Faculty Bibliography

OBJECTIVE: To test the hypothesis that panic disorder (PD) patients have a heightened or deregulated autonomic nervous system at rest and during autonomic challenge compared with healthy controls (HC); and to test a second hypothesis that severity of illness differentiates patients'; sympathovagal balance both at rest and during orthostatic challenge. METHODS: Spectral analysis of heart rate (HR) and blood pressure was performed on 30 PD and 10 HC participants during an orthostatic challenge (head-up tilt). RESULTS: PD patients presented higher HR (p < .001), lower heart rate variability (HRV) (p < .015), higher mean diastolic blood pressure (p < .006), higher low-frequency component of HR (p < .001), and a higher ratio of low-frequency to high-frequency component of HR (LF/HF) (p < .022) than HC at baseline. During tilt, PD patients responded with higher HR (p < .039), lower HRV (p < .043), increased mean diastolic blood pressure (p < .028), and a mild increase in LF/HF, whereas controls responded with a five-fold increase in LF/HF (p < .022). Patients with higher illness severity ratings (Clinical Global Impression Scale) showed higher HR (p < .002), lower HRV (p < .026), and a lower total power of systolic blood pressure (p < .02) compared with less ill patients. CONCLUSION: These findings demonstrate a consistently higher or deregulated autonomic arousal in PD patients at rest and during orthostatic challenge compared with HC. These data also reveal a possible association between the level of anxiety illness severity and sympathovagal balance, which may imply greater cardiac risk

Renal failure is a common problem in patients with familial dysautonomia (FD). By age 25, 20% of patients with FD have end stage renal disease. To determine the role of arterial hypertension in the development and progression of kidney disease, we compared glomerular filtration rate (Cockcroft-Gault equation) over time in 50 patients with FD according to their level of arterial hypertension throughout childhood (until age 15). In addition, to assess the possible impact of increased blood pressure variability on renal function we examined the relationship between the standard deviation of ambulatory blood pressure over 24-h, an indicator of blood pressure volatility, and glomerular filtration rate. Patients with average systolic blood pressure[180 mmHg during childhood (stage III and IV hypertension American Heart Association) had a faster decline in glomerular filtration rate over time than patients with lower blood pressures (Kaplan-Meyer survival curve). There was an inverse relationship between the standard deviation of ambulatory blood pressure over 24-h and glomerular filtration rate, i.e., patients with higher standard deviation had lower glomerular filtration rates (y = - 3.3044x + 167.54, R² = 0.1949, p<0.01). Our results indicate that arterial hypertension during childhood and the magnitude of blood pressure volatility are risk factors for the development of renal failure in patients with familial dysautonomia. Prospective studies are warranted to determine whether controlling hypertension and blood pressure variability can delay the onset or slow the progression of renal failure in these patients

Background: Neurogenic orthostatic hypotension (NOH) is a disabling feature of autonomic failure. NOH causes a variety of symptoms such as dizziness, vision disturbance, fatigue, generalized weakness and impairment or loss of consciousness. Symptomatic NOH results from impaired norepinephrine release from sympathetic nerve terminals leading to low blood pressure (BP) upon standing and tissue hypoperfusion. Droxidopa is a synthetic amino acid that can augment norepinephrine levels and improve standing BP thereby reducing the signs and symptoms of NOH. We are conducting a study to evaluate the clinical benefit, safety and tolerability of droxidopa to treat symptomatic NOH. Methods: This clinical trial is being conducted at 85 centers in Austria, Canada, Czech Republic, France, Germany, Italy, Romania, Ukraine, and USA. The study enrolled 142 patients between January 2008 and May 2010. It is projected that the complete sample size of 150 will be enrolled by the end of June 2010. Patients were confirmed to have symptomatic NOH of non-diabetic origin during a 2-week baseline evaluation period. At the time of writing, 39% of patients were diagnosed with Parkinson's disease, 15% with multiple system atrophy, 33% with pure autonomic failure and 13% with other autonomic neuropathies. The population is equally distributed between females (51%) and males (49%) and is predominantly Caucasian (98%) with a mean age of 54 years. Patients enter an open-label, forced titration to determine an optimal treatment dose of droxidopa ranging from 100 mg T.I.D. to 600 mg T.I.D in 100 mg T.I.D. increments. No apparent trend has emerged to date with respect to dose as an approximately equal number of patients have been determined to be optimally treated at all dose levels. Following titration, patients are washed out of drug for 1 week. Subsequently, patients are randomized in a blinded fashion to either resume droxidopa treatment at their previously determined optimal dose or receive placebo (1:1). Study outcome measures are assessed 1 week later. Results/Conclusion: The clinical effectiveness of droxidopa will be discussed in terms of its impact on each of the 10 components of the Orthostatic Hypotension Questionnaire (OHQ), clinical global impressions of disease severity and hemodynamics. The primary efficacy variable for the trial is the OHQ composite score, which measures the global impact of NOH in a patient's life. Data currently available from the open-label titration on the first 120 patients indicates a highly significant average improvement in standing systolic blood pressure of 23 mmHg measured during clinical testing. Finally, the safety of droxidopa based on the occurrence of treatment-emergent adverse events, ECG, and laboratory findings across the study will be presented

