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I have an HIV-positive patient who complains of headache. How do I determine the cause🚧 施工中
I have an HIV-positive patient who complains of headache. How do I determine the cause?
CHIEF COMPLAINT
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?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
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.
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.
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.
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.
Figure 5-4. Diagnostic approach: Headache in HIV-positive patients.
Differential Diagnosis of Headache in Patient with HIV
A. Acute neurologic presentation
1. Bacterial meningitis due to Neisseria meningitidis, S pneumoniae, or Listeria monocytogenes
2. Aseptic meningitis due to HIV or syphilis (especially secondary syphilis)
3. Meningoencephalitis due to HSV-1, West Nile virus, or acute HIV infection
4. Guillain-Barré syndrome associated with HIV infection
B. Neurologic presentation with subacute meningitis
1. Cryptococcal meningitis
2. Coccidioidomycosis (southwestern United States)
3. Histoplasmosis and blastomycosis (Midwest)
4. TB meningitis
5. Meningovascular syphilis
C. Nonfocal neurologic presentation with diffuse, chronic brain involvement
1. HIV encephalopathy in advanced AIDS
2. CMV encephalitis
3. Neurosyphilis with general paresis and dementia
D. Mass lesions or focal demyelination
1. Toxoplasmosis (rim-enhancing mass lesions)
2. PCL (diffusely-enhancing mass lesions)
3. PML (focal areas of demyelination without enhancement or mass effect)
4. Uncommon mass lesions: tuberculoma, cryptococcoma, Nocardia brain abscess, bacterial or fungal brain abscess
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?
RANKING THE DIFFERENTIAL DIAGNOSIS
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.
Table 5-2. Diagnostic hypotheses for Mr. S.
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?
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.
Leading Hypothesis: Cryptococcal Meningoencephalitis
Textbook Presentation
Patients typically have a subacute headache, malaise, and fever that develop over days to weeks. Mental status changes may be seen. Importantly, meningismus is often absent due to the host’s inability to mount an inflammatory reaction.
Disease Highlights
A. Most common cause of meningoencephalitis in AIDS
B. Encapsulated fungus acquired via inhalation
C. CNS infection due to dissemination of primary infection
D. Usually in patients with CD4TL < 100 cells/mcL
E. Subacute onset over 2–4 weeks
F. Basilar meningitis or meningoencephalitis: classic meningeal symptoms and signs (neck stiffness, photophobia) present in a minority of patients (25–30%)
G. 70% of patients have increased intracranial pressure: > 20 cm H2O in lateral decubitus position.
1. Elevated intracranial pressure associated with increased risk of death
2. Patients with elevated intracranial pressure have worse symptoms (headaches, clouded sensorium).
H. Meningovascular presentation (cerebrovascular accident from arteritis) and cryptococcoma (mass lesion) may be seen.
I. Mortality 6–12%
Evidence-Based Diagnosis
A. History
1. Fever: 65–95%
2. Headache: 73–100%
3. Median duration of symptoms: 31 days (1–120 days)
B. Physical exam
1. Stiff neck: 22–27%
2. Photophobia: 18–22%
3. Mental status changes: 22%
4. Focal neurologic signs or seizures: 10%
5. No CNS signs or symptoms: 14%
Cryptococcal meningitis in AIDS patients is often indolent. Only a minority of patients exhibit meningismus or photophobia. Some patients have only low-grade fever and malaise. A supple neck does not rule out the diagnosis, and a high index of suspicion is required.
C. Laboratory findings
1. Blood tests
a. Blood cultures positive in 55% in AIDS, much higher than in other populations with cryptococcal meningitis
b. Serum cryptococcal antigen (CRAG)
(1) 95–100% sensitive, 96% specific
(2) LR+, 24; LR–, 0.05
(3) Negative serum CRAG makes cryptococcal meningitis unlikely.
(4) A positive serum CRAG may precede clinical cryptococcal meningitis by weeks to months.
2. LP
a. Neuroimaging required before LP to rule out mass effect. Mass lesions are often due to concomitant toxoplasmosis or PCL, and only rarely due to cryptococcoma.
b. A platelet count, prothrombin time, and partial thromboplastin time are performed before LP to rule out a bleeding diathesis, with its risk of spinal epidural hematoma.
c. LP is required in patients with suspected cryptococcal meningoencephalitis regardless of serum CRAG results.
