Anti NMDAR encephalitis

Anti NMDAR encephalitis is an acute Encephalitis associated with antibodies against N-methyl-D-aspartate (NMDA)-type glutamate receptors and is now considered a distinct clinical entity.

Introduction

In 1997 a syndrome of Ovarian teratoma-associated limbic encephalitis (OTLE) was reported in 1 Japanese girl and 1 woman, both of whom improved following tumor resection.In 2004 Vitaliani et al described a treatment-responsive paraneoplastic encephalitis in relatively young women associated with ovarian teratoma and antibodies against the cell membrane of hippocampal neurons .

The target autoantigens were identified as heteromers containing NR1 and NR2 subunits of the N-methyl-D-aspartate receptor (NMDAR). In 2005,Dalmau et al first demonstrated antibodies to novel neuronal cell membrane antigens in 4 women with Ovarian teratoma-associated limbic encephalitis (OTLE) in a non-permeabilized culture of hippocampal neurons. Subsequently the same group reported a severe but treatment-responsive encephalitis associated with antibodies to NR2B and NR2A containing heteromers of the NMDAR and referred to the condition as Paraneoplastic Anti–N-methyl-D-aspartate Receptor Encephalitis.

Anti-NMDAR encephalitis are associated with tumours (commonly teratomas) in about 60% cases. Recent studies have however shown that this disorder can occur even in the absence of teratomas and is increasingly recognized in adolescents and children.

Pathophysiology

NMDA Receptors

NMDAR is responsible for initiating many forms of synaptic plasticity in different areas of the brain and has a principal role in controlling memory function. It is a heterotetramer consisting of two obligatory NR1 subunits and two of four possible NR2 subunits: NR2A, NR2B,NR2C, and NR2D. The NR2 subunits in the adult hippocampus and cortex are usually NR2A and NR2B, and the ratio of NR2B to NR2A has been shown in animals including humans to decreases with age.The greater plasticity of the juvenile brain is thought to be due to the relative abundance of NR2B..

Activation of NMDA receptor results in calcium influx from the extracellular milieu, resulting in large intracellular calcium concentration. The resulting excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke. Decreased NMDAR activity on the other hand produces symptoms of schizophrenia.

Autopsy studies in Anti NMDAR encephalitis have demonstated high IgG deposits in the hippocampus, extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus. The nervous tissues of the tumors when present exhibit not only strong expression of the NR2B subunits but also reactivity with the patients' antibodies.

The anti NMDAR antibodies cause inhibition of NMDAR, rather than stimulation, in presynaptic GABAergic interneurons, and inhibits the release of GABA. The resulting disinhibition of postsynaptic glutamatergic transmission causes excessive release of glutamate in the prefrontal/subcortical structures, and glutamate and dopamine dysregulation contributing to the development of schizophrenia-like psychosis and bizarre dyskinesias.

Clinical features

Anti-NMDA-receptor encephalitis has well defined clinical charactaristics.

• Psychiatric symptoms (frequent presentation):Change of personality and behavior, irritability, anxiety, aggressive behavior, delusional thoughts, paranoia, catatonia
• Short-term memory loss (rare presentation) Similar to classical limbic encephalitis
• Seizures Partial complex or generalized seizures
• Autonomic instability Hyperthermia (sometimes alternating with hypothermia), hypoventilation, fluctuations of blood pressure, tachycardia, bradycardia, constipation, ileus
• Abnormal movements Orofacial dyskinesias, dystonic posturing of the extremities, choreoathetoid movements, oculogyric crises, myoclonus, opisthotonos

Five stages have been describednamely, the prodromal phase, psychotic phase, unresponsive phase, hyperkinetic phase, and gradual recovery phase. The hyperkinetic phase is the most prolonged and crucial. This disorder is usually severe and can be fatal, but it is potentially reversible. Once patients overcome the hyperkinetic phase, gradual improvement is expected with in months and full recovery can also be expected over 3 or more years.

Neuroimaging

Neuroimaging is often unremarkable.

MRI scan of at presentation and follow-up

However small areas of FLAIR abnormalities in cerebral cortex (outside the medial temporal lobes), sometimes involving cerebellum and brainstem; transient enhancement of overlying meninges have been frequently reported. Medial temporal and frontal abnormalities are also seen, though less common.

Early white matter changes and bilateral periventricular, multifocal hyperintense lesions on T2-weighted FLAIR images over the frontal, parietal, and occipital regions without enhancement have also been reported.

Neurophysiology

EEG shows diffuse delta slowing.

Laboratory diagnosis

Demonstration of N-methyl-D-aspartate receptor antibodies in the CSF

Nonspecific changes with pleocytosis, increased protein concentration, normal glucose, oligoclonal bands and high IgG index have been described in the CSF.

