Acute meningoencephalitis and meningitis due to primary HIV infection

A wide differential diagnosis exists for meningoencephalitis and meningitis: causes include tuberculosis and infections caused by viruses such as enteroviruses, human herpesviruses (types 1-4, 5 (cytomegalovirus), and 6), paramyxovirus (mumps), measles virus, and adenoviruses. In one cohort, viral genomes were detected in consecutive samples of cerebrospinal fluid from 5% of patients (22 of 410); enteroviruses and human herpesviruses types 1-5 accounted for over 95% of cases.¹ HIV infection was not detected. It is often overlooked as a potential cause of meningoencephalitis and meningitis.

The clinical manifestations of primary HIV infection are well characterised and include fever, lethargy, flu-like illness, headache, pharyngitis, generalised rash, lymphadenopathy, and gastrointestinal disturbances.² Neurological features, including aseptic meningitis, meningoencephalitis, and encephalitis, occur in up to 17% of patients and may be associated with more rapid progression of HIV related disease.^3–11 Neurological symptoms may occur or develop up to 3 months after the onset of symptoms of primary HIV infection, when the other symptoms have resolved. We discuss one patient with meningoencephalitis and two patients with meningitis associated with primary HIV infection. In each patient the underlying diagnosis of primary HIV infection was not suspected initially resulting in a delay to diagnosis.

Case reports

Over a 16 month period three men with viral symptoms had presented to their general practitioner (n=2) and local emergency department. One patient required immediate admission and the others were subsequently admitted through the emergency department and local genitourinary clinic. The patients failed to disclose any risk factor for acquiring HIV infection and none had clinical stigmata of immunosuppression. The table summarises the clinical details of these patients. Here we report on case 1.

A 34 year old man presented with a one week history of fever, nausea, and confusion. The previous month he had had a brief febrile illness associated with a non-specific rash on his limbs and a mild intermittent headache that persisted until presentation. He was previously fit and well and had returned, one month earlier, from a two week visit to the Caribbean. He was in a stable heterosexual relationship with his partner of over five years and denied being an injecting drug user.

His temperature and blood pressure were normal. Respiratory, cardiovascular, and abdominal examination was also normal. His mini-mental state examination score was 1 out of 10, indicating severe confusion. He was drowsy, had no meningism, and could move all four limbs. No focal neurological signs were evident.

Haematological and biochemical investigations were normal apart from a peripheral blood neutrophilia (11.7 × 10⁹/l; reference range 3-10 × 10⁹/l). A septic screen including culture of urine and blood was negative and a chest x ray film was normal. Viral encephalitis was provisionally diagnosed and intravenous aciclovir started. A lumbar puncture, performed after a computed tomogram of the brain was shown to be normal, showed lymphocytic cerebrospinal fluid (33 lymphocytes).

The next day the patient became more obtunded, and empirical antituberculosis therapy with adjuvant glucocorticoids was started. Electroencephalography showed diffuse symmetrical slow wave activity consistent with a diffuse cerebral abnormality. A HIV antibody test was positive and a CD4 T lymphocyte count was 204 × 10⁶/l (reference range 270-1350 × 10⁶/l). Serology showed no recent mycoplasma, legionella, or rickettsial infection, and a serum cryptococcal latex agglutination test was negative. Viral encephalitis secondary to cytomegalovirus or HIV infection was provisionally diagnosed. Foscarnet and ganciclovir were given empirically.

Seven days after admission he had several grand mal seizures. Another lumbar puncture showed monocytic cerebrospinal fluid (18 monocytes) and electroencephalography showed resolution of the diffuse slow wave changes, with no epileptiform activity. Over the next week the seizures reduced in frequency and the confusion resolved. Ganciclovir therapy was continued until day 17, when cerebrospinal fluid was negative for human herpesviruses (types 1-5) and enteroviruses. Antituberculosis therapy was stopped 5 days later.

The CD4 T lymphocyte count 21 days after admission was 650 × 10⁶/l (45%), and the HIV viral load was 5800 copies/ml. The initial serum sample was positive for anti-HIV immunoglobulin G, A, and M, and negative for p24 antigen, indicating recent acute HIV infection. Antiretroviral therapy was not started after confirmation of the diagnosis as the patient had improved, the CD4 T lymphocyte count had returned to normal, and the HIV viral load was low.

The patient recovered and had no further seizures. One year later the CD4 T lymphocyte count was 350 × 10⁶/l (20% of total lymphocytes in blood; reference range 25-64%) and the HIV viral load was 68 000 copies/ml. Further history taking revealed that he had occasional homosexual relationships.

Discussion

It is important to consider a wide differential diagnosis in patients presenting acutely unwell with meningoencephalitis. Although tuberculosis and viral infections account for most of these cases other causes such as primary HIV infection should not be forgotten.

It is difficult to identify patients with primary HIV infection when they fail to disclose risk factors for acquiring the virus and there are no clinical stigmata of immunosuppression. The neurological manifestations of infection may occur several weeks after the resolution of other symptoms related to the infection, necessitating the need for thorough history taking. A recent negative HIV antibody test result does not exclude primary HIV infection. A diagnosis usually relies on serial HIV antibody tests in parallel with assays for detecting the virus, such as those for detecting p24 antigen, HIV proviral deoxyribonucleic acid, or plasma HIV ribonucleic acid. HIV p24 antigenaemia, as in case 1, may be present only during the first few weeks of primary HIV infection, therefore the test should be performed promptly.¹² Case 1 was not able to give informed consent to tests at the time of presentation.

Failure to identify primary HIV infection denies patients the opportunity of receiving potent antiretroviral therapy at the time of HIV seroconversion. Early therapy may result in a more rapid resolution of symptoms and a reduced chance of developing opportunistic infections. It may also reduce the risk of symptoms related to HIV infection or acquired immunodeficiency syndrome developing in the short term.¹³ Early treatment has been associated with improvements in CD4 T lymphocyte cell counts, decreased immune activation, and preservation of HIV-1 specific T helper cell responses.¹⁴,¹⁵

Table.

Clinical details of patients with primary HIV infection

	Case 1	Case 2	Case 3
Clinical features:
At presentation	Fever, headaches, confusion, rash (limbs), nausea	Flu-like illness, headache, sore throat	Flu-like illness, sore throat, nausea, diarrhoea
Subsequent	Obtunded, grand mal seizures	Headaches, meningism, maculopapular rash, nausea, lymphadenopathy, oral ulcers	Headache, meningism, generalised rash, lymphadenopathy
Time delay for diagnosis of infection*	3 days	8 days	9 days
Neurological diagnosis	Meningoencephalitis	Meningitis	Meningitis

Patients had primary HIV infection with presence of anti-HIV immunoglobulin M antibodies (n=1) or evolving HIV specific antibody profile (n=2). All described febrile illness preceding onset of headaches. Three had had a rash (two had received antibiotics) and two had had upper respiratory tract symptoms. 

^*Calculated from day of initial presentation to day that first positive HIV test result was confirmed. 

Meningoencephalitis and meningitis can be associated with primary HIV infection