(1) In patients with positive serum CRAG, LP is necessary to confirm cryptococcal meningitis, measure opening pressure, manage high intracranial pressure, and exclude other diagnoses.
(2) In patients with negative serum CRAG, LP is necessary to evaluate other diagnoses.
d. Routine CSF findings are often normal or minimally abnormal in patients with cryptococcal meningitis.
(1) Normal glucose, protein, and WBC: 19–30%
(2) Glucose < 50 mg/dL: 64%
(3) Protein > 40 mg/dL: 64%
(4) CSF WBCs > 5 cells/mcL: 35%
(5) Increased opening pressure: 50–75%
Routine CSF findings in patients with cryptococcal meningitis may be normal. Specific studies (fungal culture, cryptococcal antigen) must be obtained.
e. Special CSF studies
(1) CSF CRAG: 91–100% sensitive, 93–98% specific
(2) CSF fungal culture: 95–100% sensitive, 100% specific
(3) CSF Gram stain may be positive, and India ink detects encapsulated yeast in 60–80% of cases but is no longer performed routinely.
(4) Cryptococcus polymerase chain reaction (PCR) may be included as part of a CSF multi-target PCR panel used for the diagnosis of meningoencephalitis (see below).
Treatment
A. Mortality is increased in patients with abnormal mental status, an increased opening pressure on LP, and those with a markedly elevated CSF CRAG (> 1:1024). Low glycorrachia and normal CSF cell counts also predict poor outcomes.
B. Induction therapy relies on the combination of IV liposomal amphotericin B (3–4 mg/kg) and oral flucytosine (100 mg/kg) for at least 2 weeks, and at least until clinical improvement and sterilization of CSF cultures.
C. After successful induction therapy, high-dose fluconazole (400 mg/day) is substituted for an additional 8–10 weeks.
D. Maintenance therapy should then be continued with lower-dose fluconazole (200 mg/day) for a minimum of 1 year. Usually fluconazole is then stopped in patients with an excellent response to ART and CD4TL > 100 cells/mcL.
E. In patients with high intracranial pressure, serial LPs are performed to lower opening pressure to < 20 cm H2O or by 50%; patients with hydrocephalus may require ventricular shunts.
F. Optimal timing of starting ART is controversial in cryptococcal meningitis. Clearly, ART-associated IRIS can result in worsening intracranial pressure and neurologic status. It is reasonable to delay initiation of ART for at least 4 weeks or even longer if intracranial pressure remains elevated.
MAKING A DIAGNOSIS
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?
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.
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).
Alternative Diagnosis: Toxoplasmic Encephalitis
Textbook Presentation
Toxoplasmic encephalitis (TE) in AIDS patients typically presents subacutely over 1–2 weeks. Focal neurologic manifestations are common. Confusion and mental status changes may dominate the clinical picture.
Disease Highlights
A. Seroprevalence of asymptomatic Toxoplasma infection (positive T gondii IgG) is around 11% in the US population versus 40–80% in some European, African, and Asian countries.
B. Primary infection is acquired after eating undercooked meat with tissue bradyzoites (tissue cysts) or ingesting oocysts shed in cat feces and matured in the environment for > 24 hours. In the United States, eating raw oysters, clams, and mussels has recently been identified as a risk factor.
C. TE usually causes focal abscess with headache, confusion, motor weakness, and fever. Focal neurologic findings may be present. Seizures and altered mental status may develop in untreated patients. CT scan and MRI of the brain often show multiple ring-enhancing mass lesions with significant surrounding edema, located in the gray matter of the cortex and basal ganglia. TE is the most common etiology of CNS mass lesion in AIDS patients.
D. TE is secondary to reactivation of latent toxoplasmosis in brain tissue cysts: > 95% of patients have positive IgG titers, but IgM is not usually identified. False-negative IgG may be seen even with reactivation.
E. CD4TL < 100 cells/mcL in 80% of patients; CD4TL < 50 cells/mcL increases the risk further
F. Before ART, the 12-month probability of developing TE was 33% in AIDS patients with CD4TL counts < 100 cells/mcL and positive toxoplasmosis serology if not receiving prophylaxis for TE. ART has decreased the incidence of TE.
