This 3-year-old boy was admitted to the hospital with headache and neck pain of 1-day duration. He had been well until the night before admission, when he developed a temperature of 102° and began vomiting. After approximately 12 hours of vomiting, he developed neck pain and was taken to the emergency room. There was no history of diarrhea, rash, rhinorrhea, or other symptoms.
His medical history was remarkable in that he had been hospitalized 6 months earlier for a 3-day illness consisting of vomiting that was diagnosed as viral. Immunizations were up to date. The family and birth history were unremarkable. His development was normal.
In the emergency room, he was alert and interactive. Temperature was 39.4°, pulse 148, respiratory rate 28, and blood pressure 110/60. Height and weight were in the 50th percentile. On HEENT exam, he had photophobia. Pupils were equal, round, and reactive to light. There was no papilledema. Neck was supple; Kernig and Brudzinski signs were negative. Lungs were clear. S1 and S2 were normal without murmurs. The abdomen was soft and nontender, without masses or organomegaly. Neurologic examination was unremarkable.
Hemoglobin was 11.3 g/L and WBC was 9,800/mm3 with 84% neutrophils, 4% immature neutrophils, and 9% lymphocytes. The diagnosis of viral meningitis was made based on the physical findings; no lumbar puncture was performed. He was admitted to the hospital for observation.
Robert Listernick, MD, moderator: Can viral meningitis be a clinical diagnosis?
Ben Katz, MD, pediatric infectious disease specialist: I would feel more comfortable making a clinical diagnosis in an adolescent with fever, headache, and photophobia in the summertime. I have to admit that I'm a little uncomfortable not performing a lumbar puncture in a 3-year-old.
Robert Tanz, MD, general academic pediatrician: The critical point is the epidemiology. If one is in the middle of an enteroviral outbreak, as we are each summer, I believe that performing a lumbar puncture is not necessary, even in a fairly we 11- appearing 3-year-old. However, this child was seen in the winter when enteroviral disease is unusual - I absolutely would have performed a lumbar puncture.
Stanford S. Shulman, MD, pediatric infectious disease specialist: I'm very uncomfortable not performing a lumbar puncture, even in the summer. Even though bacterial meningitis is uncommon now compared with when all of us trained, the consequences of missing the diagnosis are devastating.
Dr. Listernick: I'm glad we all agree. The day after admission, he started vomiting continuously. Although his mental status was normal, he was having difficulty steeping and was making "jerking movements" while asleep. The physical exam at that time had changed. He continued to be febrile and had meningismus. On neurologic examination, he had developed a right sixth nerve palsy and truncal ataxia. An MRI of the head was normal.
Lumbar puncture was performed. The CSF cell count had 203 WBC/mm3 and 2 RBC/mm3 with a differential count of 56% neutrophils, 33% lymphocytes, and 11% monocytes. Gram stain of CSF was negative. The CSF protein and glucose concentrations were normal. Bacterial culture of the CSF was negative. Ultimately, a polymerase chain reaction (PCR) test for enteroviral DNA was positive. Over the next several days, his sixth nerve palsy and ataxia improved to the point that he was able to walk alone and fever and meningismus resolved. He spent 7 days in the hospital. He developed vesicular lesions below the left lower lip 3 days prior to discharge. A direct fluorescent antibody stain for HSV-I was positive and he was discharged. A diagnosis of enteroviral meningitis was made.
Dr. Listernick: First, can someone interpret the CSF findings?
Dr. Shulman: They're classic for viral meningitis. Often we'll see a polymorpho-nuclear predominance early in the course that rapidly shifts towards a lymphocytic or mononuclear predominance. In addition, the normal CSF glucose and protein, as well as the negative Gram stain, all point to a viral infection.
Dr. Tanz: I agree, but I'm extremely concerned about his clinical course. Focal neurologic findings are rarely part of the clinical picture of viral meningitis. Even with the MRI scan being normal, I'm worried about alternative diagnoses.
Dr. Listernick: It's important to note that these are the CSF findings of aseptic meningitis, a category of disease of which viral meningitis is just one diagnosis. Other causes of aseptic meningitis include various vasculitides, parameningeal foci of bacterial infection, malignancies, and more unusual infections caused by mycobacteria and fungi.
