Objective
To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE).
Methods
Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients’ serum was studied in cultures of primary mouse hippocampal neurons.
Results
N-Methyl-d-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons.
Interpretation
Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy.
Background
Anti-NMDA receptor (NMDAR) encephalitis is a recently characterised
autoimmune disorder mainly affecting young women. Although the clinical
features of the acute disease are well characterised, cognitive long-term
outcome has not been examined in detail.
Methods
The authors investigated cognitive performance in nine patients with
proven anti-NMDAR encephalitis after recovery from the acute disease period
(median 43 months after disease onset, range 23 to 69). Patients underwent a
comprehensive neuropsychological assessment, including memory tasks that
have previously been shown to be sensitive for hippocampal dysfunction.
Results
Substantial persistent cognitive impairments were observed in eight
out of nine patients that mainly consisted of deficits in executive
functions and memory. The severity of these deficits varied
inter-individually. Patients with early immunotherapy performed
significantly better. The most severe deficits were observed with
inefficient or delayed initial treatment.
Conclusion
Our results suggest that cognitive deficits constitute a major
long-term morbidity of anti-NMDAR encephalitis. These deficits relate to the
distribution of NMDARs in the human brain and their functional role in
normal cognition. Good cognitive long-term outcome may depend on early and
aggressive treatment.
IMPORTANCE Limbic encephalitis with leucine-rich, glioma-inactivated 1 (LGI1) antibodies is one of the most frequent variants of autoimmune encephalitis with antibodies targeting neuronal surface antigens. However, the neuroimaging pattern and long-term cognitive outcome are not well understood. OBJECTIVE To study cognitive outcome and structural magnetic resonance imaging (MRI) alterations in patients with anti-LGI1 encephalitis.
Anti-NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis.
Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.
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