G. TE may be the initial manifestation or a subsequent manifestation of HIV infection.
H. 27% mortality despite treatment
I. Other concurrent CNS infections common
Evidence-Based Diagnosis
A. History
1. Headache (often frontal and bilateral): 49–73%
2. Seizures: 15–31%
3. Hallucinations: 8%
4. Fever: 4–68%
B. Physical exam
1. Focal findings (weakness, abnormal gait, or other): 73–88%
2. Mental status changes: 50–67%
3. Mental status changes dominating clinical picture: 40%
4. Cognitive impairment (with normal arousal): 66%
5. Stiff neck: 0%
Meningismus is distinctly uncommon in TE and suggests an alternate or additional disease process.
C. Laboratory findings
1. Serology
a. Toxoplasma IgG: ≈ 97% sensitive but does not confirm active TE
TE unlikely in patients with negative Toxoplasma IgG
b. Toxoplasma IgM: insensitive (15%) because disease is usually secondary to reactivation.
c. Probability of TE in seropositive patients with mass effect markedly reduced in patients receiving TMP-SMX prophylaxis (from 87% to 59%)
2. CSF analysis
a. Standard CSF analysis may be normal or nonspecifically elevated.
b. Percentage of patients with abnormal findings
(1) WBC > 5 cells/mcL: 50%
(2) Protein > 40 mg/dL: 81%
(3) Low glucose: 14%
c. CSF PCR insensitive for CNS toxoplasmosis but highly specific
(1) 54% sensitive, 99% specific
(2) LR+, 54; LR–, 0.46
3. Neuroimaging
a. MRI is test of choice.
(1) Superior to contrast CT, affecting course in 40% of patients
(2) One or more ring-enhancing lesions with mass effect and edema (Figure 5-5)
Figure 5-5. Typical MRI appearance of common CNS disorders in AIDS. A: Toxoplasmosis. (Reproduced with permission from Simon RP, Aminoff MJ, Greenberg DA: Clinical Neurology, 10th ed. New York, NY: McGraw-Hill Education; 2017.) B: Progressive multifocal leukoencephalopathy (PML). (Reproduced with permission from Ropper AH, Samuels MA: Adam’s & Victor’s Principles of Neurology, 9th ed. New York, NY: McGraw-Hill Education; 2009.) C: Primary central nervous system lymphoma (PCNSL). (Reproduced with permission from Jameson JL, Fauci AS, Kapser DL, et al: Harrison’s Principles of Internal Medicine, 20th ed. New York, NY: McGraw-Hill Education; 2018.)
(3) Lesions may be located in gray matter of basal ganglia, thalamus, and cortex.
(4) Single lesion in 14% of patients, multiple lesions in 86%
(5) Single lesion on MRI makes TE less likely and increases likelihood of PCL.
b. CT scan with contrast abnormal in 87–96%
(1) Single ring-enhancing lesion: 35%
(2) ≥ 2 ring-enhancing lesions: 62%
(3) Hypodense lesions: 13%
(4) Moderate to severe cerebral edema: 48%
(5) 75% of lesions located in cerebral hemispheres
(6) MRI is recommended in patients with normal contrast CT scan or a single enhancing lesion.
c. Positron emission tomography or single-photon emission computed tomography (SPECT) is helpful in distinguishing between TE and PCL, but no imaging technique is completely specific. SPECT thallium 201 reveals decreased isotope activity in patients with TE versus increased uptake in patients with PCL.
4. Brain biopsy
a. When positive, brain biopsy is the only method that confirms cerebral toxoplasmosis with certainty.
(1) False-negative results can occur due to sampling error.
(2) May diagnose concomitant infection
b. Sensitivity of standard hematoxylin & eosin staining only 50–66%. Immunoperoxidase staining improves sensitivity.
c. Brain biopsy is associated with 0.5–3.1% mortality and high morbidity.
d. Brain biopsy is not done routinely due to complications and imperfect sensitivity.
Treatment
A. Empiric treatment for TE instituted in patients with all of the following criteria: multiple mass lesions, CD4TL < 100 cells/mcL, positive serum Toxoplasma IgG, and patient not already taking toxoplasmosis prophylaxis (Figure 5-6). Biopsy is reserved for atypical cases (ie, negative serology or nonresponders within 7–10 days).
Figure 5-6. Empiric therapy for CNS toxoplasmosis in AIDS patients.
