Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Anti-NMDA receptor encephalitis is an autoimmune disorder that affects people of all ages, but predominantly young women (about 50% with an associated ovarian teratoma) and children of both sexes. Patients present with neuropsychiatric manifestations and memory and cognitive deficits and usually progress to catatonia, seizures, autonomic dysfunction, stereotypic movements, and coma. Recovery can be prolonged. The diagnosis can be strongly suspected by history and clinical evaluation and confirmed by detection of CSF IgG antibodies to the GluN1 subunit of the NMDA receptor. Patients often respond to a combination of immunotherapy, including corticosteroids, IVIg or plasma exchange, or rituximab or cyclophosphamide.
• Anti-NMDA receptor encephalitis is mediated by specific IgG autoantibodies to the GluN1 subunit of the NMDA receptor.
• Most patients present with neuropsychiatric symptoms that progress to include seizures, movement disorders, autonomic dysfunction, and decreased level of consciousness.
• The underlying mechanism of the disorder is a reversible antibody-mediated reduction of synaptic NMDA receptors.
• Almost 80% of patients have full or substantial recovery with early initiation of immunotherapy, and removal of an associated tumor, if present (usually ovarian teratoma), is associated with better outcomes.
In 2005, 4 young women with ovarian teratoma and subacute psychiatric symptoms, seizures, decreased level of consciousness, and frequent central hypoventilation of unknown etiology were reported (47). The patients had inflammatory abnormalities in the cerebrospinal fluid, and all improved after tumor resection, immunotherapy, or both. This supported a paraneoplastic etiology, but some of the teratomas were benign and none of the patients had paraneoplastic (onconeural) antibodies, which target intracellular neuronal antigens (21). Rather, all had an immune response targeting an antigen enriched in the neuropil of the hippocampus that was subsequently identified to be the N-methyl-D-aspartate (NMDA) receptor (14). The response to immunotherapy and the location and function of the NMDA receptor suggested that the disorder, now called anti-NMDA receptor encephalitis, was mediated by the antibodies. Using the presence of the antibodies as a diagnostic test, it soon became clear that this disorder occurs with and without a tumor association and can occur in men (11). It was also shown that similar previously reported cases (some grouped under the term “acute nonherpetic encephalitis of juvenile onset”) were, in fact, cases of anti-NMDA receptor encephalitis (30). The characterization of anti-NMDA receptor encephalitis led to the identification of other encephalitic syndromes, each associated with a specific pathogenic autoantibody that targets neuronal receptors, channels, or synaptic proteins (12). This group of disorders is now often referred to as “antibody-mediated encephalitis” or “autoimmune encephalitis.”
NMDA receptor encephalitis primarily affects young women (median age 21 years) who represent about 80% of cases; 40% of the cases are younger than 18 years of age, with babies as young as 2 months old (46). There is an age-related relationship with the presence of a teratoma in almost 50% of women older than 12 years of age having ovarian teratoma (either uni- or bilateral) compared with only 8% of younger girls. About 5% of male patients have tumors, most often a testicular germ cell tumor. Rare associations with other tumors (small cell lung cancer, breast cancer, Hodgkin lymphoma, among others) have been reported (13).
Most patients present with acute changes in behavior and personality, with memory loss that worsens over a few days or weeks and can manifest as anxiety, paranoia, delusions, hallucinations, pressured speech, manic or aggressive behavior, and alternating episodes of extreme agitation and catatonia. In retrospect, almost 70% of patients report a viral-like prodrome with headache or fever. Almost all patients have insomnia, but this can be missed if not specifically addressed when obtaining the medical history (02). In some patients, the insomnia can predate by weeks the onset of other symptoms. In children under 12 years of age, initial manifestations are more commonly behavioral changes (irritability, agitation), insomnia, movement disorders, seizures, and decreased verbal output (04). Despite this age-related difference in initial presentation, within a few weeks of onset, patients evolve to a similar spectrum of symptoms that include the development of abnormal movements (often oral-facial or limb dyskinesias, choreoathetosis, dystonic postures), seizures, autonomic instability (eg, central hypoventilation, tachycardia, hyperthermia, hypertension, and less frequently bradycardia or cardiac pauses), and decline in the level of consciousness to a comatose state. Atypical symptoms such as cerebellar ataxia or hemiparesis are rare and more commonly seen in children. Isolated psychiatric episodes have been reported, but most of these patients have subtle neurologic findings or abnormalities on ancillary testing such as CSF pleocytosis or MRI findings (31). Recovery is usually in inverse order of symptom development with initial resolution of seizures, abnormal movements, and autonomic dysfunction that eventually allows the patient to leave the medical facility. During the recovery phase, insomnia is replaced by hypersomnia (02). Full recovery of memory, attention, and normal sleep and behavior is slow and can take months. During this time patients often have adjustment difficulties that should not be ignored.
