Faculty Bibliography

Autonomic neuropathy may contribute to the pathophysiology of both open-angle and normal-pressure glaucoma. However, autonomic function has not been studied extensively in these diseases. We evaluated baroreflex control of the heart and blood vessels in open-angle and normal-pressure glaucoma. We studied 14 patients with open-angle glaucoma, 15 with normal-pressure glaucoma and 17 controls. Sinusoidal neck suction (0 to -30 mmHg) was applied at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Baseline recordings showed no significant differences between the groups. The RR-interval response of the controls to neck suction at 0.1 Hz (3.88+/-0.32 to 6.65+/-0.44 lnms2) was significantly greater than that of the open-angle glaucoma patients (4.22+/-0.28 to 5.56+/-0.26 lnms2) and the normal-pressure glaucoma patients (4.53+/-0.27 to 5.53+/-0.37 lnms2) (P<0.05).The low-frequency power of diastolic blood pressure increased significantly in the controls (0.48+/-0.08 to 2.76+/-0.72 mmHg2; P<0.01) during 0.1 Hz neck suction, but did not change significantly in patients with either open-angle glaucoma or normal-pressure glaucoma. The RR-interval response in the control group (3.45+/-0.52 lnms2) to neck suction at 0.2 Hz was significantly greater than that of the normal-pressure glaucoma patients (1.84+/-0.32 lnms(2)) and the open-angle glaucoma patients (1.58+/-0.35 lnms2) (P<0.05). The decreased sympathetic and parasympathetic modulation during baroreceptor stimulation in patients with open-angle glaucoma and normal-pressure glaucoma suggests that autonomic dysfunction may contribute to the pathogenesis of both diseases

OBJECTIVE: Cerebral autoregulation was assessed by transcranial Doppler sonography in 10 patients with familial dysautonomia and 10 age matched controls. METHODS: Blood pressure, heart rate, and middle cerebral artery blood flow velocity (CBFV) were simultaneously recorded when supine and during 180 seconds of head up tilt. Cerebrovascular resistance (CVR) was calculated from CBFV and mean blood pressure was adjusted to brain level. RESULTS: In the controls, mean blood pressure remained stable during tilt, but heart rate increased significantly. In the patients with familial dysautonomia, mean (SD) blood pressure decreased by 15.0 (10.8)% (p < 0.05). Heart rate remained unchanged. In controls, systolic and mean CBFV decreased by 9.1 (4.7)% and 9.4 (7.0)%, respectively, while diastolic CBFV remained stable. In the patients, diastolic and mean CBFV decreased continuously by 32.1 (13.9)% and by 14.8 (31.4)%. Supine CVR was 28% higher in patients than in controls and decreased significantly less during head up tilt. CONCLUSIONS: Tilt evokes orthostatic hypotension without compensatory tachycardia in patients with familial dysautonomia owing to decreased peripheral sympathetic innervation. High supine CVR values and relatively preserved CVR during tilt suggest preserved central sympathetic activation in familial dysautonomia, assuring adaptation of cerebrovascular autoregulation to chronic supine hypertension and orthostatic hypotension

