Acute HSV and anti-NMDA encephalitis occurring as a neurosurgical complication

Abstract

We present a 24-year-old man with a 2-year history of progressive right-sided monocular vision loss with no other symptoms. An MRI showed a meningioma compressing the right optic nerve and the cavernous sinus. The tumour was partially resected. Eight days after discharge the patient was admitted with fever, a severe stabbing headache, insomnia, nausea and vomiting. A FilmArray panel and a cerebral biopsy were performed which were positive for herpes simplex virus 1 (HSV-1). An MRI of the brain showed asymmetric bilateral lesions in the frontobasal region with predominance of the right side. Acyclovir was started and continued until completing 21 days. A month after discharge, he started experiencing insomnia, trichotillomania, limb tremor, persistence of abulia, apathy and emotional lability. An HSV-1 encephalitis relapse was suspected, acyclovir and foscarnet were started. Due to the poor response to antiviral therapy CSF was tested, which was positive for anti-NMDA receptor encephalitis. A treatment course of intravenous immunoglobulin was started with a favourable outcome.

Background

Herpes simplex virus encephalitis (HSVE) clinical course is aggressive and leads to a wide range of neurological and psychiatric sequelae. In fact, 89% of patients who survive remain with moderate or severe disability 1 year after the disease course. Mortality despite treatment is between 5.5% and 25%, but it can go as high as 70% if untreated.^{1 2} The early recognition of this pathology and the timely administration of acyclovir as a first-line treatment are important factors to improve the results and reduce the disease burden.³ HSVE after neurosurgery is an unusual postoperative complication and only a small number of cases have been reported in the literature.⁴ It has been proposed that the reactivation of the virus results from immunosuppression associated with surgery, steroid therapy or radiation. The cases reported suggest that this complication has a poor prognosis, even with adequate treatment.^{5 6}

HSVE is related with the development of anti- N-methyl-D-aspartate receptor encephalitis, as evidenced by the presence of IgG antibodies against the NMDA receptor of the GluN1 subunit in patients recovering from HSVE.^{5 7} This complication should always be suspected when the clinical course is unfavourable after an initial period of improvement. The diagnosis is confirmed with the presence of IgG antibodies against the GluN1 subunit of the NMDA receptor in serum or cerebrospinal fluid. Treatment includes immunosuppression with intravenous methylprednisolone, intravenous IgG or plasma exchange.⁸

Case presentation

A 24-year-old man presented with a 2-year history of progressive right-sided monocular vision loss, with no other associated symptoms. Four months prior to admission, he completely lost sight in his right eye. His medical and family history was unremarkable, he reported taking no medications and no history of herpesviruses infections. Physical examination showed visual loss in the right eye with pallor of the optic disc. The rest of the neurological and physical examinations were normal. An MRI showed a tumour compressing the right optic nerve and the cavernous sinus. A pterional craniotomy was performed without immediate complications and its pathology was consistent with a paraclinoid meningioma. Eight days after discharge, the patient was admitted to the emergency department with fever, a severe stabbing headache, insomnia, nausea and vomiting. On examination, he was disoriented in time and place but there were no other neurologic abnormalities. Later on, he developed hypoprosexia, apathy and abulia.

Investigation

Our patient’s blood workup showed mild leucocytosis, HIV and syphilis serology were negative. The CSF analysis revealed a protein level of 59 mg/dL, 39 white blood cells ×10⁹/L and was negative for postoperative bacterial meningitis. A FilmArray panel was positive for herpes simplex virus-1 (HSV-1). Initial MRI of the brain showed asymmetric bilateral lesions in the frontobasal region with predominance of the right side (figure 1A, B). An Electroencephalogram showed diffuse non-specific non-epileptiform background slowing with anterior predominance. Treatment with acyclovir was started. Subsequently, he developed stereotyped movements and cacosmia consistent with an uncinate crisis, which were treated with valproic acid.

Figure 1.