Proposed diagnostic criteria for probable anti-NMDA receptor encephalitis requires the presence of 1) the rapid onset of at least 4 of the following symptom groups: abnormal behavior or cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, autonomic dysfunction, or hypoventilation (or 3 of these plus ovarian teratoma); 2) abnormal EEG or CSF pleocytosis or oligoclonal bands; and 3) reasonable exclusion of other disorders (22). A definite diagnosis can be made in the presence of 1 or more of the symptom groups in point 1 and the detection of IgG anti-NMDA receptor antibodies, after reasonable exclusion of other disorders. Testing CSF is preferable as studies have shown that about 13% of patients with positive CSF can have negative serum studies (23; 24).
The prognosis of anti-NMDA receptor encephalitis is good, and about 80% of patients have substantial or full recovery by 24 months (modified Rankin scale scores 0-2) (46). Independent predictors for good outcome are lack of need for intensive care, early initiation of immunotherapy (within 4 weeks of presentation), clinical improvement within 4 weeks of treatment, normal brain MRI at diagnosis, and normal cerebrospinal fluid or mild pleocytosis (< 20 WBC/ml). The NMDA receptor encephalitis 1-year functional status score (NEOS) assigns 1 point to each of these variables and strongly correlates with the probability of poor functional status at 1 year (05). As patients can have slow but continual improvement for up to 2 years, the NEOS score more closely aligns with the velocity of clinical improvement rather than final outcome.
A 21-year-old female in prior good health was brought to the emergency room by her family for an abrupt change in behavior described as bizarre and aggressive alternating with periods of calm and inattention. She had stopped eating and was sleeping poorly. In the emergency room she had moments of being appropriate but would suddenly become agitated. Medical and neurologic examinations were without focal findings, and she was afebrile. An unenhanced CT scan of the brain, electrocardiogram, toxicology screen, and general blood tests were normal. She was admitted to the psychiatric ward for further evaluation. Observations over several days noted disorganized thinking and auditory hallucinations consistent with psychosis. She was started on antipsychotic and sedative medications, but continued to worsen over 1 week. A day before institution of electroconvulsive therapy, she had a generalized seizure and was transferred to the ICU. Examination revealed decreased consciousness and orofacial dyskinesias. Routine CSF studies and MRI were normal. The EEG showed diffuse slowing. She was empirically given antiviral treatment. After 1 week, results of CSF testing revealed antibodies to the NMDA receptor, and she was started on high-dose corticosteroids and IVIg. Pelvic MRI was normal. Over 3 weeks, her seizures and level of consciousness improved, and she was discharged after 8 weeks. She recovered to baseline over 8 months.
In some patients, the trigger of the autoimmune response appears to be the systemic expression of NMDA receptors by an associated tumor (often ovarian teratoma).
The preceding viral prodrome reported by many patients may play a role in priming the immune system. Some patients have other autoimmune phenomena suggesting a predisposition to develop autoimmunity. About 20% of patients with herpes simplex viral encephalitis develop neurologic symptoms and anti-NMDA receptor antibodies after recovery from the viral illness (03). It has been postulated that the destruction of brain tissue by the virus results in the release of neuronal antigens and subsequent development of autoimmunity. In many patients, the trigger remains unknown. In some patients, anti-NMDA receptor encephalitis occurs simultaneously or sequentially with clinical or imaging features of demyelinating disorders (45). Many of these patients have immunity to myelin oligodendrocyte glycoprotein or AQP4 (37). Whether there is a pathogenic relationship between these disorders is unclear.
Pathophysiology. Patients with anti-NMDA receptor encephalitis have antibodies that target the GluN1 subunit of the NMDA receptor.
