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ObjectiveThe primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures.MethodsIn this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures.ResultsSixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32–65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3(SD 97 cells/mm3, range 1–416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147–657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r= −0.344,p= 0.04) and sural nerve amplitude (r= −0.359,p= 0.004).ConclusionsBoth IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.

Distal symmetrical axonal polyneuropathy (DSP) is due to injury to peripheral sensory, motor, and autonomic nerve fibers, resulting in distal predominant sensory loss, pain, and gait instability. DSP occurs as a complication of multiple medical conditions including diabetes or HIV, or following exposure to various toxins such as chemotherapy. It affects at least 10% of the United States population. Few treatments for DSP are approved by regulatory agencies. Reliable and responsive outcome measures are integral to developing new DSP treatments. Multiple clinician-rated measures that incorporate neuropathy signs exist, however, it is not clear which of these measures performs best for various DSP phenotypes. This systematic review summarizes the content of 18 published measures of DSP identified using PubMed and from personal archives of the authors. The relative percentage of scoring dedicated to motor, reflex, large and small fiber sensory, and autonomic domains varied considerably among measures. The most common neurologic examination items included in the scales were (1) vibration perception (n = 18, 100%), (2) reflexes (n = 16, 89%), (3) pinprick perception (n = 14, 78%), (4) muscle strength (n = 11, 61%), (5) touch–pressure perception (n = 9, 50%), and (6) joint position perception (n = 8, 44%). This review can be used to inform decisions regarding which of the available clinician-rated sign outcome measures would be most appropriate for use in a particular DSP population, based on the domains most affected by that neuropathy or on the domains most likely to be affected by a particular experimental therapy.

ObjectiveTo determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals.MethodsWe conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition.ResultsPatients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition.ConclusionsThese findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy–treated HIV-infected patients.

ObjectiveTo investigate the diagnostic challenges of congenital myasthenic syndromes (CMS) in adult neuromuscular practice.MethodsWe searched the Mayo Clinic database for patients with CMS diagnosed in adulthood in the neuromuscular clinic between 2000 and 2016. Clinical, laboratory, and electrodiagnostic data were reviewed.ResultsWe identified 34 patients with CMS, 30 of whom had a molecular diagnosis (14 DOK7, 6 RAPSN, 2 LRP4, 2 COLQ, 2 slow-channel syndrome, 1 primary acetylcholine receptor deficiency, 1 AGRN, 1 GFPT1, and 1 SCN4A). Ophthalmoparesis was often mild and present in 13 patients. Predominant limb-girdle weakness occurred in 19 patients. Two patients had only ptosis. Age at onset ranged from birth to 39 years (median 5 years). The median time from onset to diagnosis was 26 years (range 4–56 years). Thirteen patients had affected family members. Fatigable weakness was present when examined. Creatine kinase was elevated in 4 of 23 patients (range 1.2–4.2 times the upper limit of normal). Repetitive nerve stimulation revealed a decrement in 30 patients. Thirty-two patients were previously misdiagnosed with seronegative myasthenia gravis (n = 16), muscle diseases (n = 15), weakness of undetermined cause (n = 8), and others (n = 4). Fifteen patients received immunotherapy or thymectomy without benefits. Fourteen of the 25 patients receiving pyridostigmine did not improve or worsen.ConclusionMisdiagnosis occurred in 94% of the adult patients with CMS and causes a median diagnostic delay of nearly 3 decades from symptom onset. Seronegative myasthenia gravis and muscle diseases were the 2 most common misdiagnoses, which led to treatment delay and unnecessary exposure to immunotherapy, thymectomy, or muscle biopsy.

Objective: The location of comprehensive stroke centers (CSCs) is critical to ensuring rapid access to acute stroke therapies; we conducted a population-level virtual trial simulating change in access to CSCs using optimization modeling to selectively convert primary stroke centers (PSCs) to CSCs. Methods: Up to 20 certified PSCs per state were selected for conversion to maximize the population with 60-minute CSC access by ground and air. Access was compared across states based on region and the presence of state-level emergency medical service policies preferentially routing patients to stroke centers. Results: In 2010, there were 811 Joint Commission PSCs and 0 CSCs in the United States. Of the US population, 65.8% had 60-minute ground access to PSCs. After adding up to 20 optimally located CSCs per state, 63.1% of the US population had 60-minute ground access and 86.0% had 60-minute ground/air access to a CSC. Across states, median CSC access was 55.7% by ground (interquartile range 35.7%–71.5%) and 85.3% by ground/air (interquartile range 59.8%–92.1%). Ground access was lower in Stroke Belt states compared with non–Stroke Belt states (32.0% vs 58.6%, p = 0.02) and lower in states without emergency medical service routing policies (52.7% vs 68.3%, p = 0.04). Conclusion: Optimal system simulation can be used to develop efficient care systems that maximize accessibility. Under optimal conditions, a large proportion of the US population will be unable to access a CSC within 60 minutes.

Objective: To investigate predictors of outcome in patients with all-cause encephalitis receiving care in the intensive care unit. Methods: A retrospective analysis of encephalitis cases at The Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center was performed. Using multivariate logistic regression analysis, we examined mortality and predictors of good outcome (defined as modified Rankin Scale scores of 1–3) and poor outcome (scores 4 and 5) in those surviving to hospital discharge. Results: In our cohort of 103 patients, the median age was 52 years (interquartile range 26), 52 patients (50.49%) were male, 28 patients (27.18%) had viral encephalitis, 19 (18.45%) developed status epilepticus (SE), 15 (14.56%) had cerebral edema, and 19 (18.45%) died. In our multivariate logistic regression analysis, death was associated with cerebral edema (odds ratio [OR] 18.06, 95% confidence interval [CI] 3.14–103.92), SE (OR 8.16, 95% CI 1.55–43.10), and thrombocytopenia (OR 6.28, 95% CI 1.41–28.03). Endotracheal intubation requirement with ventilator support was highly correlated with death (95%). In addition, in those patients who survived, viral, nonviral, and unknown causes of encephalitis were less likely to have a poor outcome at hospital discharge compared with an autoimmune etiology (viral encephalitis: OR 0.09, 95% CI 0.01–0.57; nonviral encephalitis: OR 0.02, 95% CI 0.01–0.31; unknown etiology: OR 0.18, 95% CI 0.04–0.91). Conclusions: Our study suggests that predictors of death in patients with encephalitis comprise potentially reversible conditions including cerebral edema, SE, and thrombocytopenia. Further prospective studies are needed to determine whether aggressive management of these complications in patients with encephalitis improves outcome.

