Abstract
Background: Encephalitis caused by Herpes Simplex Virus-1 is a devastating disease with high mortality and disability rates despite adequate treatment. No clear risk factors have been identified although iatrogenic immunosuppression has been suggested, among others. Case Report: A 59-year-old male smoker was diagnosed with metastatic lung adenocarcinoma and was treated with brain and spinal irradiation. Ten days after the completion of radiotherapy and before initiating platinum-based front-line chemotherapy, he developed low grade fever and personality change. Over the next few days, high fever and refractory seizures developed and the patient was diagnosed with Herpes simplex-associated encephalitis after detection of viral DNA in the cerebrospinal fluid via polymerase chain reaction. Despite treatment with acyclovir, the patient remained comatose and died three months after the initial presentation. Conclusion: This case illustrates a possible association between brain irradiation and increased risk for Herpes simplex-associated encephalitis. However, the underlying mechanisms have not been elucidated.
Central nervous system (CNS) infection caused by the Herpes Simplex Virus type-1 (HSV-1) is the most common sporadic encephalitis, accounting for approximately 20% of the total cases, with an incidence of 2-4 per million population per year (1). Herpes simplex encephalitis (HSE) is a devastating disease despite appropriate treatment, with a mortality rate of 20%; moreover, more than half of the survivors suffer from long-term disability (2). Its clinical hallmarks are fever, impaired mental status and focal neurological deficits, a combination of which is present in over 90% of the patients. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain usually show lesions with characteristic anatomic distribution in the inferomedial temporal, inferior frontal lobes and insula, and cerebrospinal fluid (CSF) examination shows lymphocytosis, high red blood cell count and elevated protein levels, all of which may help in the diagnosis. However, the gold standard test for establishing the diagnosis of HSE is detection of HSV-1 DNA in the CSF by polymerase chain reaction (PCR), with a sensitivity and specificity of approximately 98% (3). Prompt initiation of treatment with intravenous acyclovir before loss of consciousness is of outmost importance, as it reduces overall mortality from over 50% to 20% (4, 5).
No clear risk factors for HSE have been identified. However, immunosuppression due to bone marrow transplant (6), brain radiotherapy in patients with cancer (7, 8) or treatment with tumor necrosis factor-α (TNFα) inhibitors (9) have all been described in case reports of HSE. Herein, we present the case of a patient with metastatic lung cancer who developed HSE shortly after completing brain radiotherapy and prior to receiving first-line chemotherapy and we briefly review the relevant published literature.
Case Report
A 59-year-old male patient with a smoking history of 40 pack-years and a medical history of type-2 diabetes mellitus and arterial hypertension presented with one month history of progressively worsening left shoulder pain and limited range of motion. He underwent MRI of the shoulder which showed the presence of a lytic bone lesion on the coracoid process. Further imaging with thoracic CT scan revealed a right hilar mass 6×3 cm and suspicious lesions on his skull, thoracic spine and right ribs on whole-body bone scintigraphy. He was then referred to our Department for further evaluation. A biopsy from the shoulder lesion was diagnostic for metastatic adenocarcinoma. Immunohistochemistry testing revealed positive staining for cytokeratin-7 (CK-7) and p63 and was negative for thyroid transcription factor-1 (TTF-1), Napsin-a, glial fibrillary acidic protein (GFAP), CK-20, prostate-Specific antigen (PSA) and vimentin. Testing for the presence of activating epidermal growth factor receptor (EGFR) mutations was negative (EGFR wild-type). MRI of the brain and thoracic spine to further characterize the suspicious bone lesions revealed the presence of a skull mass in close proximity to the superior sagittal sinus and a T10 mass which extended into the spinal canal but did not compress the spinal cord. Due to the possibility of neurologic sequelae (risk of sinus thrombosis and spinal cord compression), it was initially decided the patient would be treated with external-beam radiotherapy (30 Gy and a 6 Gy boost for the skull lesion, and 30 Gy for the spinal lesion) and thereafter with systemic chemotherapy.
Magnetic resonance imaging of the brain revealing bilateral symmetric areas, hyperintense on FLAIR sequence (upper row) and mild hypointense on T1 sequence (middle row), involving the anterior and medial parts of the temporal lobes and hippocampi, the inferior and medial parts of the frontal lobes, and the insula, sparing the basal ganglia. There is no enhancement, with the exception of the left insular cortex (arrow). There is also restricted diffusion in the cortex of the involved areas, appearing as hyperintensities on diffusion-weighted imaging (lower row) that indicate cytotoxic edema.
