LETTERS TO THE EDITOR
Herpes Simplex Virus 2 Encephalitis in Adults To the Editor: Herpes simplex virus (HSV) 2 encephalitis in adults is rare, reportedly comprising less than 2% of all HSV encephalitis cases.1,2 Many known cases were diagnosed before polymerase chain reaction (PCR) was available or represent atypical presentations of encephalitis. After ethics board approval, a search was performed of the medical records system at Mayo Clinic in Rochester, Minnesota, for the terms herpes simplex AND encephalitis OR meningitis in patients presenting between January 1, 1995 (when PCR for HSV-2 detection became readily available at Mayo Clinic), and December 31, 2008. Each record was reviewed by 2 neurologists (SAM, AJA) to ensure that (1) encephalitis was diagnosed by the treating physician, (2) the condition presented with seizures, encephalopathy, or both and lacked meningismus and other predominant meningeal signs, and (3) HSV-2 was detected in the cerebrospinal fluid by PCR. Five patients were diagnosed as having HSV-2 encephalitis compared with 28 patients diagnosed as having HSV-2 meningitis during the same time period.3 No patient was from Olmsted County, Minnesota (the location of Mayo Clinic’s campus in Rochester). The observed presentation was the first known manifestation of HSV-2 infection in all cases. No patient was treated with acyclovir before presentation. The mean age of the 5 patients was 72 years (Table), more than 3 decades older than the mean age of patients with HSV-2 meningitis (38 years).3 Immunocompromise was noted in all 5 cases. No patient was infected with human immunodeficiency virus. In 2 patients, neuroimaging studies revealed abnormalities more typical of
274
an HSV-1 limbic encephalitis. One patient (case 3) had neurosurgical resection of a right temporal glioblastoma 10 days before the onset of encephalitic illness. By 16 days after surgery, magnetic resonance imaging showed bilateral asymmetric temporal, insular, and right cingulate gyrus abnormal fluid-attenuated inversion recovery signal, consistent with HSV encephalitis, despite treatment. A second patient (case 4) had encephalitis with abnormal fluid-attenuated inversion recovery signal in the left anterior and medial temporal, insular, and inferofrontal areas on MRI, more typical of HSV-1 encephalitis. The remaining 3 patients had generalized encephalitis with altered mental status, no focal neurologic findings, and normal or nonspecific neuroimaging findings. Despite acyclovir treatment, outcomes were poor. Our case series highlights the following key points: (1) HSV-2 encephalitis occurs in elderly, immunocompromised patients, (2) the presentation may be clinically indistinguishable from HSV-1 encephalitis in adults, and (3) the prognosis of immunocompromised adults with HSV-2 encephalitis may be unfavorable, even when antiviral therapy is administered. In 1993 in Sweden, Aurelius et al1 described 6 previously healthy adults with HSV-2 encephalitis diagnosed by indirect enzyme-linked immunosorbent assay using intrathecal antibody responses to type 2especific antigen in the cerebrospinal fluid and serum. There were no deaths after a mean follow-up of 6 years, but only one patient had a complete neurologic recovery. In 2008 in Denmark, Omland et al4 reported a retrospective study of 49 adults with HSV-2 detected in the cerebrospinal fluid, 6 (12%) of whom had encephalitis. Finally, 2 cases of PCR-confirmed HSV-2 encephalitis were reported at Mayo Clinic in
www.mayoclinicproceedings.org
n
20035 and are not included in this report. Although our case series is small, the number of reported cases of HSV-2 encephalitis in adults remains surprisingly limited given the seroprevalence of the virus. Herpes simplex virus 2 encephalitis may be underreported in adults because it is not suspected, and screening is not performed in this population. However, PCR for HSV-2 detection in cerebrospinal fluid is specific. We propose that patients who have encephalitis that typifies HSV-1 but in whom HSV-1 is not detected also be tested for HSV-2, especially if they are immunocompromised. Farrah J. Mateen, MD* Massachusetts General Hospital Boston, MA
