A 21-year-old woman who is living in relative poverty with several friends in the inner city is brought to the emergency room by one of her roommates because she has been exhibiting rather bizarre behavior. When she woke up that morning, she was convinced that Martian aliens who wanted to abduct her were lurking in the kitchen, so she started to pile all of the living room furniture against the kitchen door. On the way to the hospital, the woman had frequent hallucinations and made references to elephants chasing the car, a distinct odor of cinnamon, and various other nonsensical things.

At the ER, the woman was found to have a low-grade fever. She wasn't overly coherent, so the attending physician asked her roommates if they had noticed any additional symptoms. They said that their friend had had some mild nausea and vomiting a few days earlier. She might have said something about a stiff neck as well, but they couldn't remember for sure, nor could they remember when that might have been. What they could remember for sure was that the woman experimented with some "angel dust" (phencyclidine) a few days ago, and traces of this drug were detected in her urine.

Primarily because of her history of drug use, the woman was first admitted to the psychiatric ward, where her low-grade fever persisted. She was given a phenothiazine tranquilizer in hopes of alleviating the hallucinations. After two days, however, she underwent a generalized seizure and become comatose.

Question 2.1: What is your diagnosis?

Convulsions are not associated with phencyclidine intoxication, and they are not a side effect of phenothiazines either. Therefore, the fever and seizures are more likely to indicate some type of CNS infection, possibly encephalitis (which can also lead to medical aberrations such as hallucinations). The physician in the ER missed the diagnosis because he or she was misled by the history of recent drug use and the vagueness on the part of the woman's roommates about additional possible symptoms of encephalitis (e.g., stiff neck).

Question 2.2: What tests should you perform?

The top priority would be a lumbar puncture and analysis of the CSF. CT or MR imaging can be performed.

Test Results:

The CSF contained 280 erythrocytes/microliter and 350 mononuclear leukocytes/microliter. CSF glucose was 48 mg/dL (normal) and CSF protein was 127 mg/dL (elevated). These results, along with those of the MR imaging, are sufficient to confirm a case of acute encephalitis.

Question 2.3: What is the causative agent?

Acute encephalitis is almost always caused by a virus. Herpes simplex virus (HSV-1) is, by far, the most frequent cause of encephalitis in the U.S. Moreover, the temporal lobe is the preferred site of infection for HSV. Other common causes of viral encephalitis in the U.S. include enteroviruses, arboviruses, and the mumps virus. Many other viruses have been identified as less common or rare causes of acute encephalitis. In this case, stereotactic biopsy of the temporal lobe was performed and immunofluorescence microscopy revealed the presence of HSV antigen in a sectioned sample of the brain tissue. HSV grew in cell cultures inoculated with biopsy material.

Question 2.4: What is the differential?

Viral encephalitis classically presents with initial fever and evidence of meningeal irritation (i.e., headache and stiff neck). Later, any degree of altered consciousness may develop, ranging from mild lethargy to coma. Patients often become confused, delirious, and disoriented. Mental aberrations may include hallucinations, agitation, personality change, behavioral disorders, or even a frankly psychotic state. Focal or generalized seizures are noted in >50% of patients. Depending on which symptoms actually present in a particular case, the differential might include a bacterial infection (brain abscess, tuberculosis, syphilis, brucellosis, Lyme disease, etc.), protozoan infections (especially toxoplasmosis), cryptococcus, multiple sclerosis, Mollaret's meningitis, leukemic or lymphomatous meningitis, and a few other conditions.

Question 2.5: How did the causative agent reach its present location?

Several routes of infection are possible. In children and young adults, it is thought that primary HSV infection can lead directly to encephalitis when exogenously acquired virus enters the CNS by neurotropic spread from the periphery via the olfactory bulb. On the other hand, most adults with HSV encephalitis display clinical or serologic evidence of mucocutaneous HSV-1 infection prior to the onset of their CNS symptoms. The HSV-1 strains from the oropharynx and brain tissue differ in about 25% of these cases, so some patients might be re-infected with another HSV-1 strain that reaches the CNS. When ganglionic and CNS HSV isolates are the same, it is possible that reactivation of latent HSV-1 infection in trigeminal or autonomic nerve roots is associated with extension of the virus into the CNS via nerves innervating the middle cranial fossa. HSV-1 DNA has been found (by DNA hybridization methods) in brain tissue obtained at autopsy from healthy adults. This suggests that reactivation of long-standing latent CNS infection could be yet another mechanism for development of HSV encephalitis.

Question 2.6: How prevalent is this disease?

Overall, about 20,000 cases of viral encephalitis are reported to the CDC each year. The specific incidence for HSV-1 encephalitis is about 2.3 cases per 1,000,000 people per year in the U.S.

Question 2.7: How should you treat this case?

HSV encephalitis can be treated with acyclovir, but there are no specific antiviral drugs for most other forms of viral encephalitis. In this case, the woman was treated with acyclovir for 2 weeks. This effectively halted the progression of her neurological symptoms, but she had many residual signs of neurological impairment and needed extensive rehabilitation therapy. Other treatments that might be used in cases of encephalitis include supportive care, frequent neurological examination, avoidance of hypotonic fluids to minimize the risk of hyponatremia, anticonvulsant therapy for patients who develop seizures, short course of corticosteroids to control brain edema and prevent herniation, etc.