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.     

Negative association of Epstein-Barr virus or herpes simplex virus-1 with tumefactive central nervous system inflammatory demyelinating disease

Central nervous system (CNS) demyelination has been suggested to be associated with infections caused by the Epstein-Barr virus (EBV) or herpes simplex virus (HSV)-1. CNS inflammatory demyelinating disease (IDD) rarely presents as a large lesion. We evaluated samples of serum and cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay to detect recent infection with these viruses and analyzed CSF and brain specimens by polymerase chain reaction (PCR) or immunohistochemical studies for evidence of these viruses in three patients with biopsy-proven CNS IDD. The results of PCR tests for EBV and HSV in CSF or brain specimens were negative. Elevated anti-EBV or -HSV antibody levels were not found in serum or CSF in any patient. Immunohistochemical studies showed that IDD lesions were negative for latent membrane protein (LMP)-1, Epstein-Barr nuclear antigen (EBNA)-2, and EBNA noncoding RNA (EBER)-1. These results suggest a negative association between CNS IDD and EBV or HSV.     

Stem cell therapy for central nervous system demyelinating disease

Recent advances in cell-based therapies for demyelinating central nervous system diseases have demonstrated the ability to restore damaged neuronal architecture and function. Demyelinated axons in patients with multiple sclerosis can spontaneously remyelinate over time; however, the rate and extent at which remyelination occurs is inadequate for complete recovery. Previous attempts aimed at regenerating myelin-forming cells have been successful but limited by the multifocal nature of the lesions and the inability to produce large numbers of myelin-producing cells in culture. Stem cell-based therapy can overcome these limitations to some extent and may prove useful in the future treatment of demyelinating diseases.     

Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system

PURPOSE OF REVIEW: The epidemiology of HIV infection is changing rapidly in the era of highly actively antiretroviral therapy, as the use of such therapy is increasing in all countries. This has had a significant impact on the neurological manifestations of HIV infection, posing new challenges in diagnosis and treatment. This review provides a critical analysis of the recent literature on the impact of highly actively antiretroviral therapy on HIV-related neurological complications and changes in treatment strategies. RECENT FINDINGS: It is becoming clear that the brain is an important reservoir for the virus, and neuroinflammatory and neurodegenerative changes may continue despite the adequate use of highly actively antiretroviral therapy. Although this antiretroviral therapy has had a significant impact on the severity of HIV dementia, cognitive impairment persists. With improvement in the immune status following treatment with antiretrovirals, in rare cases the brain can become a target of the immune reconstitution. SUMMARY: Highly actively antiretroviral therapy may need to be optimized in patients with HIV-associated cognitive impairment to achieve maximal central nervous system penetration; however, this therapeutic strategy may not be sufficient for halting the process. In some instances, the antiretroviral drugs themselves may become the problem. New strategies for neuroprotection that also target host genes which control HIV replication are being developed.     

The effect of highly active antiretroviral therapy on outcome of central nervous system herpesviruses infection in Cuban human immunodeficiency virus-infected individuals

With the rapid progress in the development of highly active antiretroviral therapy (HAART), the observed patterns in human immunodeficiency virus (HIV) encephalitis has changed, allowing herpesvirus (HV) infection to be controlled. HAART was first administered to HIV patients in Cuba in 2001. Consequently with the aim of investigate the behavior of the HVs causing neurological disorders in this population in the post-HAART era, the authors perform a clinical evaluation by a multiplex nested polymerase chain reaction (PCR) assay for simultaneous detection of human HVs--herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV). The authors studied 241 samples of cerebrospinal fluid (CSF) received at the Sexually Transmitted Diseases Laboratory between 2001 and 2005 inclusive. Of the 241 CSF studied, 10.4% resulted positive for HV infections. Of these, 92% of patients were acquired immunodeficiency syndrome (AIDS) individuals at the C3 stage. CMV (44%), EBV (28%), and dual-HV (16%) infections were the most important agents identified. The principal clinical manifestations were fever, headache, vomiting, and focal abnormalities; the latter being associated with an increased risk of death. A statistically significant result was observed when central nervous system (CNS) disease evolution was compared between patients who were under HAART against those who were not, before they developed encephalitis. It was therefore concluded that it is more likely that HIV individuals receiving HAART have a better recovery of CNS infections than those who are not receiving it.     

Progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent infected with perinatal human immunodeficiency virus (HIV)

Progressive multifocal leukoencephalopathy is an infectious demyelinating brain disease caused by the JC virus that is associated with significant morbidity and mortality in the immunocompromised host. We report a case of progressive multifocal leukoencephalopathy successfully treated with highly active antiretroviral therapy and cidofovir in an adolescent patient perinatally infected with human immunodeficiency virus (HIV).     

Isolated central nervous system aspergillosis in the acquired immunodeficiency syndrome.

Aspergillus infection involving the central nervous system are unusual, but should be included in the differential diagnosis in patients with the acquired immunodeficiency syndrome and neurologic signs and symptoms. Of the few reported AIDS cases with central nervous system aspergillosis, the majority have had focal brain abscesses. We report an atypical case that presented as a basal meningitis with pontine infarction secondary to invasive Aspergillus sinusitis.     

Aspergillus infection of the central nervous system in patients with acquired immunodeficiency syndrome

Infections of the central nervous system in patients with the acquired immunodeficiency syndrome are common. Of the many microorganisms that have been implicated, infection with Aspergillus is rare. We describe three patients with Aspergillus infection of the nervous system. Two patients had cerebral lesions due to Aspergillus flavus, and one patient had Aspergillus fumigatus infection of the spinal cord. Diagnosis of the infections was difficult, and therapy appeared to be ineffective.     

Magnetic resonance imaging in five patients with a tumefactive demyelinating lesion in the central nervous system

Five patients with a tumefactive lesion were clinically followed from 1992 to 1993. Four patients were female; age ranged from 32 to 57 years, the duration of symptoms varied from 3 days to 3 years. Neurological examination disclosed dementia in two patients, aphasia in three, hemiparesis in four, hemihypoaesthesia in three, optical neuritis in two, tetraparesis with sensitive level and neurogenic bladder in one. MRI disclosed lesions with a hypersignal on images assessed at T2 and hyposignal at T1, and gadolinium heterogeneous enhancement; these lesions were located in the: a) temporooccipital region bilaterally and brain stem, b) frontoparietal white matter, c) basal ganglia, bilateral white matter and brain stem, d) left parietal region, e) cervical spinal cord, with enlargement of this region. Cerebral biopsy was performed in three patients; acute and subacute demyelinating disease was diagnosed by histological examination. Two patients had an evolutive diagnosis; exclusion of other pathologies and clinical and radiological improvement after corticotherapy, pointed to an inflammatory disease.     

Adaptation of antiretroviral therapy in human immunodeficiency virus infection with central nervous system involvement

The authors describe a patient with known human immunodeficiency virus (HIV)-1 infection who presented with two generalized seizures and was found to have extensive white matter disease and a left/bilateral temporo-occipital focal slowing on electroencephalography (EEG). There were no magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) indications for opportunistic infection. Plasma viremia was controlled, whereas viral replication was uncontrolled in CSF. CSF-specific genotype-guided adaptation of the antiretroviral therapy in order to optimize central nervous system (CNS) penetration resulted in clinical improvement and normalization of MRI and EEG. Our case report illustrates the importance of individualized antiretroviral therapy in HIV infected patients with neurological complications.     

以中枢神经系统症状为首发表现的AIDS

目的探讨以中枢神经系统症状为首发表现的AIDS的临床特征及预后,提高对这部分患者的诊断识别能力。方法连续选择云南省德宏州盈江县人民医院的AIDS住院患者共165例,并对其中以中枢神经系统症状为首发表现的32例患者的临床资料进行回顾性分析。结果 32例患者中AIDS痴呆综合征10例,结核性脑膜炎4例,隐球菌脑膜炎5例,脑弓形虫病11例,蛛网膜下腔出血1例,脊髓损伤但性质未明确者1例。本组32例患者中1年内死亡的有26例,占81.2%。结论以中枢神经系统症状为首发表现的AIDS患者病情复杂,多合并中枢神经系统机会性感染,且进展快,预后差,死亡率高。     

Combined peripheral nerve and central nervous system demyelination in a patient with chronic inflammatory demyelinating polyneuropathy

We report the case of a 49-year-old woman suffering combined central and peripheral demyelination, with serial magnetic resonance images scans illustrating the development of central demyelination in a patient with established chronic inflammatory demyelinating polyneuropathy. This is the sixth patient with this rare overlap syndrome reported to date. We review the available literature and argue that an inherited predisposition to both diseases is the most likely explanation for its occurrence.     