Stephanie A. Miller, MD* Sanford Clinic Bismarck, ND
Allen J. Aksamit Jr, MD Mayo Clinic Rochester, MN *Drs Mateen and Miller were at Mayo Clinic in Rochester, Minnesota, when this work was done. 1. Aurelius E, Johansson B, Sköldenberg B, Forsgren M. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol. 1993; 39(3):179-186. 2. Kupila L, Vuorinen T, Vainionpää R, Hukkanen V, Marttila RJ, Kotilainen P. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66(1):75-80. 3. Miller S, Mateen FJ, Aksamit AJ JrJr. Herpes simplex virus 2 meningitis: a retrospective cohort study. J Neurovirol. 2013;19(2):166-171. 4. Omland LH, Vestergaard BF, Wandall JH. Herpes simplex virus type 2 infections of the central nervous system: a retrospective study of 49 patients. Scand J Infect Dis. 2008;40(1):59-62. 5. O’Sullivan CE, Aksamit AJ, Harrington JR, Harmsen WS, Mitchell PS, Patel R. Clinical spectrum and laboratory characteristics associated with detection of herpes simplex virus DNA in cerebrospinal fluid. Mayo Clin Proc. 2003;78(11):1347-1352. http://dx.doi.org/10.1016/j.mayocp.2013.12.003
Mayo Clin Proc. n February 2014;89(2):274-276 ª 2014 Mayo Foundation for Medical Education and Research
Case No./ age (y)/ sex
Presenting symptoms
Time from symptom onset to PCR detection Encephaof HSV-2 (d) Feverb lopathy Seizure
1/79/M Encephalopathy, left) temporal, detection of insular, and HSV-2 orbitofrontal consistent with limbic encephalitis
Residual aphasia and cognitive deficits; died w5 y later Renal failure from acyclovir at 1 mo, then lost to follow-up
CSF ¼ cerebrospinal fluid; CT ¼ computed tomography; HSV-2 ¼ herpes simplex virus 2; IV ¼ intravenous; MRI ¼ magnetic resonance imaging; NA ¼ not available; PCR ¼ polymerase chain reaction; RBCs ¼ red blood cells; WBCs ¼ white blood cells. b Oral temperature of 38 C. c Dose decreased due to acute renal insufficiency. a
LETTERS TO THE EDITOR
Mayo Clin Proc. n February 2014;89(2):274-276 www.mayoclinicproceedings.org
TABLE. Demographic and Clinical Characteristics of Patients With HSV-2 Encephalitisa
275
Herpes Simplex Virus 2 Encephalitis in Adults To the Editor: Herpes simplex virus (HSV) 2 encephalitis in adults is rare, reportedly comprising less than 2% of all HSV encephalitis cases.1,2 Many known cases were diagnosed before polymerase chain reaction (PCR) was available or represent atypical presentations of encephalitis. After ethics board approval, a search was performed of the medical records system at Mayo Clinic in Rochester, Minnesota, for the terms herpes simplex AND encephalitis OR meningitis in patients presenting between January 1, 1995 (when PCR for HSV-2 detection became readily available at Mayo Clinic), and December 31, 2008. Each record was reviewed by 2 neurologists (SAM, AJA) to ensure that (1) encephalitis was diagnosed by the treating physician, (2) the condition presented with seizures, encephalopathy, or both and lacked meningismus and other predominant meningeal signs, and (3) HSV-2 was detected in the cerebrospinal fluid by PCR. Five patients were diagnosed as having HSV-2 encephalitis compared with 28 patients diagnosed as having HSV-2 meningitis during the same time period.3 No patient was from Olmsted County, Minnesota (the location of Mayo Clinic’s campus in Rochester). The observed presentation was the first known manifestation of HSV-2 infection in all cases. No patient was treated with acyclovir before presentation. The mean age of the 5 patients was 72 years (Table), more than 3 decades older than the mean age of patients with HSV-2 meningitis (38 years).3 Immunocompromise was noted in all 5 cases. No patient was infected with human immunodeficiency virus. In 2 patients, neuroimaging studies revealed abnormalities more typical of
274
