Herpes simplex virus-1 encephalitis (HSVE) is the most common cause of fatal sporadic
encephalitis worldwide. Recently, post-HSVE relapses due to autoimmune encephalitis
with NMDA receptor antibodies and other synaptic autoantibodies have been reported
in up to 27% of patients within 1–2 months after HSVE.
1,2
We report an unusual case of a patient with refractory status epilepticus due to HSVE
with antibodies against GABAA receptors (GABAAR).
Case report
A 47-year-old man was admitted with a new-onset generalized seizure. Two days before
admission, behavioral changes were observed. No psychiatric symptoms, headaches, or
feverish infections had occurred in the previous weeks. He had a B-cell non-Hodgkin
lymphoma 5 years ago and a Hodgkin lymphoma 16 years ago, both in complete remission
after radiochemotherapy. Eventually, focal status epilepticus developed provoking
intensified anticonvulsive treatment.
Initial brain MRI showed hyperintense fluid-attenuated inversion recovery (FLAIR)
signal of the left prefrontal gyrus without diffusion restriction (figure 1, A and
D) or contrast enhancement. CSF analysis on the day of admission revealed lymphocytic
pleocytosis (13 leukocytes/μL), elevated protein (574 mg/L), and lactate (2.74 mmol/L).
IV acyclovir 750 mg TID was started. CSF herpes simplex virus-1 (HSV-1) quantitative
polymerase chain reaction (qPCR) was negative. A second lumbar puncture (day 5 of
admission) showed 29 lymphocytes/μL, normal protein, and slightly elevated lactate
(2.27 mmol/L). HSV-1 DNA remained undetectable. Immunoglobulin G-HSV antibody index
was unremarkable (<1.3); further analysis revealed no other infectious causes. However,
GABAAR antibodies were detected in serum (1:1,600) and CSF (1:32) of the second lumbar
puncture using cell-based assays, tissue-based assays, and life embryonal hippocampal
neuron cultures (figure 1, G–I)
3
; no other neuronal antibodies were identified.
Figure
MRI findings and laboratory studies
MRI 1st day of admission (A and D) and 14 days after admission (B, C, E, and F), showing
progression of the left frontal hyperintense lesion and new diffusion restriction
left frontally and bilaterally in the operculum on day 14. (A–C) Axial fluid-attenuated
inversion recovery-weighted images with hyperintense lesion of the left prefrontal
gyrus (A and B) and the operculum bilaterally (C). (D–F) Diffusion-weighted images
and apparent diffusion coefficient images (small insets) without diffusion restriction
(D) and marked diffusion restriction in the left prefrontal gyrus (E) and the operculum
bilaterally (F). (G) Immunolabeling of sagittal rat brain sections with the patient's
CSF antibodies showing a characteristic pattern. Patient and control CSF 1:4. Anti-human
IgG (H + L). Human IgM and IgA did not show immunoreactivity. Scale bar 1 mm. (H)
Detection of antibodies to the GABAA receptors (GABAAR) using HEK293 cell-based assay.
Patient's but not control serum detects GABAAR. Human GABAAR subunits transfected
into HEK293 cells and stained via life cell staining (serum 1:40). Green human IgG,
red commercial GABAAR antibody. Scale bar 20 μm. (I) Patient's but not control serum
detects neuronal surface antigens. Nonpermeabilized embryonic rat hippocampal neuron
cultures DIV21 life cell stained with human IgG and nuclear counterstaining with DAPI
(blue). Scale bar 20 μm. (J) Postmortem herpes simplex virus antigen staining of the
patient's hippocampus. Scale bar 5 mm. DAPI = 4′,6-diamidino-2-phenylindole; IgG =
immunoglobulin G.
Acyclovir was stopped, yet IV methylprednisolone did not induce clinical improvement.
Follow-up MRI showed expansion of the left frontal hyperintense FLAIR lesion with
accompanied diffusion restriction and new bilateral opercular diffusion restrictions
(figure 1, B, C, E, F). Refractory status epilepticus continued (EEG, figure e-1,
links.lww.com/NXI/A145). The patient died of bowel ischemia due to thrombosis of the
mesenteric artery. Postmortem revealed extensive HSVE with necrosis, inflammation,
positive HSV antigen, and tissue PCR (figure 1J). No evidence of lymphoma was found.
Discussion
We describe an unusual case of CSF-qPCR-negative HSVE with concomitant GABAAR antibodies.
We confirmed presence and specificity of GABAAR antibodies in serum and CSF with high
titers, typical staining on rat brain immunohistochemistry and neuronal synapses of
live neurons in vitro.
Our patient was initially misdiagnosed with idiopathic GABAAR encephalitis owing to
detection of GABAAR antibodies, 2 negative HSV-1 qPCR in CSF, and characteristic clinical
presentation with severe encephalitis and refractory status epilepticus.
3,4
HSVE was only diagnosed postmortem by demonstration of widespread viral replication
in brain tissue. Coincidental development of HSVE and GABAAR encephalitis is unlikely
because of the low incidence of both diseases; rather breakdown of immunologic tolerance
toward GABAAR likely provoked by virus-induced destruction of neurons would be a plausible
explanation.
5
Previous post-HSVE autoimmune encephalitis cases predominantly had a biphasic course.
However, development in contiguity with HSVE symptoms similar to our case has been
described in adults,
1
and relapses have been observed as early as 7 days after HSVE in a 2-month-old boy.
5
Furthermore, a case of post-HSVE GABAAR encephalitis was recently described in a 15-month-old
child occurring 8 weeks after herpes infection, and a second case occurred following
HHV6 encephalitis.
4
We are not aware of a case of post-HSVE GABAAR encephalitis in an adult patient. However,
because of the unavailability of initial CSF antibody testing, we cannot exclude the
presence of “premorbid” GABAAR antibodies as a coincidental finding related to previous
lymphoma. Although, the “premorbid” presence of high-titer CSF GABAAR antibodies without
a history of seizures appears less plausible than our current hypothesis of continuous
post-HSVE GABAAR encephalitis.
Pathologic-proven HSVE without detectable HSV-1 DNA in CSF is another unusual feature
and was rarely reported.
6,7
Hypothetical explanations could be early lumbar puncture and analysis under pretreatment
with acyclovir. The previous lymphoma could have predisposed toward (1) the development
of HSVE as has been noted in inborn errors of pattern-recognition pathways and (2)
a breakdown of immune tolerance and consecutively development of systemic GABAAR antibodies
predisposing to rapid development of CNS autoimmunity after HSVE.
In summary, this single case illustrates the occurrence of GABAAR antibodies in PCR-negative
HSVE in an immunosuppressed patient resulting in misdiagnosis of idiopathic GABAAR
encephalitis. Key clinical points are (1) the difficulty of ruling out HSVE with qPCR
and immunoglobulin G antibody index, (2) the occurrence of GABAAR antibodies in parallel
to HSVE, and (3) the possibility of unusual clinical courses of HSVE and post-HSVE
autoimmune encephalitis in patients with immune deficiencies.