A 19-year-old man with no significant medical history noted 3 weeks of right facial numbness and slurred speech. On examination, he had decreased sensation in the right middle and lower trigeminal nerve distributions, right tongue deviation, and bilateral facial weakness. A lumbar puncture yielded CSF with a lymphocytic predominant pleocytosis (50 leukocytes/mm3, 95% lymphocytes), elevated protein (260 mg/dL), and normal glucose (49 mg/dL), without other evidence of inflammation or infection, while serum studies were normal. Brain MRI with gadolinium demonstrated a subcentimeter left frontal subcortical white matter lesion on fluid-attenuated inversion recovery images and a nonenhancing pineal cyst.

To study the incidence and pattern of neurologic disorders in a large cohort of HIV-positive men, compared with HIV-negative men, in the era of highly active antiretroviral therapy (HAART).The Multicenter AIDS Cohort Study is a prospective study of men who have sex with men enrolled in 4 cities in the United States. We compared HIV-positive vs HIV-negative men for incidence and category of neurologic diagnoses in the HAART era (July 1, 1996, to last known follow-up or death, on or before July 1, 2011).There were 3,945 participants alive during the HAART era (2,083 HIV negative, 1,776 HIV positive, and 86 who became infected with HIV during the study period) including 3,427 who were older than 40 years of age. Median age at first neurologic diagnosis among all participants alive in the HAART era was lower in HAART-treated HIV-positive vs HIV-negative men (48 vs 57 years of age, p0.001). Incidence of neurologic diagnoses was higher in HAART-treated HIV-positive vs HIV-negative men (younger than 40 years: 11.4 vs 0 diagnoses per 1,000 person-years [p0.001]; 40-49 years: 11.6 vs 2.0 [p0.001]; 50-60 years: 15.1 vs 3.0 [p0.001]; older than 60 years: 17.0 vs 5.7 [p0.01]). Excess neurologic disease was found in the categories of nervous system infections (p0.001), dementia (p0.001), seizures/epilepsy (p0.01), and peripheral nervous system disorders (p0.001), but not stroke (p = 0.60).HIV-positive men receiving HAART have a higher burden of neurologic disease than HIV-negative men and develop neurologic disease at younger ages.

The 2004 approval of natalizumab provided great hope for the multiple sclerosis (MS) community, while its withdrawal from the market shortly thereafter, following reports of treatment-related progressive multifocal leukoencephalopathy (PML),1 was a crushing blow. Its reintroduction in 2006 was accompanied by a formal safety monitoring program.2 Subsequently, risk factors were identified for natalizumab-associated PML: a history of prior immunosuppression, length of natalizumab therapy, and baseline positive JC virus (JCV) serostatus.1 Among those who have not previously used immunosuppressive therapies, the JCV antibody titer may help further characterize PML risk.3 Those with a detectable but low JCV antibody titer (≤0.9) carry a small risk of the complication, while those with titers >1.5 appear to be at much higher risk of PML. One calculation suggested increasing risk based on epochs of treatment, defined as 1–24, 25–48, or 49–72 months. The apparent risk inflection point that occurs after 24 months has led some neurologists to counsel patients that the risk of PML is very low within the 2 years on nataluzimab.4

Objective: To define a clinical syndrome associated with active drug abuse in HIV-infected individuals. Methods: We performed a retrospective review to identify individuals treated at the Johns Hopkins Hospital from 1993 to 2008 who were HIV-infected and were actively abusing drugs and had bilateral basal ganglia lesions on MRI. They were identified using a key word search in the radiology database, autopsy database, and the Moore HIV clinic database. Clinical, laboratory, and radiographic findings were correlated to define the syndrome. Results: Ten individuals were identified who presented with a change in mental status or seizures, used cocaine or cocaine with heroin, had uncontrolled HIV infection (>190,000 copies/mL of plasma), elevated CSF protein (63–313 mg/dL), and diffuse hyperintense bilateral basal ganglia lesions on imaging. The majority of patients (8/10) had renal failure and despite supportive therapy most (7/9) ultimately died (median survival 21 days). Postmortem examination in one individual showed the presence of overwhelming microglial activation in the basal ganglia. The 2 surviving individuals were started on combined antiretroviral therapy (CART) during hospitalization. Conclusion: We describe a unique clinical syndrome of a fulminant encephalopathy associated with primarily basal ganglia involvement in HIV-infected drug abusers. This syndrome is a rare but serious condition that is associated with a high mortality rate. Early CART institution may be useful and neuroprotective in this disorder, although this requires further investigation.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Objective:To demonstrate the relationship between epidermal nerve fiber density (ENFD) in the leg and the phenotype of HIV-associated distal sensory polyneuropathy (HIV-DSP) in a multicenter prospective study (ACTG A5117).Methods:A total of 101 HIV-infected adults, with CD4 cell count 3and who had received antiretroviral therapy (ART) for at least 15 consecutive weeks, underwent standardized clinical and electrophysiologic assessment. All 101 subjects were biopsied at the distal leg (DL) and 99 at the proximal thigh (PT) at baseline. ENFD was assessed by skin biopsy using PGP9.5 immunostaining. Associations of ENFD with demographics, ART treatment, Total Neuropathy Score (TNS), sural sensory nerve action potential (SNAP) amplitude and conduction velocity, quantitative sensory testing (QST) measures, and neuropathic pain were explored.Results:ENFD at the DL site correlated with neuropathy severity as gauged by TNS (p< 0.01), the level of neuropathic pain quantified by the Gracely Pain Scale (GPS) (p= 0.01) and Visual Analogue Scale (VAS) (p= 0.01), sural SNAP amplitude (p< 0.01), and toe cooling (p< 0.01) and vibration (p= 0.02) detection thresholds. ENFD did not correlate with neurotoxic ART exposure, CD4 cell count, or plasma HIV-1 viral load.Conclusions:In subjects with advanced HIV-1 infection, epidermal nerve fiber density (ENFD) assessment correlates with the clinical and electrophysiologic severity of distal sensory polyneuropathy (DSP). ENFD did not correlate with previously established risk factors for HIV-DSP, including CD4 cell count, plasma HIV-1 viral load, and neurotoxic antiretroviral therapy exposure.