an HSV-1 limbic encephalitis. One patient (case 3) had neurosurgical resection of a right temporal glioblastoma 10 days before the onset of encephalitic illness. By 16 days after surgery, magnetic resonance imaging showed bilateral asymmetric temporal, insular, and right cingulate gyrus abnormal fluid-attenuated inversion recovery signal, consistent with HSV encephalitis, despite treatment. A second patient (case 4) had encephalitis with abnormal fluid-attenuated inversion recovery signal in the left anterior and medial temporal, insular, and inferofrontal areas on MRI, more typical of HSV-1 encephalitis. The remaining 3 patients had generalized encephalitis with altered mental status, no focal neurologic findings, and normal or nonspecific neuroimaging findings. Despite acyclovir treatment, outcomes were poor. Our case series highlights the following key points: (1) HSV-2 encephalitis occurs in elderly, immunocompromised patients, (2) the presentation may be clinically indistinguishable from HSV-1 encephalitis in adults, and (3) the prognosis of immunocompromised adults with HSV-2 encephalitis may be unfavorable, even when antiviral therapy is administered. In 1993 in Sweden, Aurelius et al1 described 6 previously healthy adults with HSV-2 encephalitis diagnosed by indirect enzyme-linked immunosorbent assay using intrathecal antibody responses to type 2especific antigen in the cerebrospinal fluid and serum. There were no deaths after a mean follow-up of 6 years, but only one patient had a complete neurologic recovery. In 2008 in Denmark, Omland et al4 reported a retrospective study of 49 adults with HSV-2 detected in the cerebrospinal fluid, 6 (12%) of whom had encephalitis. Finally, 2 cases of PCR-confirmed HSV-2 encephalitis were reported at Mayo Clinic in
www.mayoclinicproceedings.org
n
20035 and are not included in this report. Although our case series is small, the number of reported cases of HSV-2 encephalitis in adults remains surprisingly limited given the seroprevalence of the virus. Herpes simplex virus 2 encephalitis may be underreported in adults because it is not suspected, and screening is not performed in this population. However, PCR for HSV-2 detection in cerebrospinal fluid is specific. We propose that patients who have encephalitis that typifies HSV-1 but in whom HSV-1 is not detected also be tested for HSV-2, especially if they are immunocompromised. Farrah J. Mateen, MD* Massachusetts General Hospital Boston, MA
Stephanie A. Miller, MD* Sanford Clinic Bismarck, ND
Allen J. Aksamit Jr, MD Mayo Clinic Rochester, MN *Drs Mateen and Miller were at Mayo Clinic in Rochester, Minnesota, when this work was done. 1. Aurelius E, Johansson B, Sköldenberg B, Forsgren M. Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid. J Med Virol. 1993; 39(3):179-186. 2. Kupila L, Vuorinen T, Vainionpää R, Hukkanen V, Marttila RJ, Kotilainen P. Etiology of aseptic meningitis and encephalitis in an adult population. Neurology. 2006;66(1):75-80. 3. Miller S, Mateen FJ, Aksamit AJ JrJr. Herpes simplex virus 2 meningitis: a retrospective cohort study. J Neurovirol. 2013;19(2):166-171. 4. Omland LH, Vestergaard BF, Wandall JH. Herpes simplex virus type 2 infections of the central nervous system: a retrospective study of 49 patients. Scand J Infect Dis. 2008;40(1):59-62. 5. O’Sullivan CE, Aksamit AJ, Harrington JR, Harmsen WS, Mitchell PS, Patel R. Clinical spectrum and laboratory characteristics associated with detection of herpes simplex virus DNA in cerebrospinal fluid. Mayo Clin Proc. 2003;78(11):1347-1352. http://dx.doi.org/10.1016/j.mayocp.2013.12.003
Mayo Clin Proc. n February 2014;89(2):274-276 ª 2014 Mayo Foundation for Medical Education and Research
Case No./ age (y)/ sex
Presenting symptoms
Time from symptom onset to PCR detection Encephaof HSV-2 (d) Feverb lopathy Seizure
1/79/M Encephalopathy, left) temporal, detection of insular, and HSV-2 orbitofrontal consistent with limbic encephalitis
Residual aphasia and cognitive deficits; died w5 y later Renal failure from acyclovir at 1 mo, then lost to follow-up
CSF ¼ cerebrospinal fluid; CT ¼ computed tomography; HSV-2 ¼ herpes simplex virus 2; IV ¼ intravenous; MRI ¼ magnetic resonance imaging; NA ¼ not available; PCR ¼ polymerase chain reaction; RBCs ¼ red blood cells; WBCs ¼ white blood cells. b Oral temperature of 38 C. c Dose decreased due to acute renal insufficiency. a
LETTERS TO THE EDITOR
Mayo Clin Proc. n February 2014;89(2):274-276 www.mayoclinicproceedings.org
TABLE. Demographic and Clinical Characteristics of Patients With HSV-2 Encephalitisa
275