B. Pyrimethamine plus sulfadiazine (pyrimethamine plus high-dose clindamycin if allergy or intolerance to sulfonamides)
C. Folinic acid also administered to patients taking pyrimethamine to decrease toxicity
D. TMP-SMX is a less effective alternative therapy.
E. Clinical improvement within first 2 weeks of drug therapy in > 90% of responders
F. Radiologic improvement in most patients within 3 weeks of treatment
G. After induction therapy for 6 weeks, suppressive therapy with lower doses is used. Suppressive therapy can be discontinued in asymptomatic patients in whom ART has restored CD4TL to > 200 cells/mcL for ≥ 6 months.
H. Corticosteroids are only indicated for patients with cerebral edema and midline shift, or clinical deterioration within first 48 hours of therapy. Corticosteroids complicate interpretation of response to therapy since they reduce edema and the size of PCL lesions.
I. ART should be started quickly, usually within 2–4 weeks after diagnosis of any OI in AIDS, except in CNS cryptococcosis. IRIS associated with TE is not as common (about 5%) and can be managed well with corticosteroids.
J. Prevention
1. HIV-positive patients with CD4TL < 200 cells/mcL and positive serum Toxoplasma IgG should receive daily TMP-SMX as primary prophylaxis.
2. If patients are allergic to sulfa, they may instead receive atovaquone (also effective in preventing Pneumocystis pneumonia) or dapsone plus pyrimethamine.
3. The risk of TE is low unless the CD4TC count is < 100 cells/mcL.
Alternative Diagnosis: Progressive Multifocal Leukoencephalopathy
Textbook Presentation
PML typically presents with progressive neurologic deficits, in particular weakness or gait disorders, over weeks to months. PML may also present with visual problems, headache, alterations in mental status, or dementia with focal signs.
Disease Highlights
A. Etiologic agent is JC virus, a polyomavirus (not to be confused with Creutzfeldt-Jakob disease, a prion-related illness).
B. Primary JC virus infection is common in childhood and usually asymptomatic, with seroprevalence of 39–69% among adults.
C. PML is much more common in AIDS than in non–HIV-infected immunosuppressed persons: before ART, PML developed in 3–7% of persons with AIDS. Profound immunosuppression allows latent JC virus in reticuloendothelial system and kidney to gain access to CNS and replicate.
D. Subsequent infection and lysis of the myelin-producing oligodendrocytes results in PML. Astrocytes may be infected.
E. Multifocal or unifocal white matter lesions seen, forming large plaques distributed asymmetrically.
F. Mean CD4TL count 84–104 cells/mcL: 25% of patients have CD4TL count > 200 cells/mcL
G. ART is the mainstay of treatment: 63% of patients started on ART because of PML survive > 2 years. A majority of them have either improvement or stabilization of neurologic function.
Evidence-Based Diagnosis
A. History and physical exam
1. Limb weakness: 50–70%
2. Gait disorder: 26–64%
3. Speech disorder: 31–51%
4. Visual impairment (hemianopsia): 21–50%
5. Seizures: 5–23%
6. Headaches: 23%
7. Cognitive abnormalities/mental status changes: 25–65%
8. Cranial nerve palsies: 31%
B. Laboratory findings
1. Serum antibodies to JC virus are not useful due to high prevalence of infection.
2. CSF
a. Routine studies may be normal or nonspecifically elevated.
b. CSF PCR for JC virus DNA:
(1) 70–90% sensitive, 98% specific
(2) LR+ (average), 40; LR–, 0.20
(3) Some tests are more sensitive (detect low level of JC virus) and repeat analysis increases sensitivity to 90%.
(4) Sensitivity is diminished in patients receiving ART.
3. CNS imaging
a. Typically shows extensive multifocal patchy white matter demyelination with sparing of the cortical gray matter
b. MRI more sensitive than CT scanning (CT 63% sensitive) (See Figure 5-5)
c. Lesions hypodense on CT scanning, low intensity on T1-weighted MRI, hyperintense on T2-weighted MRI
d. On imaging, lesions are restricted to the subcortical white matter, respecting the gray-white junction of the cerebrum.
e. There is overlap in the MRI features of TE, PCL, and PML. However, certain features suggest PML:
(1) Lack of enhancement (except peri-plaque enhancement after starting ART, consistent with IRIS)
(2) Lack of mass effect
(3) Less well-circumscribed lesions
f. MRI typically shows scalloping at gray-white matter interface (see Figure 5-5).
g. CT scanning typically demonstrates white matter hypodense lesions.
h. Brain biopsy: 100% specific but sensitivities only 64% to 96% due to sampling error
MRI is markedly superior to CT for diagnosis of PML.
