NMDA Encephalitis Case File

NMDA Encephalitis Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 3

You are called for a consult on a 28-year-old woman in the psychiatric ward of the hospital who has a seizure. The patient was admitted 2 weeks ago for a new onset of psychosis. Her mom notes the patient had “the flu” for a few days at the beginning of the month. She was recovering but then started to make odd statements, like mentioning someone was following her on the street. One day, the patient’s mother got a call that her daughter had not shown up to work that morning, which is not typical. When the mom arrived at the patient’s apartment, she found her cowering in a corner, yelling at an imaginary attacker. The patient had no history of psychiatric illness, so her mother called emergency medical services (EMS). Once admitted to the psychiatric ward, the patient was treated with neuroleptics and her hallucinations improved, but her mother feels she continues to decline in other ways. The patient no longer recognizes friends and family, does not understand where she is, and spends all day sleeping. After the new-onset seizure, the psychiatrist agreed neurology needed to be involved. On your examination, painful stimulus is required to wake the patient. She is not oriented to place or time. Most questions are not answered, and instead the response is tangential or stereotyped. Both her blood pressure and pulse are high, although review of her vital signs over 24 hours shows that her blood pressure and pulse have been fluctuating wildly throughout her stay. The patient does not participate in a formal neurologic examination. You do note she has abnormal movements of the mouth and tongue. Her mother says these were present even before she was started on antipsychotics.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 3:

NMDA Encephalitis                                        

Summary: The patient is a 28-year-old woman with a subacute onset of psychosis following a flu-like prodrome. Several weeks into the illness, she becomes hard to arouse, disoriented, and tangential. Her vital signs have fluctuated irregularly throughout her stay, and she has abnormal facial movements. Neurology is consulted for a new-onset seizure.

• Most likely diagnosis: Autoimmune (or paraneoplastic) encephalitis, most likely N-methyl-d-aspartate (NMDA) receptor encephalitis.
• Next diagnostic step: Magnetic resonance imaging (MRI) of the brain; electroencephalography (EEG), lumbar puncture (LP), and computed tomography (CT) of the chest/abdomen/pelvis.
• Next step in therapy: Plasma exchange, corticosteroids, and tumor resection.

ANALYSIS

Objectives

1. Describe the typical presentation of anti-NMDA receptor (NMDAR) encephalitis.
2. Understand the diagnostic and treatment approach for NMDAR encephalitis.
3. Know how to differentiate NMDAR encephalitis from diseases with similar presentation.

Considerations

This is a young woman with no psychiatric history who presented with frank psychosis. Given that the most likely explanation for this scenario is an initial presentation of schizophrenia, it is unsurprising this patient was admitted to a psychiatric ward. It is thus essential that primary care providers, emergency physicians, and psychiatrists are familiar with the features of organic diseases that may present with prominent psychosis in this population.

On further examination, this patient’s illness began with flu-like symptoms prior to the onset of psychosis. Later, after the psychotic symptoms were treated, she developed a depressed level of consciousness (stupor), disorientation, dysautonomia, orofacial dyskinesia, and finally a seizure. The subacute course, global cognitive symptoms, and lack of glaring focal neurologic findings suggest an inflammatory etiology for this patient’s condition, either infectious or autoimmune. Given the vastly divergent treatments these two classes of disease would require, the first priority is to rule out an infection.

Bacterial meningitis or encephalitis is typically fatal within days if not treated, so this is less likely. Fungal or mycobacterial infections are possible, though unusual in a young patient with an intact immune system. The classic infection in this presentation would be viral encephalitis, most commonly herpes simplex virus (HSV) or related herpes viruses, enterovirus, or one of the named encephalitis viruses (eg, West Nile or St. Louis). Cerebrospinal fluid (CSF) studies should be obtained. In addition to cell count, glucose, and protein levels, one should send specific viral serologies when possible. Since it is the only virus with a specific treatment, HSV is of particular significance, and some neurologists will treat empirically with acyclovir until the HSV polymerase chain reaction (PCR) comes back negative.

