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PATIENT
Mr. S is a 46-year-old man with AIDS and a CD4TL of 80 cells/mcL. He arrives at the hospital complaining of having a headache for 2 weeks and low-grade fever for 5 days. He denies confusion, focal weakness, or seizures. He is febrile to 38.8°C. His neck is supple. The neurologic exam is nonfocal.
What is the differential diagnosis of headache in HIV-positive patients? How would you frame the differential?
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CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
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Three pivotal considerations help frame the differential diagnosis in HIV-infected persons with neurologic complaints: (1) the acuity of the symptoms, (2) the degree of immunosuppression (CD4TL), and (3) whether the patient has focal neurologic signs and/or a focal abnormality on neuroimaging.
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The first pivotal step in evaluating the HIV-positive patient with headache is to determine the acuity of the presentation. Most OIs have a subacute onset. In HIV-infected patients with an acute onset of headache and fever (< 3 days), virulent pathogens must be considered including bacterial meningitis and viral encephalitis, most commonly herpes simplex-1 (HSV-1) and West Nile virus encephalitis.
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The second pivotal issue is to assess the degree of immunosuppression. HIV-positive patients with intact immunity and CD4TL > 200 cells/mcL are at markedly diminished risk of OIs. The differential diagnosis of such headaches is therefore similar to patients without HIV infection; however, HIV itself can cause aseptic meningitis or encephalopathy in acute HIV with high viral loads. As the immunosuppression worsens and the CD4TL falls < 200 cells/mcL, the differential diagnosis broadens to include OIs and PCL.
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The third pivotal issue is to determine whether or not the patient has focal neurologic signs typically associated with a focal abnormality on neuroimaging (mass lesion or focal white matter disease). The most common diagnoses in HIV-infected patients with low CD4TL who have focal neurologic signs or mass lesions on neuroimaging are toxoplasmosis and PCL, as well as PML (plaques of demyelination). The most common diagnoses in HIV-infected patients with low CD4TL who have a nonfocal neurologic presentation and without focal findings on neuroimaging are cryptococcal meningitis, other fungal meningitis (coccidioidomycosis and histoplasmosis), TB meningitis, and syphilis. Both CNS imaging (CT and MRI) and lumbar puncture (LP) are frequently required to confirm the diagnosis. In clinical practice, a CT scan is usually performed prior to LP because it rapidly rules out a large mass lesion that may cause post LP herniation. Platelet count, prothrombin time, and partial thromboplastin time should be checked to ensure the patient is not at an increased risk for developing a spinal epidural hemorrhage from the LP. An MRI is often performed subsequently due to its substantially increased sensitivity for several diagnoses. A diagnostic algorithm for the evaluation of headache in HIV-positive patients is summarized in Figure 5-4.
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Mr. S reports that his headache began 14 days ago. The headache is described as frontal, unrelenting, and pounding. He complains of subjective fevers, sweats, and chills. He admits to mild photophobia. Persistent vomiting has developed over the last 6 days. He denies any history of confusion or seizures.
Past medical history is remarkable for a long history of IDU. His last reported IDU was 2 years ago. HIV was diagnosed 9 years ago. He has not been adherent with ART or PJP prophylaxis with daily TMP-SMX. He takes no medications. A CD4TL count 1 year ago was 2 cells/mcL.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
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RANKING THE DIFFERENTIAL DIAGNOSIS
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The first pivotal consideration is that Mr. S has had a headache for 2 weeks (subacute). This suggests a relatively less virulent OI rather than a virulent bacterial meningitis or HSV-1 encephalitis. Second, his prior CD4TL indicates profound immunosuppression. Therefore, he is at risk for all the serious OIs listed above. The third pivotal issue is whether there is a mass lesion. Ultimately, this will be confirmed or excluded on neuroimaging, but his photophobia suggests some form of meningoencephalitis. Cryptococcal meningitis is the most common meningitis seen in AIDS and is the leading hypothesis. Less common causes of meningoencephalitis include neurosyphilis, TB meningitis, and other fungal meningitis (coccidioidomycosis in the southwestern United States, and histoplasmosis and blastomycosis in the Midwest). HIV aseptic meningitis may present with headache. Should neuroimaging confirm a focal abnormality, common causes include toxoplasmosis, PML, and PCL. Since Mr. S has not taken TMP-SMX prophylaxis, he is at increased risk for toxoplasmosis, the most common CNS mass lesion in AIDS patients. Finally, given his history of IDU, he is also at risk for a brain abscess secondary to Staphylococcus aureus. Table 5-2 lists the differential diagnoses.
