Anti-NMDA receptor encephalitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] AE Dheeraj Makkar, M.D.[2]

Anti-NMDA encephalitis is an autoimmune disorder where antibodies attack NMDA receptors in the brain. It presents with psychiatric symptoms, seizures, memory loss, and movement abnormalities. Treatment involves immunotherapy, such as corticosteroids and intravenous immunoglobulin, along with tumor removal if applicable. Symptom management includes antiepileptic drugs, sedatives, and supportive care. Early diagnosis and prompt treatment are crucial for better outcomes in managing this potentially severe and life-threatening condition.

Anti-NMDA encephalitis, initially documented in a case report dating back to 1830, is an autoimmune condition marked by neuropsychiatric manifestations. In some instances, the presence of an ovarian teratoma is observed. The case of Susannah Cahalan played a significant role in raising public awareness regarding this disorder.

Anti-NMDA encephalitis can be categorized into three distinct subtypes based on the timing of onset and duration of the illness.

Anti-NMDA receptor encephalitis is an autoimmune disorder characterized by the presence of autoantibodies directed against the GluN1 subunit of the NMDA receptor. The presence of tumors, particularly ovarian teratomas in women and testicular teratomas or lung carcinomas in men, is frequently associated with the condition. Dysregulation of NMDA receptors contributes to the development of diverse neurological and psychiatric symptoms.

In anti-NMDA receptor encephalitis, autoantibodies targeting the GluN1 subunit of the NMDA receptor are present. These antibodies lead to internalization of NMDA receptors, disrupting synaptic plasticity and causing a range of neurological and psychiatric symptoms. Various causes of the antibodies include , infections, vaccinations and tumors

In the differential diagnosis of anti-NMDA encephalitis, other autoimmune encephalitides with specific antibody associations should be considered, including those associated with antibodies against AMPA receptors, GABA-B receptors, LGI1, Caspr2, and MOG. Clinical and serological evaluations are crucial for accurate diagnosis and appropriate management.

Encephalitis has an annual incidence of 2-3 per 100,000, with 40% being infectious, 40% of unknown cause, and 20% immune-mediated. Anti-NMDA receptor encephalitis and VGK Complex antibody-positive encephalitis are major immune-mediated categories. It is more common in women and younger patients.

Risk factors for anti-NMDA encephalitis include female predominance, higher incidence in young individuals, and increased likelihood of underlying teratoma in African-Americans and teratomas in Asians.

Anti-NMDA encephalitis typically exhibits a characteristic trajectory, wherein initial neuropsychiatric manifestations advance to neurological symptoms.

The acute phase of the condition can be severe and protracted, extending over a period of weeks to months. Timely initiation of immunotherapy and surgical intervention for tumor removal have shown to enhance prognosis. Gradual amelioration of symptoms occurs, although the duration of recovery varies. Long-term neurological and psychiatric recuperation may necessitate several months to years, with the possibility of relapses. Mortality rates are associated with complications such as infections, cardiac arrest, and respiratory distress. Favorable prognostic indicators include early intervention, milder symptomatology, and resection of associated tumors.

Anti-NMDA receptor encephalitis presents with neuropsychiatric manifestations, neurological symptoms, altered consciousness, and a subacute time frame. Early recognition is important for prompt intervention.

The physical examination findings in Anti-NMDA encephalitis are non-specific. Patients may exhibit symptoms of widespread encephalopathy, altered states of consciousness, orofacial dysostosis, dyskinesis, dystonia, and autonomic storming. Neurological examination may reveal signs of diffuse cerebral dysfunction, including reflex abnormalities and mild ataxia.

In Anti-NMDA encephalitis, cerebrospinal fluid (CSF) analysis often shows mildly elevated white blood cell count, modestly increased protein levels, and the presence of oligoclonal bands. CSF-specific tests like IgG index and oligoclonal band tests can provide diagnostic value.

There are no distinctive electrocardiogram (ECG) findings associated with Anti NMDA encephalitis.

Chest X-ray imaging does not reveal any characteristic findings specifically associated with Anti-NMDA receptor encephalitis

CT imaging has limited diagnostic utility in anti-NMDA encephalitis, but it can help exclude other conditions, identify associated tumors, and detect complications. MRI is the preferred imaging modality for this condition.

In approximately 50% of cases, brain magnetic resonance imaging (MRI) may appear normal in Anti-NMDA receptor encephalitis. Non-specific abnormalities, such as temporal lobe involvement, can be observed in the remaining cases. However, neuroimaging alone is not sufficient for diagnosis due to the lack of specific patterns of brain involvement.