Binding of the antibodies to the receptor results in antibody-mediated cross-linking and internalization of the receptors in both inhibitory and excitatory neurons and a reduction of NMDA receptor-mediated currents (40; 34). This alteration of NMDA receptor function results in the learning, memory, and other behavioral deficits observed in patients with the disorder and is similar to the symptoms seen with the use of NMDA receptor antagonists (32). The decrease of NMDA receptors is reversible on removal of the antibodies, which explains the ability of patients to recover. The antibodies are of the IgG subclass and are highly specific for anti-NMDA receptor encephalitis. Antibodies targeting other NMDA receptor units or of IgA or IgM subclass have been described in low titers in patients with a variety of immune and nonimmune conditions, as well as neurologically normal subjects, and are unrelated to this disease (08; 25). A study including 2 series of patients found that between 4% and 7.5% of patients with anti-NMDA receptor encephalitis harbored concurrent antibodies against glial proteins such as MOG, AQP4, or GFAP or against other neuronal cell surface antigens, including the AMPA, GABA(A), and GABA(B) receptors (37). Except for GFAP, which did not associate with distinct clinical-radiological features, the presence of the other antibodies conferred additional clinical features including MRI findings not commonly seen in anti-NMDA receptor encephalitis, as well as unusual comorbidities and atypical tumor associations. Patients with concurrent neuronal antibodies had poorer outcomes compared to patients with only anti-NMDA receptor antibodies.
The incidence and prevalence of NMDA receptor encephalitis are not described. Data suggest that it is the second most common cause of autoimmune encephalitis after acute demyelinating encephalomyelitis and a more frequent cause of encephalitis than any single viral entity. It is at least 4 times as frequent as herpes simplex type 1, West Nile, or varicella zoster viral encephalitis (20).
No preventative strategies are known at this time.
Patients presenting with acute changes in behavior or new-onset psychiatric manifestations may initially be diagnosed with a psychiatric disorder (acute psychosis or schizophrenia), drug abuse, or malingering. Diagnostic clues of anti-NMDA receptor encephalitis include the presence of sleep dysfunction (mainly insomnia at disease onset), disinhibition, agitation, fluctuating catatonia, absence of a history of psychiatric disease, and cognitive impairment, among others (10). Careful examination often reveals associated neurologic findings that may initially be subtle and should lead to further evaluation. New-onset seizures, encephalopathy, and CSF pleocytosis can suggest infectious encephalitis, but evaluations for an infectious agent are negative. If neuroleptics have been given, the development of rigidity, catatonia, and fever (possibly as a result of autonomic dysfunction) can suggest malignant neuroleptic syndrome (35). Repetitive stereotypic movement such as orofacial dyskinesias can be mistaken for seizures or status epilepticus that can be ruled out with video-EEG (16). Some cases of postpartum psychosis or those diagnosed as encephalitis lethargica have been shown to be cases of anti-NMDA receptor encephalitis (09; 17).
Evaluation includes a detailed clinical history and medical and neurologic examinations, routine blood and CSF analyses, and MRI and EEG to rule out infectious, metabolic, or structural causes. In 80% of patients, the CSF will show lymphocytic pleocytosis, at times with increased proteins or oligoclonal bands. Testing for anti-NMDA receptor antibodies should initially be done in CSF as 13% to 15% of cases can have negative serum studies (23; 24). Less than 50% of patients have MRI findings, usually transient increased signal in brain cortical or subcortical regions, cerebellar cortex, or, less frequently, brainstem. Less often, there is mild or transient meningeal or cortical enhancement. Almost 90% of patients have EEG abnormalities, including generalized slow or disorganized activity that may overlap with electrographic seizures (18). A unique EEG pattern called extreme delta brush is found in about 30% of cases (42). A search for an underlying tumor should be carried out, especially an ovarian teratoma in young women.
