Faculty Bibliography

In Parkinson disease (PD), symptoms and signs of autonomic failure occur commonly, especially in cardiovascular, gastrointestinal, and genitourinary domains. Most patients with PD have neuroimaging evidence of cardiac sympathetic denervation. In PD, orthostatic hypertension (OH) can be an early finding and is associated with extracardiac noradrenergic denervation and reduced baroreflex-cardiovagal and sympathoneural responses. Recognition of autonomic impairment is important because symptomatic treatment is frequently effective.

Familial dysautonomia (FD) is a rare hereditary disorder caused by mutations within the gene that encodes for I-kappa-B kinase complex associated protein (IKAP). A deficiency of IKAP affects the development of primary sensory neurons including those carrying baroreflex afferent volleys, a feature that explains their characteristic sensory loss and labile blood pressure. This review describes the history, the genotype of FD and the unusual cardiovascular autonomic phenotype of these patients. We outline the main consequences of a failure to receive information from arterial baroreceptors, including the characteristic "autonomic storms" and severe end-organ target damage.

OBJECTIVE: To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival. STUDY DESIGN: Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years +/- 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years. RESULTS: Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P < .005 and P < .001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048). CONCLUSION: The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.

Orthostatic hypotension (OH) defined as a reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 min of active standing or head-up-tilt (HUT) is common in Parkinson disease (PD). We compared the frequency of OH when assessed by head-up-tilt test (HUT) versus active standing in 233 patients with PD. 116 patients (73 men and 43 women) underwent a 60degree HUT and 117 patients (62 men and 53 women) underwent an active standing procedure. Blood pressure and heart rate were measured before and after 3 min in the upright position. The average dose of levodopa and direct dopaminergic agonists and the frequency of other medications was similar in both cohorts. The prevalence of OH was 70 % in those undergoing HUT and 41 % in those undergoing active standing (p<0.001). However, patients undergoing HUT were significantly older (72.1 vs. 61.2 years, p<0.001) and had higher systolic blood pressure while supine (151 vs. 134 mmHg, p<0.001). Prevalence of OH by age showed that the 40-50 years old group (n:15) had 20 % prevalence of OH with HUT versus 40 % with active standing (NS); in the 50-60 years old group (n:38), 33 % had OH with HUT versus 47 % with active standing (NS), in the 60-70 years old group (n:67), 78 % had OH with HUT versus 43 % with active standing (p<0.004), and in the 70-80 years old group (n:85), 60 % had OH with HUT and 36 % with active standing (p<0.04). Thus, in younger patients with PD active standing and HUT showed similar prevalence of OH. However, among PD patients 60 years and older the prevalence of OH was significantly higher with HUT than active standing. These findings have practical implication for diagnosis and clinical management

Drinking pure water markedly increases blood pressure in patients with chronic autonomic failure because water-induced hypo-osmolarity, sensed by peripheral osmoreceptors, triggers sympatho-excitation likely arising from a spinal mechanism. Osmosensory transduction involves transient receptor potential vanilloid 4 channels (TRPV4) expressed on afferent neurons with their cell bodies in the dorsal root ganglia (delta;RG). Patients with familial dysautonomia (FD, hereditary sensory and autonomic neuropathy type-III) have a reduced number of afferent neurons in the DRG. The aim of our study was to investigate whether a pronounced osmopressor responsewas also present in patientswith FD. Nine patients withFDand 6with chronic autonomic failure participated in this study (5 with MSA and 1 with PAF). Beat-to-beat BP was recorded in a supine position before and following the ingestion of 500 ml of room temperature water for 30 min. As expected, in patients with autonomic failure, mean blood pressure (MBP) increased significantly after water ingestion (from 104 +/- 13 to 128 +/- 20 mmHg, p<0.05, max response 19 +/- 9 mmHg, p<0.01). In contrast, in patients with FD, water ingestion did not increase MBP significantly over the 30 min period (90 +/- 13 to 94 +/- 13 mmHg, NS, max response 7 +/- 11 mmHg, NS,). Thus, the response to water drinking differed significantly between the two groups (2-way ANOVA: p<0.0001). These findings suggest an absence of functional peripheral osmoreceptors in FD patients and may have therapeutic implications

BACKGROUND: There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. METHODS: The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test-retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients' underlying disease status produced an appropriate change in OHQ scores. RESULTS: Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test-retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH. CONCLUSION: These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.

BACKGROUND:: To define the clinical neuro-ophthalmic abnormalities of patients with familial dysautonomia (FD). METHODS:: Sixteen patients (32 eyes) with the clinical and molecular diagnoses of FD underwent thorough neuro-ophthalmic clinical evaluation. RESULTS:: Visual acuity ranged from 0.05 to 1.0 decimal units and was reduced in 15 of 16 patients. Mild to moderate corneal opacities were found in most patients but were visually significant in only 2 eyes. Red-green color vision was impaired in almost all cases. Depression of the central visual fields was present on automated visual fields in all patients, even in those with normal visual acuity. Temporal optic nerve pallor was present in all cases and was associated with retinal nerve fiber layer loss in the papillomacular region. Various ocular motility abnormalities also were observed. CONCLUSION:: Patients with FD have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with FD

The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 microA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::