To evaluate whether baseline levels of plasma and CSF HIV RNA, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase-2 (MMP-2), or macrophage colony stimulating factor (M-CSF) are predictors of incident HIV-associated dementia (HIVD) in a cohort with advanced HIV infection.A total of 203 nondemented subjects with CD4 lymphocyte counts less than 200/muL, or300/microL but with cognitive impairment, underwent semiannual neurologic, cognitive, functional, and laboratory assessments. HIVD and minor cognitive motor disorder (MCMD) were defined using American Academy of Neurology criteria. The cumulative incidence of HIVD was estimated using Kaplan-Meier curves. Cox proportional hazards regression models were used to examine the associations between biologic variables and time to HIVD, adjusting for age, sex, years of education, duration of HIV infection, type of antiretroviral use, premorbid IQ score, and presence of MCMD.After a median follow-up time of 20.7 months, 74 (36%) subjects reached the HIVD endpoint. The dementia was mild in 70% of cases. The cumulative incidence of HIVD was 20% at 1 year and 33% at 2 years. Highly active antiretroviral therapy (HAART) was used by 73% of subjects at baseline. A plasma HIV RNA level was undetectable in 23% of subjects and a CSF HIV RNA level was undetectable in 48% of subjects. In adjusted analyses, neither plasma nor CSF HIV RNA levels (log10) were associated with time to HIVD; log10 levels of plasma TNFalpha (HR 3.07, p = 0.03) and CSF MCP-1 (HR = 3.36, p = 0.06) tended to be associated with time to HIVD.The lack of association between baseline plasma and CSF HIV RNA levels and incident dementia suggests highly active antiretroviral therapy may be affecting CNS viral dynamics, leading to lower HIV RNA levels, and therefore weakening the utility of baseline HIV RNA levels as predictors of HIV-associated dementia.

Objective: To determine the inter-rater reliability of a modification of the Memorial Sloan-Kettering (MSK) Staging for HIV-associated cognitive impairment. Methods: Data were abstracted on neurologic, neuropsychological, and functional status on 100 individuals participating at four sites in the Northeast AIDS Dementia (NEAD) Consortium cohort study, a longitudinal study of predictors of cognitive impairment in HIV-infected individuals. Neuropsychological performance was defined 1) based on the neuropsychologist’s global impression and 2) solely based on neuropsychological test scores. Raters at each site used the abstracted data to assign an MSK stage to each subject blind to any identifying information. Inter-rater reliability was assessed using kappa statistics. Agreement between computer-generated ratings and site-generated ratings was also assessed. Results: Kappa statistics for pair-wise agreement among the sites regarding MSK stage ranged from 0.70–0.91, representing good to excellent agreement between sites. Agreement between computer-generated ratings and site-generated ratings was in the good to excellent range (0.62–0.79). Conclusions: The authors have modified the MSK rating scale and developed a reliable instrument that can be used in multicenter studies. This instrument will be useful in staging HIV-dementia in future longitudinal studies and will be valuable in increasing accuracy of clinicopathologic studies.

Objective: To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies. Methods: In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART). Results: The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART ( p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain ( p ≤ 0.02). The incidence of adverse events, including rash, was similar between LTG and placebo. Conclusions: Lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy. Additional research is warranted to understand the differing response among patients receiving neurotoxic antiretroviral therapy compared with those not receiving neurotoxic antiretroviral therapy.

Background: CPI-1189 is a compound with antioxidant properties that blocks tumor necrosis factor-α (TNFα) effects in animal models. It has neuroprotective properties in model systems for HIV-associated neurotoxicity and thus is a candidate for neuroprotective therapy in humans with HIV-associated CNS disease. Objective: To assess the tolerability and safety of CPI-1189 in treating HIV-associated cognitive–motor impairment. Methods: Sixty-four subjects with mild to moderate HIV-associated cognitive–motor impairment were randomized to receive either placebo or 50 or 100 mg daily of CPI-1189 in addition to optimal HIV therapy. Subjects were followed prospectively in a double-masked study for 10 weeks. The primary assessment was tolerability and safety of the compound. Secondary objectives examined neuropsychological and functional change associated with this treatment. Results: The study compound was well tolerated, with 91% of CPI-1189-treated subjects and 76% of placebo-treated subjects completing the trial. Skin rash was seen equally in placebo and active arms, but the only study withdrawals due to skin rash occurred in CPI-1189-treated subjects (n = 2). One subject developed a cataract on drug (100 mg/day). CD4 lymphocyte counts and plasma HIV viral load remained stable in all groups throughout the trial. No significant treatment effects were observed on the change in composite Z -scores for eight neuropsychologic measures (NPZ-8). The Grooved Pegboard Test (nondominant) showed improved performance with CPI-1189 at 100 mg/day ( p = 0.01), but no other neuropsychometric or functional measures demonstrated significant improvement. Conclusions: CPI-1189 was well tolerated in HIV subjects with cognitive–motor disorder. This study was not powered to conclusively determine efficacy and showed no consistent treatment-associated improvement in cognitive or functional measures.

