Herpes simplex virus type 1 (HSV-1) is the most common cause of sporadic encephalitis worldwide. In the California Encephalitis Project, 24% of the cases of viral encephalitis were caused by HSV-1 and 3% were caused by HSV-2.1
Key words: HIV/AIDS, Herpes simplex virus, Encephalitis, Cerebral hemorrhage, Acyclovir
Herpes simplex virus type 1 (HSV-1) is the most common cause of sporadic encephalitis worldwide. In the California Encephalitis Project, 24% of the cases of viral encephalitis were caused by HSV-1 and 3% were caused by HSV-2.1 In addition, HIV-positive persons are at an increased risk for mucosal reactivation of HSV.2,3 Despite these observations, HSV-associated neurological disease is surprisingly rare in HIV-infected patients. In several large studies, HSV-associated neurological disease was only found in up to 3% of patients.4-7 We report here a case of HSV-1 encephalitis in an HIV-positive man presenting with subacute memory loss and seizure. His hospital course was complicated by intracranial hemorrhage.
A 56-year-old man was brought to the emergency department for evaluation after he was found with diminished responsiveness following an apparent seizure. He reported no fevers, headaches, neck stiffness, or photophobia. HIV infection had been diagnosed 1 month before presentation, at which time his CD4+ cell count was 185/μL and his HIV RNA level was 444,000 copies/mL. Two weeks before admission, the patient's partner noted that the patient was becoming confused, with worsening memory. The night before admission, the patient had begun antiretroviral therapy with coformulated efavirenz/tenofovir/emtricitabine.
On physical examination, the patient was found to be well nourished. His body temperature was 38.0°C (100.4°F), with other vital signs within normal limits. He had a pleasant demeanor but exhibited poor memory and word-finding difficulty. He knew his name and the date but could not state his current location. He scored 20/30 on the mini-mental state examination with, points deducted for orientation, poor object recall at 3 minutes, and the inability to spell the word "world" backward. The results of his neurological examination were otherwise nonfocal. There was no photophobia or nuchal rigidity. There was a small tongue laceration, but the head and neck showed no other signs of trauma. The remainder of the examination findings were normal.
Figure 1. MRI scan showing T2 hyperintensity in the left medial temporal lobe on hospital day 1.
The patient's white blood cell (WBC) count was 6700/μL, and the results of other routine laboratory tests were normal. A chest radiograph and a noncontrast head CT scan showed no acute abnormalities. An electroencephalogram obtained on the day of admission showed left frontotemporal periodic lateralizing epileptiform discharges, mainly during drowsy and sleeping states. An MRI scan of the brain showed abnormal T2 signal in the medial left temporal lobe with focal areas of enhancement involving multiple vascular territories (Figure 1).
A lumbar puncture was also performed on the day of admission, with normal opening pressure. The WBC count was 30/mL (75% lymphocytes, 17% neutrophils, and 4% monocytes), red blood cell count was 9/mL, glucose level was 66 mg/dL (normal, 40 to 70), and total protein level was 87 mg/dL (normal, 10 to 44). Results of a Gram stain and bacterial culture of the cerebrospinal fluid (CSF) were negative. Polymerase chain reaction (PCR) assay of CSF was positive for HSV-1, while the results of PCR studies for HSV-2, a VDRL test, and tests for varicella-zoster virus and JC virus were negative. All blood cultures and serum treponemal antibody test results were negative.
Treatment with intravenous acyclovir was started. Because the CNS adverse effects associated with efavirenz could potentially complicate an assessment of the patient's neurological status, the antiretroviral regimen was switched to tenofovir, emtricitabine, and lopinavir/ritonavir.
Figure 2. CT scan revealing acute hemorrhage in the left temporal lobe and basal ganglia on hospital day 6.
On hospital day 6, the patient became increasingly somnolent, and a head CT scan showed an acute hemorrhage in the left temporal lobe and basal ganglia (Figure 2). Five days later, he had another precipitous mental decline and was found to have an enlarging bleed in the same area. No deficiencies were found in his platelet count, prothrombin time/partial thromboplastin time, or other coagulation studies (factor VII, VIII, XI, vWF studies; ristocetin cofactor test; and clot lysis test).