Douglas Nordli, MD, pediatric neurologist: The sixth nerve palsy is a nonspecific finding of meningeal irritation or increased intracranial pressure. However, pronounced ataxia is definitely more concerning. This indicates that he has cerebellar involvement or involvement of the cerebellar outflow tracts. Taken together, he must have either meningoencephalitis, which may be viral, or a complication of viral meningitis.
Dr. Katz: It's important to point out that viral meningitis is not necessarily a benign event. There is a small but significant mortality rate as well as neurologic sequelae, including hearing loss. Just because he's had a complicated course, I wouldn't go on a fishing trip for other diagnoses.
Dr. Shulman: Meningoencephalitis, indicating parenchyma! involvement, is more likely to have serious consequences than pure viral meningitis, which is limited to meningeal inflammation. The viral agents can overlap.
Dr. Listernick: Should we send the CSF for enteroviral PCR in every child who has viral meningitis?
Dr. Katz: Other than for epidemiologie or research purposes, the clinical utility of the test generally is low.
Dr. Listernick: How do we know that the enteroviral nucleic acid is from this illness rather than from a previous infection?
Dr. Shulman: Enteroviral nucleic acid in the CSF is very short-lived and should be interpreted as a sign of active infection. Enteroviral culture from the throat or rectum may be more difficult to interpret. In this latter case, the virus may be recovered from an asymptomatic shedder and may not be the cause of the neurologic illness. However, a positive enteroviral culture of CSF should be believed.
Dr. Listernick: Is the concurrent HSV-1 infection unusual?
Dr. Katz: Reactivation of HSV-1 during any acute illness is quite common. In contrast, one would be very concerned about the appearance of mucocutaneous HSV lesions in a 3-week-old infant with meningoencephalitis.
Dr. Listernick: Moving on, this patient was perfectly well for the following 2 months. Three days prior to this admission, he began complaining of a headache and fever that persisted until admission. In addition, he had cough and rhinitis. Six hours after evaluation in an emergency room, where he received intravenous fluids for treatment of dehydration, he developed a 15minute generalized seizure. Physical exam revealed a well -appearing, post-ictal child. HEENT exam was unremarkable. There was no meningismus. Lungs were clear. Cardiac and abdominal examinations were normal. Other than being sleepy, the neurologic examination was unremarkable.
Lumbar puncture revealed 16 WBC/mmp 3 and 70 RBC/mmp 3 with a differential count of 54% lymphocytes, 19% monocytes, and 27% eosinophils. The CSF protein was 50 mg/dL and glucose was 73 mg/dL. Several hours after admission, he developed status epilepticus and respiratory distress requiring endotracheal intubation and transfer to the intensive care unit. Can we interpret the CSF results?
Dr. Shulman: They're abnormal. There are too many white blood cells and the CSF protein is mildly elevated. It's difficult to interpret the presence of the red blood cells without knowing whether it was a traumatic lumbar puncture. I saw this child shortly after admission and the history clearly pointed to this being a new illness; he had been absolutely well since the last hospitalization. While unlikely, this could be a second episode of viral meningitis. Alternatively, it's hard to believe that there was a chronic, smoldering infection such as tuberculous meningitis that suddenly reappeared. For the same reason, I believed that both parameningeal infection and brain abscess were unlikely, but they needed to be excluded. Children who have neurocutaneous fistulae may have recurrent meningitis; however, the CSF culture is usually positive for bacteria. I also would consider the possibility of a recurrent vasculitic syndrome such as Behcet's disease or systemic lupus erythematosis.
In addition, we should discuss Mollaret's meningitis, which is a rare condition characterized by recurrent short-lived episodes of meningitis. The etiology is unclear, although some cases have been linked to HSV- 1 , suggesting a possible role for antiviral therapy.
Dr. Nordli: I would also consider the possibility of carcinomatosis of the meninges. The possibility of a demyelinating post-inflammatory process following the first episode of meningitis is possible. However, this would be an extremely late presentation. Normally, one would see such a process 1 to 2 weeks after the initial infection.
Dr. Listemick: What about the CSF eosinophilia?
Dr. Shulman: We occasionally see CSF eosinophilia in patients who have ventriculoperitoneal shunts, as a reaction to the plastic tubing. It's also worth mentioning that Illinois is a hotbed of baylisascariasis, the raccoon roundworm, which causes intense CSF eosinophilia. These children have chronic, unremitting neurologic deterioration, which didn't occur in this case.
