Antoine Moulignier

Discordance Between Cerebral Spinal Fluid and Plasma HIV Replication in Patients with Neurological Symptoms Who Are Receiving Suppressive Antiretroviral Therapy

OBJECTIVE We report data on 11 patients with neurological symptoms and human immunodeficiency virus (HIV) cerebrospinal fluid (CSF) viremia contrasting with suppressed plasma HIV RNA during receipt of combined antiretroviral therapy. DESIGN We retrospectively identified instances of central nervous system (CNS) symptoms in patients who had been receiving stable combination antiretroviral therapy. Discordance between plasma and CSF HIV RNA levels was defined by any detectable CSF HIV RNA level >200 copies/mL while plasma levels were <50 copies/mL or by a CSF HIV RNA level that was 1 log greater than the plasma HIV RNA level. RESULTS Eleven patients had experienced acute or subacute neurological symptoms. All but one patient had CSF pleocytosis and/or elevated protein levels. The median CSF HIV RNA level was 880 copies/mL (range, 558-12,885 copies/mL). Patients had been receiving stable combination antiretroviral therapy for a median of 13 months (range, 10-32 months). Eight of 11 patients had a plasma HIV RNA level <50 copies/mL, and 3 had plasma HIV RNA blips with their CSF HIV RNA level >1 log higher than their plasma HIV RNA level. Resistance-associated mutations were detected in 7 of 8 CSF HIV RNA genotypic strains. The median number of resistance-associated mutations was 6 (range, 2-8) to nucleoside reverse-transcriptase inhibitors and 3 (range, 1-9) to protease inhibitors. One patient had a virus harboring nonnucleoside reverse-transcriptase inhibitor mutations. The median central nervous system penetration-effectiveness (CPE) rank was 2 (range, 1-3), and 5 patients had a CPE 1.5. After antiretroviral therapy optimization based on genotypes and CPE, all patients clinically improved, with normalization of CSF. CONCLUSIONS Despite successful suppression of plasma viremia with antiretroviral therapy, HIV may replicate in CSF, with development of CSF HIV resistance resulting in acute or subacute neurological manifestations.

Central nervous system immune reconstitution disease in acquired immunodeficiency syndrome patients receiving highly active antiretroviral treatment.

Highly active antiretroviral therapy (HAART)-induced immune restoration has been very beneficial for acquired immunodeficiency syndrome (AIDS) patients. In rare instances, HAART may induce a paradoxical clinical deterioration due to an immune reconstitution inflammatory syndrome (IRIS). This syndrome has been described with a wide variety of systemic infections and, in the central nervous system, with Cryptococcus neoformans infection, cytomegalovirus retinitis, and progressive multifocal leukoencephalopathy (PML). The authors have examined brain tissue in eight cases of IRIS: two autopsy cases and three biopsy cases of HIV encephalitis with IRIS and one autopsy case and two biopsy cases of PML with IRIS. All the patients presented with clinical deterioration following initiation of HAART and imaging showed contrast enhancement of the lesions. The symptoms regressed in four patients whereas the other four patients died. Neuropathological examination revealed severe inflammatory and demyelinating lesions with marked intraparenchymal and perivascular infiltration by macrophages and T lymphocytes. In some cases abundant viral proliferation was identified by immunocytochemistry or in situ hybridization, but in others the infectious agent could only be detected using PCR. T lymphocytes were predominantly CD8(+). In those cases with the more favorable course, inflammation was less severe with marked macrophage activation and a number of CD4(+) lymphocytes; in contrast, in the lethal cases inflammation was severe and mostly composed of CD8(+) cytotoxic lymphocytes. We conclude that HAART-induced paradoxical aggravation of HIV encephalitis or AIDS-related PML due to IRIS is reversible in most cases but may be lethal in others. In fatal cases, fulminant viral infection and/or acute perivenous leukoencephalitis may result from a dysregulation of the CD8(+)/CD4(+) T-cell balance.