Objective: To assess the incidence of and risk factors for distal sensory polyneuropathy (DSP) in a cohort of HIV-infected subjects.Methods: We followed 272 subjects semiannually for up to 30 months. DSP was diagnosed if subjects had decreased or absent ankle jerks, decreased or absent vibratory perception at the toes, or decreased pinprick or temperature in a stocking distribution. Subjects were further classified at each visit as having asymptomatic DSP (ADSP) (signs only) or symptomatic DSP (SDSP) if, in addition to the neurologic signs, paresthesias or pain was reported.Results: At baseline, 45% of the subjects did not meet criteria for DSP, 20% met criteria for ADSP, and 35% met criteria for SDSP. Dideoxynucleoside therapy was used by 23% of the patients, and this treatment was independent of their neuropathy status. In longitudinal univariate analyses, history of AIDS diagnoses (hazard ratio [HR] = 1.89; p = 0.02) and lower CD4 cell count (HR = 0.69; p = 0.0006) were risk factors for incident DSP (ADSP or SDSP). However, for incident SDSP only, in addition to history of AIDS diagnoses, mood and neurologic (other than DSP) and functional abnormalities were significant risk factors. Functional abnormalities remained a significant risk factor in a multiple regression analysis. The presence of ADSP and the use of dideoxynucleosides at baseline were not significant risk factors for incident SDSP. The Kaplan–Meier estimate of the 1-year incidence of SDSP was 36%.Conclusion: Subjects with moderate-to-severe immunosuppression from HIV infection commonly have SDSP. However, sex, use of dideoxynucleosides, and presence of ADSP were not significant risk factors for SDSP.

Objective: To explore the relationship between intraepidermal nerve fiber (IENF) density in HIV-associated sensory neuropathy (HIV-SN) to measurements of neuropathy severity and progression of HIV disease. Background: SN affects 30% of individuals with AIDS, and treatment is often ineffective. Recombinant human nerve growth factor (rhNGF) has been proposed as a trophic factor for unmyelinated nerve fibers injured in HIV-SN, and a clinical trial has recently concluded. Skin biopsy with IENF density determination has emerged as a diagnostic test for patients with small-fiber sensory neuropathy. Methods: Sixty-two of the 270 patients with HIV-SN who participated in the trial of rhNGF were included in a substudy examining epidermal nerve fibers. IENF density was compared with neuropathic pain intensity (measured with the Gracely Pain Scale), patient and physician global pain assessments, quantitative sensory testing, CD4 counts, and plasma HIV RNA levels both at baseline and at conclusion of the placebo-controlled phase. Results: IENF density was inversely correlated with neuropathic pain as measured by patient (p = 0.004) and physician (p = 0.05) global pain assessments, but not using the Gracely Pain Scale. Decreased IENF density at the distal leg was associated with lower CD4 counts and higher plasma HIV RNA levels. IENF density measurements were stable over time. Conclusions: IENF loss at the distal leg is associated with increased neuropathic pain, lower CD4 counts, and higher plasma viral load in HIV-SN. The robustness of the longitudinal measurement of IENF density supports its use in future longitudinal studies and clinical trials.

OBJECTIVE:While HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline). METHODS:A total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood. RESULTS:The ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not. CONCLUSIONS:This longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

Objective: To examine the association between HIV RNA levels, patterns of antiretroviral resistance, and neurologic status. Methods: Autopsy samples from 13 HIV-infected subjects were examined for HIV-1 viral RNA (vRNA), and viral reverse transcriptase (RT) genotype was determined. All subjects had been clinically characterized using standard instruments before death. Results: The median HIV-1 vRNA level in brain samples from subjects with moderate dementia was 7.79 log 10 copies/g (range 5.56 to 9.75 log 10 copies/g) compared with 5.44 log 10 copies/g (range 3.51 to 9.32 log 10 copies/g) for mildly demented subjects and 4.87 log 10 copies/g (3.51 to 6.86 log 10 copies/g) for those obtained from nondemented individuals. There were differences between subjects with moderate dementia and nondemented subjects ( p = 0.0002) and between subjects with moderate and mild dementia ( p = 0.0128). No significant differences among the groups were observed for vRNA levels in peripheral tissues. Some demented subjects had relatively low levels of HIV-1 vRNA, and paradoxically some nondemented subjects had high vRNA brain levels. Little subject effect in vRNA was noted in peripheral regions, but high regional variation in vRNA was noted within the brain. Patterns of the major zidovudine (ZDV) RT mutations in brain and peripheral tissues were concordant in most subjects. Subjects with longer duration of exposure to ZDV tended to have lower brain vRNA levels and a greater number of RT mutations than those with limited to no exposure. Conclusions: The presence and severity of HIV dementia correlates with the levels of productive HIV replication within the brain. Other pathophysiologic events (including macrophage activation) probably also contribute to neurologic dysfunction.

Cognitive and functional outcomes are of primary interest in the design of efficacy trials in HIV-associated cognitive impairment. In a longitudinal cohort study, weak associations were found between measures of cognitive performance and commonly used measures of daily functioning (mostly self-report measures) in HIV-infected individuals. Modifications of current functional scales or new functional instruments are needed to assess the clinical relevance of cognitive changes in clinical trials of HIV-associated cognitive impairment.

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

To determine the prevalence of different forms of peripheral neuropathy in patients with restless legs syndrome (RLS) and correlate the findings with other clinical characteristics.RLS is characterized by a desire to move the extremities, often associated with paresthesias or dysesthesias, motor restlessness, worsening of symptoms with rest with relief by activity, and worsening of symptoms in the evening or night. The association between RLS and peripheral neuropathy remains controversial. The observation that many patients with small-fiber neuropathy also complain of RLS prompted this prospective case series.Twenty-two consecutive patients with RLS were evaluated for evidence of large-fiber neuropathy (LFN) and small sensory fiber loss (SSFL).In eight of the 22 (36%) patients, neuropathy was identified. Three patients had pure LFN; two had mixed LFN and SSFL; and three had isolated SSFL. The SSFL group had a later onset of RLS (p0.009), reported pain in their feet with RLS more frequently (p0.001), and tended to have no family history of RLS (p0.078). Patients with LFN did not have similar associations with age at onset, family history status, or presence of pain.The results suggest that two forms of RLS exist: one is triggered by painful dysesthesias associated with SSFL, has later onset, and no family history; and one without involvement of SSF, with an earlier onset age, positive family history for RLS, and no pain. The authors hypothesize that patients with the SSFL subtype of RLS will preferentially respond to neuropathic pain medications.