Treatment
A. ART is associated with improvement or cure in some patients.
1. Survival pre-ART averaged 4–6 months. Survival has improved to 60% since the introduction of ART.
2. 80% of survivors have significant residual neurologic deficits
3. Some patients receiving ART develop IRIS with worsening of symptoms and enhancement around the PML plaques on MRI; this is managed with corticosteroids.
B. Initiation of ART occasionally results in PML in previously asymptomatic patients due to increased inflammation associated with IRIS (unmasking IRIS).
Alternative Diagnosis: Primary CNS Lymphoma (PCL)
Textbook Presentation
Typically, PCL develops in patients with advanced AIDS. While patients may present with focal signs such as weakness, many patients present with altered mental status or seizures.
Disease Highlights
A. Biologically distinct from PCL in other immunocompromised states
B. Diffuse, high-grade, B cell, non-Hodgkin lymphoma arising and confined to the CNS (not due to CNS involvement by systemic lymphoma)
C. CD4TL usually < 50 cells/mcL
D. Consistently associated with EBV (early EBV RNA transcripts detected in 100% of biopsies)
E. Pathogenesis likely involves activation of latent EBV genes due to immunodeficiency. The relative immunologic sanctuary of the CNS from immune surveillance may facilitate growth of these tumors at this location.
F. Rapidly progressive with a short interval from symptoms to diagnosis (1.8 months)
G. Median survival without treatment is about 1 month.
H. Supratentorial location 3 times more common than infratentorial.
I. Most common cause of death in patients with PCL is other OI.
J. Marked reduction in PCL incidence (about 90%) from 1995 to 2000 because of the introduction of ART
Evidence-Based Diagnosis
A. History and physical exam
1. B symptoms (weight loss > 10% body weight, unexplained temperatures > 38.0°C, drenching sweats): present in 80%
2. Focal neurologic deficits: 51%
3. Mental status changes: 53%
4. Seizures: 27%
B. Laboratory findings
1. CSF EBV PCR:
a. 87% sensitive, 98% specific
b. LR+, 43; LR–, 0.13
2. Positive CSF cytology only 15–23% sensitive. Special studies are required to distinguish monoclonal proliferations from reactive T cell populations.
C. Radiologic studies
1. CT scanning
a. 90% sensitive
b. Usually reveals contrast enhancement (90%), characteristically diffuse rather than ring enhancement
c. 48% single lesion, 52% multiple lesions
d. Usually associated with mass effect (as in toxoplasmosis but not seen in PML)
2. MRI more sensitive than CT scanning (see Figure 5-5)
3. SPECT thallium imaging
a. PCL usually demonstrates early uptake and retention (compared with decreased uptake in necrotic centers of toxoplasmosis).
(1) 86–100% sensitive, 77–100% specific (higher specificity if retention index measured).
(2) Increased uptake is noted in 15% of patients with TE not receiving ART but up to 50% of patients with TE receiving ART, making this test less useful when on ART.
D. Biopsy
1. Positive CSF EBV PCR makes biopsy unnecessary if imaging is typical.
2. Biopsy is useful when CSF EBV PCR is negative.
3. Lympholytic effect of corticosteroids may render biopsy nondiagnostic.
Corticosteroids should generally not be administered before brain biopsy in patients with suspected PCL unless the patient is at an increased risk for herniation.
Treatment
A. AIDS-related PCL is a complication of end-stage AIDS, and prognosis is grave without therapy, with a median survival of 3 months.
B. Options for treatment include whole-brain radiation therapy and high-dose methotrexate-based chemotherapy.
1. Whole-brain radiation therapy is no longer considered first-line therapy, since it is associated with irreversible cognitive dysfunction and does not improve survival.
2. Adding ART to high-dose methotrexate-based chemotherapy improves the prognosis.
CASE RESOLUTION
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.
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.
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.
REVIEW OF OTHER IMPORTANT DISEASES
HIV Encephalopathy (HIV-associated Dementia)
Textbook Presentation
Patients with severe HIV encephalopathy typically have advanced AIDS with a slowly progressive dementia eventually accompanied by motor symptoms.
