Anti-NMDAR Encephalitis: Challenges in Early Diagnosis and Management

A woman in her 20s, with no personal or family history of mental illness, presented to her GP with anxiety and a bad mood. Her stressful sick leave from work did not give her relief. 

Over 5 weeks, his mood, appetite, and sleep rapidly worsened. She experienced severe panic attacks and, later, an auditory hallucination, on at least one occasion.

Mirtazapine and zopiclone did not provide any immediate benefit, so she was urgently referred to the Mental Health service. Her behavior was seriously disturbed at her house. She showed a rapid alternation between anger and a curious silence. She spoke in strange voices, sometimes with absurd content. From time to time, and randomly, she would start singing. She repeatedly squatted down and bit her lip. She followed her parents into her house, fearing they would be harmed.

At different times, he complained of having a "headache" and "limp" legs. Given the severe deterioration of her mental health, she was urgently hospitalized. Upon her admission, she had a complete medical history and routine tests and C-reactive protein, which were normal .

In the room, she seemed deeply depressed, with extremely impoverished and indiscernible language. She sometimes seemed terribly hypervigilant or perplexed. She exhibited mutism, stereotyped looks, and gestures suggestive of catatonia. Her social judgment was affected and she lacked insight. She directly needed intensive care, especially with hygiene and clothing, which implies severe cognitive dysfunction.

The initial diagnosis was a severe depressive episode with symptoms of psychotic episodes, marking the importance of his severely depressed mood that preceded disorganized behavior, impoverished speech, and psychomotor retardation. In the 4 weeks that she was hospitalized she received venlafaxine, olanzapine (low doses) and lorazepam (for catatonia), her mood partially improved.

After a few days without incident, she was discharged from the hospital, with her father’s collaboration. However, the clinical review a few days later confirmed her cognitive worsening, a decrease in her motor skills, both fine and gross, and involuntary hand movements.

Given the onset of new focal neurological deficits, blood tests were ordered to detect autoimmune encephalitis (AD). The finding of antibodies against the N-methyl-D-aspartate receptor (NMDAR) in the serum led to his urgent admission to the Neurology Service, where treatment for probable anti-NMDAR encephalitis was initiated .

Cerebrospinal fluid (CSF) analysis also detected NMDAR antibodies, confirming the diagnosis. In particular, the results of head magnetic resonance imaging (MRI) and EEG (EEG) were normal.

The encephalitis progressed, despite treatment with steroids and intravenous immunoglobulins, resulting in fluctuations in consciousness and autonomic instability for 1-2 weeks. Treatment with rituximab was then initiated , with a gradual, marked and sustained response.

The images ruled out the presence of ovarian teratoma and other tumors. One year after the onset of the illness, the patient’s recovery continued at her home.

AD refers to autoantibody-mediated inflammation of the brain. It manifests itself with a pattern of psychiatric and/or neurological symptoms, dependent on specific autoantibodies.

The number of known autoantibodies that are pathologically implicated in cases of AD expands each year, as new discoveries are made, such as the anti-voltage-gated potassium channel (VGKC) autoantibody-complex proteins LGI1 and CASPR2, AMPA and GABAB. However, the most common type of AD, and the one most frequently associated with psychiatric symptoms at onset, is anti-NMDAR encephalitis.

> Pathophysiology

In anti-NMDAR encephalitis, the action of immunoglobulin G (IgG) autoantibodies specific to the GluN1 subunit of the NMDA glutamate receptor results in general glutamatergic hypofunction. This causes disruption of cortical and subcortical network activity, even in the absence of notable structural neuronal lesions.

Sometimes the trigger for these autoantibodies can be an ovarian teratoma or infections (eg, herpes simplex); However, in most cases, the etiology remains unclear.

>  Epidemiology

The demographic groups most commonly affected by anti-NMDAR encephalitis are adolescent females and young adults (median 21 years; female/male ratio 8:2). It is a rare condition, with an estimated incidence of only 1.5 cases per million per year. However, 1 in 5 cases in the UK and 4 in 5 in the US presented with psychiatric symptoms. Therefore, it is important for psychiatrists working in all settings to be aware of this disease.

>  Presentation

Initially, in most cases, there is a nonspecific prodromal phase of flu-like symptoms (headache, fever, vomiting, diarrhea, and upper respiratory tract and digestive tract symptoms). Within several days, a wide spectrum of psychiatric symptoms appear. This motivates initial contact with health professionals.

This phase is highly variable and lasts 1 to 2 weeks. It is marked by significant psychopathology in relation to behavior, psychosis, mood, catatonia and sleep, with the complexity of the psychiatric presentation. This is a consistent and distinctive feature of anti-NMDAR encephalitis.

• In a third of cases the main symptoms are mood symptoms: anxiety, mood instability, depression and mania.
   
• Anterograde memory loss is considered a hallmark feature, but it is often masked by other symptoms.

Subsequently, a clear characteristic neurological disorder develops (with generalized tonic-clonic seizures or partial complex), dyskinesias and movement disorders (e.g., orofacial dyskinesia and choreoathetosis), severe cognitive dysfunction, autonomic instability (e.g., fluctuations in heart rate, thermoregulation and blood pressure), central hypoventilation, fluctuating consciousness or coma.

