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"Child`s Health" 3 (46) 2013

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Encephalitis, caused by antibodies to NMDA-receptors of neurons.

Authors: Igor V. Bogadelnikov, Alyona V. Bobrysheva, Yuliya V. Vyaltseva, Elena S. Chernyaeva, Crimean State Medical University named after S.I Georgievsky

Categories: Neurology, Pediatrics/Neonatology

Sections: Specialist manual

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Summary

Encephalitis, caused by antibodies to NMDA-receptors of neurons is a recently determined, acute and severe form of encephalitis. Its development is provoked by the generation of antibodies to NRI and NR2-heteromers NMDA-receptors of neurons. In the article pathogenesis, epidemiology, clinical presentation, diagnostics and approaches to treatment of this type of encephalitis are the presented.


Keywords

encephalitis, antibodies, NMDA-receptors

This is a recently determined, acute and severe form of encephalitis. Its development is provoked by the generation of antibodies to NRI and NR2-heteromers NMDA-receptors of neurons (3, 23). The etiology was discovered by Josep Dalmau, et al., in 2003, when the disease received its present name.

The disease has been known in the past and it has the full phenotypic accordance with previously described encephalitis of unknown etiology, it was called: acute diffuse lymphocytic meningoencephalitis; acute reversible limbic encephalitis; acute juvenile female nonherpetic encephalitis; juvenile acute nonherpetic encephalitis. In childhood medicine this clinical phenotype of NMDA-R-encephalitis was previously interpreted as dyskinetic lethargic encephalitis or syndrome of immune choreic encephalopathy (20).

Epidemiology. It has been determined that the disease is more common among women, while only few male cases have been described. Young people, on average  23-25 ​​y. o., are more prone to the disease (5, 16).

Pathogenesis. The evidence for the pathogenic role of anti-NMDA-receptor antibodies in the development of encephalitis includes:

  1. The presence of antibodies to NMDA-receptor neurons in the central nervous system in cerebrospinal fluid and serum in the acute period and their decrease in the recovery phase of the disease in all cases of encephalitis. Furthermore, there is a direct correlation between the titer of antibodies to NMDA-receptors and neurological outcome has;
  2. The ability of a number of NMDA-receptor antagonists (MK801, ketamine, fentseklidin) to cause symptoms similar to those of anti-NMDA-receptor encephalitis, including the psychotic symptoms (9, 11), and both the symptoms of the dopaminergic structures involvement (rigidity, dystonia, orofacial movements, tremor) (10, 11, 12), and autonomic dysfunction (cardiac arrhythmia, hypertension, hypersalivation) (13,16,17). The development of the central hypoventilation is typical for the majority of cases of anti-NMDA-receptor encephalitis. It is explained by the fact that the main targets of autoimmune response – NR1/NR2V-geteromery NMDA-receptor – are predominantly expressed in the forebrain of adults, including the prefrontal cortex, hippocampus, amygdala and hypothalamus, i.e. those structures, which, according to T. Iizuka, et al. (18), are most frequently involved in the development of anti-NMDA-receptor encephalitis.

The proposition is supported by the fact that after disengagement of NR1 animals die from hypoventilation (19). Therefore, it is the generation of antibodies to the NR1-subunit of NMDA-receptors that explains the frequent development of respiratory disorders at the peak of the disease;

  Hyperkinesis associated with anti-NMDA-receptor encephalitis has a non-epileptic nature, because it is resistant to antiepileptic and sedative drugs, as evidenced by data of prolonged EEG monitoring (5,6,18).

   The viral pathogenesis of the disease was excluded in all encephalitis cases in question based on the negative test results for the presence of viral agents in the CSF and brain biopsy at autopsy (5,6).

Clinical picture. The disease develops gradually. The prodrome period  is characterized by non-specific flu-like symptoms (fatigue, headache, fever, which were determined in 86% of cases, lasting for up to 5 days (3). The visible clinical manifestations are associated with the psychopathological disorders, which complicate the detection of organic brain lesion at this stage. Major adult clinical symptoms include sleeping and behavior disorders, psychosis, hallucinations, memory and speech disorders. The development of encephalitis adds to the severity of disease, manifested in seizures and mental disorders. It may also lead to such symptoms as dyskinesia, dystonia, disavtonomiya (hypoventilation, cardiac arrhythmias), anxiety, catatonia. Hypoventilation and hemodynamic abnormalities call for the intensive care. However, despite the severity of the disease, about 75% of patients recover completely or with little residual neurological disorders.

It is important to understand that anti-NMDA-receptor encephalitis is often a first sign indicating the presence of a possible tumor in the body. Therefore, cancer screening is essential for the diagnostic algorithm of this type of encephalitis, even in childhood cases (3, 23).

Laboratory diagnosis.

1. CSF test. It discovers lymphocytic pleocytosis (up to 480 cells in 1 ml) is revealed, increased protein concentration (49-213 mg / dL) and elevated levels of immunoglobulin G. in 95% cases (5,7).

2. Serology. Specific test to determine the titer of antibodies to NMDA-receptor in CSF and serum.

3. MRI. The FLAIR mode registers the signal change foci primarily in the deep temporal lobe.

Morphological studies. Dalmau, et al. (2008) report the results of brain biopsy of 14 patients with anti-NMDA-receptor encephalitis: in 2 cases there was no brain substance change, in 12 cases perivascular lymphocytic infiltrates were found, in 10 cases - activation of microglia. The virological examination showed negative results in all cases (5).

Treatment. Due to the frequent life-threatening (respiratory and hemodynamic disturbances) complications the treatment of anti-NMDA-receptor encephalitis should be carried out in ICU (5.18). Pathogenetic therapy involves glucocorticoids (methylprednisolone) and intravenous immunoglobulin (5.18), occasionally plasmapheresis and the introduction of monoclonal antibodies (rituximab), in particular cases - cytotoxic agents (cyclophosphamide, azatiaprin) (5), drugs with anticonvulsant activity (phenytoin, phenobarbital, clobazam, clonazepam), to control dyskinesias - typical and atypical neuroleptics.

Tumors, if detected, should be removed at the earliest stage possible, since they act as a source, which triggers the generation of antibodies that cross-infect the nervous tissue.

Notwithstanding the negative studies on viral antigens, due to similarity of  anti-NMDA-receptor and herpes encephalitis, acyclovir must be prescribed until the final diagnosis will be established (7, 18).

Disease outcomes. 47% have fully recovered, 28% had a stable mild residual deficit, 18% - severe deficit, 7% died as a result of neurological disorders. After discharge, the majority of patients (85%) had either a mild deficit in the form of neuropsychiatric symptoms of frontal dysfunction, or, completely recovered. About 20% of people had a distinct sleeping disorder: hypersomnia and inversion of sleep - wakefulness (5.18, 23).



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