Herpes simplex reactivation following neurosurgery: case report and review of the literature

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Herpes simplex encephalitis is a common viral encephalitis associated with significant morbidity and mortality if not diagnosed and treated early. Neurosurgery may be an impetus for viral reactivation, either from direct nerve manipulation or high-dose steroids often administered during cases. The authors present the 40th known case of herpes simplex virus (HSV) encephalitis following neurosurgical intervention and review the previously reported cases. In their review, the authors observed positive HSV polymerase chain reaction (PCR), which had initially been negative in several cases. In cases in which there is high suspicion of HSV, it may be prudent to continue antiviral therapy and retest CSF for HSV PCR. Antiviral therapy significantly reduces mortality associated with HSV encephalitis.

ABBREVIATIONS CN = cranial nerve; HSE = herpes simplex encephalitis; HSV = herpes simplex virus; PCR = polymerase chain reaction; POD = postoperative day.

Herpes simplex encephalitis is a common viral encephalitis associated with significant morbidity and mortality if not diagnosed and treated early. Neurosurgery may be an impetus for viral reactivation, either from direct nerve manipulation or high-dose steroids often administered during cases. The authors present the 40th known case of herpes simplex virus (HSV) encephalitis following neurosurgical intervention and review the previously reported cases. In their review, the authors observed positive HSV polymerase chain reaction (PCR), which had initially been negative in several cases. In cases in which there is high suspicion of HSV, it may be prudent to continue antiviral therapy and retest CSF for HSV PCR. Antiviral therapy significantly reduces mortality associated with HSV encephalitis.

Herpes simplex encephalitis (HSE) is the most common cause of acute viral encephalitis in the United States.25 Many cases, as many as two-thirds, are due to virus reactivation rather than a primary infection, as 90% of the population is infected with herpes simplex virus (HSV).7,25 Neurosurgical intervention can potentially cause reactivation of HSV, although the true incidence rate is unknown since it is rarely considered a postoperative complication. We present the case of a 72-year-old immunocompetent man with HSE following craniotomy for meningioma resection.

Case Report

A 72-year-old man without a known history of HSV infection presented with 2 years of progressive diplopia on leftward gaze and several months of left eye drooping. CT scanning of the head showed a right sphenoid wing/cavernous sinus lesion suspicious for meningioma. The lesion encased the ipsilateral anterior and middle cerebral arteries and extended extracranially to the anterior clinoid process, causing compression of cranial nerves (CNs) II and III on that side. MRI demonstrated the mass abutting the anterior aspect of Meckel’s cave, with the contour of the trigeminal ganglion remaining intact (Fig. 1). CNs III, IV, and VI were engulfed within the tumor, with V1 and V2 of the trigeminal nerve just inferior to the tumor.

FIG. 1.
FIG. 1.

Axial MR image of the right meningioma with cranial nerve involvement.

The patient underwent partial resection to remove mass effect on CN II and remove tumor from around the middle cerebral artery, anterior cerebral artery, and internal carotid artery, as well as the clinoid due to tumor invasion with associated hyperostosis. To accomplish this, a pterional incision was made with the bone flap centered over the sylvian fissure and the clinoid. The dura was found to adhere to the skull and was opened. The sylvian fissure was opened under microscopic visualization, and the case was completed using microsurgical technique. The tumor was found to be deep and lateral in the fissure over the medial sphenoid wing. The tumor was coagulated and debulked, with time taken to remove tumor from the anterior and middle cerebral arteries the and supraclinoid carotid artery, as well as from CNs II and III. Intraoperatively, CNs IV, V, and VI were not visualized or manipulated in any way. Of note, the patient received 40 mg Decadron intraoperatively, 4 mg every 6 hours scheduled postoperatively with taper to off in 2 days. Additional plans were made for follow-up Gamma Knife surgery. The pathology returned as psammomatous meningioma (WHO grade I). The patient’s intraoperative course was complicated by a small right frontal ischemic infarction, and postoperatively the patient had worsening of his CN III palsy. He was subsequently discharged home on postoperative day (POD) 4.