OBJECTIVE: To determine whether the heart rate changes during tilt table testing could be used in the differential diagnosis between vasovagal syncope and chronic autonomic failure. METHODS: We compared the relationship between electrocardiographic R-R intervals and beat-to-beat blood pressure in 43 patients with typical vasovagal responses and 30 patients with chronic autonomic failure (6 pure autonomic failure, 23 multiple system atrophy, and 1 Parkinson's disease). RESULTS: In every patient with vasovagal syncope, at the time when the blood pressure was falling, it was possible to identify at least 12 successive heart beats (mean 33 +/- 2 heart beat, range 12-57) when blood pressure and heart rate fell in parallel, i.e., there was a negative relationship between blood pressure and R-R intervals (P < 0.001). In contrast, the relationship between blood pressure and R-R intervals in patients with chronic autonomic failure was never negative, i.e., heart rate always increased, albeit less than expected for the given fall in blood pressure, or remained unchanged. INTERPRETATION: The heart rate changes during the fall in blood pressure can distinguish patients with vasovagal responses from those with chronic autonomic failure

To clarify whether the R3 component of the electrically elicited blink reflex is a nociceptive response we studied two patients with congenital insensitivity to pain due to the impaired development of Adelta and C nerve fibers (hereditary sensory and autonomic neuropathy types III and IV). We postulated that if the R3 component is a nociceptive reflex, it should be absent in these patients. The R3 responses were elicited in both sides in both the patients at all intensities, strongly suggesting that the R3 component of the blink reflex is not a nociceptive response

Background: Panic disorder (PD) patients have been shown to have reduced heart rate variability (HRV). Low HRV has been associated with elevated risk for cardiovascular disease. Our aim was to investigate the effects of treatment on heart rate (HR) in patients with PD through a hyperventilation challenge. Methods: We studied 54 participants, 43 with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) PD and 11 controls. Subjects lay supine with their heads in a plastic canopy chamber, resting for 15 min and then breathing at a rate of 30 breaths per minute for 10 min. HRV was sampled for spectral analysis. Clinical and behavioral measures of anxiety were assessed. Treatment was chosen by patients: either 12 weeks of CBT alone or CBT with sertraline. Results: All patients showed significant decrease on clinical measures from baseline and 31 were treatment responders, 8 dropped out of the study before completion of the 12-week treatment phase and 4 were deemed nonresponders after 12 weeks of treatment. Although both treatments led to significant clinical improvement, only CBT alone demonstrated a significant reduction in HR and increase in HRV. Conclusions: Our study replicated the finding that increased HR and decreased HRV occur in PD patients. Given the evidence of cardiac risk related to HRV, CBT appears to have additional benefits beyond symptom reduction. The mechanisms of this difference between CBT and sertraline are unclear and require further study. Depression and Anxiety 0:1-8, 2008. (c) 2008 Wiley-Liss, Inc

BACKGROUND: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. METHODS: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. RESULTS: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. CONCLUSIONS: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I-IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. RESULTS: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). RECOMMENDATIONS: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data