A Case of Herpes Simplex Virus-2 Encephalitis in the Setting of Pembrolizumab Exposure

ContagionContagion, October 2021 (Vol. 06, No. 5)
Volume 6
Issue 5

Final Diagnosis

Herpes Simplex Virus-2 (HSV-2) Encephalitis in the Setting of Pembrolizumab Exposure

History of Present Illness

A 54-year-old man presented with stage IV non–small cell lung cancer (NSCLC), seizures, hypertension (HTN), and chronic obstructive pulmonary disease (COPD). The patient completed 4 cycles of pembrolizumab/pemetrexed/carboplatin and was on maintenance pembrolizumab/pemetrexed. On the day of admission, he was seen for a routine outpatient visit, with complaint of 2 weeks of unsteadiness and gait imbalance. Because of concern for metastasis to the brain, the patient was directly admitted to a community affiliate hospital. A stat MRI of the brain was performed. This imaging study demonstrated a solitary, large cerebellar mass with vasogenic edema and partial compression of the fourth ventricle. The patient was started on intravenous (IV) dexamethasone, and neurosurgery evaluated him for surgical intervention.

Medical History

The patient has a history of NSCLC with known metastasis, COPD, and HTN.

Key Medications


Epidemiological History


Physical Examination

General: The patient was somnolent and minimally arousable.

Head, Eyes, Ears, Nose, and Throat (HEENT): His head showed evidence of a recent craniotomy. A nasogastric tube and nasal cannula were both in place.

Heart: His heart beat was regular with regular rhythm. No murmurs, rubs, or gallops identified.

Lungs: clear to auscultation bilaterally, normal work of breathing

Extremities: No gross deformity of the extremities was noted.

Skin: No lesions were noted on the exposed skin.

Neurologic: His neurologic exam was notable for patient being minimally arousable to voice or noxious stimuli. He had occasional, incoherent vocalization.


Cerebrospinal fluid (CSF) cell count/Gram stain

Few white blood cells (WBCs)

No organism seen

Clinical Course

On hospital day (HD) 7 the patient underwent suboccipital craniotomy for resection of the cerebellar lesion. Per operative notes, the tumor was visualized during surgery and could be seen protruding into the subarachnoid space. No residual tumor was left after resection. The patient was monitored in the neurology intensive care unit, and IV steroids were continued with slow taper. Per notes, the patient’s mental status improved. However, on post-operative day (POD) 7, the patient had overnight agitation and acute encephalopathy. Head CT demonstrated findings consistent with post craniotomy but without acute changes to account for mental status changes. MRI brain similarly demonstrated postoperative changes with stable fluid collection but no focal abnormality. The patient was transferred to our tertiary care facility for further evaluation. A fever was noted, and the patient was started on IV vancomycin and piperacillin-tazobactam.

Electroencephalogram was completed, which was consistent with a metabolic encephalopathy and no focal seizure activity. On POD 11, with no improvements in mental status and ongoing intermittent fevers, lumbar puncture (LP) was performed to look for an infectious etiology. Infectious Diseases was consulted at that time for recommendations.

Diagnostic Procedures

CT Head

MRI Brain

The patient had multiple tests from his CSF after lumbar puncture. His CSF culture did not grow any organisms. His HSV 1/2 polymerase chain reaction (PCR) testing came back as HSV-1 not detectable and HSV-2 greater than 2,000,000 copies/mL. Cryptococcal antigen from cerebrospinal fluid (CSF), Toxoplasma gondii antibody from CSF, Varicella Zoster Virus antibody from CSF, and Venereal Disease Research Laboratory (VDRL) from CSF. An autoimmune encephalitis panel showed no fluorescence observed on neuronal tissue.

Treatment and Follow-up

The patient was started on IV acyclovir for HSV encephalitis. His mental status gradually improved, and he was transferred to the floor. He was discharged from the hospital on HD 28 to an acute rehabilitation facility.


HSV is the most commonly identified cause of viral encephalitis.1 Early CSF evaluation, including polymerase chain reaction (PCR) testing, is vital in diagnosing and treating this disease. HSV-1 is most often implicated in encephalitis, whereas HSV-2 more commonly causes meningitis. The mechanism of HSV encephalitis is not fully understood, and whether it represents a new infection or reactivation is debated.2 The virus must breach the blood-brain barrier to cause central nervous system disease. Inflammation has been identified as one potential causal mechanism.1 Other pathways include retrograde nervous system and hematogenous spread.2 Our patient had multiple risk factors, including recent surgery, immunosuppression, and metastatic cancer. His previous HSV infection status was not known; thus, we cannot delineate between reactivation or hematogenous spread in this case.

Pembrolizumab is a monoclonal antibody for PD-1 that is used to treat certain types of lung cancer. Monoclonal antibodies generally can affect immune response. Pembrolizumab can cause rare immune-mediated adverse events, including encephalitis, according to the manufacturer insert.3 The pharmaceutical documentation, however, does not specify a viral etiology for encephalitis. No case reports have documented HSV encephalitis in a patient on pembrolizumab.

In our case, imaging of the brain did not show focal findings outside of the previous craniotomy, but the patient’s CSF cell counts demonstrated a lymphocyte predominance that helped focus our differential on possible viral etiologies. Given the patient’s immunosuppression, it was reasonable to send viral PCR studies. The literature supports early diagnosis and treatment as paramount to patient survival in viral encephalitis.4 In our case, initial clinical suspicion and treatment may have expedited improvement in mental status because of early use of acyclovir. Although a definitive link between pembrolizumab and HSV infection has not been established, it is important to keep this on the differential given the high risk of late recognition to patient morbidity and mortality.


  1. Stahl JP, Mailles A. Herpes simplex virus encephalitis update. Curr Opin Infect Dis. 2019;32(3):239-243. doi:10.1097/QCO.0000000000000554
  2. Bradshaw MJ, Venkatesan A. Herpes simplex virus-1 encephalitis in adults: pathophysiology, diagnosis, and management. Neurotherapeutics. 2016;13(3):493-508. doi:10.1007/s13311-016-0433-7
  3. Keytruda (pembrolizumab). Prescribing information. Merck & Co, Inc; 2014. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
  4. Rabinstein AA. Herpes virus encephalitis in adults. Neurol Clin. 2017;35(4):695-705. doi:10.1016/j.ncl.2017.06.006
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