Faculty Bibliography

Takotsubo cardiomyopathy is an acute reversible cardiac dysfunction syndrome associated with high circulating catecholamine levels. Our objective was to investigate whether abnormal cardiovascular control might play a role in the pathophysiology. We studied autonomic cardiovascular reflexes in 10 women who had takotsubo (33+/-7 months after being hospitalized) and 10 age/BMI matched healthy women. In the women with takotsubo, indices of vagal modulation of heart rate induced by respiration were uniformly reduced (expiratory:inspiratory ratio: p<0.01, pnn50%: p<0.02, rMSSD: p<0.03). Cognitive (stroop test: p<0.03) and emotional arousal (event recall: p<0.05) produced exaggerated pressor responses, without detectable ECG changes. Pressor responses to hemodynamic stimuli were also amplified (Valsalva SBP overshoot: p<0.05). Takotsubo women had increased BP variability in the short-term (St. Dev. SBP: p<0.01). Ambulatory recordings captured an exaggerated morning surge in SBP after awakening from sleep (p<0.05). Cardiovagal baroreflex gain was significantly lower in the takotsubo women (sequence analysis: p<0.01, regression method: p<0.001, transfer function gain: p<0.001). Women with takotsubo have heightened sympathetic responsiveness, labile BP and reduced vagal modulation of the heart. This shift in sympathovagal balance could play a role in the pathophysiology

OBJECTIVE: To determine if carbidopa, a dopa-decarboxylase inhibitor that blocks the formation of dopamine outside the brain, is an effective antiemetic in patients with familial dysautonomia (FD). BACKGROUND: Patients with FD, an hereditary neuropathy that affects the development of sensory neurons of the baroreflex, are unable to restrain the release of catecholamines from sympathetic nerve terminals at times of stress. Recurrent attacks of nausea, retching and vomiting, associated with high levels of circulating dopamine are a disabling feature of the disease for which there is no effective treatment. DESIGN/METHODS: We enrolled 12 patients with FD in an open-label titration and treatment study to assess the safety of carbidopa, an inhibitor of the enzyme dopa decarboxylase that does not cross the blood brain barrier. We then conducted a randomized, double-blind, placebo-controlled, crossover study to evaluate its antiemetic efficacy. RESULTS: All patients experienced severe cyclical nausea and uncontrollable retching that was refractory to standard treatments. Carbidopa at an average daily dose of 480 mg (range 325 to 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 ug/g crt) than while on placebo (222+/-41 ug/g crt, p<0.05). CONCLUSIONS: Carbidopa appears to be a safe and effective antiemetic in patients with FD likely by reducing the formation of dopamine outside the brain. Larger trials are warranted

Familial dysautonomia (Riley-Day syndrome) is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced pain and temperature sensibilities and absent baroreflexes, causing orthostatic hypotension as well as labile blood pressure that increases markedly during emotional excitement. Given the apparent absence of functional baroreceptor afferents, we tested the hypothesis that the normal cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in patients with familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 12 patients with familial dysautonomia. Spontaneous bursts of MSNA were absent in all patients, but in five patients we found evidence of tonically firing sympathetic neurones, with no cardiac rhythmicity, that increased their spontaneous discharge during emotional arousal but not during a manoeuvre that unloads the baroreceptors. Conversely, skin sympathetic nerve activity (SSNA), recorded in four patients, appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia, and that the increase in tonic firing of muscle vasoconstrictor neurones contributes to the increase in blood pressure during emotional excitement.

GOALS: : To analyze the neurochemical profile during the recurrent attacks of nausea and vomiting in patients with Riley-day syndrome. BACKGROUND: : One of the most disabling features of patients with Riley-day syndrome are recurrent attacks of severe nausea/retching/vomiting accompanied by hypertension, tachycardia, and skin flushing, usually triggered by emotional or other stresses. STUDY: : We monitored blood pressure and heart rate and measured plasma catecholamines during typical dysautonomic crises triggered by emotionally charged situations. For comparison, measurements were repeated at follow-up after the symptoms had resolved and the patients were feeling calm and well. RESULTS: : During a typical attack, patients were hypertensive and tachycardic. In all patients, circulating levels of norepinephrine (P<0.002) and dopamine (P<0.007) increased significantly. CONCLUSIONS: : Activation of dopamine receptors in the chemoreceptor trigger zone may explain the cyclic nausea/retching/vomiting of patients with Riley-day syndrome.

Riley Day syndrome, commonly referred to as familial dysautonomia (FD), is a genetic disease with extremely labile blood pressure owing to baroreflex deafferenation. Chronic renal disease is very frequent in these patients and was attributed to recurrent arterial hypotension and renal hypoperfusion. Aggressive treatment of hypotension, however, has not reduced its prevalence. We evaluated the frequency of kidney malformations as well as the impact of hypertension, hypotension and blood pressure variability on the severity of renal impairment. We also investigated the effect of fludrocortisone treatment on the progression of renal disease. Patients with FD appeared to have an increased incidence of hydronephrosis/reflux and patterning defects. Patients <4 years old had hypertension and normal estimated glomerular filtration rates (eGFR). Patients with more severe hypertension and greater variability in their blood pressure had worse renal function (both, P<0.01). In contrast, there was no relationship between eGFR and the lowest blood pressure recorded during upright tilt. The progression of renal disease was faster in patients receiving fludrocortisone (P<0.02). Hypertension precedes kidney disease in these patients. Moreover, increased blood pressure variability as well as mineralocorticoid treatment accelerate the progression of renal disease. No association was found between hypotension and renal disease in patients with FD.Journal of Human Hypertension advance online publication, 1 December 2011; doi:10.1038/jhh.2011.107

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.

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