Non‐paraneoplastic limbic encephalitis and central nervous HHV‐6B reactivation: Causality or coincidence?

Abstract

Autoantibody-related encephalopathies represent an important differential diagnosis in adult onset epilepsy. Here, we report the case of a 25-year-old patient with new-onset epilepsy and psychotic syndrome, who underwent biopsy resection for etiological classification. MRI analysis and neuropathological examination showed a T-lymphocytic dominated encephalitis with involvement of the limbic system. An indirect immunohistochemistry approach identified autoantibodies against glutamic acid decarboxylase (GAD) in cerebral spinal fluid and serum, which were confirmed by affinity purification / mass spectrometry analysis. Further examinations revealed evidence of chromosomally integrated human herpes virus type 6B (HHV-6B). However, astrocytic expression of HHV-6 lytic protein was detected by double immunofluorescence analysis. The cerebral expression of HHV-6 antigen, a clinical improvement under antiviral therapy as well as an initial finding of HHV-6 IgM antibodies strongly argue for an additional active HHV-6B infection. Review of the literature reveals singular reports of patients with GAD antibody-positive limbic encephalitis and central nervous system infections with HHV-6B. Since herpes simplex virus encephalitis has been recently reported as a trigger of N-methyl-D-aspartate receptor antibody encephalitis, it is tempting to speculate that HHV-6B infections may trigger a non-paraneoplastic form of limbic encephalitis in a parallel cascade.

HHV‐6 and hippocampal volume in patients with mesial temporal sclerosis

“…HHV‐6 might also cause indirect damage via autoimmunity. The herpes simplex virus (HSV) can lead to later development of autoantibodies against CNS antigens, and HHV‐6B has been co‐present with autoantibodies against glutamic acid 43,44 . Recurrent activation of HHV‐6 and consequent inflammation might support neuro‐inflammatory epileptogenesis leading to epilepsy 45 .…”

Occupation-Associated Fatal Limbic Encephalitis Caused by Variegated Squirrel Bornavirus 1, Germany, 2013

“…The disease is associated with paraneoplastic (epiphenomenal) nonpathogenic autoantibodies directed against intracellular epitopes (Hu, Ri, Ma2, and GAD), and pathogenic neuronal cell surface autoantibodies (against AMPA, GABA, and voltage-gated potassium-receptor complexes) ( 2 – 4 ), none of which were detected in the zoo worker. Recently, the triggering of an autoantibody-positive, nonparaneoplastic limbic encephalitis by human herpesvirus 6B was speculated ( 24 ), similar to the induction of NMDA (N-methyl-D-aspartate) receptor encephalitis as clinical relapse after herpes simplex virus encephalitis ( 25 ). Of note, several cases of limbic encephalitis without autoantibodies and with unknown etiology have been reported ( 5 – 8 ).…”

Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

“…Hence molecular mimicry is considered as one of the potential mechanisms for HHV-6 mediated autoimmune diseases. Clinical cases showing increased glutamic acid decarboxylase (GAD) antibodies and HHV-6 infection has been reported where antiviral therapy improved patient’s clinical condition [ 241 ].…”