Objective: To investigate the analgesic efficacy of lamotrigine in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP).Background: The pathogenesis of HIV-associated DSP is unknown and there is no effective treatment. A novel anticonvulsant, lamotrigine, blocks voltage-sensitive sodium channels and inhibits the release of glutamate and aspartate. There have been anecdotal reports of efficacy of lamotrigine in the treatment of painful neuropathy and trigeminal neuralgia.Methods: In a multicenter, randomized, double-blind, placebo-controlled study, lamotrigine was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Study duration was 14 weeks. The primary outcome measure was change in pain on the modified Gracely scale with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief.Results: Of 42 enrolled subjects, 13 did not complete the 14-week study endpoint. In five of these, rash was the cause for dropout. In the remaining 29 evaluable subjects, 20 patients received placebo and 9 received lamotrigine. The pain scores at baseline were not significantly different. The reduction in average pain from baseline to week 14 was greater (p = 0.03) in the lamotrigine group (−0.55) than in the placebo group (−0.18), adjusting for baseline levels of pain. There was no difference between the groups on the change in peak worst pain.Conclusions: In this small trial, lamotrigine showed promise in the treatment of pain associated with HIV-related DSP. The frequency of rash was greater than in lamotrigine studies in epilepsy. A larger controlled study of lamotrigine is warranted.

Objective: To evaluate the safety and efficacy of recombinant human nerve growth factor (rhNGF) in HIV-associated sensory neuropathy (SN) within a multicenter, placebo-controlled, randomized trial (ACTG 291). Background: SN affects 30% of individuals with AIDS, is worsened by neurotoxic antiretrovirals, and its treatment is often ineffective. NGF is trophic for small sensory neurons and stimulates the regeneration of damaged nerve fibers. Methods: A total of 270 patients with HIV-associated SN were randomized to receive placebo, 0.1 μg/kg rhNGF, or 0.3 μg/kg rhNGF by double-blinded subcutaneous injection twice weekly for 18 weeks. The primary outcome was change in self-reported neuropathic pain intensity (Gracely Pain Scale). Secondary outcomes included an assessment of global improvement in neuropathy by patients and investigators, neurologic examination, use of prescription analgesics, and quantitative sensory testing. In a subset, epidermal nerve fiber densities were determined in punch skin biopsies. Results: Both doses of NGF produced significant improvements in average and maximum daily pain compared with placebo. Positive treatment effects were also observed for global pain assessments ( p = 0.001) and for pin sensitivity ( p = 0.019). No treatment differences were found with respect to mood, analgesic use, or epidermal nerve fiber densities. Injection site pain was the most frequent adverse event, and resulted in unblinding in 39% of subjects. Severe transient myalgic pain occurred in eight patients, usually from accidental overdosing. There were no changes in HIV RNA levels or other laboratory indices. Conclusions: We found a positive effect of recombinant human nerve growth factor on neuropathic pain and pin sensitivity in HIV-associated sensory neuropathy. rhNGF was safe and well tolerated, but injection site pain was frequent.

Both Wong et al.1 and Brew and Gonzalez-Scarano2 make a strong case that HIV-associated dementia (HAD) merits more attention in sub-Saharan Africa, not only because it is treatable, but also because of HAD's possible adverse effects on HIV treatment compliance. Treatment guidelines vary between countries in sub-Saharan Africa, but many recommend treatment initiation not only for patients with CD4 counts under 200 cells/μL but also with WHO stage IV clinical disease (which includes HAD).3 The overall CD4 counts quoted include patients taking treatment and might overestimate the prevalence of HAD in patients presenting with CD4 counts over 200. It would be helpful if the authors could describe how many of their patients would have qualified for treatment on CD4 criteria and how many would require a clinical diagnosis to start treatment. Regardless of whether a diagnosis of HAD is required to start treatment, monitor progress, or predict treatment outcome, the challenges of diagnosing HAD in resource-constrained settings are substantial. Wong et al.1 used a battery of neuropsychological tests and a neurological assessment to diagnose HAD. Most health care systems in sub-Saharan Africa have few clinical staff and are unlikely to be able …

Background: Few effective treatments are available for AIDS dementia complex (ADC) and HIV-associated neuropathy. However, recent in vitro studies indicate that nimodipine, a voltage-dependent calcium channel antagonist, can prevent HIV-related neuronal injury and may provide a novel form of treatment for these disorders. Methods: To determine the safety and possible efficacy of this agent, 41 patients with mild to severe ADC, including 19 patients with neuropathy, were entered into the AIDS Clinical Trial Group multicenter, phase-I and phase-II study. Nimodipine at 60 mg po, five times daily; 30 mg po, three times daily; or placebo was administered for 16 weeks as adjuvant treatment to antiretroviral therapy. Results: Neuropsychological performance at baseline, measured by the composite neuropsychological Z score (NPZ-8), correlated significantly with the ADC stage and with CSF levels of neopterin, a marker of immune activation. No significant differences in toxicity were observed among the three arms. Intent-to-treat analysis showed no significant change in the NPZ-8, although improvement was suggested in the high-dose arm. In addition, a trend toward stabilization in peripheral neuropathy was observed in both nimodipine arms compared with placebo. Conclusions: Nimodipine and other similar nonantiretroviral agents may provide a safe and promising avenue of treatment for neurologic disorders associated with HIV infection. The results of this study indicate that further clinical trials are warranted.

