Faculty Bibliography

It is now well recognized that there is a premotor phase of Parkinson's disease (PD) with hyposmia and REM sleep behavior disorder caused by degeneration of specific CNS neurons. Most patients with PD describe autonomic symptoms at the time of diagnosis suggesting that these features may have potential sensitivity as clinical biomarkers of the premotor phase. The recognition that damage to peripheral autonomic neurons is present in the early stages of PD has led to a search for specific abnormalities in autonomic function that could serve as predictive biomarkers. There is evidence that constipation, urinary and sexual dysfunction and more recently decreased cardiac chronotropic response during exercise, are part of the premotor parkinsonian phenotype. The sensitivity and specificity of these features has yet to be accurately assessed. We briefly review the evidence for autonomic dysfunction as biomarker of premotor PD.

Objective: To determine the prevalence and impact of depression in patients with multiple system atrophy (MSA). Methods: 31 patients with a diagnosis of probable MSA (age 61 +/- 8.8 years, mean +/- SD), 15 (5 men, 10 women) with predominant cerebellar ataxia (MSA-C) and 16 (9 men and 7 women) with predominant parkinsonism (MSA-P) were enrolled in the study. All assessments were performed at baseline and repeated after 6-12 months. After complete neurological examination and autonomic testing, patients completed the Zung Depression scale, Spielberg's state-trait anxiety scales, Body Vigilance Scale, Scale for Outcomes in Parkinson disease-autonomic (SCOPA-AUT), the Composite Autonomic Symptom Score (COMPASS) and Short Form Quality of Life (SF36) scale. A trained investigator administered the Unified Multiple System Atrophy Scale (UMSARS-I and UMSARSII) and the Orthostatic Hypotension Questionnaire (OHQ). Results: Twenty patients (65 %) scored as having depressive symptoms (10 mild, 8 moderate and 2 severe). Depressed patients had significantly higher scores of trait-anxiety (p<0.02) and body vigilance (p<0.04), higher UMSARS-I scores at follow-up (p<0.02) with faster progression of symptoms from baseline to follow-up visit, and more pronounced symptoms of orthostatic hypotension (p< 0.003). Depression scores correlated with lower physical (p<0.02) and social functioning (p<0.001) on the SF36-quality-of-life questionnaire, with the gastrointestinal dysfunction domain (p<0.005) of the SCOPA questionnaire, with the COMPASS score (p<0.01) and with higher UMSARS-I (p<0.02) and UMSARS-II (p<0.01) scores at follow-up. For each unit increase in the depression scale the UMSARS-I increased by 0.214 points (p<0.056) and UMSARS-II increased by 0.035 points per month (p<0.046). Conclusion: Depression affects more than half of MSA patients. It impacts the perceived progression and severity of motor and autonomic symptoms and is associated with decreased physical and social functioning. Appropriate psychologic!

Spinal pseudomeningoceles are extramural cerebrospinal fluid (CSF) collections that communicate with the CSF space around the spinal cord. We describe an 81-year-old man who presented with recurrent episodes of brief loss of consciousness (LOC) and collapse following an L3-4 discectomy complicated by the development of a spinal pseudomeningocele containing approximately 200 cc of CSF (as determined by MRI). LOC occurred both when standing and when the pseudomeningocele in his back was compressed when laying down. Transcranial Doppler (TCD) of his right middle cerebral artery (MCA) during manual compression of the pseudomeningocele (in the sitting position) showed maintained systolic but absent diastolic blood flow while systemic blood pressure was unchanged. When standing, TCD of the MCA showed similar findings and a small fall in systemic blood pressure. The absence of blood pressure changes and the observed TCD pattern in the MCA, which is consistent with collapse of the artery during diastole, suggest that the episodes of loss of consciousness were due to increased intracranial pressure (ICP). Increased ICP is easily explained as a result of displacement of CSF from the pseudomenigocele towards the cranium. Standing, however, should cause a reduction in ICP as CSF could travel down towards the lumbar pseudomeningocele. Possible explanations of increased ICP while standing include involuntary Valsalva-like maneuver similar to "cough syncope," mechanical obstruction preventing CSF outflow, or external compression of the pseudomeningocele by extensor back muscles. In patients with syncopal episodes following discectomies the possibility of a pseudomeningocele should be considered