Disease Highlights
A. Subcortical dementia characterized by cognitive, behavioral, and psychomotor slowing
B. Prevalence 15–20% in AIDS prior to introduction of ART
C. 40–50% decrease in incidence since the introduction of ART. However, prevalence is rising due to increasing survival.
D. Severe form of HIV encephalopathy effectively eliminated if treated with ART
E. Milder deficits still commonly detected by neuropsychological testing
F. Principal target of HIV virus is perivascular CNS macrophages. Astrocytes may also become infected.
G. Severe HIV encephalopathy develops late with CD4TL typically < 200 cells/mcL.
H. Two-fold increased risk in patients aged ≥ 50 years.
I. Neurotoxicity of HIV may be synergistic with that of cocaine or methamphetamine.
Evidence-Based Diagnosis
A. History and physical exam
1. Memory complaints: 70%
2. Cognitive slowing: 25–30%
3. Gait difficulty: 45%
4. Behavioral changes: 10–20%
5. Seizures: 5–10%
6. Focal findings uncommon
B. Laboratory findings
1. MRI: T2 images with hyperintensities in the deep white matter and basal ganglia without contrast enhancement and/or atrophy; the distribution of lesions is symmetrical in contrast to PML lesions.
2. CSF
a. Useful to rule out other infections
b. Mild CSF leukocytosis and protein elevations may be seen.
c. CSF HIV RNA levels are not useful because they do not correlate with the severity of HIV encephalopathy.
d. Cannot diagnose HIV encephalopathy with certainty
3. Neuropsychological testing useful in evaluating the severity and response to ART
HIV encephalopathy is a diagnosis of exclusion. Diagnostic evaluations serve to exclude other OIs, malignancy, or substance abuse.
Treatment
A. Most patients treated with ART show only partial reversal of neurologic deficits. Early therapy is therefore important.
B. Elevated levels of CSF beta-microglobulin (suggesting ongoing inflammation) predicted better neurologic recovery with ART.
Neurosyphilis in HIV-Positive Patients
Textbook Presentation
Patients with neurosyphilis may be asymptomatic or have a number of clinical presentations, including aseptic meningitis, stroke-like symptoms, visual impairment, hearing loss, dementia, and various focal deficits.
Disease Highlights
A. Caused by the spirochete T pallidum
B. High-risk groups: MSMs, IDUs, and patrons of sex workers
C. Association of HIV and syphilis infection
1. Studies document a high HIV coinfection rate in patients with syphilis: CDC reports that in 2016 among primary and secondary syphilis cases with known HIV-status, 47.0% of cases among MSM were HIV-positive, compared with 10.7% of cases among men who have sex with women, and 4.1% of cases among women.
HIV infection in patients with syphilis is common, especially in MSMs.
2. Neurosyphilis in HIV-infected less frequent (1%)
D. Syphilis commonly infects the CNS early in the course of disease in both HIV-infected and non–HIV-infected persons (25–33%).
E. The CNS infection is more often progressive in HIV-infected persons, increasing the need for detection in this group.
F. Infections develop in characteristic stages.
1. Primary syphilis: syphilitic chancre
a. Characterized by chancre: a 0.5- to 2-cm painless, indurated, well-circumscribed ulceration at the site of primary inoculation approximately 2–3 weeks after contact (Figure 5-7)
Figure 5-7. Primary syphilis. A: Chancre on glans penis in primary syphilis. B: Chancre in tongue in primary syphilis. (A: Reproduced with permission from Public Health Image Library, Centers for Disease Control and Prevention. B: Reproduced with permission from Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Center for Disease Control and Prevention.)
b. Atypical presentations are common. Multiple chancres may be seen more often in HIV-infected patients.
c. Lesion resolves with or without therapy.
2. Secondary syphilis
a. Symptoms usually start with a rash that is usually not itchy and may appear as the chancre is healing or up to several weeks later.
b. The secondary syphilis rash is macular or maculopapular, and often involves the palms and/or soles, but may have an atypical aspect or be completely unnoticed (faint rash or darker skin) (Figure 5-8).
Figure 5-8. Secondary syphilis rash. A: Rash in secondary syphilis. B: Palmar rash in secondary syphilis. (A: Reproduced with permission from Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Center for Disease Control and Prevention. B. Reproduced with permission from Usatine RP, Smith MA, Mayeaux EJ, et al: The Color Atlas of Family Medicine, 3rd ed. New York, NY: McGraw-Hill Education; 2019, Photo contributor: Jonathan B. Karnes, MD.)
