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Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger ( Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population. Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.

Background Neurofilament light (NFL) chain concentrations, reflecting axonal damage, are seen in several polyneuropathies but have not been studied in human immunodeficiency virus (HIV) distal sensory polyneuropathy (DSP). We evaluated NFL in cerebrospinal fluid (CSF) and plasma in relation to DSP in people with HIV (PWH) from 2 independent cohorts and in people without HIV (PWoH). Methods Cohort 1 consisted of PWH from the CHARTER Study. Cohort 2 consisted of PWH and PWoH from the HIV Neurobehavioral Research Center (HNRC). We evaluated DSP signs and symptoms in both cohorts. Immunoassays measured NFL in CSF for all and for plasma as well in Cohort 2. Results Cohort 1 consisted of 111 PWH, mean ± SD age 56.8 ± 8.32 years, 15.3% female, 38.7% Black, 49.6% White, current CD4+ T-cells (median, interquartile range [IQR]) 532/µL (295, 785), 83.5% with plasma HIV RNA ≤50 copies/mL. Cohort 2 consisted of 233 PWH of similar demographics to PWH in Cohort 1 but also 51 PWoH, together age 58.4 ± 6.68 years, 41.2% female, 18.0% Black, Hispanic, non-Hispanic White 52.0%, 6.00% White. In both cohorts of PWH, CSF and plasma NFL were significantly higher in both PWH with DSP signs. Findings were similar, albeit not significant, for PWoH. The observed relationships were not explained by confounds. Conclusions Both plasma and CSF NFL were elevated in PWH and PWoH with DSP. The convergence of our findings with others demonstrates that NFL is a reliable biomarker reflecting peripheral nerve injury. Biomarkers such as NFL might provide, validate, and optimize clinical trials of neuroregenerative strategies in HIV DSP.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause neurological sequelae after the resolution of symptomatic COVID-19 illness, but the occurrence of peripheral neuropathy symptoms and cranial nerve dysfunction is unknown. This study aimed to characterize the occurrence and severity of pain and peripheral neuropathy symptoms in patients with SARS-CoV-2 infection. An observational cohort study included adults tested for a SARS-CoV-2 infection at an academic medical center (assigned as CV+ or control, based on test results). Thirty to 90 days after the index SARS-CoV-2 test, patients completed a web-based questionnaire assessing pain, peripheral neuropathy-related sensory symptoms, and symptoms in the distribution of cranial nerves (current symptoms, symptoms at testing and 2 weeks thereafter). Univariate analyses compared the outcomes between the groups. Multivariable analysis was used to determine the odds for neuropathy symptoms after adjusting for key baseline variables. A total of 1556 participants were included: 542 CV+ patients and 1014 control subjects. CV+ patients reported a higher occurrence of peripheral neuropathy symptoms in the extremities anytime within 90 days postinfection (28.8% vs 12.9%, odds ratio [OR] [95% confidence interval] = 2.72 [2.10-3.54]), as well as such symptoms persisting up to 90 days after infection (6.1% vs 1.9%, OR = 3.39 [1.91-6.03]). The occurrence of pain in the extremities was higher in the CV+ group (24.2% vs 9.8%, OR = 2.95 [2.21-3.91]). SARS-CoV-2 infection was also associated with higher occurrence of peripheral neuropathy symptoms, after adjusting for the history of chronic pain and neuropathy (OR = 3.19 [2.37-4.29]). The results suggest that SARS-CoV-2 infection was independently associated with an increased risk of pain and peripheral neuropathy symptoms.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

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.

