Severe Headache, Photophobia, and Neck Pain in a Young Woman


The patient has a history of migraine. Is this another attack-or is something else going on?

blood test vials

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A 24-year-old woman* presents to the emergency department with headache accompanied by neck and shoulder pain of 2 weeks’ duration. She is unable to conduct normal daily activities and feels confused. She denies fever, chills, and rash.


Past medical history includes migraine, HIV infection, and a cesarean section. This headache is similar to her typical migraine pain but is much more severe.

The patient has had HIV infection for the past 6 years, but she refuses to take highly active antiretroviral therapy (HAART) because of nausea. She does not smoke or drink but previously abused drugs. She is single, has one child, and is unemployed. Family history is remarkable for maternal migraine.

Physical examination

The patient lies quietly in a darkened room. Temperature is 98.4ºF (36.9ºC); pulse, 87 beats/min; respirations, 19 breaths/min; and blood pressure, 152/103 mm Hg. Throat examination reveals a white exudate. She resists neck flexion. Brudzinski and Kernig signs are positive.

Neurological examination

She is sleepy and irritable. Cranial nerve examination reveals bilateral papilledema and bilateral sixth nerve palsies. Vision is blurry; however, she cooperates poorly with acuity testing. Peripheral reflexes are brisk. Babinski signs are absent.

Laboratory and imaging studies

Results of CT of the brain with and without contrast are negative. MRI with and without contrast reveals a few nonspecific white matter lesions but no enhancement.

Total white blood cell count is low at 3800 cells/µL (normal, 4000 to 10,000 cells/µL), but red blood cell and platelet counts are normal. Chemistry panel, coagulation studies, electrolyte levels, and liver tests are normal. Rapid plasma reagin test is negative.

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Hospital course

Meningoencephalitis is suspected, and a lumbar puncture (LP) performed. Opening pressure is elevated at 40 cm H2O (normal, 10 to 20 cm of H2O). Cerebrospinal fluid (CSF) results include one white blood cell and three red blood cells, glucose level of 32 mg/dL (normal, 30 to 60 mg/dL), elevated protein level of 47 mg/dL (normal, 15 to 45 mg/dL), and cryptococcal antigen titer of 1:1024 (normal, 0). Repeated CSF cryptococcal antigen titer is 1:4096. India ink stain is positive.

Remaining CSF studies include a negative Gram stain and culture, fungal stain, and Venereal Disease Research Laboratory test. Immediately following the LP, the patient’s headache improves.

The patient’s HIV-1 RNA viral count is 82,800 copies/mL (normal, 0). Absolute CD4 helper T cell count is only 15 cells/µL (normal, 359 to 1519 cells/µL). CD4/CD8 ratio is severely reduced at 0.05 (normal, 0.92 to 3.72).

The patient starts antifungal treatment (amphotericin B and flucytosine) for AIDS-related cryptococcal meningoencephalitis.

Over the next 6 weeks, the patient has recurrent headaches, which are treated with pain medication and repeated LPs. After each procedure, the headache transiently improves. Her vision remains persistently blurry, with the ability to see shapes but not detail. Ophthalmologic exam confirms decreased visual acuity but no retinitis. Her right sixth nerve palsy improves, but the left remains complete. HAART is started several weeks after admission.


The patient’s headache was similar to her prior migraines but more severe and accompanied by photophobia, neck pain, and blurry vision. The patient had nuchal rigidity and positive Brudzinski and Kernig signs. Although these classic meningeal signs have low sensitivity, they pointed to meningitis rather than a migraine attack.1

Neurological examination revealed bilateral papilledema and bilateral sixth nerve palsies. Both abnormalities suggest increased intracranial pressure. After a CT scan ruled out a space-occupying lesion, an LP revealed cryptococcal meningoencephalitis. Headaches resolved after 6 weeks of antifungal treatment and multiple LPs.

The patient had HIV infection but did not take antiretroviral therapy. The typical treatment target of HAART is a CD4 count of at least 500 cells/µL.2 The patient’s CD4 count was only 15 cells/µL. This profound CD4 lymphocytopenia made her vulnerable to opportunistic infections by Cryptococcus neoformans, Mycobacterium avium,Pneumocystis carinii, Toxoplasma gondii, and other pathogens. The white exudate in her throat was thrush due to Candida albicans, another opportunistic infection.

Although contrast enhancement often occurs with meningitis because of disruption of the blood-brain barrier by inflammation, it was not observed on CT or MRI. There were only a few white cells in the CSF, further evidence of the patient’s failure to mount an inflammatory response to the cryptococcal infection because of her immunocompromised state.

The patient received a combination of amphotericin B and flucytosine for several weeks before transitioning to a suppressive dose of fluconazole per Infectious Diseases Society of America guidelines.3 HAART was initially delayed to avoid triggering the immune reconstitution inflammatory syndrome (IRIS).

Cryptococcal meningoencephalitis rarely occurs in immunocompetent individuals but is a common infection in immunosuppressed patients with HIV infection.4 The global burden of HIV-associated cryptococcal infection is approximately one million cases worldwide.3 It may also occur in patients with chronic corticosteroid use, hematological malignancies, idiopathic CD4 lymphopenia, liver and renal failure, and organ transplants.4

Cryptococcal meningoencephalitis is a leading cause of death in HIV-infected individuals with decreased cell-mediated immunity and should be suspected in patients with low CD4 counts, particularly if they are seropositive for cryptococcal antigen.5 Mortality from cryptococcal meningoencephalitis approaches 100% without treatment. Even with modern treatment, mortality is approximately 20%.3

Outcome of this case

This patient suffered cryptococcal meningoencephalitis due to chronic HIV infection and noncompliance with HAART. Partial blindness and a left sixth cranial nerve palsy persisted despite antifungal treatment.

*Details of this case were significantly changed to protect patient confidentiality.

About the author
Andrew Wilner, MD, is a neurologist who blogs at His latest book is The Locum Life: A Physician’s Guide to Locum Tenens.


1. Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis. 2002;35:46-52.

2. Diaconu IA, Stratan LM, Nichita L, et al. Diagnosing HIV-associated cerebral diseases-the importance of neuropathology in understanding HIV. Rom J Morphol Embryol. 2016;57(2 suppl):745-750.

3. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322.

4. Shribman S, Noyce A, Gnanapavan S, et al. Cryptococcal meningitis in apparently immunocompetent patients: association with idiopathic CD4+ lymphopenia. Pract Neurol. 2018;18:166-169.

5. Chen J, Zhang R, Shen Y, et al. Serum cryptococcal antigen titre as a diagnostic tool and a predictor of mortality in HIV-infected patients with cryptococcal meningitis. HIV Medicine. 2019;20:69-73.

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