Reversible ALS-like disorder in HIV infection

Objective: To describe the clinical features, treatment, and outcome of six cases of HIV-1-associated ALS-like disorder. Methods: The authors reviewed patients with HIV infection with neurologic symptoms seen over a 13-year period. Patients were identified by using the El Escorial research diagnostic criteria defining three categories of certainty for definite, probable, or possible ALS. Clinical features, EMG, CSF, serum analyses, and imaging and virological studies were assessed. Results: Six patients with immunodepression (mean CD4+ cells = 86.2/mm3; mean age = 34 years) developed distal motor weakness mimicking a monomelic amyotrophy that subacutely progressed regionally or assumed a symmetric distribution on more than one region. EMG was characteristic of motor neuron disease with no multifocal conduction block. Causes other than HIV-1 were ruled out. The unusual rapid extension of the disease and the positive response to antiretroviral therapy suggest that ALS syndrome and HIV infection are etiologically related. HIV-1 might cause an ALS-like disorder by several mechanisms—via neuronal infection, by secretion of toxic viral substance, by inducing the immune system to secrete cytokines, or by inducing an autoimmune disease. Conclusion: These cases suggest that the association between some motor neuron diseases and HIV infection is not coincidental but pathogenetically related and that ALS-like disorder should be considered an HIV-related neurologic complication.

CD8 Encephalitis in HIV-Infected Patients Receiving cART: A Treatable Entity

BACKGROUND Despite its overall efficacy, combined antiretroviral therapy (cART) has failed to control human immunodeficiency virus (HIV) infection of the central nervous system (CNS). New acute and chronic neurological complications continue to be reported. METHODS We conducted a retrospective study of 14 HIV-infected patients with documented encephalitis, which was initially attributed to an undetermined origin. Brain magnetic resonance imaging (MRI) uniformly revealed unusual, multiple linear gadolinium-enhanced perivascular lesions. RESULTS All patients had manifested acute or subacute neurological symptoms; the brain MRIs indicating diffuse brain damage. The mean duration of HIV infection was approximately 10 years, and 8 patients were immunovirologically stable. Cerebrospinal fluid abnormalities with mildly elevated protein and pleocytosis with >90% lymphocytes, predominantly CD8, were found in all but 1 patient. The mean cerebral spinal fluid HIV load was 5949 copies/mL. Six patients reported a minor infection a few days prior to neurological symptoms, 2 patients presented criteria for the immune reconstitution inflammatory syndrome of the CNS, 2 were in virological escape, and 1 developed encephalitis after interruption of cART. Brain biopsies revealed inflammatory encephalitis associated with astrocytic and microglial activation as well as massive perivascular infiltration by polyclonal CD8(+) lymphocytes. All patients had been treated with glucocorticosteroids. The long-term therapeutic response varied from excellent, with no sequalae (n = 5), to moderate, with cognitive disorders (n = 4). The mean survival time was 8 years; however, 5 patients died within 13 months of initiation of treatment. CONCLUSIONS CD8 encephalitis in HIV-infected patients receiving cART is a clinical entity that should be added to the list of HIV complications.

Neuropathy in diffuse infiltrative lymphocytosis syndrome An HIV neuropathy, not a lymphoma

Objective: To determine whether CD8 lymphoid infiltrates in nerves of patients with HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) corresponds to a lymphomatous neoplastic process or to a proliferation of T cells reactional to HIV. Background: DILS is characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. Methods: Presence of monoclonal T cells and HIV-1 proviral load were evaluated by polymerase chain reaction (PCR) techniques in frozen peripheral nerve samples from six patients with DILS neuropathy and 22 patients with other HIV-associated peripheral neuropathies, including mononeuritis multiplex(MM:6), inflammatory demyelinating polyneuropathies (IDP:6), distal sensory polyneuropathy (DSP:5), and toxic distal sensory polyneuropathy (TDSP:5). Results: Five of six patients with DILS showed no detectable monoclonal T-cell clones in their nerves. Nerve proviral load in DILS (6.8 ± 0.2 log/105 cells) was much higher than in MM (p < 0.008), IDP (p < 0.001), DSP (p < 0.001), and TDSP(p < 0.005). Conclusions: DILS neuropathy represents a separate entity among HIV-associated neuropathies. It is associated with massive HIV proviral load in nerve and must not be confused with a peripheral nerve T-cell lymphoma.