NMDAR antibodies are present in serum and CSF, usually with intrathecal synthesis, and are sometimes only detected in the CSF. The main target epitopes are in the NR1/NR2 heteromers of the NMDAR. The major antigen is NR1/NR2B, which is predominantly expressed in the hippocampus and forebrain, but reactivity with other NR1/NR2 heteromers have also been reported.

Differential Diagnosis

Diagnosis	Remarks
Toxic and Metabolic disorders
Drug ingestion (salicylates, amphetamine, cocaine, phencyclidine, carbon monoxide, methanol, cyanide)	Toxicology screening
Porphyria	Increased urine aminolevulinic acid and porphobilinogen
Mitochondrial disorders (Leigh’s syndrome, MELAS syndrome)	Lactic acidosis
Disorders of amino and organic acid metabolism	Hyperammonemia, triggered by metabolic stress causing acute decompensation
Autoimmune encephalitides
Paraneoplastic encephalitis	Frequently associated cancers: small-cell lung cancer, thymoma, germ-cell tumors of the testis; usually associated with classical paraneoplastic antibodies
Encephalitis associated with voltage-gated potassium channel. antibodies (20% paraneoplastic)	Limbic encephalitis, Morvan's syndrome; frequent hyponatremia; voltage-gated potassium channel. antibodies
Systemic lupus erythematosus cerebritis	Anti-double-stranded DNA antibodies
Antiphospholipid antibody syndrome	Systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibodies
Sjögren’s syndrome	Sjögren’s syndrome antigen A (SSA/Ro) and B (SSB/La), salivary gland biopsy
Hashimoto’s encephalopathy	Antithyroglobulin, antithyroid peroxidase antibodies
Primary and systemic angiitis	CNS angiography; often all tests are negative in CNS angiitis (requires biopsy); ANCA
Viral encephalitides
Herpes simplex virus, Varicella zoster virus, Epstein–Barr virus, cytomegalovirus encephalitis	CSF polymerase chain reaction
Human herpesvirus 6 encephalitis	CSF human herpesvirus 6 polymerase chain reaction; usually affects immunosuppressed patients
Arboviral encephalitis	CSF antibodies
Rabies	Corneal smear for antigen; serum and CSF antibodies
Disorders presenting with the triad of psychiatric symptoms, muscle rigidity, and dysautonomia
Neuroleptic malignant syndrome	Normal pupils, no hyperreflexia, normal or decreased bowel sounds after administration of dopamine antagonists
Lethal catatonia	Pre-existing schizophrenia, depression, or mania(can be indistinguishable from neuroleptic malignant syndrome)
Serotonin syndrome	Hyperreflexia, clonus, mydriasis, diaphoresis, hyperactive bowel sounds after administration of serotonergic medications
From: Nat Clin Pract Neurol. 2007 May ; 3(5): 291–296.

Antibodies to NR2 subunits of the NMDAR have been reported in several other disorders.These antibodies (IgG or IgM) target linear epitopes and are detectable by immunoblot, often in the intracellular domain. The IgG antibodies of patients with paraneoplastic anti-NMDAR encephalitis on the other hand target conformal extracellular epitopes of NR1/NR2 heteromers and are not detectable by immunoblot, and are likely to be pathogenic.

Patients with Anti NMDAR encephalitis often fulfill the criteria for a diagnosis of Encephalitis Lethargica. Serologic antibody testing is hence very important in patients with encephalitis since the Anti NMDAR encephalitis generally tends to respond well to treatment.Encephalitis lethargica is defined as an acute or subacute encephalitic illness including at least three of the following criteria, where all other known causes of encephalitis have been excluded:(i) signs of basal ganglia involvement, (ii) oculogyric crises, (iii) ophthalmoplegia, (iv) obsessive-compulsive behaviour, (v) akinetic mutism, (vi) central respiratory irregularity, (vii) somnolence and/ or sleep inversion.

Other related disorders include Acute Diffuse Lymphocytic Meningoencephalitis and Acute Juvenile Female Non-Herpetic Encephalitis (AJFNHE)

Treatment

Treatment includes tumour resection(if relevant) combined with immunotherapy. (methylprednisolone, plasma exchange or IVIg).

Prognosis

The condition is usually severe and fatal but is potentially reversible on treatment. In some patients, tumor removal results in noticeable neurological improvement in a matter of days or after several weeks. Following recovery, most patients continue to improve over weeks or months until full recovery and would need prolonged physiotherapy Adult studies have shown that clinical improvement correlates with decrease in changes in NMDA receptors.

Relapse rates of 25% have been reported following treatment.

Further research

• Is there any relation between Anti NMDA Receptor antibody levels in serum/CSF and clinical severity in children ?

References

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