Although plasma D-dimer levels are high in patients with some types of peripheral neuropathy, this has not been examined in people with HIV (PWH). We tested the hypothesis that higher plasma D-dimer levels would be related to the presence and severity of HIV-associated distal sensory peripheral neuropathy (DSP). Participants in a U.S. research cohort were evaluated using standardized clinical examinations and interviews for findings of DSP and distal neuropathic pain by trained clinicians. D-dimer levels in the two neuropathy groups (0 or 1 versus 2 or more neuropathy signs), were compared using the Wilcoxon rank sum test. Multivariable regression assessed the effects of age and other covariates. Participants were 185 PWH, mean (SD) age 56.2 (8.10), 19.7% females, 56.4% non-White, median nadir and current CD4 lymphocytes 107 (IQR 20, 210) and 567 (348, 817), undetectable plasma HIV RNA 79.9%; and 210 people without HIV (PWoH), mean age 50.6 (15.8) years, 38.6% female, 18.1% non-White. Among PWH, 50 had 0 signs, 47 had 1 and 88 had 2 or more; among PWoH, 149 had 0 signs, 38 had 1 sign, and 23 had 2 or more signs (PWH versus PWoH p = 1.36e-20). Log10 plasma D-dimer levels were higher in PWH than PWoH (2.78±0.233 versus 2.66±0.253, p = 5.20e-6). D-dimer was significantly higher in those with DSP (2 or more DSP signs) compared to those without (p = 0.0017, Wilcoxon rank sum test). In multivariable analyses this relationship was independent of potential confounders. This association persisted in a sensitivity analysis that was limited to only the subset of participants with undetectable plasma HIV RNA (Wilcoxon p = 0.041). In PWoH, d-dimer levels were numerically higher in those with DSP (2.75±0.206 versus 2.65±0.256, p = 0.0604). Neuropathy symptoms (pain, paresthesias) were not significantly related to D-dimer levels. Since DSP is a major cause of disability in PWH, identifying biomarkers such as D-dimer may enable future investigations to assess prognosis or response to therapy.

Human immunodeficiency virus (HIV) infection is potentially associated with premature aging, but demonstrating this is difficult due to a lack of reliable biomarkers. The mitochondrial (mt) DNA "common deletion" mutation (mtCDM) is a 4977-bp deletion associated with aging and neurodegenerative diseases. We examined how mtDNA and mtCDM correlate with markers of neurodegeneration and inflammation in people with and without HIV (PWH and PWOH). Data from 149 adults were combined from two projects involving PWH (n = 124) and PWOH (n = 25). We measured buccal mtDNA and mtCDM by digital droplet PCR and compared them to disease and demographic characteristics and soluble biomarkers in cerebrospinal fluid (CSF) and blood measured by immunoassay. Participants had a median age of 52years, with 53% white and 81% men. Median mtDNA level was 1,332 copies/cell (IQR 1,201-1,493) and median mtCDM level was 0.36 copies × 102/cell (IQR 0.31-0.42); both were higher in PWH. In the best model adjusting for HIV status and demographics, higher mtDNA levels were associated with higher CSF amyloid-β 1-42 and 8-hydroxy-2'-deoxyguanosine and higher mtCDM levels were associated with higher plasma soluble tumor necrosis factor receptor II. The differences in mtDNA markers between PWH and PWOH support potential premature aging in PWH. Our findings suggest mtDNA changes in oral tissues may reflect CNS processes, allowing the use of inexpensive and easily accessible buccal biospecimens as a screening tool for CSF inflammation and neurodegeneration. Confirmatory and mechanistic studies on mt genome alterations by HIV and ART may identify interventions to prevent or treat neurodegenerative complications.

