Postherpes simplex encephalitis: a case series of viral-triggered autoimmunity, synaptic autoantibodies and response to therapy

Abstract

Background:Recent evidence suggests that patients with herpes simplex virus (HSV) encephalitis may relapse because of autoimmunity against the N-methyl-D-aspartate receptor (NMDAR). We present a case series of post-HSV relapsing encephalopathy associated with antibodies to central nervous system (CNS) synaptic antigens.Patient/Methods:Sera and cerebrospinal fluid (CSF) from five patients with HSV encephalitis who relapsed after antiviral therapy were tested for anti-NMDAR, gamma-aminobutyric acid b receptor (GABAbR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), Leucine-rich, glioma inactivated 1 (LGI1), anti -contactin-associated protein-like 2 (CASPR2) and dipeptidyl-peptidase-like protein-6 (DDPX) antibodies using cell-based assays.Results:Five patients (two infants, one child and two adults) developed post-HSV autoimmune encephalitis. The infants, aged 9 months and 10 months, after prompt and seemingly successful anti-HSV therapy, were readmitted with typical signs of NMDAR-encephalitis evolving within days, with NMDAR antibodies detected in both serum and CSF. Although they were promptly treated with intravenous immunoglobulin (IVIg) and with IVIg followed by rituximab, respectively, they were both left with psychomotor deficits. A 14-year-old girl with seizures due to HSV encephalitis improved with anti-HSV therapy. Later, she manifested intractable seizures and she was found positive for anti-NMDAR antibodies which persist. The two adults were women, aged 58 and 33 years. The first recovered after anti-HSV therapy and remained asymptomatic for 6 months, until she developed generalized seizures with persisting CSF anti-NMDAR antibodies; the second, who continued to be encephalopathic after 2 weeks of anti-HSV therapy, tested positive for anti-NMDAR antibodies in the serum and anti-GABAbR antibodies in the serum and CSF. She recovered fully following IVIg therapy but her serum anti-GABAbR antibodies persist 34 months later.Discussion:Infection of the CNS with HSV can trigger CNS autoimmunity associated not only with anti-NMDAR but also with anti-GABAbR antibodies. These antibodies can persist in the serum, even without associated symptoms, but their presence in the CSF is firmly associated with disease development. In contrast to children and adults who responded well to therapies, the infants had an incomplete recovery with severe psychomotor deficits probably due to the interference of anti-NMDAR antibodies with neuro-developmental processes.

Post-infectious neurological disorders

“… 44 Antibodies targeting alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA), dopamine-2 receptors, glial fibrillary acidic protein (GFAP), gamma-aminobutyric acid (GABA)-A, and GABA-B have also been reported in cases of post-HSE autoimmune encephalitis, while a high proportion of cases have had antibodies to yet unidentified antigens. 44 – 48 …”

Antibody negative autoimmune encephalitis- Does it differ from definite one?

“…Infectious causes such as herpes simplex encephalitis, malignancies such as carcinoma lung, thymoma etc., or any autoimmune disease, such as systemic lupus erythematous can predispose to the development of autoantibodies against cell-surface, synaptic or intracellular antigens. [123] Sometimes, it becomes difficult to ascertain whether the clinical presentations are due to the premorbid disease, it's relapse or due to the subsequently triggered auto-antibodies. Moreover, the clinical presentation of different causes of AE are more or less overlapping, leaving very few of them to be called as specific for a particular disease.…”

Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle?

“…Patients who are initially diagnosed as HSV-1 encephalitis based on polymerase chain reaction testing may develop another encephalitic illness approximately 4–8 weeks after recovery, marked by the presence of NMDAR antibodies and typical phenotypic features of the latter disease (115). A recent report suggests a similar sequence in a case of GABA B antibody associated AIE (116). In epidemiological studies, there is also a higher incidence of non-encephalitic HSV-1 infections in patients with NMDAR antibody associated AIE as compared with controls (117).…”