Brain MRI axial views in Diffusion-weighted imaging and T2- Fluid attenuated inversion recovery (FLAIR) sequences demonstrating the evolution from acute herpes simplex virus encephalitis (HSVE) to anti-NMDAR encephalitis. (A) Diffusion restriction in the straight gyri and insular cortices bilaterally consistent with cytotoxic oedema and a (B) right parasellar hyperintense region in T2-FLAIR consistent with postsurgical changes. (C) Enlargement of the area compromised by cytotoxic oedema to the right fronto orbital region white matter, right basal ganglia, medial aspect of the left frontal lobe and left insular cortex. (D) signs of cortical laminar necrosis are seen in the right basal ganglia area. (E) Signal normalisation in the DWI sequence and (F) bilateral white matter and cortical hyperintensities in both anterior frontal and fronto orbital regions seen in T2-FLAIR.

Ten days after starting antiviral therapy an MRI of the brain was repeated because there was deterioration in the patient’s clinical condition. The image showed progression of the disease with enlargement of the lesions and development of cortical laminar necrosis (figure 1C, D). The treatment was continued until completing 21 days. The patient recovered slowly and was discharged with mild behavioural impairment. A month after discharge, he started experiencing insomnia, trichotillomania, limb tremor, persistence of abulia, apathy and emotional lability. In the course of the disease, he developed hypersexuality, aggressive behaviour and ideas of regression in which he stated that he was 3 years old and that his parents, both living, had died.

A relapse of HSVE was suspected and a cerebral biopsy was performed. The brain biopsy was compatible with encephalitis and was positive for HSV-1. The MRI showed extension of the lesion to the bilateral frontal regions (figure 1E). A course of high-dose intravenous acyclovir and foscarnet was started. Another lumbar puncture was performed and a FilmArray was done, which was negative for HSV-1. Due to the poor response to antiviral therapy, CSF was tested for anti-NMDA receptor antibodies, which were positive. Treatment was started with intravenous immunoglobulin, with a good clinical response. Subsequently, the patient developed diabetes insipidus that was successfully treated with vasopressin.

Differential diagnosis

The main differential diagnosis to consider in this patient readmission after an initial treatment for HSVE are shown in table 1. This encompasses many pathologies that could explain the new symptoms of this patient.

Table 1.

Differential diagnosis of neuropsychiatric symptoms of acute onset

Diagnosis	Clinical clues and presentation	Radiological and laboratory findings
HSVE	Headache Focal neurologic deficits Encephalopathy Seizures	CSF: lymphocytic pleocytosis, elevated protein levels, may have RBCs MRI of the brain may show hyperintensity on T2 with areas of restricted diffusion
Anti-NMDA receptor encephalitis	Prominent neuropsychiatric manifestations Seizures Movement disorders Decreased level of consciousness Autonomic dysfunction	CSF: lymphocytic pleocytosis, presence of OCBs EEG: normal or slow waves and disorganised activity MRI of the brain: abnormalities in cortical or subcortical regions IgG antibodies against the GluN1 subunit of the NMDA receptor in serum or CSF
Limbic encephalitis Anti-LGI1 encephalitis Anti-Caspr2 associated encephalitis GABAB-R associated encephalitis AMPA-R associated encephalitis	Acute or subacute mood changes Memory deficits Focal seizures and cognitive dysfunction	EEG: focal or generalised slowing or epileptiform activity maximal in the temporal regions MRI: hyperintensities in the medial temporal lobes in T2-FLAIR CSF: pleocytosis
	Faciobrachial dystonic seizures REM sleep disorders	Anti-LGI1 antibodies in CSF
	Morvan syndrome: neuromyotonia, memory deficit, confusion, sleep disturbances and autonomic disorders	Anti-Caspr2 antibodies in CSF
	Prominent seizures 50% associated with cancer, mainly small-cell lung carcinoma	GABAB-R antibodies in CSF
	Prominent psychotic symptoms Association in 65% of cases with cancer, mainly thymoma and small cell lung carcinoma	AMPA-R antibodies in CSF
Anti-Hu encephalomyelitis	Preceding subacute sensory neuropathy Progression to involvement of areas such as: temporal lobes, brainstem, cerebellum and autonomic nervous system >95% associated with cancer, specially small-cell lung cancer	Positive anti-Hu antibodies in CSF
Seizure disorders Mesial temporal Lobe Seizures Non-convulsive status epilepticus	Anxiety  Psychic or experiential phenomena  Epigastric aura  Automatisms	EEG shows epileptiform sharp waves over the temporal region  MRI findings due to hippocampal sclerosis are hippocampal atrophy
	Speech disorders Catatonia Confusion Diminished responsiveness	EEG: Focal or generalised spikes, sharp waves, or sharp-and-slow complexes at frequencies>2.5 Hz
Acute psychotic episode	Delusions Hallucinations Thought disorganisation Agitation or aggression	Exclusion diagnosis

AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Anti-Caspr2, anti-contactin-associated protein-like 2; Anti- LGI1, anti-leucine-rich glioma inactivated 1; EEG, Electroencephalogram; GABAB, B1 subunit of the gamma-aminobutyric acid B; HSVE, Herpes Simplex Virus Encephalitis; NMDA, N-methyl-D-aspartate; OCBs, oligoclonal bands; REM, Rapid Eye Movements.

Outcome and follow-up

At follow-up, the patient was seen continuously for the next 9 months after discharge and he was recovering well. He did not have seizures, nor new episodes of affective or cognitive disorders. However, he still had mild dysexecutive alterations but was completely functional. After his relapse, he suffered an abrupt change in his personality due to the frontal lobe dysfunction. The benzodiazepine and the antipsychotic were gradually discontinued without relapses.

Discussion

HSVE is considered the most frequent cause of acute infectious encephalitis in the general population. It has an incidence of 2–4 cases per 1 000 000 people, affecting men and women equally.^{1 2}

A characteristic HSVE CSF profile shows moderate lymphocytic pleocytosis, an increased erythrocyte count and elevated proteins.¹ The gold standard for diagnosing HSVE is the presence of HSV-1/HSV-2 DNA in the CSF polymerase chain reaction. MRI should be performed given the increased sensitivity and specificity of this examination for the evaluation of encephalitis.⁸ Characteristic MRI findings in a patient with HSVE include asymmetric hyperintense lesions in the mesiotemporal, orbitofrontal lobes and insular cortex.⁹

Two-thirds of HSVE cases occur through reactivation of latent infection.¹⁰ HSVE after neurosurgery is an unusual postoperative complication and only a small number of cases have been reported in the literature.⁸ It is proposed that this results from immunosuppression associated with surgery, steroid therapy or radiation. The cases reported suggest that this complication has a poor prognosis, even with adequate treatment.^{7 8}

HSVE is related with the development of anti-NMDA receptor encephalitis, as evidenced by the presence of IgG antibodies against the NMDA receptor of the GluN1 subunit in patients recovering from HSVE.^{5 8} Symptoms begin four to 4–6 weeks after initial viral infection and it clinically presents with prominent psychiatric manifestations (agitation, bizarre behaviour, hallucinations, delusions and disorganised thinking), insomnia, memory deficits, decreased level of consciousness and language dysfunction.^3–5 This complication should always be suspected when the clinical course is unfavourable after an initial period of improvement. The diagnosis is confirmed with demonstration of IgG antibodies against the GluN1 subunit of the NMDA receptor in serum or CSF. Treatment includes immunosuppression with intravenous methylprednisolone, intravenous IgG or plasma exchange.⁶

The neuropsychiatric complications of patients with anti-NMDA receptor encephalitis are usually difficult and refractory. Effective treatments have not been clearly defined. Second-generation antipsychotics are preferred because of their safety profile and low extrapyramidal side effects. For mania, anxiety and insomnia benzodiazepines are widely used.^{5 10}

The anti-NMDA receptor encephalitis is a well-known immune-mediated complication of HSVE. Both conditions present with acute-onset neuropsychiatric symptoms due to the involvement of the frontobasal region of the brain. Thus, besides giving specific treatment for these conditions, it is necessary to treat these symptoms appropriately.

Learning points.

• Herpes simplex virus encephalitis (HSVE) after neurosurgery is an unusual postoperative complication and only few cases have been reported in the literature.

• After a new onset of psychiatric symptoms despite the administration of the appropriate HSVE treatment, one must consider anti-NMDA receptor encephalitis as a possible diagnosis.

• Neuropsychiatric symptoms of autoimmune encephalitis are difficult to manage and refractory. However, the use of second-generation antipsychotics and benzodiazepines has been shown to be beneficial.