Secondary syphilis should always be considered in the differential diagnosis of rash in sexually active patients.
c. Other skin findings may be present:
(1) Mucosal patches are superficial erosions in the mouth and genital areas.
(2) Condyloma lata are large, moist, pink to gray/white raised lesions seen in perianal area, vulva, or scrotum.
d. Other symptoms include fever, myalgias, sore throat, lymphadenopathy, headaches, and hair loss.
3. Latent syphilis: 60–70% of untreated patients have no disease progression.
a. Early latent syphilis: < 1 year duration
b. Late latent syphilis: > 1 year duration
c. Latent syphilis of unknown duration: no prior negative serology to determine duration
4. Tertiary stage
a. Develops in one-third of untreated patients
b. Gummas (syphilitic granulomas with caseating necrosis) affect involved organs and usually develop over 4–10 years but may develop earlier in HIV-infected patients.
c. Protean manifestations of tertiary syphilis include heart (aortic root and coronary artery involvement), eyes, skin, and CNS involvement
5. Neurosyphilis
a. May be asymptomatic (positive CSF findings) or symptomatic
b. Neurosyphilis can develop early after syphilis infection in HIV-infected patients.
(1) Typical early symptoms include cranial nerve palsies, meningitis, or meningovascular symptoms (strokes secondary to arteritis). One report found visual symptoms in 51%; headache in 32%; and gait difficulty, hearing loss, meningismus, or altered mental status in < 5%.
(2) Early neurosyphilis develops in 1.7% of HIV-infected MSMs who acquire syphilis.
c. Typical late symptoms of neurosyphilis include tabes dorsalis or syphilitic myelopathy with demyelination of the posterior columns and dorsal roots (sensory symptoms of formication and shooting pains, impaired proprioception with ataxic gait and positive Romberg signs) and general paresis of the insane or parenchymal brain syphilis (personality changes, progressive dementia associated with motor and psychotic features, seizures, and generalized or focal weakness with the Argyll-Robertson pupil which accommodates but does not react to light).
d. Persons with secondary syphilis or neurosyphilis may have ophthalmic symptoms (anterior uveitis, panuveitis, optic atrophy) or neurosensory hearing loss.
Evidence-Based Diagnosis
A. Serologic diagnosis of syphilis
1. Types of syphilis tests
a. Nontreponemal tests serum rapid plasma reagin (RPR) and CSF VDRL
(1) Detect antibodies to cardiolipin
(2) Not specific for treponemal infection (false-positive in 1–2% of the US population)
(3) Decrease in titer and may become negative after appropriate treatment of syphilis
(4) May be falsely negative in long-standing latent infection
b. Treponemal tests: fluorescent treponemal antibody absorbed (FTA-ABS), T pallidum enzyme immunoassay (TP-EIA), T pallidum particle agglutination (TP-PA), and T pallidum microhemagglutination (MHA-TP)
(1) Detect specific treponemal antibodies
(2) May remain positive for life even after appropriate treatment
(3) Cannot distinguish between treated and untreated infections
2. Classic algorithm for diagnosis of syphilis
a. Nontreponemal test (RPR) is performed first
b. If RPR is positive, a confirmatory treponemal test is performed (FTA-ABS)
c. If RPR is positive, the lab determines the quantitative RPR titer (1, 2, 4, 8, 16…), useful to follow treatment responses.
d. If both RPR and FTA-ABS are positive, syphilis is confirmed. Prior syphilis history and current symptoms are taken into account to decide whether and how to treat the patient.
e. If RPR is positive and FTA-ABS is negative, the results are presumed to be a false positive.
3. Reverse algorithm for diagnosis of syphilis (Figure 5-9)
Figure 5-9. Recommended algorithm for reverse sequence syphilis screening. (Reproduced with permission from Centers for Disease Control and Prevention: Discordant results from reverse sequence syphilis screening—five laboratories, United States, 2006-2010, MMWR Morb Mortal Wkly Rep. 2011 Feb 11;60(5):133–137.)
a. Larger labs use the reverse sequence syphilis algorithm because it is much less time-consuming for a large number of screenings.
b. An initial treponemal test easily automated (TP-EIA) is performed first.
c. If TP-EIA is negative, syphilis is ruled out.
d. If TP-EIA is positive, a nontreponemal test (RPR) is performed. If RPR is positive, the lab determines the quantitative RPR titer.
e. If RPR is negative, a second treponemal test (T pallidum particle agglutination) is performed.
f. If only the initial TP-EIA is positive, it is most likely a false-positive.
g. If two tests are positive (TP-EIA plus either RPR or T pallidum particle agglutination), the patient has evidence of either current or past syphilis. The screening does not differentiate prior treated and cured syphilis from current syphilis. Whether and how to treat depend on syphilis history and current clinical presentation.
