47 YEAR‐OLD MAN WITH HIV INFECTION AND HEMIPLEGIA

CLINICAL HISTORY

A 47‐year old Hispanic male with end‐stage AIDS was admitted to the hospital with pneumonia, altered mental status and right‐sided weakness. His previous medical history was obscure. He had never received antiretroviral treatment. Upon his arrival he was cachectic, tachycardic and lethargic. His neurologic exam showed left facial palsy, right hemiparesis, hyperreflexia and a positive right Babinski sign. He had no signs of meningeal irritation. On admission his white blood cell count was 8400/mm³ (98% neutrophils), and his CD4+ cell count was 8 cells/mm³. The serum cryptococcal antigen was negative. IgG and IgM toxoplasma antibodies were positive. A MRI was ordered which was suggestive of neurotoxoplasmosis. He was started on piperacillin‐tazobactam, clarithromycin and trimethoprim / sulfamethoxazole for pneumonia, valgancyclovir for skin biopsy proven CMV infection, fluconazole for oral candidiasis and pyrimethamine and clindamycin for toxoplasmosis. Although he continued disoriented and sleepy, he was stable for a few days. On the 18^th hospital day he developed severe respiratory distress. He became stuporous and presented right mydriasis and ptosis, impaired adduction of the right eye, and generalized seizures. He required immediate ventilatory support and high doses of vasoactive amines. Intravenous amphotericin B infusion was started in order to broaden the antimicrobial coverage, but the patient died five days later.

LABORATORY AND BRAIN RADIOLOGY

Neutrophil cell counts during his stay were always within the normal range. The initial CSF analysis showed 20 cells/mm³ (95% of PMN), glucose of 51 mg/dL (serum glucose of 90 mg/dL), proteins of 44 mg/dL, and negative PCR for VHS, VHZ, CMV and M. tuberculosis. The Gram stain was negative for organisms, and subsequent cultures for bacteria and fungi were without growth. India Ink stain and cryptococcal antigen in the CSF were negative. A second CSF analysis showed no signs of inflammation, with cero cells/mm³, proteins of 55 mg/dL and glucose of 69 mg/dL (serum glucose of 90 mg/dL). All blood and CSF cultures continued to be negative.

An axial T2 FLAIR and T1 MRI with gadolinium of the brain performed before initiating anti‐toxoplasmosis treatment showed multiple non‐enhancing hyperintense lesions (Figure 1a,b). A subsequent MRI showed marked improvement, with evident reduction in size of the previous lesions (Figure 2a,b,c). A third MRI performed after the neurological deterioration showed bilateral well‐demarcated T2 FLAIR hyperintense lesions without contrast enhancement, and high signal‐intensity lesions in the diffusion‐weighted images, suggestive of early ischemic areas (Figure 3a,b,c).

Figure 1.

Figure 2.

Figure 3.

PATHOLOGY

On post‐mortem inspection, the fresh brain weighted 1390 grams. On gross assessment, multiple ischemic and hemorrhagic mass lesions in the brainstem, basal nuclei, internal capsule, corpus callosum, frontal, parietal and occipital hemispheres were seen (Figure 4a, b, c, d). The left occipital lobe was completely necrotic (Figure 4d). There was no basal meningitis. Microscopically, hematoxylin and eosin (Figure 5a) and Grocott (Figure 5b) stained preparations on multiple sites showed numerous septated, 45° angle dichotomous branching hyphae. There was widespread infiltration of the parenchyma and blood vessel walls (Figure 5a). Penetration into the vessel walls was associated with a diffuse inflammatory response, multiple hemorrhagic infarcts and necrosis. A recent right parietal subarachnoid hemorrhage with acute inflammation in the surrounding parenchyma was also present. Two small subacute infarcts were seen in the frontal lobes.

Figure 4.

Figure 5.

DIAGNOSIS

Invasive aspergillosis of the CNS with secondary hemorrhagic infarcts and subarachnoid hemorrhage in a patient with AIDS.

DISCUSSION

CNS invasive aspergillosis (IA) is often described in patients treated with intensive chemotherapy or immune suppressive therapy after solid organ or bone marrow transplantation. Patients with AIDS have a very low incidence of IA, ranging between 4 and 7% in the pre‐HAART autopsy series 5, 8, The low incidence of aspergillosis in the HIV population is probably the result of a relative intact phagocytic cell function in these patients. CNS invasion is even less common, reported only in 10–25% of the HIV‐infected patients with IA (5). When CNS invasion occurs, it is usually in the setting of advanced HIV infection. Other major risk factors include neutropenia after ganciclovir use, high‐dose corticosteroids, broad‐spectrum antibiotics, and previous episodes of opportunistic infections.

Not‐surprisingly, IA is often misdiagnosed or missed in the setting of HIV infection and AIDS. Generalized meningitis is a rare condition in aspergillosis, as a result, there are no abnormalities typical of Aspergillus infection in the CSF and cultures fail to grow Aspergillus. The absence of inflammation in the CSF analysis is probably the result of the hematogenous dissemination of the fungus sparing basilar meningitis. Angioinvasion, as seen in this case, is more frequently in immunosuppressed individuals. Immunocompetent patients with secondary intracranial extension after sinus or nasal infection seem to have a less aggressive form without true angioinvasion (7).

Several CNS patterns of Aspergillus lesions have been reported in the brain MRI (4). The radiological appearance of cerebral aspergillosis in patients with HIV is different from the one seen in bone marrow recipients where isointense to low signal in T1WI and contrast enhancement are more common 2, 3, 5, 7. Solitary lesions have been described in the majority of cases (4) but it varies according to the degree of immunosuppression (7). Most of the lesions are often located in the cerebral hemispheres, basal ganglia, thalami, corpus callosum and perforating artery territories (7). Involvement of the basal ganglia indicates a predominant affection of the lenticulo‐striate and thalamo‐perforator arteries. Callosal lesions are more often associated with toxoplasmosis, however, its presence has been previously described in IA (1) and indicates the involvement of the perforating arteries (6). The lack of contrast enhancement is typical in severe immunosuppressed patients, suggesting the absence of an inflammatory response (7). The angioinvasive character of cerebral Aspergillus infection usually leads to brain infarcts with or without hemorrhage. Recently, these ischemic lesions have been described as key factor for early detection using diffusion‐weighted imaging (DWI) 3, 5.

Invasive aspergillosis is associated with poor prognosis among HIV‐infected individuals. Mortality rate is high, reaching as much as 85 to 100% 4, 7 with a mean survival time of 48 days (2). Aggressive treatment should be instituted in an attempt to decrease the high mortality. Intravenous antifungal therapy with amphotericin is ineffective in most cases. Response rates of about 35% have been achieved with voriconazole (7).

CNS aspergillosis should be considered in the differential diagnosis in patients with advanced HIV infection. Risk factors that should lead the suspicion of this condition include a very low CD4+ cell count, previous treatment with ganciclovir, valganciclovir or steroids, neutropenia, normal CSF analysis, rapidly progressive lesions in the MRI, and hyperintense lesions in the diffusion‐weighted MRI.

ABSTRACT

CNS aspergillosis is often missed in the setting of advanced HIV infection, especially in the absence of presumed risk factors such as neutropenia or prior steroid treatment. We describe the postmortem evaluation of the brain of a patient with AIDS that developed progressive neurologic deterioration. Sequence brain MRIs, CSF analysis, and multiple presumed treatments failed to reveal the possible causes or improve his ongoing condition. His brain autopsy showed numerous abscesses with septated hyphae consistent with CNS angioinvasive aspergillosis.