Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy.

OBJECTIVE: The 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. METHODS: In 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. RESULTS: Sixty-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). CONCLUSIONS: Both 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.

Sudden Sensorineural Hearing and Vestibular Loss in a Case of Relapsing Polychondritis.

OBJECTIVES: To report a case of profound bilateral sensorineural hearing and vestibular loss from relapsing polychondritis and hearing outcomes after cochlear implantation. METHODS: Case report and literature review. RESULTS: A 43 year-old woman developed sudden loss of hearing and balance that progressed over several weeks to bilateral, profound hearing and vestibular loss. Steroid treatments were ineffective. She underwent vestibular physical therapy and left cochlear implantation. About 10 months after her initial presentation, she developed erythema, warmth, swelling, and pain of the left auricle sparing the lobule, flattening of the bridge of her nose, and right ankle swelling, warmth, and skin erythema. A biopsy of the left auricle revealed histopathologic findings consistent with relapsing polychondritis. She was treated with high dose prednisolone. The ear inflammation resolved, however, despite excellent auditory response to pure tone thresholds, the patient reported no improvement in speech perception after cochlear implantation. CONCLUSIONS: Relapsing polychondritis can present with rapidly progressive, profound loss of hearing and vestibular function. Hearing outcomes after cochlear implantation can include poor speech discrimination despite good pure tone detection thresholds.

Neurological manifestations associated with COVID-19: a review and a call for action.

While the epidemic of Coronavirus disease 2019 (COVID-19) continues to spread globally, more and more evidences are collected about the presence of neurological manifestations and symptoms associated with it. A systematic review has been performed of papers published until 5 April 2020. 29 papers related to neurological manifestations associated with COVID-19 were examined. The results show presence of central and peripheral nervous system manifestations related to coronavirus. Neurological manifestations, or NeuroCOVID, are part of the COVID-19 clinical picture, but questions remain regarding the frequency and severity of CNS symptoms, the mechanism of action underlying neurological symptoms, and the relationship of symptoms with the course and severity of COVID-19. Further clinical, epidemiological, and basic science research is urgently needed to understand and address neurological sequalae of COVID-19. Concomitant risk factors or determinants (e.g. demographic factors, comorbidities, or available biomarkers) that may predispose a person with COVID-19 to neurological manifestations also need to be identified. The review shows that although more and more papers are reporting neurological manifestations associated with COVID-19; however, many items remain unclear and this uncertainty calls for a global action that requires close coordination and open-data sharing between hospitals, academic institutions and the fast establishment of harmonised research priorities and research consortia to face the NeuroCOVID-19 complications.

Chronic inflammation mediates brain injury in HIV infection: relevance for cure strategies.

PURPOSE OF REVIEW: Chronic inflammation is a major component of HIV infection, the effects of which can be devastating in the central nervous system (CNS). Protecting the brain is, therefore, critical as efforts proceed to cure HIV infection by reactivating latent viral reservoirs and driving immune responses. We review the clinical presentation and pathology findings of inflammatory processes in the CNS in patients managed with ART and the drivers of these processes. RECENT FINDINGS: Chronic inflammation is associated with increased mortality and morbidity and HIV infection increases the risk for chronic diseases, especially cognitive impairment. Latent viral reservoirs, including microglia and tissue macrophages, contribute to inflammation in the CNS. Inflammation is generated and maintained through residual viral replication, dysregulation of infected cells, continuously produced viral proteins and positive feedback loops of chronic inflammation. Novel therapeutics and lifestyle changes may help to protect the CNS from immune-mediated damage. SUMMARY: As therapies are developed to cure HIV, it is important to protect the CNS from additional immune-mediated damage. Adjunctive therapies to restore glial function, reduce neuroinflammation and systemic inflammation, and inhibit expression of viral proteins are needed.

Clinician-rated measures for distal symmetrical axonal polyneuropathy: ACTTION systematic review.

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.

Correlates of HIV RNA concentrations in cerebrospinal fluid during antiretroviral therapy: a longitudinal cohort study.

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<0·0001), increased CSF leucocyte count (2·01 per 5 cells per µL, 1·61 to 2·39; p<0·0001), decreased CD4 cell count (0·53 per 5 square-root cells per µL, 0·35 to 0·79; p=0·0025), decreased CNS penetration-effectiveness value (0·71 per unit, 0·56 to 0·92; p=0·0078), increased CD8 cell count (1·51 per 5 square-root cells, 1·11 to 2·06; p=0·0089), and protease inhibitor use (3·26, 1·04 to 10·23; p=0·039; model R2=0·22, p<0·0001). Analyses of continuous HIV RNA concentration in CSF that accounted for censoring below the lower limit of quantification had similar findings, although increased HIV RNA concentrations in CSF were also associated with black ethnicity (change in log10 HIV RNA concentration in CSF 0·205, 0·0367 to 0·3733; p=0·017), increased total protein in CSF (0·0025, -0·0002 to 0·0052; p=0·069), and the presence of addictive-drug metabolites in urine (0·103, -0·013 to 0·219; p=0·081). 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.

Acute myocardial infarction associated with initial alemtuzumab infusion cycle in relapsing-remitting multiple sclerosis.

Alemtuzumab is an anti-CD52 monoclonal antibody used for the treatment of lymphoproliferative disorders and relapsing-remitting multiple sclerosis. We report a 30-year-old woman with relapsing-remitting multiple sclerosis who developed a type 2 non-ST elevated myocardial infarction (NSTEMI) during her first alemtuzumab infusion cycle. While acute coronary syndrome has been described with alemtuzumab in the treatment of lymphoma, alemtuzumab-associated cardiac ischemia in multiple sclerosis is uncommon and can occur in patients without cardiovascular risk factors.

Cognitive Trajectory Phenotypes in Human Immunodeficiency Virus-Infected Patients.

OBJECTIVE: The presentation of cognitive impairments in HIV-infected individuals has transformed since the introduction of antiretroviral therapies. Although the overall prevalence of cognitive impairments has not changed considerably, frank dementia is now infrequent, and milder forms of cognitive impairments predominate. Mechanistic insights to the underlying causes of these residual cognitive impairments have been elusive, in part due to the heterogenous etiology of cognitive dysfunction in this population. Here, we sought to categorize longitudinal change in HIV-infected patients based on the performance in specific cognitive domains. DESIGN: This study consisted of 193 participants from the CHARTER cohort with detailed demographic, clinical, and neuropsychological testing data obtained from 2 study visits interspersed by ∼6 months. Cognitive testing assessed executive function, learning and delayed recall, working memory, verbal fluency, speed of information processing, and motor skills. Change scores were calculated for each domain between the 2 study visits. Dimension reduction and clustering was accomplished by principal component analysis of change scores and k-means clustering to identify cognitive domains that group together and groups of subjects with similar patterns of change. RESULTS: We identified 4 distinct cognitive change phenotypes that included declines in: (1) verbal fluency, (2) executive function (3) learning and recall, and (4) motor function, with approximately equal numbers of participants in each phenotype. CONCLUSIONS: Each of the 4 cognitive change phenotypes identify deficits that imply perturbations in specific neural networks. Future studies will need to validate if cognitive change phenotypes are associated with alterations in associated neural pathways.