Herpes Simplex Encephalitis Occurring After Chemotherapy, Surgery, and Stereotactic Radiotherapy for Medulloblastoma.
REPORT OF A CASE
A 22-year-old woman gave a 1-month history of occipital headaches associated with dizziness, unsteadiness, and fatigue. An admission computed tomography (CT) scan revealed a cystic mass in the cerebellum (Figure 1) and biopsy and partial excision of this lesion revealed a medulloblastoma. The patient subsequently underwent complete excision. Extension through the superior aspect of the left cerebellar hemisphere into the subarachnoid space was noted during the surgery. The patient underwent postoperative radical craniospinal radiotherapy with a boost to the posterior fossa. Chemotherapy was not administered. Two and a half years later, the patient re-presented with fatigue. A CT scan confirmed tumor recurrence and radical tumor debulking was performed. The postoperative course involved chemotherapy with a regimen of carboplatin and cyclophosphamide, and the patient was referred for stereotactic radiotherapy.
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Three weeks following radiotherapy, the patient presented to the emergency room in a confused state. A contrast CT scan showed no evidence of tumor recurrence, but hypodense areas were present in the temporal lobes bilaterally (Figure 2). Clinical deterioration was rapid postadmission, and the patient died 15 days later. The clinical impression was radiation-induced brain necrosis.
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Gross examination of the brain revealed symmetrical areas of softening and discoloration affecting the temporal lobes bilaterally. Microscopic examination demonstrated necrosis with macrophage accumulation and a rare vessels cuffed by mononuclear cells, which were primarily lymphocytes and plasma cells (Figure 3). Inclusion bodies were not identified.
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Residual primitive neuroectodermal tumor was present in the roof of the fourth ventricle, together with subarachnoid spread in the region of the cerebellum (Figure 4). However, spinal cord subarachnoid spread was not present, nor was there any extension of tumor into the supratentorial space.
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Four-micrometer sections of brain were immunostained with anti-HSV-1 and anti-HSV-2 antibodies (primary antibody, 1:50; avidin-biotin detection; BioGenex, Labchem, Dublin, Ireland). Neurons stained positive for both antigens (Figures 5 and 6).
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Polymerase Chain Reaction
Polymerase chain reaction (PCR), using HSV 1,2 pol gene-specific primers, of DNA recovered from formalin-fixed paraffin-embedded brain tissue revealed a 92-base pair (bp) product, confirming the presence of HSV in the brain of this patient (Figure 7). Control DNA was extracted from HSV-free, formalin-fixed paraffin-embedded brain tissue and PCR using the same HSV-specific primers was negative.
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Herpes simplex encephalitis (HSE) is the most common form of sporadic nonepidemic encephalitis in immunocompetent individuals, with an incidence of 0.1 to 0.4/100,000.[5,6] It is widely accepted that HSV-1 resides in a latent phase in the trigeminal ganglion, having spread there by way of retrograde axonal transport from a primary infection of the lip or buccal mucosa. HSV-1 DNA may be recovered in as many as 50% of trigeminal ganglia sampled at autopsy. Latency-associated transcripts are important mediators of latency. The mechanism whereby HSV-1 reactivation occurs remains to be determined, but stress, ultraviolet light, and immunosuppression are regularly involved in HSV-1 reactivation. It is tempting to suggest that HSV-1 encephalitis results from reactivation of trigeminal HSV-1 with anterograde spread via nervii tentorii to orbitofrontal and temporal cortex. However, there is still reason to believe that rare seronegative patients develop HSV-1 encephalitis as a result of a new primary infection; alternately, HSV-1 encephalitis may be due to infection with another HSV-1 strain, rather than reactivation of latent virus from the trigeminal ganglia.
Immunosuppression has not been implicated as a condition predisposing to HSE until relatively recently. Typically, reports of HSE in immunosuppressed patients are confined to patients who have undergone organ transplantation, patients who have a malignancy and patients with the acquired immunodeficiency syndrome.[11,12] The independent roles of radiotherapy, chemotherapy, or surgery in the reactivation of latent herpes have not been extensively evaluated. However, HSE has been described following brain surgery, and experimental evidence shows that rabbits infected with HSV-1 by nasal instillation develop a necrotizing temporal lobe encephalitis when given intravenous dexamethasone and cyclophosphamide. Additionally, in latently infected mice, reactivation of HSV-1 in the trigeminal ganglia has been induced by ultraviolet radiation of the cornea. These findings are consistent with the current findings in a patient who developed HSE 4 weeks following stereotactic radiotherapy. Adjuvant treatment in this case included steroids and chemotherapy.
Reactivation has been shown in animals to be influenced by viral, neuronal, and immune factors. Infectious viral particles are not present during latent infection. Latent-phase HSV-1 transcriptional activity has been postulated to augment reactivation via several mechanisms. This activity may increase latent viral DNA; may counteract putative neuronal inhibitory factors; or may help initiate peripheral replication, thereby aiding transfer of viral nucleic acid from the axon to the periphery via the peripheral sensory ganglion. There, the virus can resume replication and reactivation without damaging the neuron and viral reservoir. With respect to cellular factors, nerve growth factor may render a neuron nonpermissive for viral replication. Immune factors such as host immunosuppression can induce viral reactivation, emphasizing the importance of the immune response for both latency and reactivation. However, recurrent disease usually occurs in immunocompetent individuals, suggesting that external factors also play a role. Precisely how immunosuppressive agents work is not clear, but it has been suggested that if in fact a low level of viral replication is constantly or intermittently taking place in the latent phase, suppression of the host's immune defense mechanisms may give the virus a better opportunity to replicate and spread.[17,18] In the case we report, risk factors for reactivation included surgery, chemotherapy, and radiotherapy, as well as an underlying diagnosis of an aggressive, recurrent intracranial neoplasm.
This patient presented with an acute neurologic illness 3 weeks after stereotactic radiotherapy, which may have confounded clinical efforts at diagnosis. The risk of HSE underdiagnosis has raised concerns. This risk can be particularly high in immunocompromised patients who have atypical presentations. Diagnosis has been further complicated by the lack of specific diagnostic tests. The advent of PCR has revolutionized the latter limitation; this method has a sensitivity of 98%. An inability to mount an adequate immune response may also affect the host's capacity to limit the nature and course of the HSE disease process. This is the most likely explanation for the paucity of inflammatory cells in the brain of this patient.
This case emphasizes the importance of considering the diagnosis of HSE in patients, regardless of their underlying pathology or immune status. Although the prognosis of HSE is often poor, this disease is treatable and potentially curable. Studies have repeatedly emphasized the value of instituting therapy at the earliest possible opportunity to decrease both the morbidity and mortality associated with HSE.
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Accepted for publication May 30, 2000.
From the Departments of Neuropathology (Drs Molloy, Farrell, Perryman, and Brett), Neurosurgery (Dr Allcutt), and Neuroradiology (Dr Brennan), Beaumont Hospital, Dublin 9, Ireland.
Reprints: F. Brett, MD, MRCPath, Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland (e-mail: email@example.com).