Given the substantial overlap of the typical age of onset with the primary presenting psychiatric symptoms of anti-NMDAR encephalitis (such as first-episode psychosis/schizophrenia and bipolar disorder), it is important to have a high index of suspicion, from the outset. Timely diagnosis is especially important because treatment can change the course of the disease.

(Below, the text in English to be able to correlate the acronym with the menmotécnico. In the following table, the text in Spanish.)

Once the differential diagnosis of anti-NMDAR encephalitis is considered, the priority investigation should be the detection of NMDAR antibodies in serum.

In practice, this can be easily achieved in mental health settings, by simply drawing blood into a yellow/gold colored tube (serum separated tube; SST). For gold standard testing, a CSF sample must also be obtained at the same time; However, the puncture requires the patient to be hospitalized, for this reason, the test is usually done at a later stage.

Importantly, anti-NMDAR antibody seropositivity rates (of all Ig classes targeting GluN1, including IgG) in healthy individuals are strikingly high, >10%. Furthermore, seropositivity rates in healthy individuals are not significantly different from the rates in affected individuals.

It is believed that the main determining factors in the development of the disease are: the permeability of the blood-brain barrier and the activation of intrathecal antibody production. Therefore, in practice, a seropositive result, even in a patient with psychosis, does not automatically equate to the diagnosis of anti-NMDAR encephalitis. This drawback implies the need for further research and studies of CSF, EEG, MRI, and specialist opinion.

In most cases of anti-NMDAR encephalitis, both serum and CSF have detectable NMDAR antibodies. However, at least 1 in 10 cases is seronegative , but with positive CSF. Therefore, apart from the serum result, when there is a high clinical suspicion, a lumbar puncture is justified .

Other findings in the CSF that support the diagnosis of anti-NMDAR encephalitis are lymphocytic pleocytosis, slightly elevated protein concentration, and the presence of oligoclonal bands, restricted to the CSF (indicating intrathecal IgG synthesis). It should be taken into account that it is sometimes difficult to perform a lumbar puncture or MRI in an agitated patient with psychotic symptoms.

In these cases, the intervention of the psychiatrist can provide the legal framework for the entire research process. Nursing staff must have experience in managing these patients. Early diagnosis and treatment with immunotherapy, regardless of the specialty of the treating physician, is of great importance, given the overwhelming benefits of this practice.

Currently, antibody testing in reference laboratories is the only option in many settings, and may require a turnaround time of several weeks.

In the future, testing accessibility will grow as local laboratories develop their capabilities to test for neuronal antibodies most commonly implicated in autoimmune encephalitis. The delay in obtaining laboratory results should not postpone the start of treatment, if the level of suspicion of auto-NMDAR encephalitis or organic lesion is high.

Routine blood test results (including C-reactive protein and white blood cell count) are often normal , as are REM and EEG. Sometimes, neuroimaging can show mild and transient (non-specific) alterations in the white matter of any brain area (67-89% of cases).

Compared with MRI, head CT provides less detail for the detection of any CNS inflammatory abnormalities, which may be seen in autoimmune encephalitis, and therefore MRI is preferred. However, as a broad and rapid approach, CT remains useful in excluding serious CNS pathology, such as space-occupying lesions and intracranial hemorrhage.

EEG findings are abnormal in 90% of anti-NMDAR encephalitis, but are generally nonspecific (slow focal or diffuse, disorganized, or epileptic activity). However, it is suggested that an “extreme delta brush” pattern is a unique feature of anti-NMDAR encephalitis.

Therefore, it is important that normal results from these investigations, or even any of them (routine blood tests, CT, MRI and EEG), do not rule out a possible diagnosis of anti-NMDAR encephalitis. This reinforces the diagnostic importance of serum and CSF antibody testing in suspected cases.

In confirmed cases of anti-NMDAR encephalitis, whole-body imaging should be done to detect tumors . Specifically, ovarian teratoma should be looked for in adolescent and young adult women, using ultrasound. and MRI of the pelvis.

Importantly, anti-NMDAR antibody seropositivity rates (of all Ig classes targeting GluN1, including IgG) in healthy individuals are strikingly high, >10%. Furthermore, seropositivity rates in healthy individuals are not significantly different from the rates in affected individuals.

The permeability of the blood-brain barrier and the activation of intrathecal antibody production are believed to be the main factors determining the development of the disease. Therefore, in practice, a seropositive result even in a patient with psychosis does not automatically equate to the diagnosis of anti-NMDAR encephalitis. This means that further investigation is warranted, at a minimum with CSF analysis, EEG, and head MRI, in addition to specialist care.

In most cases of anti-NMDAR encephalitis, both serum and CSF have detectable NMDAR antibodies. However, at least 1 in 10 cases is seronegative but CSF positive. Therefore, regardless of the serum result, in cases of high clinical suspicion, CSF testing is indicated.