The five different types of the rare hereditary sensory and autonomic neuropathies (HSAN) are classified by their mode of inheritance, pathology, natural history, biochemical, neurophysiologic and autonomic abnormalities. Clinically, the different types of HSANs can be identified by a detailed history and examination and 'bedside' tests of sympathetic or parasympathetic function such as active standing, metronomic breathing or the Valsalva maneuver, sensory and motor nerve conduction studies, quantitative sensory testing of thermal and vibratory perception, and the analysis of sudomotor function by recordings of the sympathetic skin response (SSR) or the sweat output during quantitative sudomotor axon reflex testing (QSART). The slowly progressive, symmetrical HSAN type I manifests between the second and fourth decade with ulcers or mutilations of the lower extremities, low normal sensory and motor nerve conduction velocities, but abnormal warm, cold and heat pain perception and distal anhidrosis. In HSAN type II, symptoms occur already in infancy, trophic alterations affect fingers and toes. There are acral anhidrosis and various autonomic dysfunctions such as tonic pupils, eating and swallowing difficulties, constipation, episodic fever, profound hypotonia and episodes of apnea. Sensory perception is severely impaired and accounts for elevated vibratory but also thermal perception thresholds. Sensory nerve conduction is highly abnormal while motor nerve conduction studies are almost normal. Type III, the autosomal recessive familial dysautonomia (FD), is the most common of the HSANs. FD is characterized by pronounced autonomic, primarily sympathetic dysregulation with severe orthostatic hypotension, repeated episodes of autonomic crises with excessive arterial hypertension, profuse sweating, skin blotching, puffy hands and behavioral abnormalities. FD manifests only in children of Ashkenazi Jewish ancestry. Cardinal findings are diminished deep tendon reflexes, absence of overflow tears, absence of fungi-form papillae of the tongue and of axon flare response following intradermal histamine injection. Thermal and vibratory testing show pronounced impairment of temperature and pain but also of vibratory perception. Children with HSAN IV, 'congenital insensitivity to pain with anhidrosis' experience repeated episodes of high fevers during high environmental temperature due to anhidrosis. The anhidrosis of the hyperkeratotic skin accounts for absence of the SSR or lack of sweat output during QSART. The patients' insensitivity to superficial as well as deep, visceral pain can be demonstrated e. g. by quantitative heat pain testing. Patients develop severe mutilations e. g. of the tip of their tongue, they might have severe burn injuries and multiple, unnoticed fractures with neuropathic joints. Children with the very rare HSAN type V respond normally to tactile, vibratory or thermal stimuli, but have a selective loss of pain perception with otherwise normal neurological examination. Painful stimuli reveal no signs of discomfort

In temporal lobe epilepsy (TLE), there is evidence of ictal and interictal autonomic dysregulation, predominantly with sympathetic overactivity. The effects of TLE surgery on autonomic cardiovascular control and on baroreflex sensitivity (BRS) have not been studied. To evaluate such effects, we monitored heart rate (HR), systolic blood pressure (BP(sys)) and respiration in 18 TLE patients 3-4 months before and after TLE surgery. We used Blackman-Tukey spectral analysis to assess sympathetic and parasympathetic modulation as powers of HR and BP(sys) oscillations in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.5 Hz) bands. BRS was determined as the LF transfer function gain between BP and HR. After surgery, HR, BP(sys), respiration and HF powers remained unchanged, while LF powers of HR (1.57 +/- 1.54 bpm(2)) and BP(sys) (2.19 +/- 1.34 mmHg(2)) and BRS (0.68 +/- 0.31 bpm/mmHg) were smaller than pre-surgical LF powers of HR (3.87 +/- 3.26 bpm(2)) and BP(sys) (4.80 +/- 3.84 mmHg(2)) and BRS (1.12 +/- 0.39 bpm/mmHg; P < 0.05). After TLE surgery, there is a reduction of sympathetic cardiovascular modulation and BRS that might result from decreased influences of interictal epileptogenic discharges on brain areas involved in cardiovascular autonomic control. TLE surgery seems to stabilize the cardiovascular control in epilepsy patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive bradycardiac counter-regulation, both of which might be relevant for the pathophysiology of sudden unexpected death in epilepsy patients (SUDEP). Thus, TLE surgery might contribute to reducing the risk of SUDEP

In familial dysautonomia (FD), i.e. Riley-Day-syndrome, sympathetic cardiovascular function, as well as afferent temperature and pain mediating neurons, are significantly reduced. Thus, it was questioned if cold pressor test (CPT), which normally enhances sympathetic outflow and induces peripheral vasoconstriction by the activation of thermo- and nociceptive system activation, could be used to assess sympathetic function in FD.To evaluate whether CPT can be used to assess sympathetic activation in FD, we performed CPT in 15 FD patients and 18 controls. After a 35-min resting period, participants immersed their right hand and arm up to the elbow into 0-1 degrees C cold water while we monitored heart rate (HR), respiration, beat-to-beat radial artery blood pressure (BP), and laser Doppler skin blood flow (SBF) at the right index finger pulp. From these measurements, heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low and high frequency (LF, HF) power spectra of the electrocardiogram (ECG).All participants perceived cold stimulation and indicated discomfort. In controls, SBF decreased and HR and BP increased rapidly upon CPT. After 60 s, SBF indicated secondary vasodilatation in six controls, BP rise attenuated and HR returned to baseline in all controls. In the patients, SBF remained unchanged, HR and BP increased significantly, but after 50-60 s of CPT and changes were lower than in controls (p<0.05). RMSSD and CV decreased and LF increased significantly only in the controls.We conclude that CPT activates sympathetic HR and BP modulation despite impaired pain and temperature perception in FD patients. BP increase in the presence of almost unchanged SBF might be due to HR increase and to nociceptive arousal and emotionally induced catecholamine release as seen in emotional crises of FD patients. CPT assesses sympathetic cardiovascular responses independently from baroreflex function, which is compromised in FD