A consecutive series of 71 patients diagnosed with HIV-associated dementia (HAD) (1984-1994) were studied to characterize the clinical course of HAD, and to identify predictive markers of rapid neurologic progression. Neurologic progression rate was determined from the change in the Memorial Sloan Kettering (MSK) dementia severity score from diagnosis to death. Those with the most rapid progression in neurologic disability were compared with those with slow or no progression. Autopsy material was immunostained for macrophage activation markers and gp41 in 30 individuals. Median survival was 3.3 months and 6.1 months for rapid-progression and no-progression patients, respectively. Rapid progression was associated with injection drug use but not with race, gender, or age. CD4+ cell counts were lower at diagnosis among rapid-progression than no-progression patients but no differences in AIDS-defining illnesses or patterns of antiretroviral therapy were found. At presentation, rapid-progression patients had more prominent symptoms of mental slowing than those with no progression; however, no other clinical features, CSF, or imaging features distinguished the groups. Less abundant macrophage activation in both basal ganglia and midfrontal gyrus regions, as judged by HAM56 immunostaining, was noted in 9 no-progression patients, compared with 12 rapid-progression patients. Neurologic progression and survival with HAD is highly variable. A significant proportion of individuals with dementia have prolonged survival of more than 12 months and remain cognitively stable. A history of injection drug use and presentation with prominent psychomotor slowing is associated with more rapid neurologic progression, and these patients tend to show more abundant macrophage activation within the CNS.

Article abstract-Despite prominent symptoms of neuropathic pain, patients with small-fiber sensory neuropathies have few objective abnormalities on clinical examination and routine electrodiagnostic studies. We quantified intraepidermal nerve fiber (IENF) density in sections of skin obtained by punch skin biopsy, and found it to be significantly reduced in patients with painful sensory neuropathies compared with age-matched control subjects. In addition, IENF density correlated with clinical estimates of neuropathy severity, as judged by the extent of clinically identifiable sensory abnormalities. IENF density at the calf was lower than that obtained from skin at more proximal sites, indicating the length dependency of small-fiber loss in these neuropathies.NEUROLOGY 1997;48: 708-711

Article abstract-We investigated the possible mechanisms of paralysis and recovery in a patient with the acute motor axonal neuropathy (AMAN) pattern of the Guillain-Barre syndrome. The AMAN pattern of GBS is characterized clinically by acute paralysis without sensory involvement and electrodiagnostically by low compound motor action potential amplitudes, suggesting axonal damage, without evidence of demyelination. Many AMAN patients have serologic or culture evidence of recent Campylobacter jejuni infection. Pathologically, the most severe cases are characterized by wallerian-like degeneration of motor axons affecting the ventral roots as well as peripheral nerves, but some fatal cases have only minor changes in the roots and peripheral nerves, and some paralyzed patients with the characteristic electrodiagnostic findings of AMAN recover rapidly. The mechanism of paralysis and recovery in such cases has been uncertain. A 64-year-old woman with culture-proven Campylobacter upsaliensis diarrhea developed typical features of AMAN. She improved quickly following plasmapheresis. Her serum contained IgG anti-GM1 antibodies. The lipopolysaccharide of the organism bound peanut agglutinin. This binding was blocked by cholera toxin, suggesting that the organism contained the Gal(beta 1-3)GalNAc epitope of GM1 in its lipopolysaccharide. Motor-point biopsy showed denervated neuromuscular junctions and reduced fiber numbers in intramuscular nerves. In contrast, the sural nerve biopsy was normal and skin biopsy showed normal dermal and epidermal innervation. In AMAN the paralysis may reflect degeneration of motor nerve terminals and intramuscular axons. In addition, the anti-GM1 antibodies, which can bind at nodes of Ranvier, might produce failure of conduction. These processes are potentially reversible and likely to underlie the capacity for rapid recovery that characterizes some cases of AMAN.NEUROLOGY 1997;48: 717-724

Objective: To determine whether subjects coinfected with HTLV-I and HIV have a higher frequency of myelopathy than subjects singly infected with HIV. Design: A prospective, nested case-control study of HTLV-I and HIV coinfected (cases) and HIV singly infected adults (controls) participating in a prospective HIV cohort study at a university hospital outpatient HIV clinic in Rio de Janeiro, Brazil. Measurements: Subjects were evaluated for evidence of myelopathy by a neurologist unaware of their HTLV serologic status. Patients with at least two pyramidal signs, such as paresis, hypertonicity or spasticity, hyperreflexia, clonus, diminished or absent superficial reflexes, or the presence of pathologic reflexes (e.g., Babinski or Hoffmann), were defined as having myelopathy. Myelopathy severity was quantified using the Kurtzke Functional Disability Scale (FDS); patients with FDS scores >or=to4 were considered to have significant myelopathy. Selected patients with myelopathy underwent lumbar puncture for the evaluation of intrathecal synthesis of HTLV-I antibodies. Results: Of 15 coinfected subjects, 11 (73%) had evidence of myelopathy versus 10 of 62 subjects (16%) with HIV single infection (adjusted odds ratio [OR] = 13.0, p = 0.00002). When only myelopathy patients with FDS scores of >or=to2 or >or=to4 were included, the association between coinfection and the presence of myelopathy remained (OR = 7.3, p = 0.0003 for scores >or=to2; and OR = 8.9 for scores >or=to4, p = 0.04). In addition, a higher proportion of coinfected subjects had peripheral neuropathy (40%) than controls (16%) (OR = 3.5, p = 0.07). Conclusion: Coinfection with HTLV-I was strongly associated with myelopathy among subjects infected with HIV. The relative contribution of HTLV-I versus HIV in the pathogenesis of coinfection-associated myelopathy is not known. Coinfection may also be associated with peripheral neuropathy. Further studies are needed to elucidate the mechanisms of coinfection-associated neurologic conditions. NEUROLOGY 1997;48: 13-18

We studied the features and frequency of sensory neuropathy among 79 HIV-1-infected individuals participating in a multicenter clinical trial of zalcitabine (2 prime 3 prime-dideoxycytidine, or ddC) antiretroviral therapy. The trial compared zalcitabine monotherapy (2.25 mg/day) versus combination therapy (2.25 mg/day ddC) with zidovudine (ZDV, formerly AZT) versus monotherapy with ZDV alone. Neuropathy developed in 34% of ddC recipients but in only 4% of comparable patients treated with ZDV alone--a 7.9-fold increase in the attack rate of neuropathy. Using risk factor analysis, we found that diabetes mellitus was significantly associated with the development of toxic neuropathy (p equals 0.02), and weight loss may contribute to its appearance. Like HIV-associated sensory neuropathy, ddC-related toxic neuropathy is a predominantly sensory, length-dependent, symmetric, painful neuropathy. Dose reduction lessened the severity of symptoms, although objective signs of neuropathy persisted. Patients with subclinical neuropathies or significant neuropathy risks such as diabetes may be poor candidates for ddC therapy. NEUROLOGY 1996;46: 999-1003.

