Jessica Robinson-Papp

Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial

IMPORTANCE Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P < .001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P < .001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (<2-point increase in NIS+7 score; P = .007). CONCLUSIONS AND RELEVANCE Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00294671.

Neuromuscular Diseases Associated with HIV-1 Infection

Neuromuscular disorders are common in human immunodeficiency virus (HIV); they occur at all stages of disease and affect all parts of the peripheral nervous system. These disorders have diverse etiologies including HIV itself, immune suppression and dysregulation, comorbid illnesses and infections, and side effects of medications. In this article, we review the following HIV‐associated conditions: distal symmetric polyneuropathy; inflammatory demyelinating polyneuropathy; mononeuropathy; mononeuropathy multiplex; autonomic neuropathy; progressive polyradiculopathy due to cytomegalovirus; herpes zoster; myopathy; and other, rarer disorders. Muscle Nerve, 2009

Diagnosis and Management of HIV-Associated Neuropathy

Distal sensory polyneuropathy (DSP) is the most common neurologic complication of HIV infection and a major cause of morbidity in HIV-infected patients. DSP may occur secondary to HIV (HIV-DSP) or be due to antiretroviral drug toxicity. Timely detection of the symptoms and signs of DSP in patients who have HIV may allow for the reversal of the toxic effects of antiretrovirals and for the initiation of symptomatic treatment. The pathogenic mechanism of HIV-DSP is likely multifactorial. Restorative therapies for DSP are not currently available but recent advances have led to novel symptomatic therapies. This article highlights the risk factors, pathogenesis, pathology, clinical features, diagnostic studies, differential diagnosis, and treatment of HIV-associated neuropathy.

Motor Function and Human Immunodeficiency Virus-Associated Cognitive Impairment in a Highly Active Antiretroviral Therapy-Era Cohort

BACKGROUND Cognitive impairment has long been recognized as a manifestation of human immunodeficiency virus (HIV) infection. However, highly active antiretroviral therapy (HAART) has altered the neurologic manifestations of HIV. OBJECTIVES To develop a measure to quantify the motor abnormalities included in the original descriptions of HIV-associated dementia (HAD); to determine whether motor, affective, and behavioral dysfunction predict cognitive impairment; and to determine whether quantitative motor testing is a helpful adjunct in the diagnosis of HAD in a complex population from the HAART era. DESIGN Neurologic and neuropsychological data were collected from the Manhattan HIV Brain Bank, a longitudinal cohort study of patients with advanced HIV. The HIV-Dementia Motor Scale (HDMS) was developed and validated and cognitive and affective or behavioral function was quantified using global neuropsychological T scores, the Beck Depression Inventory (BDI), and an independent assessment of apathy. Relationships among cognitive, motor, affective, and behavioral performance were examined using correlation, linear regression, and analyses of variance. SETTING An urban AIDS research center. PARTICIPANTS A total of 260 HIV-positive, predominantly minority patients. MAIN OUTCOME MEASURES The HDMS scores and global neuropsychological T scores. RESULTS The HDMS and BDI scores were independent predictors of cognitive impairment. Significant cognitive impairment was found in patients with motor dysfunction. Patients diagnosed as having HAD had a greater degree of motor impairment than those with other neurocognitive diagnoses. CONCLUSIONS Motor, affective, and behavioral abnormalities predict cognitive impairment in HIV-positive patients in this HAART-era cohort. The HDMS may be useful in the assignment of HIV-associated neurocognitive impairment in HIV populations in which normative data or neuropsychological test design is not optimal.

Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy

&NA; Sensory neuropathy (HIV‐SN) is a common cause of pain in HIV‐infected people. Establishing a diagnosis of HIV‐SN is important, especially when contemplating opioid use in high‐risk populations. However physical findings of HIV‐SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self‐report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV‐SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV‐SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self‐report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self‐report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV‐infected patients reporting symptoms consistent with HIV‐SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV‐SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.

Health-Related Quality of Life ‘Well-Being' in HIV Distal Neuropathic Pain is More Strongly Associated with Depression Severity than with Pain Intensity

BACKGROUND Despite modern antiretroviral treatment, HIV-associated distal neuropathic pain (DNP) remains one of the most prevalent and debilitating complications of HIV disease. Neuropathic pain is often accompanied by depressed mood, and both pain and depression have been associated with decreased health-related quality of life (HRQOL) well-being. The relative contribution of depression and pain to worse life quality has not been addressed, however, even though a better understanding might sharpen intervention strategies. METHODS We used the Medical Outcomes Study HIV (MOS-HIV) Health Survey and the Beck depression inventory-II and linear regression models to investigate HRQOL well-being in HIV-infected patients with DNP (n = 397) participating in an observational cohort study at six U.S. sites (CNS HIV Antiretroviral Treatment Effects Research Study, CHARTER). RESULTS For this sample of patients with HIV DNP, severity of depressed mood was more highly correlated with HRQOL well-being than was pain intensity. CONCLUSIONS These results suggest that interventions to improve HRQOL well-being in individuals with HIV-associated DNP may need to address not only pain intensity but mood state as well.