The cold face test (CFT) is a non-invasive challenge maneuver of the autonomic nervous system which activates the peripheral sympathetic and the cardiac parasympathetic nervous system and induces peripheral vasoconstriction and bradycardia. The physiology of CFT-induced bradycardia is still controversial. The heart rate decrease might result from a direct central up-regulation of cardiovagal activity or might be a secondary effect of baroreceptor activation or of changes of respiration. The purpose of this study was to analyze the origin of CFT-induced bradycardia. To evaluate the influence of respiration on bradycardia during CFT, we studied cardiac responses in 10 healthy volunteers during CFT (0-1 degrees C cold compresses for 60 s) with three different respiratory patterns: one with spontaneous and two with paced respiration (6 and 15 cycles/minute). We continuously monitored heart rate (HR), blood pressure (BP) and respiration and determined heart rate variability by assessment of coefficient of variation (CV), standard deviation (SD) and the root mean square of successive differences (RMSSD) of HR as well as low (LF) and high (HF) frequency spectra power of HR and BP. When coherence was above 0.5, we calculated the transfer function gain between HR and respiration in the HF band, as an index of respiratory sinus arrhythmia, and between HR and BP in the LF band, as an index of baroreflex sensitivity. HR decreased and BP increased significantly during the three types of CFT. The decrease of HR and the increase of BP, of time and frequency domain parameters did not differ between the three breathing patterns. Respiration, and HF and LF power of respiration did not change during CFT. The gain of the HF-transfer function between HR and respiration and the LF-transfer function gain between HR and BP increased significantly during CFT, but the increase did not differ between the three breathing patterns. The increase of the gain of both transfer functions is most likely due to an increase of vagal traffic and together with the unchanged respiratory pattern suggests that CFT-induced bradycardia is not due to baroreflex or respiratory influences, but seems to result from central vagal activation

Objective assessment of autonomic dysfunction in familial dysautonomia (FD) is largely based on the analysis of cardiovascular responses to challenge maneuvers such as orthostatic stress. Infrared pupillometry (IPM) provides an additional reliable method for cranial autonomic evaluation and has the advantage of requiring minimal cooperation.This study was performe to determine whether IPM contributes to the assessment of autonomic function in FD patients.In 14 FD patients and 14 healthy controls, we studied absolute and relative light reflex amplitude, pupillary constriction velocity (v(constr)), pupillary diameter, early and late pupillary re-dilatation velocity (v(dil 1), v(dil 2)) after dark adaptation. Prior to IPM, all patients had an ophthamological examination to evaluate refraction and corneal integrity.In comparison to controls, patients had a significant reduction of the parameters reflecting parasympathetic pupillary function (absolute light reflex amplitude 1.34plus minus0.21 vs. l.86plus minus0.14 mm, relative light reflex amplitude 22.74plus minus7.11% vs. 30.76plus minus3.57%, v(constr) 3.75plus minus1.09 vs. 5.80plus minus0.59 mm/s) and of the parameters reflecting sympathetic pupillary function (diameter 5.69plus minus0.66 vs. 6.35plus minus0.60 mm, v(dil 1) 1.29plus minus0.23 vs. 1.95plus minus0.23 mm/s, v(dil 2) 0.64plus minus0.13 vs. 0.72plus minus0.l2 mm/s; Mann--Whitney U-test: p<0.05).The non-invasive technique of IPM demonstrates dysfunction not only of the cranial parasympathetic, but also of the cranial sympathetic nervous system and, thus, further characterizes autonomic dysfunction in FD