FDG-PET scan plays a crucial role in the diagnosis, differential diagnosis, assessment of disease activity, treatment response, and prognostication of anti-NMDA encephalitis. It reveals characteristic metabolic changes in the brain, aids in distinguishing it from other conditions, monitors treatment efficacy, and identifies prognostic indicators.

Surgery plays a crucial role in the treatment of anti-NMDA encephalitis when an associated tumor, typically an ovarian teratoma, is present. Tumor removal can improve prognosis, reduce relapse risk, and enhance response to immunotherapy. A multidisciplinary approach is essential for optimal patient management.

The treatment of anti-NMDAR encephalitis involves immunotherapy, tumor diagnosis, and excision. Early immunotherapy has shown to improve outcomes. Treatment options include corticosteroids, plasmapheresis, immunoglobulins, and rituximab

Primary prevention of anti-NMDA encephalitis focuses on general measures to promote overall health and immune function, including a healthy lifestyle, good hygiene practices, and routine vaccinations. No specific preventive measures exist.

Secondary prevention of anti-NMDA encephalitis involves strategies aimed at early detection, timely intervention, and management to prevent disease progression and complications. Since anti-NMDA encephalitis often presents with neuropsychiatric symptoms, prompt recognition and appropriate referral to specialized medical care are crucial.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; AE Dheeraj Makkar, M.D.[2]

Anti-NMDA encephalitis, first described in a 1830 case report, is an autoimmune disorder characterized by neurological and psychiatric symptoms. Ovarian teratoma is sometimes associated. Public awareness increased with Susannah Cahalan’s case.

In the year 1830, a case report published in top medical journals in Hungarian, German, and Italian medical journals which can be traced back to as anti NMDA encephalitis associated with ovarian teratoma.

• A healthy 18-year-old woman experienced epileptic seizures, followed by six days of catalepsy, unresponsiveness, immobility, and shallow breathing. Her symptoms resurfaced frequently over the next 1.5 years. An ovarian tumor was diagnosed and removed leading to resolution of symptoms.

• In 2007 by Dalmau and Bataller, documented Anti-NMDA receptor encephalitis for the first time and demonstrated antibodies to a subunit of the NMDA glutamate receptor in patients with the condition neuropsychiatric manifestations.

The Susannah Cahalan case is a famous case of Anti NMDA Encephalitis and with publication of Brain on Fire—My Month of Madness in 2012 by New York Post reporter Susannah Cahalan, public awareness of this disorder rose. She described a quick progression from prodromal upper respiratory symptoms like a virus to acute psychosis which was confirmed with biopsy of her brain. She later recovered and continued her job.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; AE Dheeraj Makkar, M.D.[2]

Anti-NMDA receptor encephalitis is an autoimmune disorder characterized by autoantibodies targeting GluN1. Tumors, primarily ovarian teratomas in women and testicular teratomas or lung carcinomas in men, are associated. Dysregulation of NMDARs leads to a range of neurological and psychiatric symptoms.

Approximately sixty percent of individuals have tumors that contain nerve tissue. Majority of women have ovarian teratoma, while men have tumors like (testicular teratoma and small-cell lung carcinoma).

Anti-NMDA receptor encephalitis is predominantly caused by autoantibodies directed against the GluN1 component of the receptor.

In the acute phase of brain diseases, B cells, plasma cells, CD4 T cells, and, less frequently, CD8 T cells have been detected.

Crossing the blood-brain barrier enables systemically produced antibodies to crosslink NMDA receptors. This leads to their internalization and a severe disruption of synaptic plasticity and NMDA receptor network function.

• A model for the condition proposes that a decrease in NMDARs in inhibitory GABA neurons and glutamate synapses results in numerous effects, including dysregulation of glutamate release, elevated glutamate levels and excitatory circuits.

• The clinical syndrome disinhibits the frontostriatal network, resulting in psychotic, catatonic, stiffness, dystonia, and mutistic symptoms.
• The brainstem central-pattern generator is disinhibited, resulting in complicated movement problems, and the brainstem respiratory network is also disinhibited, leading to respiratory dysfunction.