Drug treatment. There is no standard drug treatment protocol, although most patients initially receive immunotherapy with corticosteroids often combined with either IVIg or plasma exchange (39; 46). In patients with no response to these treatments within approximately 2 weeks, rituximab or cyclophosphamide is usually initiated. Other therapies that have been reported include azathioprine, mycophenolate mofetil, methotrexate, and bortezomib. Some series suggest that the use of rituximab improves outcome and reduces the risk of relapses; many practitioners incorporate rituximab in the initial treatment regimen, especially in patients with severe symptoms. Treatment is usually continued until the patient shows substantial clinical recovery. These treatments are well tolerated, even by patients in the ICU (plasma exchange should be avoided in patients with severe autonomic dysfunction or behavioral disturbances that could impact the safety of the procedure). No disease-specific toxicities have been reported. Routine evaluation of antibody titers is not recommended. Although CSF titers appear to correlate better with clinical course than serum titers, the antibodies remain elevated in many patients, even after successful treatment and clinical improvement (23). A few studies suggest that bortezomib may be a potentially useful drug when first- and second-line treatments fail. To date, the number of patients treated with bortezomib is small; most had been heavily treated with other immunotherapies (thereby impossible to rule out a delayed effect of previous treatments), and some received other drugs simultaneously (eg, methotrexate) (41). One study showed no benefit with bortezomib (43). Therefore, future studies are needed to assess the efficacy of this drug in anti-NMDA receptor encephalitis.
Supportive care. Patients often require symptom management, including treatment for seizures, psychiatric disturbances, sleep disturbances, and movement disorders. There is some evidence to suggest increased toxicity with neuroleptic medications (35). Seizures, decreased level of consciousness, and autonomic dysfunction, including central hypoventilation, are frequent causes of admission to the ICU and are managed using standard protocols. A small number of patients (approximately 5%) develop episodes of severe bradycardia and cardiac pauses, requiring the use of a temporary pacemaker. Patients rarely develop a seizure disorder and should be weaned from antiepileptics after recovery (36; 15).
Surgery. If a tumor is identified early, removal is important to achieve a faster recovery (46).
Rehabilitation. Rehabilitation requirements vary depending on severity of illness and length of hospital stay, especially time in the ICU. Once patients are well enough to be discharged, or even when they appear to be back to baseline, they often have residual memory, behavior, and cognitive processing deficits that can lead to problems in social interactions and reintegration into normal activities, school, or work (06). These deficits usually improve over months and require a multidisciplinary team to address the specific deficits of each patient.
About 50% of patients respond to corticosteroids (methylprednisolone or equivalent) and IVIg or plasma exchange within 4 weeks of initiation (46). The remaining patients may show responses to rituximab or cyclophosphamide. Overall, 80% of patients will have substantial to full recovery that can take up to 2 years. About 12% of the patients have relapses within the first 2 years of the disease (46). Overall, about 20% of patients have relapses any time after the initial episode; relapses are often milder than the initial presentation and are responsive to treatment without cumulative disability (19). Relapses may be related to an occult or recurrent teratoma, but can occur in the absence of tumor. Although seizures are common in the acute phase of the disease, the majority of patients become seizure free and the risk of developing a chronic seizure disorder is very low (44).
There are a few case reports of NMDA receptor encephalitis onset during pregnancy or the postpartum period, as well as some, but not definitive, evidence of placental transfer of the anti-NMDA receptor antibodies (27; 33). One baby reported as having NMDA receptor antibody titers similar to the mother had cortical dysplasia, but the pregnancy was associated with uteroplacental insufficiency and additional problems, making it difficult to assess the pathogenic role of antibodies (27). Another baby developed transient neurologic symptoms that the authors postulated was due to transplacental transmission of antibodies (26). One newborn with hypotonia, hypoventilation, and abnormal movements had diffuse brain edema on MRI attributed to maternal-antibodies and died 3 weeks after birth (07). A retrospective study reported on 11 women, 6 who developed anti-NMDA receptor encephalitis during pregnancy and 5 who became pregnant while recovering from the encephalitis (29). There were no obstetrical complications but 6 of the babies were premature and 1 had transient respiratory distress. Nine of the infants with a median follow-up of 18 months had normal development. No adverse events have been reported when immunotherapy was given to mothers.
Anesthetics such as ketamine, nitrous oxide, and xenon act as direct antagonists of the NMDA receptor. Although there is theoretical concern that their use in patients with NMDA receptor encephalitis should be avoided, they have been used safely in these patients (01).
Josep Dalmau MD PhD
Dr. Dalmau of IDIBAPS, University of Barcelona, received royalties from Athena Diagnostics and Euroimmun for intellectual property rights.See Profile
Myrna R Rosenfeld MD PhD
Dr. Rosenfeld received royalties from Euroimmun and Athena Diagnostics for intellectual property rights.See Profile
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.See Profile
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