Other CSF findings that support the diagnosis of anti-NMDAR encephalitis are: lymphocytic pleocytosis, slightly elevated protein concentration, and the presence of oligoclonal bands restricted to the CSF (indicating intrathecal IgG synthesis).

Certain practical problems must be taken into account. For example, performing an MRI or lumbar puncture on an agitated patient with psychotic symptoms can be very difficult and sometimes requires intense sedation or even general anesthesia.

Psychiatrists can help by ensuring the legal framework relating to issues of detention, capacity and consent. Nursing staff must be prepared to optimize care.

The overwhelming benefits of early diagnosis and initiation of immunotherapy justify starting treatment when test results are not yet known. Currently, antibody testing in reference laboratories is the only option in many settings, and may require a wait for a response of several weeks.

In the future, testing accessibility will grow as local laboratories develop their own testing capabilities for the neuronal antibodies most commonly implicated in autoimmune encephalitis.

The clinical criteria for probable and definite anti-NMDAR encephalitis were developed by expert consensus in 2016. Until now, treatment of anti-NMDAR encephalitis has been based on expert consensus.

• In general, early and aggressive treatment provides better results. First-line treatment is usually high-dose corticosteroids (initially intravenously and then orally) and intravenous immunoglobulins.
   
• If the response is insufficient (typically observed in 50% of cases), rituximab (a treatment with monoclonal antibodies directed at B cells, therefore reducing antibody production), is indicated as second-line therapy. .
   
• Cyclophosphamide is reserved as additional therapy for refractory cases.
   
• In addition to this treatment, if a tumor is found (e.g., ovarian teratoma), it should be surgically removed.

A consultation with neuropsychiatry may be made for advice regarding symptomatic management of agitation or psychosis. The basis will be to guarantee patient safety and specialized nursing care. Detention and treatment can be done under current mental health legislation.

Caution should be exercised regarding the use of psychotropic medication, as this may complicate the fluctuation of the clinical picture.

For example, benzodiazepines can exacerbate respiratory depression and impaired consciousness. On the other hand, in anti-NMDAR encephalitis there may be an association between antipsychotics and neuroleptic malignant syndrome .

In general, these risks must be balanced with the potential benefit of alleviating distress and dangerous behavior. If the patient is using antipsychotics, it is best to discontinue them gradually once the encephalitis is under control to reduce the risk of metabolic side effects (aggravated by steroids).

There is a validated predictive prognostic tool, the Anti-NMDAR Encephalitis One-Year Functional Status score. This scale has 5 categories, depending on the severity of the prognosis:

1) Hospitalization in the intensive care unit.

2) Therapeutic delay > 4 weeks.

3) Lack of clinical improvement in 4 weeks.

4)  Abnormal MRI.

5) Pleiocytosis >20 cells/μL in the CSF. After acute recovery from anti-NMDAR encephalitis, it is advisable to transfer the patient to a center specialized in neurological rehabilitation.

Follow-up with repeated neurocognitive assessments is recommended. With treatment for 18 to 24 months, 8 out of 10 patients gradually but significantly recover. Prolonged deficits may include executive dysfunction, impulsivity, disinhibition, and sleep disturbances. Patients usually have few memories of their illness.

There is a 12% risk of relapse over 2 years, especially in cases not associated with a tumor at presentation; most are less severe in nature compared to the index disease.

Relapses require additional treatment with immunotherapy.

In particular, a quarter of relapses present with psychiatric symptoms alone. Therefore, psychiatrists should be alert to this fact when caring for a person with a medical history of anti-NMDAR encephalitis.

Retrospectively, the patient presented many of the signs of autoimmune encephalitis, and almost all of the "SEARCH cor NMDAR-A" diagnostic clues were present. This emphasizes the importance of making psychiatrists aware of the suggestive features of the disease. anti-NMDAR encephalitis, to allow its early recognition.

Furthermore, this case demonstrates the importance of a complete and systematic specialized workup, including serum/CSF antibody testing, in suspected cases of anti-NMDAR encephalitis. In this case, the EEG and MRI results corresponded to an advanced stage of encephalitis.

The true diagnosis was only revealed by serum and CSF antibody testing. Finally, physicians must be aware of the risk of missing the diagnosis because it is masked by the psychiatric condition and physical signs coexist. You need to be prepared to advocate for your patients to ensure they receive appropriate medical care.

In general, anti-NMDAR encephalitis initially presents with a complex constellation of psychiatric symptoms, with an acute onset such as agitation, psychosis, and catatonia.

As in the case described, patients can first consult the Psychiatry Service. Therefore, psychiatrists have a crucial role in the early recognition of anti-NMDAR encephalitis, and must be familiar with the characteristics of the disease, both physical (neurological status) and mental.

Clinical suspicion should trigger an early discussion with the neurologist and the indication of serological (and, ideally, CSF) testing for NMDAR antibodies. Collaborative work helps with early diagnosis and timely immunotherapy, resulting in better long-term outcomes.

In the future, routine screening for autoantibodies in patients presenting with psychiatric symptoms may become common practice, and studies are underway to evaluate the potential role of immunotherapy within psychiatric practice.