NMDAR Dysregulation Proposed Symptoms Agonist effect on NMDARs Seizures Synaptic NMDAR hypofunction Amnesia, psychosis, hypoventilation Extrasynaptic NMDAR hyperfunction Catatonia, dyskinesias, seizures Neuronal network imbalance with impaired intraneuronal activity

Synaptic effects and symptoms in anti-NMDARE: a proposed correlation

NMDAR Dysregulation	Proposed Symptoms
Agonist effect on NMDARs	Seizures
Synaptic NMDAR hypofunction	Amnesia, psychosis, hypoventilation
Extrasynaptic NMDAR hyperfunction	Catatonia, dyskinesias, seizures
Neuronal network imbalance with impaired intraneuronal activity	Seizures

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; AE Dheeraj Makkar, M.D.[2]

In anti-NMDA receptor encephalitis, autoantibodies targeting the GluN1 subunit of the NMDA receptor are present. These antibodies lead to internalization of NMDA receptors, disrupting synaptic plasticity and causing a range of neurological and psychiatric symptoms.

Antibodies and the tumors producing them

Antibodies	Antigens	Associated symptoms	Tumors
Anti-Hu (ANNA-1)	HuD	Encephalomyelitis, limbic encephalitis, cerebellar degeneration, brain stem encephalitis, multi-segmental myelitis, sensory neuronopathy, sensory motor neuropathy, autonomic neuropathy	Lung cancer (85%), mostly SCLC, neuroblastoma, prostate carcinoma
Anti-Yo (PCA-1)	CDR2, CDR62	Paraneoplastic cerebellar degeneration	Ovarian, breast cancer
Anti-CV2(CRMP5)	CRMP5	Encephalomyelitis, polyneuropathy, optic neuritis, limbic encephalitis, choreatic syndromes, cerebellar degeneration	SCLC, thymoma
Anti-Ta/Ma2	MA-proteins	Limbic encephalitis, rhombencephalitis, male>>female	Testicular cancer
Anti-Ri (ANNA-2)	NOVA-1	Opsoclonus–myoclonus syndrome, rhombencephalitis, cerebellar degeneration, myelitis, jaw dystonia, laryngospasm	Breast, ovarian carcinoma, SCLC
Anti-amphiphysin	Amphiphysin	Stiff-person syndrome, limbic encephalitis, rhombencephalitis, cerebellar degeneration, polyneuropathy	Breast cancer, SCLC
Anti-recoverin	Recoverin	Retinopathy	SCLC
Anti-SOX-1 (AGNA)	SOX-1	Non-syndrome-specific	Sensitivity 67%, specificity 95% for SCLC in LEMS

Partially characterized onconeural antibodies (antigen not characterized or positive predictive value for tumor unknown)

Antibodies	Antigens	Associated symptoms	Tumors
Anti-Tr (PCA-Tr)	DNER	Cerebellar degeneration	Hodgkin lymphoma, non-Hodgkin lymphoma
Anti-Zic4	ZIC1-4	Cerebellar degeneration	SCLC
PCA-2	280 kD	Encephalitis, Lambert–Eaton myasthenic syndrome, polyneuropathy	SCLC
ANNA-3	170 kD	Neuropathy, cerebellar degeneration, limbic encephalitis	SCLC

SCLC: Small cell lung carcinoma; LEMS: Lambert–Eaton myasthenic syndrome (LEMS) DNER: delta/notch-like epidermal growth factor-related receptor

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;AE Dheeraj Makkar, M.D.[2]

In the differential diagnosis of anti-NMDA encephalitis, other autoimmune encephalitides with specific antibody associations should be considered, including those associated with antibodies against AMPA receptors, GABA-B receptors, LGI1, Caspr2, and MOG. Clinical and serological evaluations are crucial for accurate diagnosis and appropriate management.

Antigen	NMDA receptor NR1	Lgil	CASPR2	AMPA receptor	GABA B receptor	Glycine receptor	MgluR5
Age(median)/gender female : male	0·6–85 (21) 4:1	30–80 (60) 1:2	46–77 (60) 1:4	38–87 (60) 9:1	24–75 (62) 1:1	5–69 (43) 6:5	46, 15 1:1
Clinical syndrome	1.Prodromal Syndrome 2. Psychiatric Syndrome, seizures, amnesia 3.Movement disorders catatonia, autonomic instability,	Limbic encephalitis, tonic or facio-brachial dystonic seizures, myoclonus	Morvan Syndrome, encephalitis, neuromyotonia	Limbic encephalitis, psychiatric syndrome	Limbic encephalitis	Encephalomyelitis with rigidity and myoclonus, hyperekplexia, stiff-person syndrome, (retinopathy)	Limbic encephalitis, myoclonus
MRI T2/FLAIR hyperintensities, medial temporal	25%	80%	40%	90%	70%	10%	50%
CSF pleocytosis or Oligoclonal Bands	95%	40%	25%	90%	90%	some oligoclonal bands	2/2 only cases reported and present in them

ocb: oligoclonal bands; EEG: electroencephalograph; NMDA: N-methyl-D-aspartate; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid; GABA: γ-amino-butyric acid receptor; CASPR2: contactin-associated protein-like 2; Lgi1: leucine-rich, glioma-inactivated 1; mGluR5: metabotrophic glutamate receptor 5.