On POD 6, the patient presented to the emergency department for a new left-sided headache and increased periincisional edema. He was afebrile but had mild leukocytosis (12.3 K/μL), and head CT scanning showed increased postoperative subdural and subgaleal fluid collections. He was admitted and later that day developed disorientation and hallucinations. On POD 8, the patient underwent a lumbar puncture that found xanthochromic CSF with 68,000 RBC/mm3, 1651 WBC/mm3 (43% lymphocytes, 53% monocytes/macrophages, 4% neutrophils), 208 mg/dL protein, and 40 mg/dL glucose. He became febrile to 39.3°C, increasingly confused, and restless. Blood cultures, chest radiography, and urinalysis findings were unremarkable. The encephalopathy continued to worsen, and on POD 12 the patient was admitted to the ICU for atrial fibrillation with rapid ventricular response. His subgaleal fluid was drained later that day but reaccumulated, and a lumbar drain was placed for CSF leakage on POD 14. CSF sent at that time was xanthochromic with 2000 RBC/mm3, 362 WBC/mm3, 343 mg/dL protein, and 42 mg/dL glucose; cultures would ultimately be negative. Acyclovir was started on POD 15 when HSV-1 polymerase chain reaction (PCR) returned positive. Findings from his cognitive examination remained poor; he was inattentive and nonverbal but at times made eye contact, visually tracked, and inconsistently followed simple commands. His examination findings subtly improved over the next 15 days and he began to speak again on POD 29. On POD 35 he completed his 3-week acyclovir course and he was discharged to a rehabilitation facility on POD 39 alert, oriented, able to converse normally, and with full strength throughout.

Discussion

HSE is a known, but rare, complication following neurosurgical intervention.11,29 Encephalitis results from either primary infection with HSV or reactivation of latent HSV residing within the nuclei of sensory neurons, traditionally within trigeminal nerve ganglia.17,27 While the specific mechanism for HSV reactivation following neurosurgery is unknown, steroid therapy, radiation, and stress are known factors that increase the likelihood of HSV reactivation. It is hypothesized that these factors contribute to immunocompromise, thereby creating a permissive environment for the herpes virus to escape latency.14,37 There is also evidence to suggest that direct manipulation and/or trauma to nerves or surrounding tissue may facilitate reactivation.29 Our patient received dexamethasone both intra- and postoperatively, which could have contributed to postoperative HSE. Additionally, the surgical approach may have resulted in potential trauma to the trigeminal nerve due to tumor resection within the lateral wall of the cavernous sinus, which could reactivate latent virus within the sensory ganglia. Extradural approaches are becoming more common to minimize trauma to the brain from retraction and limit contact with cranial nerves, as well as to prevent CSF leaks, which are a known potential complication of the intradural approach. An additional benefit of utilizing an extradural approach could be to limit intradural spread of HSV. In our case, the patient’s dura was essentially shredded due to its adherence to the skull, so regardless of approach it would have been broached.

The latency period for HSV can be greater than 10 days. However, on average, symptom onset occurs 6 days postoperatively.1 Viral encephalitis may clinically present in a variety of ways. Patients often present with fever, focal seizures, and altered mental status. Some possible psychiatric presentations include agitation, drowsiness, and hallucinations.28 These symptoms can mimic other postoperative complications and can make diagnosis challenging. Thus, there should be a low threshold to evaluate and treat possible HSV encephalitis in postoperative neurosurgical patients presenting with fever and seizures or altered mental status.

If there is a suspicion of HSE, diagnostic workup should include lumbar puncture, CSF analysis, and CSF HSV PCR. Common initial CSF analysis in HSE typically consists of a lymphocytic pleocytosis, erythrocytosis, normal CSF glucose, and elevated protein. However, these findings are relatively nonspecific, thereby requiring concomitant HSV PCR testing. PCR is both sensitive and specific in the diagnosis of HSV encephalitis and has revolutionized practice; however, it is important to note that the results may not become positive for 24–48 hours following initial symptoms and will remain positive for 2–5 days following treatment.7,33 If undiagnosed, HSV-1 encephalitis is associated with high mortality and high morbidity in survivors, often leaving patients with disabilities including memory changes, language disorders, and mutism.5,28 Early treatment with acyclovir decreases expected mortality from 70% to 30%.16

This case is unique with regard to the patient’s initial subtle presentation, which then progressed to more classic symptomatology for HSV encephalitis. Although not initially in the differential diagnosis, the eventual diagnosis of HSV guided treatment and the patient improved drastically. It is also unclear in this case, as in many others, the exact mechanism of HSV reactivation. The surgical approach might influence HSV reactivation, although this should not necessarily influence surgical planning, but it could more quickly prompt the provider to consider HSV encephalitis testing in patients presenting with altered mental status, fever, or seizures postoperatively.