AIDS-associated progressive multifocal leukoencephalopathy revealed by new-onset seizures

PURPOSE To describe the clinical features of new-onset seizures in HIV-1-infected persons with progressive multifocal leukoencephalopathy (PML), and to discuss potential mechanisms. PATIENTS AND METHODS Forty-nine consecutive HIV-1-infected patients with PML attended our institutions between January 1988 and September 1993. We retrospectively analyzed cases with seizures as the presenting symptom of PML. RESULTS Twenty percent of the HIV-1-infected patients with PML presented with new-onset seizures of various types, generalized or partial. None of them met the criteria of the AIDS dementia complex or had a concomitant opportunistic infection. Their mean CD4 cell count was < 60/mm3. Brain magnetic resonance imaging showed areas of increased signal intensity on T2-weighted images in 9 cases, and atrophy in only 1 case. Lesions most often involved subcortical white matter in parieto-occipital or frontal lobes, but 2 patients had posterior fossa lesions. Image-guided stereotactic brain biopsies in 8 cases and postmortem examination in 2 confirmed the diagnosis of PML. Typical histological lesions were observed in all cases, and positive immunolabelling of oligodendroglial nuclei was obtained in all cases with the polyclonal antibody directed against late SV40 antigens. Putative causative factors for the seizures include demyelinated lesions adjacent to the cerebral cortex acting as irritative foci, axonal conduction abnormalities, or disturbances of the neuron-glia balance. CONCLUSION These cases illustrate that PML should be considered as a possible cause of new-onset seizures in patients with HIV-1 infection.

Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis

Objective To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation. Methods Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared. Results During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9 months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients. Conclusions This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.

Recombinant interferon-α–induced chorea and frontal subcortical dementia

Owing to both its antiviral and antiproliferative properties, interferon-α (IFNα) therapy is widely used, and often for long periods of time, in oncologic, infectious, and autoimmune disorders. If many patients experience mild neurologic side effects, more severe neurotoxicity is uncommon.1 We report on choreic movements and frontal subcortical dementia associated with long-term recombinant IFNα therapy for chronic myelogenous leukemia (CML). A 68-year-old woman, with no psychiatric disorder, had been treated since 1997 with IFNα-2b (3 × 106 units/day) and hydroxyurea (50 mg/kg/day) for CML. She occasionally received low doses of metoclopramide (10 to 20 mg/day) for early stages chemotherapy-induced nausea, further discontinued for at least 18 months. No other concomitant medicine was prescribed. In December 1999, she presented with progressive personality changes and short-term memory loss. Permanent choreic movements of the four limbs respecting the head and the trunk appeared 2 months later. Neuropsychological tests showed frontal–subcortical dysfunction (table). Brain MRI only showed bilaterally widened ventricles without atrophy of the caudate nuclei. The lumbar …

Prognostic value of cerebrospinal fluid analysis at the time of a first demyelinating event

Background and Objective: This study aimed to assess the value of cerebrospinal fluid (CSF) findings for predicting conversion to clinically definite multiple sclerosis (CDMS). Methods: From a database of 447 patients with a first demyelinating event, the records of 208 patients less than 51 years old who had baseline magnetic resonance imaging (MRI) and CSF examinations and a follow-up of at least 1 year were included. A multivariable Cox model was used to assess the short-term risk of CDMS according to baseline CSF findings after adjustment for prognostic factors (including brain MRI) and to provide a simple classification for predicting CDMS. Results: During a median follow-up of 3.5 years, 141 (67.8%) patients converted to CDMS. In multivariate analysis, younger age (hazard ratio [HR]: 1.44 [95% CI 1.02–2.01]), spatial dissemination on brain MRI (HR: 2.07 [95% CI 1.47–2.91]) and more than 4 WBC/mm3 in CSF (HR: 1.44 [95% CI 1.03–2.02]) were independently associated with CDMS. The Cox score obtained from these three predictors enabled patients to be divided into three groups with significant increased risks of CDMS at 1, 2 and 3 years; groups were classified as high-risk (64.7%, 77.4%, 96.1%), intermediate-risk (33.3%, 51.5%, 61.5%), and low-risk (11.1%, 18.3%, 40.3%). Conclusions: Age at onset, spatial dissemination on brain MRI and CSF white blood cell count are independently associated with short-term conversion to CDMS. The three proposed risk group classifications could be a useful tool to select patients for early therapeutic intervention.

HIV Type 2 Demyelinating Encephalomyelitis

A human immunodeficiency virus (HIV) type 2 (HIV-2)-infected African patient developed inflammatory demyelinating lesions of the optic nerves, spinal cord, and brain, which coincided with a decreasing CD4 cell count and with active HIV-2 replication. This case provides evidence that HIV-2 is neurotropic, extends the range of known HIV-2-associated neurological complications, and confirms the overlap between the neurological complications of HIV type 1 and HIV-2 infection.