Varicella-zoster virus vasculopathy and central nervous system immune reconstitution inflammatory syndrome with human immunodeficiency virus infection treated with steroids

Immune reconstitution inflammatory syndrome (IRIS) is widely recognized and rarely involves the central nervous system (CNS). Patients with acquired immunodeficiency syndrome (AIDS) are at an increased risk for developing CNS-IRIS upon initiation of highly active antiretroviral therapy (HAART). This syndrome can be fatal and requires extreme vigilance in determining if a treatable underlying opportunistic infection exists. We report here a case of varicella-zoster virus (VZV) vasculopathy and CNS-IRIS in a human immunodeficiency virus (HIV)-infected patient who required prolonged steroid treatment for clinical stabilization. There are no established treatment regimens for IRIS and the use of corticosteroids in this syndrome remains controversial. Similar to our patient, severe cases of CNS-IRIS may benefit from high-dose intravenous corticosteroid treatment followed by an oral prednisone taper.     

Depressive symptoms in HIV-infected patients treated with highly active antiretroviral therapy

IntroductionThe prevalence of depressive disorders in HIV-infected patients ranges from 12% to 66% and is undiagnosed in 50% to 60% of these patients. Depression in HIV-infected individuals may be associated with poor antiretroviral treatment (ART) outcomes, since it may direct influence compliance.ObjectiveTo assess the presence of symptoms and risk factors for depression in patients on ART.MethodsCross-sectional study. Certified interviewers administered questionnaires and the Beck Depression Inventory (BDI), and participants' self-reported compliance to ART. Clinical and laboratory variables were obtained from clinical records. Patients with BDI ≥ 12 were defined as depressed.ResultsOut of the 250 patients invited to participate, 246 (98%) consented. Mean age was 41 ± 9.9 years; most were male (63%). Income ranged from 0–14 Brazilian minimum wages. AIDS (CDC stage C) had been diagnosed in 97%, and 81% were in stable immune status. One hundred ninety-one (78%) reported compliance, and 161 (68%) had undetectable viral loads. The prevalence of depressive symptoms was 32% (95% CI 26–40). In multivariate analysis, depressive symptoms were significantly associated with income (prevalence ratio [PR] = 0.85; 95% CI 0.74–0.97; p = 0.02).ConclusionsDepressive symptoms are frequent in patients on ART, and are associated with low income.     

A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease

There are no established treatments for patients with acute, severe neurological deficits caused by multiple sclerosis or other inflammatory demyelinating diseases of the central nervous system who fail to recover after treatment with high-dose corticosteroids. We conducted a randomized, sham-controlled, double-masked study of plasma exchange without concomitant immunosuppressive treatment in patients with recently acquired, severe neurological deficits resulting from attacks of inflammatory demyelinating disease, who failed to recover after treatment with intravenous corticosteroids. Patients who did not achieve moderate or greater improvement after the first treatment phase crossed over to the opposite treatment. Moderate or greater improvement in neurological disability occurred during 8 of 19 (42.1%) courses of active treatment compared with 1 of 17 (5.9%) courses of sham treatment. The primary analysis was positive. Improvement occurred early in the course of treatment, and was sustained on follow-up. However, 4 of the patients who responded to the active treatment experienced new attacks of demyelinating disease during 6 months of follow-up. Moderate or greater improvement occurred during follow-up in only 2 of 13 patients who failed to improve during the treatment phase. Plasma exchange leads to functionally important neurological recovery in an important proportion of severely disabled patients with acute attacks of idiopathic inflammatory demyelinating disease.     

The therapeutic use of gene therapy in inflammatory demyelinating diseases of the central nervous system

PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.