Meningitis from herpes simplex virus (HSV) may have a clinical presentation similar to other forms of viral meningitis. However, subtle facets of the history and use of the polymerase chain reaction (PCR) can differentiate HSV from other etiologies. During an outbreak of meningitis from enterovirus, a 32-year-old woman presented to the hospital with clinical meningitis, a history of genital HSV infection, and two previous bouts of viral meningitis. Her signs and symptoms as well as lumbar puncture results were similar to patients meeting our case definition for patients with presumed enteroviral meningitis. The cerebral spinal fluid was positive for HSV by PCR, and she was ultimately diagnosed with recurrent meningitis from HSV. We compared her presentation with patients who met our case definition for enteroviral meningitis. A thorough history and use of PCR may assist in differentiating these clinically similar presentations.
Benign recurrent lymphocytic meningitis (BRLM) is a type of recurring meningitis with asymptomatic periods. It can present as an aseptic meningitis (AM) syndrome and may be by various infections, tumors, medications, and autoimmune disorders.1,2 It is usually benign and self-limited. Meningitis from enteroviruses (EV) and herpes simplex virus (HSV) can be difficult or impossible to distinguish on initial presentation. Several case reports in the literature that include cerebral spinal fluid (CSF) studies suggest that HSV is a common etiology for BRLM.3'7 We present a case of BRLM due to HSV type 2 that occurred during an outbreak of AM. Clinical clues in the history and use of polymerase chain reaction (PCR) amplification can aid in determining the etiology of BRLM. Most important is to distinguish bacterial and treatable viral meningitis from benign self-limited meningitis.
From june to September 2001, we identified 30 patients who were diagnosed with AM on presentation to our emergency department. We generated a case definition for AM that was met by 25 of these patients. Clinically, patients were required to have a headache as well as one of the following symptoms or signs: mental status change/irritability, nausea/emesis, photophobia, meningeal signs, or fever. From a laboratory standpoint, patients were required to have greater than 5 leukocytes/mm^sup 3^ in the CSF, a Gram stain of the CSF that was negative for the presence of organisms, and bacterial cultures that yielded no growth. Of the 25 patients who met the case definition, 64% were men. The mean age was 24.7 years (range, 4-63 years) and 56% were between 17 and 29 years of age. The most common symptoms were nausea (81%), meningeal signs (65%), photophobia (58%), and fever (42%). CSF leukocytes ranged from 6 to 3,180/mm^sup 3^ (median, 62), CSF glucose ranged from 11 to 144 mg/dL (median, 57), and CSF protein ranged from 20 to 125 mg/dL (median, 45). Enteroviral PCR was performed on the CSF of 10 of 30 patients and was positive in 8 of 10 (Table I).
The last case to present in the outbreak was a 32-year-old woman with recent recurrence of oral and genital HSV followed by 2 days of sudden headache, stiff neck, photophobia, and nausea, without fever. Her symptoms did not resolve with over-the-counter nonsteroidal anti-inflammatory agents. She denied a history of rash, joint pain, or head trauma. Her past medical history revealed two previous episodes of viral meningitis associated with simultaneous oral/genital HSV type 2, which completely resolved after 7 days. Childhood and adult immunizations were up-to-date. She had no history of head trauma, intracranial surgery, or other childhood or adult medical illnesses. She was married, employed full-time as an administrator, and had two children. She denied intravenous drug use, ill contacts, animal, insect, or pet exposures, or recent foreign travel. Her tuberculin skin test had been negative in the previous year. Physical examination revealed a temperature of 36.3°C, photophobia, and she had a stiff neck with positive Brudzinski's sign and Kernig's sign. Her mental status was normal. She had a normal funduscopic eye examination. She had no visible oral or genital vesicles, ulcers, or other lesions. Computed tomography of her brain was normal. The CSF examination yielded clear, colorless fluid with 573 leukocytes/mm^sup 3^ (95% lymphocytes); the CSF protein was 121 mg/dL, and the CSF glucose was 42 mg/dL. The CSF Gram stain was negative for the presence of organisms. The patient was admitted to the hospital and received intravenous ceftriaxone until cultures of her blood and CSF were reported as yielding no growth after 48 hours. Her symptoms completely resolved after 48 hours. Antibiotic therapy discontinued at that time, and she was released from the hospital. A vaginal swab obtained during the hospitalization was positive for HSV-2 antigen, and PCR analysis of the CSF was positive for HSV-2 (test performed at Mayo Medical Labs, Rochester, MN). Serum HSV 1 immunoglobulin G was positive, with an enzyme immunoassay value of 1.79 and an index range of 0.9 to 1.10. Serum HSV 2 immunoglobulin G (IGG) was also positive, with an enzyme immunoassay value of 4.06 and an index range of 0.9 to 1.10. Enteroviral PCR performed on the CSF was negative (test performed at Quest Laboratory, El Paso, TX). Arboviral antibody panel on serum (test performed at Laboratory Corps, Dallas, TX) was negative. On follow-up in the outpatient clinic, the patient reported a history of five to six recurrences of genital HSV per year, each typically associated with headache, although not always with symptoms of meningeal irritation. She was started on oral famciclovir for prophylaxis of these recurrences and subsequently reported fewer lesions and less frequent and intense headaches associated with these episodes.