OBJECTIVE: To determine whether an intrinsic sinus node abnormality is involved in the pathophysiology of the postural tachycardia syndrome (POTS). SUBJECTS, PATIENTS, AND METHODS: In this prospective study, we compared the relationship between P-wave axis (PWA) and heart rate (HR) in 11 healthy controls and 14 patients with POTS by obtaining 12-lead electrocardiographic recordings during supine rest and during gradual head-up tilt. The HR of controls was titrated with isoproterenol infusion to match the HR of patients. The PWA was compared at different HR levels, and the relationship between HR and PWA was assessed for patients and controls. Primary end points were the PWA-HR relationship in healthy controls, comparison of these data with data from patients with POTS as a group, and identification of a possible subgroup of patients with POTS with irregular PWA-HR relationship. RESULTS: The PWA increased with increasing HR following a similar logarithmic trendline in both groups. The PWA of patients was significantly lower at the lowest comparable HR level but not different at faster HR levels. Three patients (21%) had a clearly abnormal HR-PWA relationship with substantial shift toward lower PWA. CONCLUSIONS: Our data support the hypothesis of a primary sinus node abnormality in a subset of patients with POTS. The ability to identify patients with primary sinus node abnormality may have important therapeutic implications

Syncope is defined as a temporary interruption of cerebral perfusion with a sudden and transient loss of consciousness and spontaneous recovery. Approximately one third of the population experiences syncope at least once during a lifetime.Presyncopal signs and symptoms, including weakness, headache, blurred vision, diaphoresis, nausea, and vomiting are sometimes present for seconds or minutes prior to loss of consciousness. After syncope, the patients may present with persisting drowsiness, headache, dizziness, nausea, but not usually confusion.Causes of syncope have been categorized as cardiovascular, non-cardiovascular, and unexplained. Cardiovascular causes can be subdivided into structural heart disease, coronary heart disease, and arrhythmia. Non-cardiovascular causes include neurological, metabolic, psychiatric and other disorders.Orthostatic hypotension - one of the most frequent causes of syncope - has manifold etiologies comprising various neurological and internal diseases. Orthostatic hypotension usually can be attributed to an impairment of peripheral vasoconstriction or to a reduction of the intravascular volume. Signs and symptoms, including the above prodromi are often present just after rising from a supine or sitting position. Frequently, blood pressure decreases significantly without an increase in heart rate. Autonomic cardiovascular modulation is often reduced.Many of the patients with 'unexplained' syncope experience neurally mediated (i. e. neurocardiogenic or vasovagal) syncope. In these patients, cardiovascular control may be stable for an extended period of time during orthostatic stress, then there is a sudden decrease in blood pressure and heart rate. Neurocardiogenic or neurally mediated syncope can be associated with painful or emotionally stressful situations such as anxiety or fear, with prolonged standing or specific trigger situations such as micturition, defecation, coughing or sneezing, visceral or carotid sinus stimulation, or with trigeminal or glossopharyngeal neuralgia. So far, the mechanisms of neurocardiogenic syncope are not completely understood.The passive 60 degrees to 70 degrees head-up tilt test is useful for the diagnosis of orthostatic and neurally mediated syncope. The sensitivity of the test can be improved by additional pharmacological provocation, e. g. by isoproterenol, or by increased orthostatic stress using lower body negative pressure stimulation.For the treatment of syncope one should first consider non-pharmacological options. Patients with orthostatic hypotension should avoid rapid changes of the body position from supine to standing, as well as high room temperature or other situations inducing peripheral vasodilatation. An increased intake of sodium and fluids, mild physical exercise or so-called postural counter-maneuvers can improve orthostatic tolerance.Among the drugs recommended for pharmacologic treatment are mineralocorticoids (e. g. fludrocortisone), vasoconstrictor agents (e. g. ephedrine, midodrine), adenosine receptor blockers (theophylline) and beta2-blockers (propanolol), anticholinergic agents, e. g. scopolamine or disopyramide, and negative cardiac inotropes, e. g. beta1-adrenergic blockers or disopyramide. Serotonin reuptake inhibitors (e. g. fluoxetine, sertraline), alpha2-adrenergic agonists (clonidine), central nervous system stimulants such as methylphenidate or phentermine are thought to be beneficial in specific cases. Cardiac pacemakers often seem to be recommended without adequate indication.The antidiuretic, V2-receptor specific, vasopressin analogue desmopressin increases the intravascular volume. Erythropoietin improves anemia and red blood cell decrease and augments blood pressure and cerebral oxygenation. In postprandial hypotension, octreotide, a somatostatin analogue, prostaglandin inhibitors such as indomethacin or ibuprofen, as well as metoclopramide or two cups of coffee per day might be beneficial