Soluble Fas (sFas) and soluble Fas ligand (sFasL) are associated with cellular dysfunction and death and are elevated in CSF from patients with HIV dementia (HIV-D). The authors investigated whether these markers correlated with dementia severity and course. sFas and sFasL were measured in 15 highly active antiretroviral therapy (HAART)-naïve HIV-D subjects, 30 HAART-naïve HIV+ controls, and 17 HIV-controls. HIV-D subjects had higher CSF sFas levels than controls. Subjects with moderate/severe dementia had higher CSF sFas levels than those with mild dementia. CSF sFas trended lower in those with progressive dementia.

Objective To describe changes in cognitive functioning before and after development of an acquired immune deficiency syndrome (AIDS)-defining illness or CD4+ lymphocyte count 3 in participants in the Multicenter AIDS Cohort Study. Methods The study population included participants who either were diagnosed with an AIDS-defining illness (n = 52) or had at least one measurement of CD4+ count 3 (n = 57) and who had at least four neuropsycho-logical (NP) evaluations, two or more before and two or more after the AIDS diagnosis. A group of subjects with clinical diagnosis of dementia (n = 29) was also included for comparison. The NP test battery included measures of attention, memory, constructional abilities, and psychomotor speed. Longitudinal data analysis, using the generalized estimating equation, was performed separately for each NP measure. Time was measured in months from the date of clinical AIDS or CD4+ 3 . Results Before AIDS, the dementia group showed significant decline (slope different from zero) only on measures of psychomotor speed. For all other measures, there was no evidence of decline in performance before AIDS for the other groups. ARer development of AIDS, the group with clinical AIDS showed significant decline on psychomotor speed but none on the other cognitive measures. The group with CD4+ 3 did not show significant decline on any of the cognitive measures after AIDS. As expected, the dementia group showed significant decline on all measures. Sensory neuropathy was associated with a significant decline in performance on measures of psychomotor speed after AIDS. Antiretroviral therapy was not associated with any measurable changes in NP performance. Conclusion These results are consistent with previous findings showing no significant decline in cognitive functions before AIDS, unless overt dementia is present, and no decline in immunosuppressed subjects who have had no AIDS-defining illness. By contrast, in subjects who have developed clinical AIDS, there is mild decline in fine motor skills but no significant change in other cognitive domains.

The authors evaluated the association of a virologic response to highly active antiretroviral therapy, or a subsequent rebound, with performance on two measures of psychomotor speed in HIV-positive subjects. Virologic suppression was associated with improved performance on measures of psychomotor speed, and virologic rebound was associated with psychomotor speed performance decline. Changes in plasma HIV viral load in HIV-positive individuals with cognitive slowing correlate with performance on tests of psychomotor speed.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by the JC virus usually in the context of immunodeficiency. We report a case of PML in a patient without evidence of immunosuppression and highlight several issues relating to diagnosis and management. ### Case report. A 62-year-old right-handed man presented with a 2-year history of progressive left-sided headache, speech difficulties, and hand clumsiness. Three weeks prior to admission he had substantial cognitive decline with concentration and memory difficulties. He reported fatigue and 15-pound weight loss. His background history included hypertension and coronary artery disease. He reported isolated, uncomplicated thoracic shingles 4 years prior. There was no history of alcohol abuse. On examination, he was alert but disoriented to time. He had anomia with expressive aphasia. Comprehension and repetition were intact. He recalled 2 of 3 objects. Motor and sensory examinations were unremarkable. Tendon reflexes were brisk on the right. He walked unassisted but was unsteady on tandem gait. Brain MRI (figure) revealed extensive T2/fluid-attenuated inversion recovery hyperintensities involving the left frontal subcortical white matter, sparing the overlying cortex. There was vasogenic edema with ill-defined patchy contrast enhancement. Figure Brain MRI fluid-attenuated inversion recovery sequence and immunohistopathology of the brain tissue (A) At diagnosis. (B) 2 months post mefloquine. (C) 6 months post mefloquine therapy. (D) The lesion comprises perivascular and interstitial chronic inflammation, atypical astrocytes, …

Background: Sensory neuropathy (SN) is common in patients with HIV. Hepatitis C (HCV) coinfection is often cited as an HIV-SN risk factor, but data to support this are lacking. This collaboration aimed to examine the association between HCV serostatus and SN risk among ambulatory HIV-positive patients. Methods: Patients with HIV were assessed in cross-sectional studies in Baltimore, Jakarta, Johannesburg, Kuala Lumpur, Melbourne, and Sydney for SN (defined by both supportive symptoms and signs). HCV seropositivity was assessed as an SN risk using a χ 2 test, followed by logistic regression modeling to correct for treatment exposures and demographics. Results: A total of 837 patients of African, Asian, and Caucasian descent were studied. HCV seroprevalence varied by site (Baltimore n = 104, 61% HCV+; Jakarta 96, 51%; Johannesburg 300, 1%; Kuala Lumpur 97, 10%; Melbourne 206, 16%; Sydney 34, 18%). HCV seropositivity was not associated with increased SN risk at any site, but was associated with reduced SN risk in Melbourne ( p = 0.003). On multivariate analyses, the independent associations with SN were increasing age, height, and stavudine exposure. HCV seropositivity was not independently associated with an increased SN risk at any site, but associated independently with reduced SN risk in Baltimore ( p = 0.04) and Melbourne ( p = 0.06). Conclusions: Hepatitis C (HCV) seropositivity was not associated with increased sensory neuropathy risk among HIV-positive patients at any site. While we were unable to assess HCV RNA or liver damage, the data suggest that HCV coinfection is not a major contributor to HIV-SN. HCV = hepatitis C; SN = sensory neuropathy.