Dr. Listemick: Neuroimaging was performed shortly after admission.
Delilah Burrowes, MD, pediatrie neuroradiologist: MRI scan of the brain revealed abnormal signal in the right cerebellar hemisphere, a nonspecific finding. In addition, there was diffuse enhancement in the cortices, which represents the radiographie correlate of meningeal irritation. Finally, there was extensive cerebral edema.
Dr. Listemick: Can cerebral edema occur solely as a consequence of prolonged seizures?
Dr. Nordli: While this happens occasionally, cerebral edema to this degree secondary to seizures alone would be very unusual. Given the meningeal enhancement on the MRI, the edema is more likely a result of the inflammatory process.
Dr. Listernick: This child had recurrent, prolonged seizures in the intensive care unit. Achieving seizure control was extremely difficult. After several weeks, he was transferred to the pediatrie floor. Tragically, he is neurologically devastated and has repeated choreoathetotic movements and no communicative skills. His nasal secretions on admission were positive for influenza A antigen. How should this be interpreted?
Dr. Katz: Severe influenza A encephalitis or encephalopatby has been reported in Japan; cases have been appearing in the United States during the last few influenza seasons. However, influenza is very common now, and this certainly wouldn't explain his illness 2 months ago.
Dr, Shulman: The US cases have been reported primarily in children younger than age 5. The CSF findings have been distinctly unimpressive, with WBC counts less than 50/mm3. Evidence of actual viral infection in the brain, either by viral isolation or PCR of CSF or brain tissue, has been scant. We didn't have any of this child's CSF on which to perform these studies.
Dr. Listernick: Did you start any antiviral therapy?
Dr. Shulman: After discussions with colleagues around the country who have seen influenza encephalitis, the decision was made to start treatment with oseltamivir. I had my doubts about its efficacy, but we decided that it would be worth trying.
Dr. Listernick: I still think that the two illnesses must be related given their severity and the unusual course. Could he have a form of immunodeficiency?
Dr. Katz: Children with hypogammaglobulinemia may have chronic, refractory enteroviral meningoencephalitis characterized mainly by headaches.
Gulbu Uzel, MD, pediatrie iminunologist: That's true, but these children would present earlier in life with chronic sinopulmonary infections or otitis media. This child has normal levels of immunoglobulins and normal numbers of B and T cells as measured by flow cytometry. He had high titers to both Hemophilus influenzae type B and pneumococcus, indicating normal T and B cell function. However, there are a few very rare diseases that lead to recurrent, severe viral meningoencephalitis in the face of normal B and T cell function.
If one were to theorize a defect in the immunologie pathway that may predispose a patient to severe, recurrent viral infections, one would look at interferon-alpha or interferon-gamma function. It has been known that gamma interferon receptor-deficient patients are particularly susceptible to mycobacterial disease as well as to viral infections, but not to the degree that this patient had. However, a recent article described recurrent, severe viral meningoencephalitis in two patients who had homozygous mutations in a protein called Stat-1, a signaling protein for interferon alpha and gamma receptors. Those patients came to medical attention when they developed disseminated disease following immunization with bacille Calmette-Guerin (BCG). They ultimately died of herpes encephalitis and a severe disseminated viral infection. We have sent this patient's white blood cells to look for this mutation. The assay incubates monocytes with either interferon alpha or interferon gamma and looks for phosphorylation of the Stat-1 molecule.
Dr. Listernick: If this child has this mutation, is there any therapy that could be used?
Dr. Uzel: Theoretically, if you knew a child had the Stat-1 defect, you would perform a bone marrow transplant before he had his first severe viral infection. This child is tragically now in a vegetative state; I don't believe that transplantation would be warranted. Alternately, one might try giving very high doses of interferon alpha in order to prevent infection.
Dr. Tanz: If this child had the Stat-1 mutation, why wouldn't he have had difficulty handling live attenuated viral vaccines?
Dr. Uzel: That's an excellent question. Unfortunately, this mutation has only recently been described and there isn't a lot of information about its clinical presentation.
Dr. Listernick: This was a heartbreaking case. He ultimately was transferred to a rehabilitative facility in what appeared to be a persistent vegetative state.
Two weeks after this discussion, this patient was found to have the Stat-1 mutation. As it is an autosomal recessive disease, his healthy siblings are being tested for the mutation.