Review of the Literature

A review of the literature was performed to identify cases of postoperative HSV after neurosurgery. A PubMed search was conducted utilizing the search terms HSV, herpes simplex, and neurosurgery. Study results were screened for cases that described postoperative HSV following neurosurgery. Isolated spine cases were excluded. Other reviews of literature were scanned to ensure inclusion of all reported neurosurgical cases. Thirty-nine cases were extracted from 32 case reports. Pertinent patient data were extracted and compiled into table format (Table 1). In our review of 40 cases of postoperative neurosurgical patients with HSV diagnosis following craniotomy, 12 (30%) patients died and 1 had unreported outcome due to hospital transfer.1–4,6–24,26,30–36 Fever, headache, and altered mental status were common presenting symptoms and started anywhere from POD 1 to POD 90, with a majority occurring in a delayed fashion between PODs 7 and 12.1–4,6–24,26,30–36 Surgical site varied and does not alone explain potential reactivation of HSV, although it is unknown how many of these patients received perioperative steroids. It is also unclear how many of these patients had a known preexisting history of HSV.

TABLE 1.

Review of the literature

Authors & YearPrimary LesionAge (yrs)Sx Onset (POD)SxsTime Until LPCSF Glucose*CSF Protein*CSF WBCs/mm3CSF Lymph (%)CSF PMNs (%)PCRStatus
Aldea et al., 2003Rt frontocingular oligodendroglioma287Fever, POD 8 drowsinessPOD 8Nl0.8 g/L383028 neutro, 42 monoNegAlive
POD 91.7 g/L306HSV-1
de Almeida et al., 2015Refractory epilepsy1112Fever, HA, nausea/vomiting, aLOCPOD 125583265991HSV-1Alive
Alonso-Vanegas et al., 2016Rt temporal lobectomy104Fever, HA, aLOC (POD 6)POD 6HSVAlive
Berger et al., 2016Lt sphenoid wing meningioma7012Fever, HA, nuchal rigidity, CN III palsyPOD 17241132561000HSV-2Alive
Bourgeois et al., 1999Lt AH for intractable complex partial seizure86Partial status epilepticus, aphasia, feverPOD 6Nl0.6–1.6 g/LPleocytosis75–95%HSV-1Alive
Cunha et al., 2014WHO grade IV GBM6030Fever, lt facial weakness, rt upper-/lower-extremity strengthPOD 30331000HSV-1Dead
Fearnside & Grant, 1972Case 1: Pituitary adenoma414Fever, auditory & visual hallucinationsPOD 460105320 PMN, 320 monoHSVDead
Case 2: pituitary adenoma118Fever, seizuresPOD 980454 PMN, 6 monoHSV 
Filipo et al., 2005Acoustic neuroma332 & 10HA; POD 10 fever, hypertonia, aLOCPOD 115384.4393228 neutr, 45 monoHSV-1Alive
POD 1 routine EVD<2<60Neg
Gong et al., 2010Refractory epilepsy21Fever, irritability, spellsPOD 3 routine EVD266381050131HSV-1Alive
POD 5 LP3774400435HSV-1
Case 1: MVD of lt facial nerve739Lt facial weakness; fever, malaise, nausea, memory impairmentUnk471121520HSVAlive
Hengstman et al., 2005Case 2: MVD of lt facial nerve5615Nasal CSF leakageUnk41912520HSVAlive
20Lt-sided numbness, hearing loss
Case 3: suboccipital craniectomy w/ excision of a meningioma located at lt petrosal apex6690CN V, VI, VIII, & XII neuropathiesUnk6548.31HSVAlive