The patient was taken to the operating room for urgent decompression and clot removal. Because of reports linking the use of protease inhibitors with increased bleeding risk in patients with hemophilia,8-10 the integrase inhibitor raltegravir was substituted for lopinavir/ritonavir. After receiving a 28-day course of intravenous acyclovir, the patient was discharged on a regimen of oral valacyclovir.
Over the next several months, the patient's mental status gradually improved, although impairment in word finding, reading comprehension, and memory persisted. His most recent laboratory test results, 10 months after hospitalization, showed a CD4+ cell count of 394/μL and an undetectable HIV RNA level.
T-cell–mediated immunity is essential for the control of HSV11; thus, immunosuppressed patients, including those undergoing organ transplant and chemotherapy, are at increased risk for severe HSV infections.12 While HIV-infected persons are also at increased risk for severe mucosal HSV reactivation,2,3 HSV encephalitis is surprisingly rare in this population. In several large studies of HIV-positive patients who underwent neurological evaluation, the incidence of HSV encephalitis ranged from 0% to 3%.4-7 On the other hand, cytomegalovirus infection and other human herpesvirus infections appear to be much more common.4,6,13,14 Even though HSV encephalitis is not considered an AIDS-defining illness, the vast majority of case reports in the literature involve patients who have CD4+ cell counts below 350/μL.5,7,15-18 In the HIV-positive population, the relative rarity of HSV encephalitis and the increased frequency of mucocutaneous disease are puzzling and deserve further investigation.
Unlike the acute meningoencephalitis seen in those with intact immune systems, HSV encephalitis in persons with HIV/AIDS can present in an atypical, subacute fashion with several days to weeks of confusion, depressive symptoms, and slowed mentation.5,7,15,16,19,20 Our patient presented with a 2-week history of memory impairment, possibly reflecting an attenuated immunological response to HSV infection as a consequence of his underlying HIV infection. In addition, stroke-like symptoms and seizures have also been reported to be frequently encountered.5,15,17-21
This patient's clinical course was complicated further by 2 episodes of intracranial hemorrhage. A survey of the literature found that while radiologically apparent intracranial hemorrhage is a rare sequela of HSV encephalitis,5 it has been well described that HSV causes a necrotizing encephalitis with evidence of hemorrhage seen in autopsy studies.7,15,18,21
There have been several reports linking protease inhibitor use to an increased bleeding risk in hemophiliacs.8-10 (None of the reports have demonstrated consistent laboratory abnormalities of hemostasis, and the mechanism behind the association is still unclear.) Furthermore, the prescribing information for the protease inhibitor tipranavir cites a possible association between its use and intracranial hemorrhage,22 which prompted a black box warning from the FDA.
These issues led us to switch this patient's ritonavir-boosted protease inhibitor to an integrase inhibitor, because we felt that a slight increase in the risk of bleeding might have converted a necrotizing encephalitis into a clinically important bleed.
There is no consensus on the most appropriate treatment of HSV encephalitis in HIV-positive persons. In most of the previous reports in this patient population, patients were treated with 14 to 24 days of intravenous acyclovir,7,15,16,20 a treatment similar to that given to patients without HIV infection. Given our patient's complicated recovery period, we elected to treat with an extended course of intravenous acyclovir followed by a suppressive regimen of oral valacyclovir. With this regimen, the patient has had a very good recovery, although memory deficits remain 1 year later.
While HSV is a common cause of encephalitis in immunocompetent persons, it is a surprisingly rare cause of encephalitis in the HIV-positive population. As this case demonstrates, HSV encephalitis in the immunocompromised person can present quite atypically, with symptoms such as subacute memory loss and seizure. This case was further complicated by 2 episodes of intracranial hemorrhage after the patient began an antiretroviral regimen containing a ritonavir-boosted protease inhibitor. Clinicians should remain vigilant for bleeding complications in persons with necrotizing encephalitis caused by HSV.
Dr Li has reported no potential conflict of interest relevant to this article. Dr Sax reports consulting for Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Pfizer, Merck, and Tibotec; receiving honoraria for teaching from Abbott, Bristol-Myers Squibb, Gilead, Merck, and Tibotec; and receiving grant support from Tibotec and Merck.
References1. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis. 2006;43:1565-1577.
2. McClelland RS, Wang CC, Overbaugh J, et al. Association between cervical shedding of herpes simplex virus and HIV-1. AIDS. 2002;16:2425-2430.
