Redness in the palms and soles
• Pruritus, drooling, severe constipation, excessive tearing
• Heart irregularities, high blood pressure, weight loss, skin problems
• Rarely, abnormally low sodium in the blood due to inappropriate production of an antidiuretic hormone.

The peripheral nervous system features include:

• Hyperactivity of peripheral nerves causing continuous muscle fiber activity
• Nerve pain
• Areflexia (loss of certain reflexes)
• Sensory loss, similar to the sensation of wearing a “stocking”
• Continuous muscle fiber activity, seen clinically as myokymia (involuntary muscle twitching).

These symptoms can vary widely and are usually associated with the type of antibody detected in an individual. While the presence of specific antibodies like anti-CASPR2 and anti-LGI1 can provide hints, a personalized approach should be taken when diagnosing MoS. This includes a thorough medical history, inquiry about pre-existing autoimmune disorders, cancer history, specific nervous system symptoms, autonomic dysfunction signs, and an assessment of behaviors, mental conditions, and sleep patterns.

Testing for Morvan Syndrome

In diagnosing Morvan syndrome (MoS), a test is done for VGKC antibodies in the blood. This test focuses on CASPR2 and LGI1 as these are the antibodies usually found in people with MoS. Interestingly, the CASPR2 antibody is connected with a type of cancer called malignant thymoma. It’s essential to know that VGKC abnormalities can also be found in healthy individuals, so the presence of these alone does not confirm Morvan syndrome.

Morvan syndrome can present in various ways, so it’s critical to consider it if the symptoms align, even if other tests don’t conclusively confirm it. Tests for nervous system overactivity, like analyzing cerebrospinal fluid, brain MRI scans, EEGs, and positron emission scans, might not provide a conclusive diagnosis for MoS, but they can help rule out other conditions. A specialized test called electromyography (EMG) can confirm muscle twitching, a common symptom in Morvan syndrome. However, more distinct symptoms like constant muscle contraction (myokymia) and muscle overactivity (neuromyotonia) are rarely seen in these diagnostic tests.

To sum up the diagnosis process, it’s a two-step approach: First, establish the presence of the autoantibodies in blood or cerebrospinal fluid. Second, check for underlying cancer using imaging tests like a CT scan or a PET scan.

Patients must also be assessed for other linked autoimmune diseases, such as myasthenia gravis characterized by muscle weakness or autoimmune cytopenia characterized by a low blood cell count. If the antibody test reveals high levels of CASPR2 or LGI1, it’s crucial to rule out any hidden cancer, especially malignant thymoma in individuals with CASPR2 antibodies.

An on-the-spot evaluation for dysautonomia, a disorder of the autonomic nervous system, can be done by testing heart rate changes with deep breathing, changes in body position, and the Valsalva maneuver, a breathing technique.

Sleep studies (polysomnography) could reveal disturbed sleep patterns, but these might be difficult due to patients’ behavioral changes and difficulty falling asleep. EEGs, a test of brain activity, are often normal in Morvan syndrome patients. However, if LGI1 or CASPR2 antibodies indicate autoimmune encephalitis, video-EEG telemetry is recommended as it might show that up to 20% of these patients could have continuing seizures.

In some cases, FDG-PET imaging might be helpful in diagnosing LGI1 autoimmune encephalitis. The appearance of metabolically active tissues on FDG-PET can differ in patients with Morvan syndrome, even if MRI scans and EEGs are normal. Research into how this imaging test can aid in diagnosing Morvan syndrome is still ongoing.

Finally, a muscle biopsy might still be beneficial for patients with prominent peripheral symptoms to rule out muscle diseases or mitochondrial diseases.

Treatment Options for Morvan Syndrome

There have been several methods tried to treat Morvan Syndrome (MoS), including the use of gold-based treatments, epilepsy medications like carbamazepine, valproate, phenobarbital, and phenytoin, and procedures like thymectomy, which is the removal of the thymus gland. However, these methods have generally not been very successful.

The most effective treatment we currently have for Morvan Syndrome seems to be plasma exchange, a procedure where the liquid part of your blood, or plasma, is removed and replaced. In addition to this, treatment usually also involves medications that suppress the immune system, such as corticosteroids or other immunosuppressant drugs.

For reasons that are not fully understood, patients may respond differently to these treatments. This could possibly be due to differences in the mixture of factors present in their blood that are causing symptoms. Some researchers suggest that immunosuppressant treatments might work better in cases where Morvan Syndrome occurs alongside other autoimmune conditions, like myasthenia gravis or autoimmune thyroid disorders.

Case reports have shown that even when a patient’s symptoms don’t respond to plasma exchange, they may still respond to certain medications like azathioprine, rituximab, and lacosamide. The removal of certain antibodies, CASPR2 and LGI1, may also help improve symptoms like sleeplessness and dreamlike confusion (agrypnia excitata and oneiric stupor), although the overall outlook for such cases is still poor.

