A 46-year-old homosexual male presented at the emergency room on February 22, 2002 for a 5-month progressive visual impairment, headache and occurrence of right hemiparesis in the last week.
He was diagnosed with HIV infection in December 1987. His past history was not significant except for varicella in July 1996. At this previous time, his CD4+ count was 650 cells/muL (24%) with a CD4+/CD8+ ratio of 0.37. In July 2000 and November 2001, the CD4+ cell counts were 420 and 330 cells/muL, respectively. No HIV-1 viral load measurements were available for these dates. Until he was admitted to our hospital, the patient had declined any antiretroviral therapy.
At admission, he was afebrile and his physical examination was unremarkable except for right hemi paresis and left homonymous hemianopsia. His complete blood count (CBC), liver function tests and routine biochemistry were within normal limits. The CD4+ count was 340 cells/muL (16%) with a CD4+/CD8+ ratio of 0.20. A brain CT-Scan and a magnetic resonance imaging (MRI) revealed multifocal coalescent lesions with no mass effect and very little or no enhancement in the white matter of upper left parietal and left occipital, right temporal and frontal lobes with cerebral atrophy, suggestive of progressive multifocal leukoencephalopathy (PML) (Figure  1, panels a and b).
Serologic tests for syphilis (RPR and Treponema/TP-PA), EBV-VCA IgM, toxoplasmosis (IgG and IgM) and search for cryptoccoccal antigen were negative.The patient had positive results for EBV-EBNA-1 IgG, CMV IgG, hepatitis C (anti HCV), hepatitis A, anti HBs, antiHBc. The HBs Ag was negative. He was started on AZT 300/3TC 150 mg (Combivir ) BID and lopinavir 200/ritonavir 50 mg (Kaletra ) 2 tablets BID. The HIV viral load was not performed (for technical reasons) before initiating antiretroviral therapy, but after two weeks it was 2 279 (3.36 log10) HIV-1 RNA copies/ml. Because of clinical deterioration, dexamethasone was initiated on March 15, 2002, and continued until April 8, 2002. Since no clinical improvement was apparent, i.v. cidofovir (5 mg/kg) and probenecid twice at one week intervals, then every 2 weeks were started on April 11, 2002 and continued until February 3, 2003. His immune status improved, and on June 10, 2002, the CD4+ count showed 440 (26%) with a CD4+/CD8+ ratio of 0.38, whereas the viral load decreased to 91 HIV-1 RNA copies/mL. Moreover, the patient reported a subjective improvement of his right hemiparesis. On June 26, 2002, AZT was replaced by D4T to avoid anemia due to AZT and probenecid interaction.
The patient was again hospitalized on August 22, 2002 for fever (39 C), seizures and status epilepticus, necessitating admission to the Intensive Care Unit (ICU), for intubation and mechanical ventilation. Anti-convulsive therapy with phenytoin and lamotrigine was then initiated.
Laboratory analysis revealed this time a CD4+ count of 380 (21%) with a CD4+/CD8+ ratio of 0.38 and a HIV viral load below the limit of detection (<50 HIV-1 RNA copies/mL). The brain lesions had not changed since the previous brain MRI. A lumbar puncture was performed on August 23, 2002. The cerebrospinal fluid (CSF) examination revealed proteins 0.53 g/L (normal 0.1-0.5), and glucose 4.3 mmol/L (normal 2.2-3.9). Tests for viral DNA of Poliomavirus JC, BK virus, CMV, PCR for herpes group viruses (HSV-1, HSV-2, VZV, CMV, EBV, and HHV-6/7-8), Mycobacterium tuberculosis, and search for cryptococcal antigen and VDRL all remained negative in CSF. Plasma CMV DNA, urine cultures, blood cultures for bacteria, Mycobacteria and fungi were negative.
An ophthalmologic examination confirmed bilateral blindness of the central origin, but showed no retinitis, keratoconjonctivitis or deep corneal stromal infection. He was discharged on September 19, 2002, and was seen every two weeks at the Ambulatory Unit. On September 23, 2002 his HIV viral load was again below the limit of detection; CD4+ count was 350 cells/muL (22%) and CD4+/CD8+ ratio was 0.36.
Despite an optimal control of HIV infection and continuous combination antiretroviral therapy (cART), the patient's status did not improve and he was re-admitted to the ICU for status epilepticus on April 28, 2003, intubated and mechanically ventilated. A subsequent brain MRI showed no change as compared with the previous examinations, but was still suggestive of PML. At admission, lactic acid and CK levels, as well as platelet count, remained within normal limits. AST and ALT were slightly elevated: 65 and 67 U/L respectively. While in the ICU, the patient developed multiorgan failure with rhabdomyolysis (CK 47,500), elevated liver enzymes (AST 2 557 U/L), elevated LDH (4 070 U/L) and disseminated intravascular coagulation: thrombocytopenia (12 x 109/L), diminished fibrinogen levels, increased prothrombin time (INR). Lactic acid levels rapidly increased to 17.11 mmol/L on April 29, 2003 before he expired. Rhabdomyolysis and lactic acidosis were probably the consequences of repeated muscular convulsions. Blood and urine cultures remained negative. Search for the cryptococcal antigen was again negative. Permission for post mortem examination was obtained.
At macroscopy, the cerebral hemispheres were unremarkable. The circle of Willis showed a normal architecture without significant arteriosclerotic lesions. Leuko-encephalopathic lesions associated with secondary atrophy predominantly localized in the white matter were noted. These lesions were multifocal and bilateral, the largest observed in the orbito-frontal lobes. Another grey lesion measuring 0.8 x 0.6 cm, which differed from the leuko-encephalopathic lesions was noted in the right internal pallidal nucleus. The corpus callosum had secondary atrophy. Transverse sections of the brain stem showed atrophy of the right bulbar pyramid. Sagittal sections of cerebellum revealed ill-demarcated grey areas within and around dentate nuclei.
At microscopic examination, cerebral microsporidiosis was documented affecting predominantly the white matter (mostly on the right side) of the orbito-frontal lobes with central, right temporo-parietal and cerebellum extension and a right internal pallidal abscess. Intracellular clusters of microsporidial spores were found, some of them with tubular extensions (Figure  1 panels c and d). In addition, a generalized severe anoxic ischemic encephalopathy was noted. Numerous microscopic foci of wallerian degeneration of the perivascular white matter, predominantly fronto-temporo-parietal, compatible with cerebral arterial ischemia were evidenced. No suggestive criteria for PML, such as oligodendrocytic inclusions (Papova type) or reactive dysmorphic gliosis were noted; the immunoreactivity for simian virus (SV) 40 was absent. Furthermore, the absence of giant multinucleated cells rendered a diagnosis of HIV encephalopathy improbable. Nonetheless, several extensively calcified small arteries as noted in HIV encephalopathy were present. No immune reactivity to anti Toxoplasma antibodies was present. The Grocott and PAS stainings were negative. The PCR for JCV on brain tissue was not performed.