3. Schacker T, Zeh J, Hu H, et al. Changes in plasma human immunodeficiency virus type 1 RNA associated with herpes simplex virus reactivation and suppression. J Infect Dis. 2002;186:1718-1725.
4. Quereda C, Corral I, Laguna F, et al. Diagnostic utility of a multiplex herpesvirus PCR assay performed with cerebrospinal fluid from human immunodeficiency virus-infected patients with neurological disorders. J Clin Microbiol. 2000;38:3061-3067.
5. Grover D, Newsholme W, Brink N, et al. Herpes simplex virus infection of the central nervous system in human immunodeficiency virus-type 1-infected patients. Int J STD AIDS. 2004;15:597-600.
6. Fox JD, Brink NS, Zuckerman MA, et al. Detection of herpesvirus DNA by nested polymerase chain reaction in cerebrospinal fluid of human immunodeficiency virus-infected persons with neurologic disease: a prospective evaluation. J Infect Dis. 1995;172:1087-1090.
7. Cinque P, Vago L, Marenzi R, et al. Herpes simplex virus infections of the central nervous system in human immunodeficiency virus-infected patients: clinical management by polymerase chain reaction assay of cerebrospinal fluid. Clin Infect Dis. 1998;27:303-309.
8. Kodoth S, Bakshi S, Scimeca P, et al. Possible linkage of amprenavir with intracranial bleeding in an HIV-infected hemophiliac. AIDS Patient Care STDS. 2001;15:347-352.
9. Racoosin JA, Kessler CM. Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series. Haemophilia. 1999;5:266-269.
10. Yazdanpanah Y, Viget N, Cheret A, et al. Increased bleeding in HIV-positive haemophiliac patients treated with lopinavir-ritonavir. AIDS. 2003;17:2397-2399.
11. Posavad CM, Koelle DM, Corey L. Tipping the scales of herpes simplex virus reactivation: the important responses are local. Nat Med. 1998;4:381-382.
12. Corey L. Herpes simplex virus. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Vol. 2. Philadelphia: Elsevier; 2005:1762-1770.
13. MartÃnez PA, DÃaz R, GonzÃ¡lez D, et al. The effect of highly active antiretroviral therapy on outcome of central nervous system herpesviruses infection in Cuban human immunodeficiency virus-infected individuals. J Neurovirol. 2007;13:446-451.
14. Vago L, Nebuloni M, Sala E, et al. Coinfection of the central nervous system by cytomegalovirus and herpes simplex virus type 1 or 2 in AIDS patients: autopsy study on 82 cases by immunohistochemistry and polymerase chain reaction. Acta Neuropathol. 1996;92:404-408.
15. ChrÃ©tien F, BÃ©lec L, Hilton DA, et al. Herpes simplex virus type 1 encephalitis in acquired immunodeficiency syndrome. Neuropathol Appl Neurobiol. 1996;22:394-404.
16. Miller RF, Fox JD, Waite JC, et al. Herpes simplex virus type 2 encephalitis and concomitant cytomegalovirus infection in a patient with AIDS: detection of virus-specific DNA in CSF by nested polymerase chain reaction. Genitourin Med. 1995;71:262-264.
17. Tan SV, Guiloff RJ, Scaravilli F, et al. Herpes simplex type 1 encephalitis in acquired immunodeficiency syndrome. Ann Neurol. 1993;34:619-622.
18. Moulignier A, Baudrimont M, Martin-Negrier ML, et al. Fatal brain stem encephalitis due to herpes simplex virus type 1 in AIDS. J Neurol. 1996;243:491-493.
19. Laskin OL, Stahl-Bayliss CM, Morgello S. Concomitant herpes simplex virus type 1 and cytomegalovirus ventriculoencephalitis in acquired immunodeficiency syndrome. Arch Neurol. 1987;44:843-847.
20. Osih RB, Brazie M, Kanno M. Multifocal herpes simplex virus type 2 encephalitis in a patient with AIDS. AIDS Reader. 2007;17:67-70.
21. Schiff D, Rosenblum MK. Herpes simplex encephalitis (HSE) and the immunocompromised: a clinical and autopsy study of HSE in the settings of cancer and human immunodeficiency virus-type 1 infection. Hum Pathol. 1998;29:215-222.
22. Chrysos G, Gerakari S, Stasini F, et al. Intracranial haemorrhage possibly related to Tipranavir in an HIV-1 patient with cryptococcal meningitis. J Infect. 2008;57:85-87.