When an infectious etiology is eliminated, an autoimmune process becomes the most likely diagnosis in this case, namely a syndrome called limbic encephalitis (LE). Much like HSV encephalitis, LE is characterized by inflammation affecting primarily the temporal lobes and the orbitofrontal cortex (the cortical structures that overlie the skull base). LE can be paraneoplastic, with autoimmunity triggered by a cancer, or it can be an inherent autoimmune process with no tumor. Numerous antibodies have been described as causative of LE, although the absence of these antibodies does not rule out LE in patients. Antibodies directed at the NMDA-type glutamate receptor produce a classic syndrome, often in young women, typified by this patient’s scenario (new-onset psychosis that progresses to severe cognitive impairment, seizures, and dysautonomia).

Since giving a specific diagnosis may be impossible, a priority is placed on empiric treatment with therapies to suppress the immune system. Plasma exchange, intravenous immune globulin (IVIg) or high-dose IV corticosteroids are often used in concert. If these measures offer no improvement, chemotherapeutic agents such as rituximab may be used.

APPROACH TO:

NMDA Encephalitis                                        

DEFINITIONS

LIMBIC ENCEPHALITIS: An inflammatory process involving primarily the limbic cortex (ie, the mesial temporal lobes, hippocampus, amygdala, and related structures). It is classically caused by an autoimmune or paraneoplastic process.

PARANEOPLASTIC: Any syndrome that results as a remote effect of a tumor, often an autoimmune process in which antibodies produced in response to the tumor attack otherwise normal cells in the body. Lambert-Eaton myasthenic syndrome and dermatomyositis are other examples of neurologic paraneoplastic syndromes.

HERPES SIMPLEX VIRUS: A ubiquitous virus that primarily infects the trigeminal ganglion. It can rarely travel to the brain and cause a deadly encephalitis, which targets the same limbic structures and leads to similar symptoms as autoimmune limbic encephalitis. The infection is hemorrhagic, so red blood cells (RBCs) will be found in CSF. This should be treated with acyclovir.

ANTI-NMDA RECEPTOR ENCEPHALITIS: It is a common cause of paraneoplastic or autoimmune encephalitis caused by antibodies targeting the NMDA-type glutamate receptors. It often begins with psychosis and subsequently progresses into depressed consciousness, seizures, and ultimately coma. It was first described in young women with ovarian teratomas.

CLINICAL HISTORY AND FEATURES

Anti-NMDA receptor encephalitis was first described in 2007. Patients present with rapidly progressive memory deficits, seizures, and psychiatric symptoms. About 86% of patients in one case series had a nonspecific prodrome of headache, low-grade fever, and other flu-like symptoms. This progresses to psychiatric symptoms, including agitation, bizarre behavior, disinhibition, delusions, and hallucinations. These soon blend into cognitive dysfunction of short-term memory, concentration, and orientation. Seizures are characteristic of the later stages of the disease. Patients also can have dyskinesias, particularly of the mouth and face, which can be mistaken for seizures. Neither status epilepticus nor dysautonomia is uncommon, both of which will necessitate an intensive care setting.

Pathology

NMDA receptors are a subtype of glutamate receptors in the brain. Antagonism at the NMDA receptors in the thalamus leads to disinhibition of the frontal cortex, which manifests with a syndrome summarized above. (Phencyclidine [PCP] and ketamine are both NMDA receptor antagonists that produce a similar presentation.) In the case of autoimmune encephalitis patients, the antagonism of the receptors is by antibodies directed at the NR1a subunit. NMDAR encephalitis was originally described as a paraneoplastic syndrome in a series of young women found to have ovarian teratomas. It is thought that the abnormal tissue in the teratoma resembles the receptor subunits, and antibodies developed to attack the tumor ultimately cross-react with the healthy receptors in the brain. Since the initial description of NMDAR encephalitis, many patients have been diagnosed with the anti-NMDA antibodies who were not found to have cancer. This is termed the autoimmune subtype of the disease, compared to the paraneoplastic form.

Diagnostic Studies

The definitive diagnosis of NMDAR encephalitis is performed by direct detection of the antibodies in either CSF or serum. Unfortunately, this test is a send-out laboratory test that can take a week or more to return, so an extensive initial workup is required to exclude other diagnoses, obtain circumstantial evidence to support a diagnosis of NMDAR encephalitis, and direct empiric treatment.