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Physical exam reveals a thin man in moderate distress. Vital signs: temperature, 35.9°C; BP, 154/100 mm Hg; pulse, 66 bpm; RR, 20 breaths per minute. HEENT: optic disks sharp, neck supple, Kernig and Brudzinski signs negative. Cardiac, pulmonary, and abdominal exams within normal limits. Neurologic exam: alert and oriented; cranial nerves intact; motor, sensory, and cerebellar functions normal.
A CT scan (with contrast) is normal: no mass lesions or sinusitis seen.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
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The normal CT scan markedly diminishes the likelihood of the diseases associated with mass lesion and increases the likelihood of one of the remaining causes of meningitis (Cryptococcus, neurosyphilis, TB). Cryptococcus is the most common. However, a brain MRI is more sensitive for mass lesions and demyelinating lesions and should be performed.
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Blood cultures and serum CRAG are ordered. A toxicology screen is positive for opioids and cocaine. CBC reveals WBC of 3700 cells/mcL (8% lymphocytes), HCT of 36.6 and platelet count of 240,000 cells/mcL. PT and PTT are normal. Serum Treponema pallidum enzyme immunoassay (TP-EIA) is negative, ruling out syphilis.
LP reveals opening pressure of 30 cm H20, glucose 26 mg/dL (versus serum of 127 mg/dL), and protein 68 mg/dL (normal 15–45 mg/dL). CSF cell count has 20 WBC/mcL and CSF Gram stain shows numerous yeast forms. CSF VDRL is negative.
Have you crossed a diagnostic threshold for the leading hypothesis, cryptococcal meningitis? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
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The CSF findings strongly suggest cryptococcal meningitis. Positive CRAG or fungal culture will confirm the diagnosis. However, patients with AIDS may have simultaneous infections and you review other diagnoses on the differential. There is no travel history to the southwestern United States that would increase the probability of coccidioidomycosis. Neurosyphilis is highly unlikely because of the negative CSF venereal disease research laboratory (VDRL) and serum TP-EIA. An MRI is more sensitive in the detection of CNS mass lesions than a contrast CT and is indicated to confidently exclude alternative diagnoses associated with masses or demyelination.
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Of note, multiplex (multi-target) PCR testing is available for CNS infections. For example, the BioFire FilmArray meningitis/encephalitis panel detects 14 targets including one fungal target (C neoformans/gattii), 6 bacterial targets (S pneumoniae, N meningitidis, L monocytogenes, Haemophilus influenzae, Escherichia coli K1, and Streptococcus agalactiae) and 7 viral targets (CMV, enterovirus, parechovirus, HSV-1, HSV-2, HHV-6, and VZV). The sensitivity of this test to detect Cryptococcus is reported high (96%) in untreated cryptococcal meningitis. With treatment, the PCR becomes negative rapidly, whereas the CSF CRAG remains detectable for months. When using a new diagnostic test like a multiplex PCR test for meningoencephalitis, it is essential to consider reported sensitivity and specificity as preliminary because later data may identify unrecognized test limitations (resulting in more false-positive and/or false-negative test results).
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Mr. S’s LP reveals that CSF CRAG is positive at a titer of 1:512. Both blood and CSF cultures are positive for C neoformans. A brain MRI confirmed the absence of a CNS mass. Subsequent CSF AFB cultures and VDRL were negative.
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Mr. S’s CSF culture confirms cryptococcal meningitis. The subacute course and lack of meningeal findings are common features of this disease. CSF analysis did not suggest concomitant mycobacterial infection or neurosyphilis, and the MRI did not suggest toxoplasmosis, PML or PCL.
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Mr. S received combination induction therapy with liposomal amphotericin B and flucytosine, and initially underwent daily LPs until intracranial pressure normalized. After completing induction therapy for 2 weeks, he was switched to oral fluconazole (400 mg/day), because he had excellent clinical improvement and repeat LP fungal culture was negative and was discharged to follow-up with the infectious disease clinic. ART was delayed for a total of 6 weeks to avoid IRIS-associated complications. After 8 weeks, fluconazole was decreased to 200 mg/day, which he continued for 10 more months. It was discontinued at that time, as his CD4TL had increased above 200 cells/mcL for 6 months.