Summary Background Few large projects have evaluated the factors that influence the HIV RNA concentrations (viral load) in cerebrospinal fluid (CSF) during antiretroviral therapy (ART) over time. We aimed to determine the correlates of HIV RNA in CSF in a large cohort. Methods We analysed longitudinal data from adults living with HIV in the US CHARTER cohort. Participants in the CHARTER study were recruited from six US academic medical centres—in Baltimore (MD), Galveston (TX), New York (NY), St Louis (MO), San Diego (C92A), and Seattle (WA). Participants in this study had been assessed at least three times between Sept 4, 2003, and Sept 14, 2010, and were taking ART and underwent venous and lumbar puncture with measurement of HIV RNA concentration at all assessments. The lower limit of quantification of the HIV RNA assays was 50 copies per mL. Data were analysed with longitudinal mixed effects logistic regression to identify correlates of HIV RNA concentration (as a binary [detectable or not] and as a continuous variable) in CSF over time. We tested demographic characteristics, plasma HIV RNA, nadir and current CD4 cell count in blood, current CD8 cell count in blood, estimated duration of HIV infection, AIDS diagnosis, duration of ART, adherence to ART, ART characteristics, and CSF characteristics as potential correlates. Findings At the time of analysis, 2207 assessments from 401 participants met the criteria for inclusion in this study. Mean duration of observation was 33·7 months (range 12–84). HIV RNA concentrations in 710 (32·2%) plasma specimens and in 255 (11·6%) CSF specimens were greater than the lower limit of quantification. The best multivariate model of HIV RNA concentration in CSF greater than the lower limit of quantification over time included increased plasma HIV RNA concentration (odds ratio 18·0 per 1 log10 copy per mL, 95% CI 11·3 to 28·8; p Interpretation The identified correlates of HIV RNA concentration in CSF during ART could strengthen clinical prediction of risk for failure to achieve or maintain HIV RNA suppression in CSF. Because most participants in this analysis were ART-experienced and were taking a three-drug regimen that did not include an integrase inhibitor, future research should focus on participants who are taking their first ART regimens or regimens that include integrase inhibitors or two drugs. Funding The work was supported by the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Author(s): Ellis, Ronald J; Diaz, Monica; Sacktor, Ned; Marra, Christina; Collier, Ann C; Clifford, David B; Calcutt, Nigel; Fields, Jerel A; Heaton, Robert K; Letendre, Scott L; CNS Antiretroviral Therapy Effects Research (CHARTER) Study Group | Abstract: ObjectiveDistal sensory polyneuropathy (DSP) and neuropathic pain are important clinical concerns in virally suppressed people with HIV. We determined how these conditions evolved, what factors influenced their evolution, and their clinical impact.MethodsAmbulatory, community-dwelling HIV seropositive individuals were recruited at six research centers. Clinical evaluations at baseline and 12nyears later determined neuropathy signs and distal neuropathic pain (DNP). Additional assessments measured activities of daily living and quality of life (QOL). Factors potentially associated with DSP and DNP progression included disease severity, treatment, demographics, and co-morbidities. Adjusted odds ratios were calculated for follow-up neuropathy outcomes.ResultsOf 254 participants, 21.3% were women, 57.5% were non-white. Mean baseline age was 43.5nyears. Polyneuropathy prevalence increased from 25.7% to 43.7%. Of 173 participants initially pain-free, 42 (24.3%) had incident neuropathic pain. Baseline risk factors for incident pain included unemployment (OR [95% CI], 5.86 [1.97, 17.4]) and higher baseline body mass index (BMI) (1.78 [1.03, 3.19] per 10-units). Participants with neuropathic pain at follow-up had significantly worse QOL and greater dependence in activities of daily living than those who remained pain-free.InterpretationHIV DSP and neuropathic pain increased in prevalence and severity over 12nyears despite high rates of viral suppression. The high burden of neuropathy included disability and poor life quality. However, substantial numbers remained pain-free despite clear evidence of neuropathy on exam. Protective factors included being employed and having a lower BMI. Implications for clinical practice include promotion of lifestyle changes affecting reversible risk factors.

While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect.Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes.Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes.Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases.We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies.Dose-dependent treatment effects were observed in some biomarkers.No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer’s disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed “practice effects”). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies.