We describe an outbreak of enteroviral meningitis that covered a wide age range and was characterized by symptoms of headache, nausea, and meningeal signs. There was no evidence of transmission among the cases. The eight patients (Table I) that had positive PCR results for EV in the CSF presented with findings that are typical for AM. EV is the most common cause of viral meningitis, comprising 85 to 95% of cases,1 as occurred in this outbreak. EV infection can occur at any time of the year, but it is most common from summer through early fall. It involves men and women of all age groups, but it is most common in children and young adults. Clinically, patients can present with exanthemas, conjunctivitis, diarrhea, pericarditis, or myocarditis. EV infection of the CNS can present with nonspecific fever, headache, malaise, signs of meningeal irritation, nausea with or without or vomiting, and diarrhea. Laboratory evaluation reveals a CSF pleocytosis with an early shift to mononuclear cells, mild hypoglycorrhacia, and elevated CSF protein concentration. During an acute infection, EV can be cultured from CSF, nasopharynx, and throat. PCR is a method well described to detect a variety of different viruses in CSF, including EV.4 The EV family includes the polioviruses, coxsackieviruses, and echoviruses. These viruses have a natural habitat in the gastrointestinal tract and may be isolated from stool. They are transmitted by the fecal-oral route and can spread rapidly in conditions of close contact and poor hygiene. The natural course of EV meningitis is usually benign, with the acute illness lasting only a few days. Infection is rarely life threatening, except in the neonate, immunocompromised, or organ or tissue transplant population. One report shows benefit with pleconaril in rare, life-threatening cases.8 There is no routinely recommended treatment for EV infection as the illness is usually self-limited.
During our outbreak of enteroviral meningitis, we identified a case of BRLM that we attributed to HSV-2. At the time of her presentation, the most likely basis for the patient's symptoms included viral etiologies such as EV, HSV, and Epstein-Barr virus. Less likely causes included cytomegalovirus, arboviruses, and human immunodeficiency virus. Other, even less likely, considerations included mycobacteria, syphilis, leptospirosis, Lyme disease, fungal infections, sarcoidosis, Bechet's, systemic lupus erythematosus, medication, and tumor. We felt it essential to rule out potentially life-threatening yet highly treatable bacterial meningitis.
Our patient's history of recent outbreak of genital and oral HSV type 2 before the onset of meningeal symptoms directed our testing to HSV. According to the Centers for Disease Control and Prevention, at least 50 million people in the United States have HSV type 2 genital infection, and it is responsible for 1 to 3% of all presentations of AM syndrome.9 Demographically, men and women of all age groups are afflicted. Patients can present with headache, fever, photophobia, nuchal rigidity, nausea, vomiting, and/or myalgia, which usually resolve within 1 week. Genital and oral lesions may or may not be present. The course of HSV meningitis can be chronic, recurrent, or intermittent, with full recovery between attacks. Complications such as transient focal neurological findings (more common with HSV type 1 than type 2) can occur and may include seizures, delirium, abnormal reflexes, and urinary retention. Our patient had no complications and completely recovered in 48 hours. The course of HSV meningitis is usually benign and self-limited. cases reported in the literature suggest that antiviral agents may show a benefit for the treatment of HSV meningitis.1,4,9-10
Because our patient had a history of acute, brief, recurrent meningitis, we included in our differential diagnosis Mollaret's meningitis (MM). MM is a benign recurrent endothelioleukocytic AM that was first described by Mollaret in 1944. The syndrome is rare and the cause is unknown. The CSF findings are characterized by pleocytosis in the first 24 hours with a predominance of neutrophils, elevated CSF protein, and a large type of cell called an "endothelial" or "Mollaret's cell," which appears only in the first few hours of an attack. On repeat lumbar puncture, the CSF neutrophils shift to a lymphocyte-predominant cell type by 24 hours. We did not repeat the lumbar puncture on our patient. MM occurs in men and women of all age groups, and there can be many episodes lasting for 2 to 7 days and spanning a few to many years.10-13 There are a number of studies suggesting HSV as a cause of MM,3-6,10-13 but this connection is not clear.
In summary, a detailed histoiy and CSF PCR can help differentiate potential causes of AM. Even in the situation of an outbreak of enteroviral meningitis, it is important to be vigilant to clues in the history that might suggest an alternative diagnosis. This is particularly important because certain etiologies for meningitis, such as HSV, are amenable to therapy and, potentially, to prophylaxis. As illustrated by this outbreak and case, without an in-depth history and physical examination, the correct tests may not be ordered. PCR testing has a clear role in the diagnosis and differentiation of different types of nonbacterial meningitis such as EV and HSV.
The authors thank Ms. Debora Trask for assistance with data collection.
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Guarantor: MAJ Edward L. McDaniel, MC USA
Contributors: MAJ Edward L. McDaniel, MC USA; MAJ Tomas M. Ferguson, MC USA; CPT Herbert P. Kwon, MC USA; MAJ Jennifer C. Thompson, MC USA
Department of Medicine and the Infectious Diseases Service, William Beaumont Army Medical Center, 5005 North Piedras Street, El Paso, TX 79920.
The views expressed here are those of the authors and should not be constructed as official or as reflecting those of the Department of the Army or the Department of Defense.
This work was presented at the United States Army Annual American College of Physicians Meeting, November 2002, Arlington, VA.
This manuscript was received for review in May 2003 and accepted for publication in August 2003.
Copyright Association of Military Surgeons of the United States Jun 2004
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