Faculty Bibliography

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, 3x 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.

Neurogenic orthostatic hypotension (nOH) is a fall in blood pressure (BP) on standing due to reduced norepinephrine release from sympathetic nerve terminals. nOH is a feature of several neurological disorders that affect the autonomic nervous system, most notably Parkinson disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), and other autonomic neuropathies. Droxidopa, an orally active synthetic amino acid that is converted to norepinephrine by the enzyme aromatic L-amino acid decarboxylase (dopa-decarboxylase), was recently approved by the FDA for the short-term treatment of nOH. It is presumed to raise BP by acting at the neurovascular junction to increase vascular tone. This article summarizes the pharmacological properties of droxidopa, its mechanism of action, and the efficacy and safety results of clinical trials.

Background: Cognitive deficits in MSA have been observed, although dementia is still considered as non-supporting diagnostic feature by current consensus diagnostic criteria. MMSE is commonly used in clinical practice with atypical parkinsonism, but its neuroanatomical correlates have never been investigated. Objective: The aim of this study is to investigate the MRI structural correlates of the Mini-Mental State Examination (MMSE) in Multiple System Atrophy (MSA) patients compared with a Parkinson's disease (PD) sample. Methods: Multicenter cohort of 69 MSA patients [mean age 63.8 (7.3) and education of 11.1 (4.7)], collected from four international centers and 70 PD [mean age 63.9 (7.3) and education of 10.5(4.4)] subjects matched for age and MMSE score. Freesurfer software was used to evaluate intergroup differences in cortical thickness (CTh) and subcortical areas, in relationship with MMSE scores. Results: In MSA group MMSE scores did not correlate with cortical or subcortical areas. In PD, significant positive correlations were observed between MMSE scores and cortical thickness of the left medial and lateral orbitofrontal areas, caudal middle frontal area, superior frontal area, supramarginal region and superior temporal area. More focal right hemisphere significant correlations were found in the temporal pole and pars orbitalis. Subcortical analysis showed significant positive correlation in the right hippocampus and in the middle anterior side of corpus callosum. All these areas survived after Montecarlo correction. Conclusions: Our findings in PD corroborate previous studies showing correlations between cortical areas and MMSE scores. The predominance of the left hemisphere is likely due to the presence of several verbal items included in the cognitive scale. Lack of cortical correlates of cognitive deficits in MSA suggests a different nature of cognitive decline in MSA patients

INTRODUCTION: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (ELP-1) (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception result in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. AREAS COVERED: This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene-modifying agents. EXPERT OPINION: Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to the risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression.

The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic alpha2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions. (c) 2014 International Parkinson and Movement Disorder Society.

Management of blood pressure (BP) abnormalities in patients with autonomic failure is usually based on office BP readings. It is uncertain, whether office readings reflect actual BP's [corrected] during a typical day. Therefore, in 45 patients with autonomic failure, we compared office BP values during a tilt test with those captured on a 24-h BP [corrected] ambulatory monitor. Office BP values while supine predicted well the level of nighttime hypertension. However, in only 33% of patients, office values during tilt test accurately reflected hypotension during a typical day. Therefore, BP [corrected] ambulatory monitoring is useful to gauge the true severity of hypotension in patients with autonomic failure.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in >/= 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Hereditary sensory and autonomic neuropathy type III (HSAN III, Riley-Day syndrome, Familial Dysautomia) is characterised by elevated thermal thresholds and an indifference to pain. Using microelectrode recordings we recently showed that these patients possess no functional stretch-sensitive mechanoreceptors in their muscles (muscle spindles), a feature that may explain their lack of stretch reflexes and ataxic gait, yet patients have apparently normal low-threshold cutaneous mechanoreceptors. The density of C-fibres in the skin is markedly reduced in patients with HSAN III, but it is not known whether the C-tactile afferents, a distinct type of low-threshold C fibre present in hairy skin that is sensitive to gentle stroking and has been implicated in the coding of pleasant touch are specifically affected in HSAN III patients. We addressed the relationship between C-tactile afferent function and pleasant touch perception in 15 patients with HSAN III and 15 age-matched control subjects. A soft make-up brush was used to apply stroking stimuli to the forearm and lateral aspect of the leg at five velocities: 0.3, 1, 3, 10 and 30cm/s. As demonstrated previously, the control subjects rated the slowest and highest velocities as less pleasant than those applied at 1-10cm/s, which fits with the optimal velocities for exciting C-tactile afferents. Conversely, for the patients, ratings of pleasantness did not fit the profile for C-tactile afferents. Patients either rated the higher velocities as more pleasant than the slow velocities, with the slowest velocities being rated unpleasant, or rated all velocities equally pleasant. We interpret this to reflect absent or reduced C-tactile afferent density in the skin of patients with HSAN III, who are likely using tactile cues (i.e. myelinated afferents) to rate pleasantness of stroking or are attributing pleasantness to this type of stimulus irrespective of velocity.

Consensus diagnostic criteria for multiple system atrophy consider dementia as a nonsupporting feature, despite emerging evidence demonstrating that cognitive impairments are an integral part of the disease. Cognitive disturbances in multiple system atrophy occur across a wide spectrum from mild single domain deficits to impairments in multiple domains and even to frank dementia in some cases. Frontal-executive dysfunction is the most common presentation, while memory and visuospatial functions also may be impaired. Imaging and neuropathological findings support the concept that cognitive impairments in MSA originate from striatofrontal deafferentation, with additional contributions from intrinsic cortical degeneration and cerebellar pathology. Based on a comprehensive evidence-based review, the authors propose future avenues of research that ultimately may lead to diagnostic criteria for cognitive impairment and dementia associated with multiple system atrophy. (c) 2014 International Parkinson and Movement Disorder Society.