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
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.Ances 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). 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 [Dalmau et al., 2008] 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 [Dalmau et al., 2007]. Recent studies have however shown that this disorder can occur even in the absence of teratomas and is increasingly recognized in adolescents and children [Florance et al., 2009].
2. 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 described [Iizuka and Sakai, 2008] namely, 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.
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. [Florance et al., 2009] [Sansing et al., 2007]
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 [Tan et al., 2010].
EEG shows diffuse delta slowing.
5. Laboratory Diagnosis
Sansing et al., 2007].
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 [Sansing et al., 2007].
6. Differential Diagnosis
|Toxic and Metabolic disorders|
|Drug ingestion(salicylates, 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|
|Paraneoplastic encephalitis||Frequently associated cancers: small-cell lung cancer, 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, 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|
|Herpes simplex 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, and dysautonomia|
|Neuroleptic malignant syndrome||Normal pupils, normal or decreased bowel sounds after administration of dopamine antagonists|
|Lethal catatonia||Pre-existing schizophrenia, or mania(can be indistinguishable from neuroleptic malignant syndrome)|
|Serotonin syndrome||Hyperreflexia, 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[Mochizuki et al., 2006] [Takahashi et al., 2005].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[Tan et al., 2010].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[Howard & Lees, 1987].
Other related disorders include Acute Diffuse Lymphocytic Meningoencephalitis and Acute Juvenile Female Non-Herpetic Encephalitis (AJFNHE)
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