One noteworthy case in Japan highlighted a link between Morvan Syndrome and a non-removable cancerous tumor in the thymus gland (unresectable malignant thymoma). Treatment that was intended to reduce the size of the thymoma also improved Morvan Syndrome symptoms. This suggests there could be a strong link between the presence of a tumor in the thymus and the activity of Morvan Syndrome. It also suggests the exciting possibility that chemotherapy for thymomas might be a useful treatment for Morvan Syndrome. However, more research is needed to investigate this possibility.

What else can Morvan Syndrome be?

There have been instances where Morvan’s Syndrome (MoS) has been wrongly diagnosed due to an overemphasis on positive serum antibodies, or by confusing the symptoms with those of mental health conditions or unclear cognitive symptoms.

Limbic encephalitis, a condition caused by different autoantibodies from those in MoS, displays strikingly similar traits. However, limbic encephalitis tends to present with amnesia, seizures, and structural abnormalities of the temporal lobe more often. On the other hand, MoS does not display neuromyotonia and dysautonomia as conspicuously. The diagnosis of MoS purely based on the co-occurrence of limbic encephalitis and neuromyotonia is insufficient. Identifiable features that distinguish MoS from classical limbic encephalitis include neuropathic lower limb pain, weight loss, being male, and association with malignant thymomas.

Isaac syndrome, also known as acquired neuromyotonia, shares similarities with MoS, especially the symptom of peripheral nerve hyperexcitability. However, in Isaac syndrome, overt central or autonomic nervous dysfunction is absent. MoS patients often exhibit noticeable weight loss and weakness, features not typically present in Isaac syndrome. Thus, it is crucial to differentiate between peripheral nerve hyperexcitability syndromes and other conditions like stiff person syndrome, myotonic disorders, and rippling muscle disease. Additionally, Myokymia can be an indicating symptom of multiple sclerosis and cervical radiculopathy, as well as being an adverse effect of medications like gabapentin and acetazolamide.

Guillain-Barre syndrome (GBS) is a condition where the immune system damages the peripheral nervous system, leading to muscle weakness, loss of deep tendon reflexes, and sensory deprivation. GBS is typically triggered by a viral infection, or less commonly, can occur after surgery or vaccination. The diagnosis is usually done through clinical exclusion and supported by nerve conduction studies and CSF analysis. In severe cases, prompt treatment with intravenous immunoglobulins or plasmapheresis leads to functional recovery in most people.

For a thorough diagnosis, fatal familial insomnia should also be considered while diagnosing MoS, as both conditions present with agrypnia excitata. However, unlike MoS, fatal familial insomnia is a prion disease and noticeable structural brain abnormalities can usually be seen on MRI imaging.

What to expect with Morvan Syndrome

The course of Morvan syndrome, a rare neurological disorder, can significantly differ from person to person. Some patients might recover fully, while others could face life-threatening complications, even death. In some cases, the condition has been reported to improve on its own. However, most patients need intensive treatment, primarily involving immunotherapy—a treatment method that helps boost the body’s immune system.

This immunotherapy commonly takes the form of plasma exchange—a therapeutic process that involves replacing the plasma in a person’s blood—and long-term immunosuppression, a treatment that reduces the body’s ability to reject a transplanted organ or fights diseases affecting the body’s immune system.

It’s important to note that Morvan syndrome can be a serious health threat due to severe disruptions in the body’s automatic functions, known as dysautonomia. Also, the condition often co-exists with a type of cancer called malignant thymoma, which makes it more severe. As a point of reference, 20% of Morvan syndrome patients in a 2012 case study died from the condition.

Possible Complications When Diagnosed with Morvan Syndrome

As noted earlier, carrying out a polysomnography (PSG), which is a sleep study, can often prove difficult for patients with MoS. This is usually because these patients might experience very little sleep or none at all. In some cases, they may also face difficulties cooperating with the study due to behavioral issues and encephalopathy, a type of brain disease.

Some patients exhibit unexpected throat muscle spasms during anesthesia, a phenomenon caused by neuromyotonia and hyperexcitability due to faulty potassium channels in the body. To reduce the chances of these spasms, it is recommended that local or regional anesthetics be used instead of general anesthesia. Further, it’s advisable to avoid using muscle-relaxing drugs whenever possible.

The main issues:

• Difficulty in performing polysomnography (PSG) due to little or no sleep.
• Difficulty in cooperation with PSG due to behavioral issues and encephalopathy.
• Laryngeal spasms or unexpected throat muscle spasms during anesthesia.
• The use of local/regional anesthetics over general anesthesia is recommended.
• Avoidance of muscle-relaxing drugs if possible.

Preventing Morvan Syndrome

Patients should understand that Morvan syndrome is a rare condition that can be mistaken for other diseases, and it can be linked to hidden types of cancer. It’s also important to know that Morvan syndrome, also known as MoS, tends to respond well to treatment, with some patients seeing a full recovery.

Caring for someone with MoS can be intensive, requiring a lot of support from unpaid caregivers such as family members or friends. Therapies like physical, occupational, and speech exercises can help to ease the load on these caregivers.

Before undergoing surgery or any procedure requiring general anesthesia, patients need to be aware of the risk of laryngospasm, which is a sudden tightening of the vocal cords. It’s crucial to discuss their Morvan syndrome with the doctor providing the anesthesia to reduce this risk.