Neurocognitive (NC) impairment in people with HIV (PWH) is associated with important adverse outcomes, but no markers exist to predict long-term NC decline. We evaluated depressed mood and markers of persistent inflammation, oxidative stress and altered amyloid processing (all common in PWH) as predictors of NC worsening over 12 years.PWH were enrolled and followed longitudinally in the CNS HIV Antiretroviral Effects Research (CHARTER) study at six US sites. At entry we quantified biomarkers in blood of inflammation: (interleukin-6 [IL-6], C-reactive protein [CRP], monocyte chemoattractant protein type 1 [MCP-1], D-dimer, soluble sCD14 (sCD14), soluble tumor necrosis factor receptor - type II [sTNFR-II], neopterin, and soluble CD40 ligand [sCD40L], oxidative stress (protein carbonyls, 8-oxo-2'-deoxyguanosine [8-oxo-dG]) and altered amyloid processing [amyloid beta (Aβ)-42, soluble amyloid precursor protein-α (sAPPα)] using commercial immunoassays. The Beck Depression Inventory-II (BDI-II) assessed depressed mood at entry. NC decline over 12 years was evaluated using the published and validated summary (global) regression-based change score (sRBCS). A factor analysis reduced dimensionality of the biomarkers. Univariable and multiple regression models tested the relationship between baseline predictors and the outcome of neurocognitive decline.Participants were 191 PWH, 37 (19.4%) women, 46.6% African American, 43.5% non-Hispanic white, 8.83% Hispanic, 15.7% white, 1.6% other; at study entry mean (SD) age 43.6 (8.06) years, estimated duration of HIV infection (median, IQR) 9.82 [4.44, 14.5] years, nadir CD4 104/μL (19,205), current CD4 568/μL (356, 817), and 80.1% had plasma HIV RNA50 c/mL. Participants were enrolled between 2003 and 2007; median (IQR) duration of follow-up 12.4 [9.69, 16.2] years. Three biomarker factors were identified: Factor (F)1 (IL-6, CRP), F2 (sTNFR-II, neopterin) and F3 (sCD40L, sAPPα). Participants with higher F1, reflecting worse systemic inflammation at baseline, and higher F3, had greater decline in global neurocognition (r ​= ​-0.168, p ​= ​0.0205 and r ​= ​-0.156, p ​= ​0.0309, respectively). Of the F1 components, higher CRP levels were associated with worse decline (r ​= ​-0.154, p ​= ​0.0332), while IL-6 did not (r ​= ​-0.109, p ​= ​0.135). NC change was not significantly related to F2, nor to demographics, nadir and current CD4, viral suppression or baseline NC comorbidity ratings. Individuals with worse depressed mood at entry also experienced more NC decline (r ​= ​-0.1734, p ​= ​0.0006). Together BDI-II (p ​= ​0.0290), F1 (p ​= ​0.0484) and F3 (p ​= ​0.0309) contributed independently to NC decline (p ​= ​0.0028); their interactions were not significant. Neither CRP nor IL-6 correlated significantly with depression.PWH with greater systemic inflammation and more depression at entry had greater NC decline over 12 years. Understanding the basis of this inflammatory state might be particularly important. These findings raise the possibility that targeted anti-inflammatory or antidepressant therapies may help prevent NC worsening in PWH with depression and inflammation.

Objective Distal sensory polyneuropathy (DSP) is a disabling consequence of human immunodeficiency virus (HIV), leading to poor quality of life and more frequent falls in older age. Neuropathic pain and paresthesia are prevalent symptoms; however, there are currently no known curative treatments and the longitudinal course of pain in HIV-associated DSP is poorly characterized. Methods This was a prospective longitudinal study of 265 people with HIV (PWH) enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study with baseline and 12-year follow-up evaluations. Since pain and paresthesia are highly correlated, statistical decomposition was used to separate the two symptoms at baseline. Multivariable logistic regression analyses of decomposed variables were used to determine the effects of neuropathy symptoms at baseline on presence and worsening of distal neuropathic pain at 12-year follow-up, adjusted for covariates. Results Mean age was 56 ± 8 years, and 21% were female at follow-up. Nearly the entire cohort (96%) was on antiretroviral therapy (ART), and 82% had suppressed (≤50 copies/mL) plasma viral loads at follow-up. Of those with pain at follow-up (n = 100), 23% had paresthesia at the initial visit. Decomposed paresthesia at baseline increased the risk of pain at follow-up (odds ratio [OR] 1.56; 95% confidence interval [CI] 1.18, 2.07), and decomposed pain at baseline predicted a higher frequency of pain at follow-up (OR 1.96 [95% CI 1.51, 2.58]). Conclusions Paresthesias are a clinically significant predictor of incident pain at follow-up among aging PWH with DSP. Development of new therapies to encourage neuroregeneration might take advantage of this finding to choose individuals likely to benefit from treatment preventing incident pain.