Other etiologies causing Anti NMDA encephalitis like features

Differential diagnosis
Bacterial and viral infections of the brain	Herpes simplex virus type 1, Human herpes virus type 6, Enterovirus, Mycoplasma
Autoimmune-associated encephalitis	PANDAS, Sydenham chorea, Hashimoto encephalopathy, Rasmussen encephalitis, Encephalitis lethargica
Autoimmune synaptic receptor encephalitides	Neuronal antibodies to GABA, AMPA, and LGI1receptors
CNS vasculitis	Primary CNS angiitis, Secondary (due to chronic infection, inflammatory processes)
Demyelinating disorders	Acute disseminated encephalomyelitis, Neuromyelitis optica
Medication Overdose	Ketamine, Phencyclidine

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; AE Dheeraj Makkar, M.D.[2]

Encephalitis has an annual incidence of 2-3 per 100,000, with 40% being infectious, 40% of unknown cause, and 20% immune-mediated. Anti-NMDA receptor encephalitis and VGK Complex antibody-positive encephalitis are major immune-mediated categories. It is more common in women and younger patients.

Encephalitis due to any cause has a yearly incidence of 2–3 per 100,000 in northern Europe, which is half the incidence of multiple sclerosis (4–8 per 100,000 annually).

• While 40% of cases are infectious and 40% are attributable to unknown causes, at least 20% are immune-mediated, with anti-NMDA-receptor encephalitis (4%) and VGK Complex antibody-positive encephalitis (3%) constituting the major categories.

• The condition is more prevalent among women (81%) and younger patients (37% 18 years, 95% 45 years); however, in the age categories younger than 12 years and older than 45 years, the disease is more prevalent among men nearly half of patients are male.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] AE Dheeraj Makkar, M.D.[2]

Risk factors for anti-NMDA encephalitis include female predominance, higher incidence in young individuals, and increased likelihood of underlying teratoma in African-Americans and teratomas in Asians.

The risk factors include females preponderance, the high incidence of the disease in youngsters, and the increased likelihood of an underlying teratoma among African-Americans. Asian patients had a higher incidence of teratomas.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] AE; Template:D Makkar

Anti-NMDA encephalitis follows a typical course: initial neuropsychiatric symptoms progress to neurological symptoms.

The acute phase can be severe, potentially lasting weeks to months. Early immunotherapy and tumor removal improve outcomes. Gradual symptom improvement occurs, but recovery time varies. Long-term recovery may take months to years with possible relapses. Mortality is linked to complications such as infection, cardiac arrest, and respiratory distress. The prognosis improves with early treatment, fewer severe symptoms, and tumor excision.

Onset: Initial symptoms often involve neuropsychiatric manifestations, followed by neurological symptoms such as seizures, movement disorders, and altered consciousness.

2. Acute phase: Symptoms worsen, leading to severe neurological deficits and potentially life-threatening complications. This phase can last for weeks to months.

3. Treatment: Early initiation of immunotherapy and tumor removal, if present, is crucial for optimal outcomes and improved prognosis.

4. Gradual improvement: With appropriate treatment, most patients experience a gradual improvement in symptoms. Recovery occurs in a stepwise manner, but the time frame can vary.

5. Long-term recovery: Neurological and psychiatric recovery may take several months to years. Close long-term follow-up is essential to monitor for relapses and provide ongoing management.

6. Relapses: Some individuals may experience relapses, particularly during the early stages of recovery, triggered by infections or other factors.

Among the causes of mortality were infection, sudden cardiac arrest, severe respiratory distress, refractory status epilepticus, tumor growth, and discontinuation of life-sustaining treatment.

First-line immunotherapy led to an improvement in 53% during the first 4 weeks of treatment, with 97% of this “improved” group exhibiting a statistically significant improvement positive result at 24 months. The 47% of patients who did not improve with first-line therapy and who received second-line therapy had better results than those who received only first-line therapy or no further immunotherapy (Barry et al., 2015). In addition to early detection and treatment, other positive prognostic variables include fewer severe symptoms and, if present, excision of the tumor.

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