Ihekwaba & Battersby, 2009CM-13514Progressive headachesHSV-2Alive
Jalloh et al., 2009Acoustic neuroma441Fever, vomiting, confusionHSV-1Alive
Case 1: epidermoid cyst248Fever, HAPOD 102.7 mmol/L0.94 g/L1517951 erythroHSV-1Alive
Jaques et al., 2016Case 2: WHO grade I craniopharyngioma5318Fever, drowsinessPOD 181.6 mmol/L1.25 g/L1889226 erythroHSV-2Alive
Case 3: rt temporal lobectomy & AH1211Fever, headachePOD 141.9 mmol/L2.05 g/L9196837 erythroHSV-1Alive
Kim et al., 2013Epilepsy surgery115Fever, confusionHSV-1Alive
POD 201Unk
Kuhnt et al., 2012Case 1: pituitary adenoma404SeizurePOD unk (several days later)80HSV-1Dead
Fever, aLOCPOD 7720Unk
Case 2: petroclival meningioma467Fever, aLOCPOD 1255HSV-1Dead
Kwon et al., 2008Craniopharyngioma (adamantinomatous type, WHO grade I1315Fever, decreased LOCPOD 2239113.92 neutro3PosAlive
Lellouch-Tubiana et al., 2000Refractory epilepsy86HSV-1Alive
Lund, 2011Frontal lobe epilepsy1910Fever, HAPOD 106849108UnkDead
POD 176810883HSV
Mallory et al., 2012Acoustic neuroma4910Fever, HAPOD 10Lymphocyte predominant pleocytosisHSV-1Alive
Molloy et al., 2000Medulloblastoma22>21ConfusionHSVDead
Case 6: SAH clipping6214RashUnkUnk
Nabors et al., 1986Case 7: GBM607Bilat periorbital swelling w/ chemosis & injection of lt eye consistent w/ HSVUnkDead
Navarro et al., 2013SAH517HA, somnolence, dysphagiaPOD 7657421HSV-2Alive
POD 110Unk
Perry et al., 1998Craniopharyngioma648Lethargy, confusion, vomiting, diarrheaPOD 1831171308982UnkAlive
POD 27641111130100 monoHSV-2
Ploner et al., 2005Meningioma4710Fever, confusionPOD 10<1 (POD 13, 12)HSVAlive
Lo Presti et al., 2015Refractory epilepsy176SeizuresPOD 7Nl26.9220UnkAlive
Samadian et al., 2016Meningioma552Fever, aLOC, spastic quadriparesisPOD 4HSV-1Dead
Sayal et al., 2018WHO grade IV GBM63HSV on histolDead
Sheleg et al., 2001GBM282HSV-1Dead
Spuler et al., 1999Lt parasagittal meningioma in premotor area7810Focal motor seizures, aphasic, fever, hemiparetic, somnolentPOD ∼18NlNl897026NegDead
POD 19Nl94383550 monoHSV-1
Tang et al., 2013Rt MVD for trigeminal neuralgia29Fever, HA, confusionHSV-1Alive
Uda et al., 2013MTLE2011HSVAlive
Vik-Mo et al., 2014MTLE253HA, lethargy, confusion/day 11 feverHSV-2Alive
POD 84020816516235Not tested
Present studyPsammomatous meningioma (WHO grade I)726HAPOD 13423433624455HSV-1Alive
POD 195330812946Not retested

AH = amygdalohippocampectomy; aLOC = altered LOC; CM-1 = Chiari malformation type 1; erythro = erythrocyte; EVD = external ventricular drain; GBM = glioblastoma (multiforme); HA = headache; histol = histology; LOC = level of consciousness; LP = lumbar puncture; mono = mononuclear; MTLE = mesial temporal lobe epilepsy; MVD = microvascular decompression; neg = negative; neutro = neutrophil; Nl = normal; PMN = polymorphonuclear leukocyte; pos = positive; SAH = subarachnoid hemorrhage; Sx = symptom; unk = unknown.

Values are mg/dL unless otherwise noted.