Objective: To determine the efficacy of rifampicin in multiple system atrophy (MSA). Background: MSA is a rapidly progressive disorder characterized by autonomic failure with parkinsonism and/or cerebellar ataxia. Its hallmark is glial cytoplasmic inclusions consisting of aggregated a-synuclein. In a transgenic mouse model of MSA, rifampicin inhibits formation and disaggregates a-synuclein fibrils and improves both behavioral and neuropathological changes. Methods: We undertook a randomized, double-blind, placebo-controlled 12-month clinical safety/efficacy study of 100 subjects with possible or probable MSA, 50 % randomized to active drug (rifampicin 300 mg BID), 50 % to placebo (riboflavin capsules BID). Subjects were recruited from 10 US sites. Inclusion criteria: men and women ages 30-80 years;<4 years from diagnosis; expected survival C3 years; MMSE >24. The primary outcome measure was rate of change from baseline to 12 months in total UMSARS I score (minus Q11). A planned interim analysis was conducted after 30 subjects had completed 12 months. Results: 100 subjects were randomized: 43 % women and 57 % men, mean age 61.1 +/- 9.2 (mean +/- SD, age range 41.7-79.9 years, 48 % possible MSA, 52 % probable MSA. There were 18 serious adverse events, none considered likely due to treatment. 9 subjects withdrew from study. The DSMB recommended the study stop as futility criteria were met. In final analysis on 100 subjects, the primary endpoint for placebo was 0.5 +/- 0.5, rifampicin 0.5 +/- 0.7, p = 0.82. Conclusions: No beneficial effects were observed of rifampicin in slowing or halting the progression of MSA. The ARDC consortium has established an infrastructure to carry out studies in MSA and has demonstrated the feasibility of conducting clinical trials

Afferent baroreflex failure occurs in the genetic disorder familial dysautonomia (FD) and in patients with acquired lesions of the afferent baroreflex pathways. Afferent baroreflex failure is characterized by extremely labile blood pressure, with paroxysmal hypertension due to unrestrained norepinephrine release, which may result in targetorgan damage. These hypertensive episodes are traditionally managed with the alpha-2-receptor agonist clonidine, but this produces profound hypotension, fatigue and rebound hypertension. Carbidopa is a competitive reversible inhibitor of the enzyme dopa-decarboxylase that does not cross the blood brain barrier. Here we examined the effect of carbidopa on norepinephrine production and blood pressure variability in 12 patients with FD and 3 with acquired afferent baroreflex failure. Patients underwent a 24-h urine collection and simultaneous ambulatory blood pressure monitoring at baseline (pretreatment) and while taking carbidopa. Catecholamine excretion was measured using high performance liquid chromatography (HPLC). Blood pressure variability was calculated from the standard deviation of blood pressure values captured at 20-min intervals during waking hours. Mean dose of carbidopa was 500 mg per day. Compared to baseline, carbidopa significantly reduced norepinephrine excretion (32 +/- 9 vs. 12 +/- 1 lg/gCr, p<0.001) and blood pressure variability (25 +/- 3 vs. 19 +/- 3 mmHg, p<0.03). Carbidopa reduced the highest blood pressure value captured on ambulatory monitoring from 175 +/- 6 to 155 +/- 9 mmHg (p<0.03), while the lowest captured blood pressure values were similar pre and post-treatment. Carbidopa inhibits the downstream production of norepinephrine and is a novel approach to treating paroxysmal hypertension in patients with genetic or acquired afferent baroreflex failure

