Freeman, Roy L.

Objective Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Methods Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. Results We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; −44 ± 25 vs −21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one‐third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy ( p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. Interpretation A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522–531

ObjectiveTo define the clinical features and biomarkers that predict which patients with pure autonomic failure will develop Parkinson disease, dementia with Lewy bodies, or multiple system atrophy.MethodsOne hundred patients who presented with pure autonomic failure were recruited at 5 medical centers in the United States. Seventy‐four patients agreed to be followed prospectively. Patients underwent clinical evaluations including neurological rating scales, sleep questionnaires, smell test, and sympathetic and parasympathetic cardiovascular autonomic function tests.ResultsAt enrollment, patients were 68 ± 12 years old (median ± interquartile range) and had had autonomic failure for 5 ± 7 years. Within 4 years of follow‐up, 25 of 74 subjects (34%) developed dementia with Lewy bodies (n = 13), Parkinson disease (n = 6), or multiple system atrophy (n = 6). The presence of probable rapid eye movement (REM) sleep behavior disorder was strongly associated with the development of a manifest central nervous system (CNS) synucleinopathy (odds ratio = 7.1). Patients who phenoconverted to multiple system atrophy had younger age at onset of autonomic failure, severe bladder/bowel dysfunction, preserved olfaction, and a cardiac chronotropic response upon tilt > 10 beats per minute. Those who phenoconverted to Parkinson disease or dementia with Lewy bodies had decreased olfaction, a lesser chronotropic response to tilt, and a longer duration of illness. The small group of patients retaining the pure autonomic failure phenotype had very low plasma norepinephrine levels, slow resting heart rate, no REM sleep behavior disorder, and preserved smell.InterpretationPatients presenting with pure autonomic failure are at high risk of phenoconverting to a manifest CNS synucleinopathy. Specific clinical features predict future diagnosis. Ann Neurol 2017;81:287–297

AbstractAlthough pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.

Abstract— We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100–600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa ( P =0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient’s self-reported ability to perform activities requiring standing a short time ( P =0.033) and standing a long time ( P =0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa ( P =0.013). There was no significant difference between groups for standing systolic blood pressure ( P =0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00633880.

OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.