Ten days after the completion of radiotherapy the patient returned in order to initiate platinum-based front-line chemotherapy. The patient reported liquid stools during the previous days before admission and his wife reported that his personality had changed and that “he wasn't himself”. On examination, he appeared to be in discomfort. He had low-grade fever and bilateral crackles on auscultation of the lung fields. The rest of the physical and neurological examination was unremarkable. Chemotherapy was postponed and cefepime at 2 g tid intravenously was started due to possible diagnosis of infection. The next day, the patient developed acute psychosis with hallucinations and delusions. On neurological examination, a right Babinski sign was noted. Blood tests, including sodium and calcium levels, were normal. A brain CT scan with intravenous contrast did not reveal any new findings. On the following day, he developed high-grade fever and focal seizures. A lumbar puncture was performed, which revealed the presence of 9 nucleated cells/μl and 15,000 red blood cells/μl. The protein levels in CSF was 108 mg/dl and CSF/plasma glucose level ratio was 0.38. After these CSF results became available, the patient was commenced on 1 g vancomycin bid, 2 g ampicillin q4h and 10 mg/kg acyclovir tid while cefepime treatment was discontinued. During the next two days, his fever persisted and refractory seizures (status epilepticus) developed. His CSF tested positive for the presence of HSV-1 DNA via PCR. A new brain CT scan was unchanged and to protect the airways and provide proper ventilation the patient was intubated and transferred to the ICU. He remained comatose and was extubated and discharged from the ICU 12 days later with no improvement. At that time, MRI of the brain showed bilateral, symmetric areas of abnormal signal intensity in the anteromedial temporal lobes, inferomedial frontal lobes and insula, consistent with HSE (Figure 1). Acyclovir was discontinued after 21 days of treatment when repeat PCR of CSF for HSV-1 DNA was negative. The patient remained comatose during the following month and his clinical course was complicated by multiple bacteremias by Pseudomonas aeruginosa, Acinetobacter baumanii, Klebsiella pneumonia and fungemia by Candida albicans. Due to the lack of any cognitive improvement, the presence of metastatic lung cancer and the recurring infections, the dismal prognosis was discussed with his family and with their consent only supportive measures were offered. The patient died three months after his initial presentation.
Published case reports have raised the question whether a link exists between HSE and antineoplastic treatment, including brain irradiation, chemotherapy and dexamethasone. Graber et al. published a retrospective series of seven patients with cancer with HSE, including a single patient with non-small cell lung cancer, treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) in a period of 12 years. Among a total of 997 patients receiving brain radiotherapy during that period at MSKCC, four developed HSE, an incidence ratio of 0.4% which far exceeds the expected population incidence (10). Furthermore, in their review of the published literature, the authors identified 34 cases of patients with cancer with HSE: 24 of them had received brain radiotherapy but only 15 had been treated with radiotherapy during the three months immediately prior to the onset of HSE. Our case report highlights the main differences compared to sporadic HSE, as previously described: an insidious and more subacute onset, absence of CSF pleiocytosis possibly due to the toxic effects of the radiotherapy, typical MRI findings and poor prognosis despite adequate treatment.
Radiotherapy, chemotherapy and corticosteroids may impair host immune function. However, the mechanisms leading to increased susceptibility to HSE remain unclear. Moreover, in the reported cases, patients were treated with various combinations of the aforementioned modalities, thus further complicating the ability to identify risk factors. Interestingly, data derived from animal models are also conflicting: radiotherapy does not alter toll-like receptor signaling which is crucial in CNS immunity to HSV-1 (11), but increased susceptibility was shown after administration of cyclophosphamide and dexamethasone in a rabbit model of the disease (12). The role of corticosteroids after the onset of HSE in humans is also unclear: a retrospective study showed improved outcomes among patients receiving corticosteroids (13), while the results of a large randomized trial are still pending (GACHE: German trial of Acyclovir and Corticosteroids in Herpes Simplex Virus Encephalitis, ISRCTN45122933).
In conclusion, we present the case of a patient with metastatic lung cancer who developed HSE shortly after receiving brain irradiation and we briefly review the available literature. With this case report we contribute to a growing body of literature regarding an unrecognized adverse event of anti-neoplastic treatment which requires increased awareness and a high index of suspicion for early diagnosis and successful treatment.
- Received May 5, 2014.
- Revision received June 16, 2014.
- Accepted June 20, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