MRI of the brain may show hyperintensities in the limbic cortex and other deep structures but is normal in 70% of cases.

CSF generally shows mild increase in protein and lymphocytes. LP is most valuable to exclude viral etiologies, particularly HSV. Patients with HSV classically will have elevated protein, lymphocytosis, and red blood cells not accounted for by procedure-related trauma. HSV PCR can be confirmatory.

EEG typically reveals generalized slowing unless a frank seizure is captured. This is very helpful for differentiating primary psychotic illnesses such as schizophrenia from encephalitis, as the latter usually has an abnormal EEG.

CT of the chest, abdomen, and pelvis is recommended in any patient suspected of having a paraneoplastic condition. In addition to helping to confirm the diagnosis, resection of the tumor is often curative.

Treatment

First-line treatment of the underlying autoimmune process is typically with corticosteroids, often in combination with IVIg or plasma exchange. In severe cases, it may be necessary to resort to chemotherapy, such as rituximab or cyclophosphamide. If a tumor, such as a teratoma, is found, it should be removed as soon as possible. Symptomatic treatment of psychosis and other behavioral disturbances is appropriate, though caution must be used with antipsychotics, as they contribute to movement and dysautonomia symptoms.

COMPREHENSION QUESTIONS

3.1 A 23-year-old woman presents with several days of psychosis. MRI shows hyperintensities in the temporal and orbitofrontal cortex. Interictal EEG demonstrates frequent epileptic discharges originating in the bilateral temporal lobes. CSF shows normal glucose, elevated protein, elevated white cell count with a lymphocytic predominance, and elevated red blood cell count. The spinal tap was performed by radiology and was not traumatic. Which of the following is the most likely diagnosis?

A. Bacterial encephalitis

B. Autoimmune encephalitis

C. Viral encephalitis

D. Schizophrenia

3.2 You suspect that a 27-year-old woman diagnosed with new-onset schizophrenia may actually have anti-NMDA receptor encephalitis. Which of the following tests is least likely to inform the diagnosis?

A. MRI of the brain

B. CSF

C. EEG

D. Serology for anti-NMDA antibodies

3.3 A 30-year-old woman is confirmed to have anti-NMDA encephalitis. She appears to be significantly ill. CT imaging reveals an ovarian teratoma. Which is the best initial step in the management of this patient?

A. Interferon-alpha therapy

B. IV corticosteroids

C. Transfusion with fresh frozen plasma

D. Tumor resection

ANSWERS

3.1 C. Normal glucose, elevated protein, and lymphocytosis point to a viral infection. The presence of RBCs and temporal lobe involvement with partial

seizures are all classic for HSV encephalitis. The patient should be started on acyclovir.

3.2 A. MRI is normal in 70% of patients with NMDAR encephalitis. CSF is abnormal in most patients with NMDAR encephalitis, though the abnormalities are nonspecific, and it would be normal in schizophrenia. EEG is abnormal in 90% of NMDAR encephalitis patients, whereas it would be normal in psychiatric disease. A positive serology for NMDAR encephalitis would confirm the disease.

3.3 B. Immune suppression is essential with corticosteroids being the first line of therapy. If a tumor is found in a patient with a paraneoplastic syndrome, timely resection can be curative, but medical therapy for stabilization in this patient is prudent. Fresh frozen plasma and interferon alpha have no role.

    CLINICAL PEARLS    

▶ Anti-NMDAR encephalitis is a cause of new-onset psychosis, classically in young women, that progresses to severe cognitive impairment, seizures, and dysautonomia. ▶ NMDAR encephalitis can be paraneoplastic or autoimmune (without an underlying tumor). ▶ NMDAR encephalitis should be promptly treated with immune suppression. Tumor should be sought with full-body CT and resected if found. ▶ HSV encephalitis also affects the temporal lobes. Classic CSF profile includes protein, red blood cells, and lymphocytes. Treatment is with acyclovir.

REFERENCES

Barry H, Bryne S, Cotter D, Murphy KC, Cotter DR. Anti-N-methyl-D-aspartate receptor encephalitis: review of clinical presentation, diagnosis, and treatment. BJPsych Bull. 2015;39:19-23. 

Wandinger K, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol. 2011;231:86-91.

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