Hiv-related neuropathy: Current perspectives

Distal symmetric polyneuropathy (DSP) related to human immunodeficiency virus (HIV) is one of the most common neurologic complications of HIV, possibly affecting as many as 50% of all individuals infected with HIV. Two potentially neurotoxic mechanisms have been proposed to play a crucial role in the pathogenesis of HIV DSP: neurotoxicity resulting from the virus and its products; as well as adverse neurotoxic effects of medications used in the treatment of HIV. Clinically, HIV DSP is characterized by a combination of signs and symptoms that include decreased deep tendon reflexes at the ankles and decreased sensation in the distal extremities as well as paresthesias, dysesthesias, and pain in a symmetric stocking–glove distribution. These symptoms are generally static or slowly progressive over time, and depending on the severity, may interfere significantly with the patient’s daily activities. In addition to the clinical picture, nerve conduction studies and skin biopsies are often pursued to support the diagnosis of HIV DSP. Anticonvulsants, antidepressants, topical agents, and nonspecific analgesics may help relieve neuropathic pain. Specifically, gabapentin, lamotrigine, pregabalin, amitriptyline, duloxetine, and high-dose topical capsaicin patches have been used in research and clinical practice. Further research is needed to elucidate the pathogenesis of HIV DSP, thus facilitating the development of novel treatment strategies. This review discusses the epidemiology, pathophysiology, clinical findings, diagnosis, and management of DSP in the setting of HIV.

Substance abuse increases the risk of neuropathy in an HIV-infected cohort

Introduction: Human immunodeficiency virus (HIV)‐infected patients commonly develop distal symmetric polyneuropathy (DSP). Age, ethnicity, and toxic exposures may influence the risk. In this study we examined the association between substance use, antiretrovirals, ethnicity, and incident neuropathy in an HIV‐infected cohort. Methods: Data were obtained from the National NeuroAIDS Tissue Consortium (NNTC), an ongoing, prospective cohort started in 1998. Cox proportional hazards models were used to examine the association of substance use, demographics, neurotoxic antiretrovirals, and laboratory parameters with incident neuropathy in 636 participants who were neuropathy‐free at baseline. Results: The cumulative incidence of DSP was 41%. Substance use (P = 0.04), number of substances used (P = 0.04), and longer duration of HIV infection (P = 0.05) were associated with incident DSP, but demographic factors, use of neurotoxic antiretrovirals, and laboratory parameters were not. Conclusions: Substance use and longer duration of HIV infection are risk factors for DSP in HIV‐infected patients. Use of multiple substances may be particularly risky. Muscle Nerve, 2012

The Roles of Ethnicity and Antiretrovirals in HIV-associated Polyneuropathy: A Pilot Study

Background:In the pre-highly active antiretroviral therapy (HAART) era, distal sensory polyneuropathy (DSP) was associated with markers of advanced HIV infection and the use of neurotoxic antiretrovirals (ARVs). As HAART became widespread, and the AIDS epidemic shifted into minority populations, the risk factors for DSP became less clear. We explore the roles of ethnicity and ARV in the development of DSP in an HAART era cohort. Methods:Data from 336 HIV-positive adults were obtained from the Manhattan HIV Brain Bank. One hundred four participants had no DSP at entry visit; at least 1 follow-up visit; and a self-identified ethnicity of non-Hispanic white, Hispanic, or African American. Results:Fifty percent of participants developed DSP; of those, 67% were symptomatic. Participants who developed DSP were older (P = 0.02) and had higher CD4 counts (P = 0.001). ARV-DSP was more common in Hispanics (P = 0.02) and intravenous drug users (P = 0.02). There was a trend for higher pain scores in Hispanics with symptomatic DSP (P = 0.08). Conclusions:This study suggests that there are ethnic disparities in the clinical manifestations of HIV-related neuropathies including pain and the susceptibility to ARV-DSP. Further studies of larger cohorts are indicated to explore the etiology of these differences.

Isolating Cognitive and Neurologic HIV Effects in Substance-Dependent, Confounded Cohorts: A Pilot Study

Controversy exists as to whether effects of HIV infection can be detected in the cognitive profiles of substance users, with methodological differences in degree of control for confounding factors a major contributor to empirical discrepancies. To address this shortcoming, we conducted a small but well-controlled study aimed at isolating HIV neurocognitive (NC) effects in a group of chronic substance users. Thirty HIV-negative substance users were individually matched to 30 HIV-positive substance users on relevant medical and demographic factors, including reading level and methadone therapy status. Results revealed that reading level, methadone maintenance therapy, and positive urine toxicology each exerted significant influence on NC function, and that HIV status was a significant predictor of learning and speeded processing after these control factors were considered. The HIV-positive group also displayed significantly more neurologically assessed motor impairment (p < .05), which was specifically related to impaired cognition in this group and independent of degree of immunocompromise. These data demonstrate the need for increased attention to clinical/demographic characteristics of groups under study. They also show that with applied methodological rigor, the deleterious effects of HIV on cognition can be parsed from substance use, even in small samples with chronic and active use histories.