B. Primary syphilis (chancre)
1. Most patients with identified chancre and recognized risk factors for syphilis are diagnosed clinically and treated empirically.
2. Dark-field exam of chancre, direct fluorescent antibody, and PCR may help confirm that an ulceration is indeed primary syphilis, but these tests are not readily available at the point of care.
3. The diagnosis of chancre is confirmed by serology (treponemal or nontreponemal test) about 75% of the time, but repeat testing 2 weeks later improves the sensitivity.
C. Secondary syphilis: Serology is highly sensitive for secondary syphilis, and patients usually have a high RPR titer.
D. Tertiary syphilis
1. Nonspecific treponemal tests of serum (RPR) positive in only two-thirds of patients
2. Treponemal tests highly sensitive (FTA-ABS 100% sensitive)
E. Neurosyphilis
1. Approximately half of men with neurosyphilis have no other history or evidence of syphilis.
Consider neurosyphilis in HIV-infected patients with new visual symptoms or headache.
2. CD4TL count: 25–882 cells/mcL; mean CD4TL count: 217–312 cells/mcL
3. Estimating test accuracy difficult due to the lack of a gold standard
4. Commonly used criteria include either positive CSF VDRL or positive serum serology for syphilis and CSF pleocytosis.
a. CSF VDRL is highly specific, but sensitivity is only ≈ 50%.
b. CSF pleocytosis is more sensitive but much less specific as other infections increase CSF WBCs (including HIV and OIs).
c. Reverse transcriptase PCR testing of CSF for T pallidum has limited sensitivity.
d. CSF FTA-ABS is highly sensitive but much less specific due to blood contamination during LP, even if no red blood cells are identified. A negative CSF FTA-ABS makes neurosyphilis unlikely.
5. Perform LP to look for neurosyphilis in any HIV patient with syphilis and either:
a. Neurologic symptoms of any type, including meningitis, stroke-like syndrome, visual loss, hearing loss, dementia, or CNS focal deficit
b. Persistent signs of infection despite treatment: failure of RPR to fall fourfold with treatment
6. Consider patients at higher risk for neurosyphilis if:
a. Serum RPR titer ≥ 1:32
(1) Increases the likelihood of neurosyphilis in HIV-infected persons with syphilis
(2) 76–96% sensitive, 59% specific
(3) Most experts do not perform LP in every patient with RPR ≥ 1:32, but monitor such patients closely
b. CD4TL count ≤ 350 cells/mcL
(1) Increases the likelihood of neurosyphilis in HIV-infected persons with syphilis
(2) 69% sensitive, 53% specific
c. HIV-infected patients with late latent syphilis (> 1 year) or of unknown duration
Treatment
A. Primary and secondary syphilis
1. Single-dose benzathine penicillin IM
2. Penicillin allergy: doxycycline twice daily for 2 weeks
3. Follow RPR every 3 months for 1 year to document 4-fold fall in titer.
B. Latent syphilis
1. If duration < 1 year, treat like primary and secondary syphilis
2. If duration > 1 year or unknown, administer IM benzathine penicillin weekly for 3 weeks.
3. Follow RPR every 6 months for 2 years to document 4-fold fall in titer.
C. Neurosyphilis
1. High-dose IV penicillin for 10–14 days
2. Penicillin allergy: high-dose ceftriaxone daily for 14 days, or oral doxycycline 200 mg twice daily for 28 days, or desensitization to penicillin followed by IV penicillin for 10–14 days. The latter strategy is the most effective and an infectious disease consultant should be involved in these complex cases.
A summary of the clinical and radiological features, CD4TL count, and tests of choice of the common CNS disorders in AIDS patients is presented in Table 5-3.
Table 5-3. Summary of findings in CNS disorders in AIDS patients.