Familial dysautonomia (FD) is caused by a splicing error in the IKBKAP gene that encodes human Elongator protein-1 (ELP-1). In these patients, exon 20 is frequently skipped duringmRNA splicing, but cells retain the ability to produce a lowlevel of normal (wild-type) IKBKAPmRNAand normal protein. Phosphatidylserine (PS, Sharp-thought), an acidic phospholipid, has been shown to raise elongator protein-1 levels by increasing IKBKAPtranscription in fibroblast cell-lines derived fromFD patients and, more recently, in a mouse model of FD. Given that PS is available over the counter, weconducted a study to determinewhether PS raises IKBKAP gene expression in patients with FD. We enrolled 7 patients with FD, 16-23 years old, in an open-label titration protocol. Patients were examined at baseline (visit 1), after 2 months of taking 300 mg/day (visit 2) and again after 2 months of taking 600 mg/day of PS(visit 3).Bloodwas taken at each visit. Sampleswere de-identified and investigators blinded to the sample identity. Blood was treated with Tri- Reagent, and RNA extracted according to manufacturers specifications. Quantitative polymerase chain reaction (qPCR) was performed to measure the level of normal IKBKAPmRNA. PSwas well tolerated and there were no adverse events or unexpected laboratory abnormalities. After 2 months of taking 300 mg of PS per day, there was a trend for IKBKAP mRNA levels to increase. After 2 months of 600 mg of PS per day, IKBKAPmRNAexpression increased between 2 and 8 fold in all but one patient (p<0.01). Our results indicate that PS safely raises wild-type IKBKAP mRNA levels in blood from patients with FD, opening an exciting potential therapeutic path for treatment. Clinical trials to determine whether restoring Elongator protein 1 levels impacts the phenotype are underway

Multiple system atrophy (MSA) is a fatal, relentlessly progressive, adult-onset neurodegenerative disorder that affects at least 4 per 100,000 people in the US. MSA is characterized clinically by a variable combination of parkinsonism, cerebellar ataxia and autonomic abnormalities and pathologically by cytoplasmic inclusions of fibrillized asynuclein protein aggregates in oligodendroglia and neurons. There is no effective treatment for MSA and death occurs, on average, 8 years after onset of symptoms. The cause of MSA is unknown but abnormal metabolism and aggregation of alpha-synuclein has emerged as the leading cause of neurodegeneration. Although the mechanisms that lead to synuclein aggregation are unknown, there is evidence to support roles for oxidative stress due to mitochondrial dysfunction and microglial activation. Recent experimental data suggest that alpha-synuclein can be absorbed by oligodendroglia and neurons from the extracellular space and that cell-to-cell transmission of abnormal alpha-synuclein in a prionlike manner may explain the progressive nature of MSA. Potential therapeutic strategies targeting each of the proposed mechanisms of asynuclein aggregation and propagation will be reviewed

The maintenance of blood pressure in the upright position requires intact autonomic cardiovascular reflexes. Diseases that affect the sympathetic innervation of the cardiovascular system result in a sustained fall in blood pressure upon standing (i.e., neurogenic orthostatic hypotension) that can impair the blood supply to the brain and other organs and cause considerable morbidity and mortality. Here we review treatment options for neurogenic orthostatic hypotension and include an algorithm for its management that emphasizes the importance of non-pharmacologic measures and provides guidance on pharmacologic treatment options.

BACKGROUND: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. METHODS: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7 degrees +/- 1.0 degrees , and the range was very wide (2.8 degrees -18.1 degrees ); conversely, absolute error was only 2.7 degrees +/- 0.3 degrees (1.6 degrees -5.5 degrees ) in the controls and 3.0 degrees +/- 0.2 degrees (2.1 degrees -3.4 degrees ) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III.

OBJECTIVE: The purpose of this study was to determine whether carbidopa (Lodosyn), an inhibitor of dopa-decarboxylase that blocks the synthesis of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD) and hyperdopaminergic nausea/retching/vomiting attacks. METHODS: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy. RESULTS: Previous fundoplication surgery in each patient studied prevented vomiting, but all of the subjects experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325-600 mg/day) was well tolerated. In the double-blind phase, patients experienced significantly less nausea and retching while on carbidopa than on placebo (p < 0.03 and p < 0.02, respectively). Twenty-four-hour urinary dopamine excretion was significantly lower while on carbidopa (147 +/- 32 microg/gCr) than while on placebo (222 +/- 41microg/gCr, p < 0.05). CONCLUSIONS: Carbidopa is a safe and effective antiemetic in patients with FD, likely by reducing the formation of dopamine outside the brain. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that carbidopa is effective in reducing nausea/retching/vomiting in patients with FD.