Interestingly, in patients with multiple CSF studies, HSV PCR was at times initially negative and then became positive on subsequent samples.1,10,33 In light of this, there may be a role for prophylactic acyclovir in postoperative neurosurgery patients presenting with fevers and seizures or altered mental status. It may also be prudent to continue prophylactic antiviral agents despite initially negative HSV PCR results, particularly within the first 48 hours following symptom onset, and await repeat PCR results before discontinuing. A case could also be made for consideration of perioperative administration of acyclovir in patients with a known HSV history and surgeries with probable cranial nerve manipulation.

Conclusions

HSV encephalitis is rarely reported as a postoperative infection; however, it may be underreported if untested. To our knowledge, this represents the 40th report of HSV detection following neurosurgery. In cases of delayed postoperative fever, headache, seizures, and altered mental status following neurosurgery, there should be a low threshold to obtain HSV PCR and initiate empirical treatment with acyclovir. Additionally, if the patient has not improved, HSV PCR can be retested in 48 hours prior to discontinuing. Clinical suspicion and prompt treatment of HSV can decrease patient morbidity and mortality in the neurosurgical population.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: McLaughlin. Acquisition of data: McLaughlin, Geertman. Analysis and interpretation of data: McLaughlin, Achey. Drafting the article: all authors. Critically revising the article: McLaughlin, Geertman, Grossman. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: McLaughlin. Study supervision: Geertman.

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Article Information

Correspondence Diane McLaughlin: MetroHealth Medical Center, Cleveland, OH. dmclaughlin@metrohealth.org.

INCLUDE WHEN CITING DOI: 10.3171/2019.5.FOCUS19281.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Axial MR image of the right meningioma with cranial nerve involvement.

References

  • 1

    Aldea SJoly LMRoujeau TOswald AMDevaux B: Postoperative herpes simplex virus encephalitis after neurosurgery: case report and review of the literature. Clin Infect Dis 36:e96e992003

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Alonso-Vanegas MAQuintero-López EMartínez-Albarrán AAMoreira-Holguín JC: Recurrent herpes simplex virus encephalitis after neurologic surgery. World Neurosurg 89:731.e1731.e52016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Berger AShahar TMargalit N: Herpes simplex type 2 encephalitis after craniotomy: case report and literature review. World Neurosurg 88:691.e9691.e122016

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4

    Bourgeois MVinikoff LLellouch-Tubiana ASainte-Rose C: Reactivation of herpes virus after surgery for epilepsy in a pediatric patient with mesial temporal sclerosis: case report. Neurosurgery 44:6336361999

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5

    Chaudhuri AKennedy PG: Diagnosis and treatment of viral encephalitis. Postgrad Med J 78:5755832002

  • 6

    Cunha BATalmasov DConnolly JJ: Herpes simplex virus (HSV-1) encephalitis mimicking glioblastoma: case report and review of the literature. J Clin Med 3:139214012014

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    de Almeida SMCrippa ACruz Cde Paola Lde Souza LPNoronha L: Reactivation of herpes simplex virus-1 following epilepsy surgery. Epilepsy Behav Case Rep 4:76782015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Fearnside MRGrant JM: Acute necrotizing encephalitis complicating bifrontal craniotomy and pituitary curettage. Report of two cases. J Neurosurg 36:4995021972

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Filipo RAttanasio GDe Seta EViccaro M: Post-operative herpes simplex virus encephalitis after surgical resection of acoustic neuroma: a case report. J Laryngol Otol 119:5585602005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Gong TBingaman WDanziger-Isakov LTuxhorn IGoldfarb J: Herpes simplex virus reactivation after subtotal hemispherectomy in a pediatric patient. Pediatr Infect Dis J 29:114811502010

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Hengstman GJDGons RARMenovsky TLunel FVvan de Vlasakker CJWde Vries J: Delayed cranial neuropathy after neurosurgery caused by herpes simplex virus reactivation: report of three cases. Surg Neurol 64:67702005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ihekwaba UKBattersby RD: Type 2 herpes simplex reactivation after craniocervical decompression for hind brain hernia and associated syrinx. Br J Neurosurg 23:3263282009

    • Crossref
    • PubMed
    • Search Google Scholar
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