Objective:Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.Method:Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.Results:When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.Conclusions:The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

Author(s): Saloner, Rowan; Heaton, Robert K; Campbell, Laura M; Chen, Anna; Franklin, Donald; Ellis, Ronald J; Collier, Ann C; Marra, Christina; Clifford, David B; Gelman, Benjamin; Sacktor, Ned; Morgello, Susan; McCutchan, J Allen; Letendre, Scott; Grant, Igor; Fennema-Notestine, Christine; CHARTER Study Group | Abstract: ObjectiveThe influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.DesignObservational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.MethodsA total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.ResultsComorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).ConclusionNeuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.

Author(s): Saloner, Rowan; Campbell, Laura M; Serrano, Vanessa; Montoya, Jessica L; Pasipanodya, Elizabeth; Paolillo, Emily W; Franklin, Donald; Ellis, Ronald J; Letendre, Scott L; Collier, Ann C; Clifford, David B; Gelman, Benjamin B; Marra, Christina M; McCutchan, J Allen; Morgello, Susan; Sacktor, Ned; Jeste, Dilip V; Grant, Igor; Heaton, Robert K; Moore, David J; CHARTER and HNRP Groups | Abstract: OBJECTIVES:Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. METHODS:734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. RESULTS:Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. CONCLUSIONS:Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507-519).

BackgroundDuring antiretroviral therapy, HIV RNA can be detected in cerebrospinal fluid (CSF) when it is undetectable in plasma, a condition termed 'CSF viral escape'. The aim of the current study was to determine the prevalence and risk factors for CSF viral escape in two large cohorts in the USA.MethodsA total of 1264 HIV-infected volunteers enrolled in two US cohorts at their most recent visit between 2003 and 2011 were included in this cross-sectional analysis if their HIV RNA level in plasma was less than 50 copies/ml while receiving stable antiretroviral therapy (ART) (>6 months) and if they had HIV RNA measured in CSF at their most recent visit between 2003 and 2011. Potential risk factors were identified using univariable and multivariable regression.ResultsCSF viral escape was detected in 55 adults (4.4%; 95% CI: 3.4-5.6), who had a median CSF HIV RNA of 155 copies/ml [interquartile range (IQR: 80-283)]. Patients with or without CSF viral escape had similar rates of neurocognitive impairment (38.2 vs. 37.7%; P = 0.91). CSF viral escape was independently associated with the use of ritonavir-boosted protease inhibitors [odds ratio (OR): 2.0; 95% CI: 1.1-3.8] or unboosted atazanavir (OR: 5.1; 95% CI: 1.3-16.1), CSF pleocytosis (OR: 7.6; 95% CI: 4.2-13.7) and abnormal CSF total protein (OR: 2.1; 95% CI: 1.1-3.7).ConclusionsIn this large study of aviremic patients receiving ART, CSF viral escape was uncommon and was linked to evidence of central nervous system inflammation and the use of protease inhibitors, but not with worse neurocognitive performance.

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders.