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection that develops in immunosuppressed patients with HIV infection. Paradoxically, some of these patients may develop PML during combined antiretroviral therapy in the setting of immune reconstitution. We describe the types of PML in relation to immune reconstitution inflammatory syndrome (IRIS) and the effects of steroid use in these patients. Methods: We performed a retrospective review of the literature (1998 to 2007) and of all HIV-infected patients diagnosed with PML-IRIS at Johns Hopkins Hospital (2004 to 2007). We recorded information on clinical features, microbiologic and virological analysis, neuroimaging, pathology, treatment, and outcome. Results: Of 54 patients with PML-IRIS, 36 developed PML and IRIS simultaneously (PML-s-IRIS) and 18 had worsening of preexisting PML (PML-d-IRIS) after the initiation of combined antiretroviral therapy. PML-IRIS developed between 1 week and 26 months after initiation of antiretroviral therapy. PML-d-IRIS patients developed IRIS earlier, had higher lesion loads on MRI of the brain, had shorter durations of survival, and had higher mortality rate compared to PML-s-IRIS patients. Twelve patients received treatment with steroids, of which five died and seven showed good neurologic recovery. Patients who survived had received steroids early after IRIS diagnosis for longer durations and had contrast enhancement on IRIS neuroimaging. Conclusions: Immune reconstitution following initiation of combined antiretroviral therapy may lead to activation of an inflammatory response to detectable or latent JC virus infection. Early and prolonged treatment with steroids may be useful in these patients but requires further investigation.

While it is clear that HIV-1 can cause CNS dysfunction, current approaches to classification and diagnosis of this dysfunction rely on syndromic definitions or measures of abnormality on neuropsychological testing in the background context of HIV-1 infection. These definitions have been variably applied, offer only limited sensitivity or specificity, and do not easily distinguish active from static brain injury. Supplanting or augmenting these approaches with objective biologic measurements related to underlying disease processes would provide a major advance in classification, diagnosis, epidemiology, and treatment assessment. Two major avenues are now actively pursued to this end: 1) analysis of soluble molecular markers in CSF and, to a lesser degree, in blood, and 2) neuroimaging markers using anatomic, metabolic, and functional measurements. This review considers the rationale and prospects of these approaches.

Background: Infection with HIV can result in a debilitating CNS disorder known as HIV dementia (HIV-D). Since the advent of highly active antiretroviral therapy (HAART), the incidence of HIV-D has declined, but the prevalence continues to increase. In this new era of HIV-D, traditional biomarkers such as CSF viral load and monocyte chemotactic protein 1 levels are less likely to be associated with dementia in patients on HAART and biomarkers that can predict HIV-D have not yet been identified. Objective: To identify biomarkers that are associated with and can predict HIV-D. Methods: We grouped patients with HIV based on changes in cognitive status over a 1-year period and analyzed sphingolipid, sterol, triglyceride, antioxidant, and lipid peroxidation levels in CSF. Results: We found that increased levels of the vitamin E and triglyceride C52 predicted the onset or worsening of dementia. Elevated levels of sphingomyelin were associated with inactive dementia. Elevated levels of ceramide and the accumulation of 4-hydroxynonenals were associated with active dementia. Conclusions: We interpret these findings to indicate that early in the pathogenesis of HIV dementia, there is an up-regulation of endogenous antioxidant defenses in brain. The failure of this attempted neuroprotective mechanism leads to the accumulation of sphingomyelin and moderate cognitive dysfunction. The breakdown of this enlarged pool of sphingomyelin to ceramide and the accumulation of highly reactive aldehydes are associated with declining cognitive function. Thus, elevations in endogenous protective mechanisms may identify patients who are at increased risk of the development of HIV dementia.

To determine whether abnormalities in peripheral nerve regeneration are present in HIV-infected individuals.We studied human epidermal nerve fiber reinnervation by collateral and regenerative sprouting using validated cutaneous nerve injury models in healthy control subjects and those infected with HIV. Characteristics associated with the degree of reinnervation were identified.Seventy-one healthy volunteers and 22 HIV+ individuals underwent topical capsaicin treatment at the distal lateral thigh resulting in complete epidermal denervation. Regenerative sprouting was quantified in skin biopsies at intervals up to 100 days. Five healthy subjects and 5 HIV+ individuals underwent a 3-mm distal thigh punch skin biopsy to create an intracutaneous axotomy, followed 2 months later by a 4-mm overlapping biopsy. The collateral sprouting distance was measured.The mean rate of regenerative sprouting was highest for healthy control subjects (0.17 +/- 0.073 fibers/mm/day), followed by HIV+ subjects without neuropathy (0.13 +/- 0.06) and then HIV+ subjects with neuropathy (0.097 +/- 0.07) (p = 0.002). Regenerative sprouting was significantly associated with the baseline intraepidermal nerve fiber density (p0.001) but not with HIV viral load, HIV duration, CD4 cell count, or ApoE epsilon4 status. HIV+ individuals were also found to have a reduced collateral sprouting rate compared to controls (5.31 mum +/- 0.73 vs 9.78 mum +/- 1.5/day, p = 0.03).Abnormalities in both regenerative and collateral sprouting are present in people infected with HIV, and are detectable in subjects with and without evidence of peripheral nerve dysfunction. Our results indicate that abnormalities in nerve regeneration occur early in HIV infection and provide a rationale to include neuropathy-free HIV subjects in regenerative peripheral nerve trials.

HIV-associated dementia (HAD) is not firmly established in patients with circulating recombinant form (CRF) 01_AE HIV-1. In this study, we compared neuropsychological performance among 15 Thai individuals with HAD, 15 Thai individuals without HAD, and 30 HIV-negative control subjects. HIV-1 participants were highly active anti-retroviral therapy naive and matched by age, education, and CD4 count. Neuropsychological testing abnormalities were identified in most cognitive domains among HAD vs HIV-negative participants, confirming the presence of HAD in CRF01_AE.