Importance The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Objective IgG4-related disease (IgG4-RD) is an inflammatory process that uncommonly can present in the skull base and calvarium and mimic a tumor but the nature of this condition is not well summarized in the neurosurgical literature. Methods A review was performed of 2 cases of IgG4-RD in the skull base highlighting the diagnostic challenges with assessment of these skull base lesions, and a systematic review of relevant literature was carried out. Results A systematic review of the literature conducted in accordance with PRISMA guidelines identified 113 articles, with 184 cases of IgG4-RD in the skull base or calvarium. The most commonly affected locations include the meninges, cavernous sinus, base of the posterior fossa, clivus, and mastoid bone. Headache, visual and auditory disturbances, cranial nerve dysfunction, and seizures were the most common presenting symptoms. Medical treatment was highly successful and most commonly consisted of corticosteroids coadministered with immunosuppressive agents such as rituximab. Prevalence seemed to be equal between sexes, and serum IgG4 levels were increased in 61% of patients. Delayed diagnosis and a need for multiple biopsies were reported in numerous cases. Two cases of skull base IgG4-RD from the authors' institution show the variable presentations of this disease. More invasive surgical biopsies were required in both cases, and corticosteroid treatment led to significant clinical improvement. Conclusions IgG4-RD is an uncommon condition with an increasing body of reported cases that can affect the skull base and calvarium and should be in the differential diagnosis, because delay in diagnosis and treatment may be common.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.

Author(s): Ellis, Ronald J; Letendre, Scott L; Atkinson, J Hampton; Clifford, David; Collier, Ann C; Gelman, Benjamin B; Marra, Christina; McCutchan, J Allen; Morgello, Susan; Sacktor, Ned; Tang, Bin; Heaton, Robert K | Abstract: Background and objectivesPeople with HIV (PWH) often suffer from depressive symptoms which have a deleterious impact on numerous domains including antiretroviral adherence and quality of life. In the general population, a treatment-resistant phenotype of depression is associated with systemic inflammation, which is of considerable importance as it responds favorably to anti-inflammatory medications. Aging PWH experience increasing inflammation. We sought to evaluate the impact of chronic inflammation in aging PWH on depressed mood.MethodsPWH were recruited at 6 U.S. academic medical centers. Depressed mood was assessed using the Beck Depression Inventory (BDI)-II. Inflammatory biomarkers measured at the 12-year follow-up visit in blood plasma using immunoassays were neopterin, sTNFRII, d-dimer, IL-6, CRP, MCP-1, sCD14 and sCD40L. Factor analyses with oblique Equamax rotation were employed to reduce the dimensionality of the biomarkers.ResultsParticipants were 78 PWH, 14 (17.9%) women, 40 (51.3%) non-White, mean age 55.3 (±SD 8.29), with a nadir and current CD4 of 134 (IQR 36, 204) and 567 (316, 797), respectively. 80.5% were virally suppressed. A factor analysis of the eight inflammatory biomarkers in plasma at the 12-year follow-up visit yielded 3 Factors, with Factor 1 loading on neopterin and sTNFRII, Factor 2 loading on d-dimer, IL-6 and CRP, and Factor 3 loading on sCD40L (MCP-1 and sCD14 did not appear in any of the factors). Univariate regressions of each factor vs BDI-II scores yielded significance only for Factor 2 (rn​=n​0.295; pn​=n​0.0083 (Bonferroni-adjusted pn​=n​0.0261). Of the Factor 2 component biomarkers, BDI-II scores correlated significantly with d-dimer and IL-6, but not CRP. Women had worse BDI-II scores (pn​=n​0.0127). In a logistic regression with sex and Factor 2, both variables were significant (sex pn​=n​0.0246, Factor 2 pn​=n​0.0168). The relationship between Factor 2 and BDI was significant for men (rn​=n​0.348 [95% CI 0.111, 0.547]; pn​=n​0.0049), but not women (rn​=n​0.0580 95% CI -0.488, 0.571]; pn​=n​0.844). Viral suppression was not significant in the multivariate model.ConclusionsSome PWH with depressed mood have elevated markers of inflammation in blood. Men showed this relationship, while women did not. Together with previous findings that an inflammatory depression phenotype responds to treatment with anti-inflammatory medications, our findings suggest that treatment with anti-inflammatory medications might benefit at least a subset of depressed PWH who have a high inflammatory biomarker profile, as well as poor response to antidepressant medications alone, and that the pathophysiology of depression in men and women with HIV may differ.

Key PointsTherapy with an IL-15 superagonist resulted in immune and clinical responses in a transplant recipient with PML.

Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson’s disease. Methods: We conducted a population-based case-control study of incident Parkinson’s disease in 2009 Medicare beneficiaries age 66–90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for “herpes simplex” and/or “herpes zoster” in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson’s disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care. Results: Parkinson’s disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74–0.84), herpes zoster (OR 0.88, 95% CI 0.85–0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80–0.96). Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson’s disease, but future studies will be required to explore whether this inverse association is causal.

Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus–associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00848-z) contains supplementary material, which is available to authorized users.

ObjectivePeople with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today.DesignThis time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART.MethodsSoluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders.ResultsOf 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all pG variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-valuesConclusionsHigher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.

Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

Dysregulated iron transport and a compromised blood-brain barrier are implicated in HIV-associated neurocognitive disorders (HAND). We quantified the levels of proteins involved in iron transport and/or angiogenesis-ceruloplasmin, haptoglobin, and vascular endothelial growth factor (VEGF)-as well as biomarkers of neuroinflammation, in cerebrospinal fluid (CSF) from 405 individuals with HIV infection and comprehensive neuropsychiatric assessments. Associations with HAND [defined by a Global Deficit Score (GDS) ≥ 0.5, GDS as a continuous measure (cGDS), or by Frascati criteria] were evaluated for the highest versus lowest tertile of each biomarker, adjusting for potential confounders. Higher CSF VEGF was associated with GDS-defined impairment [odds ratio (OR) 2.17, p= 0.006] and cGDS in unadjusted analyses and remained associated with GDS impairment after adjustment (p= 0.018). GDS impairment was also associated with higher CSF ceruloplasmin (p= 0.047) and with higher ceruloplasmin and haptoglobin in persons with minimal comorbidities (ORs 2.37 and 2.13, respectively; both p= 0.043). In persons with minimal comorbidities, higher ceruloplasmin and haptoglobin were associated with HAND by Frascati criteria (both p&nbsp

Purpose of review HIV-associated neurocognitive disease is the most active topic for neuroAIDS investigations at present. Although impairment is mild in patients successfully treated with modern antiviral regimens, it remains an ongoing problem for HIV patients. It is important to update the emerging research concerning HIV-associated neurocognitive disease. Recent findings The virus enters the brain during acute infection, with evidence for abnormal functioning that may occur early and often persists. Direct relationships with ongoing viral infection continue to be monitored, but chronic inflammation often associated with monocytes and macrophages appears to be the most likely driver of cognitive dysfunction. Appreciation for cerebrovascular disease as a significant comorbidity that is associated with cognitive deficits is increasing. Neuroimaging is actively being developed to address detection and measurement of changes in the brain. Optimal combined antiretroviral treatment therapy has vastly improved neurologic outcomes, but so far has not been demonstrated to reverse the remaining mild impairment. Inflammatory and vascular mechanisms of cerebral dysfunction may need to be addressed to achieve better outcomes. Summary Ongoing research is required to improve neurological outcomes for persons living with HIV. It is likely that interventions beyond antiviral approaches will be required to control or reverse HIV-associated neurocognitive disease.

A 53-year-old man with an 18-year history of multiple sclerosis (MS) was treated with natalizumab for 7 years. Two years prior to presentation, natalizumab treatment interval was increased to every 6 weeks in attempt to reduce the risk of PML. Medical history was notable for cutaneous T-cell lymphoma status-post CHOP chemotherapy. JCV serology was positive (index 2.8). He presented to our tertiary referral center for consultation due to 8 months of progressive left-sided paresthesias, 4 months of right arm clumsiness, and several weeks of expressive aphasia. Neurologic examination was consistent with these symptoms. Serial brain MRIs demonstrated progressive development of a subcortical, multifocal T2/fluid-attenuated inversion recovery hyperintensity in the left frontoparietal white matter (figure 1). Subtle but definite MRI abnormalities were present in the same area 12 months prior. His clinical course and MRI findings prompted urgent evaluation for PML.