XIIth International Symposium on the Autonomic Nervous System: Abstracts

Platform Sessions

Cerebral autoregulation is intact in patients population. Immediate precipitants are poorly understood. with head-up tilt (HUT) induced Acute withdrawal of sympathetic neuronal vasoconstrictor neurally-mediated (NMS) tone can explain the decreases in total peripheral and skel- etal muscle vascular resistance that accompany neurocardio- R. Schondorf, R. Stein, J. Benoit genie syncope but cannot explain concurrent cutaneous va- SMBD Jewish General Hospital, McGill University, Montreal, soconstriction. Circulating epinephrine produces this QC, Canada unusual hemodynamic pattern, by stimulating alpha- At syncope, during the collapse of pressure (BP), adrenoceptors on cutaneous blood vessels and beta-2 diastolic cerebral blood velocity (CBV) recorded using adrenoceptors on skeletal muscle blood vessels, and high transcranial Doppler (TCD) diminishes whereas systolic plasma epinephrine levels attend neurocardiogenic syncope, CBV is maintained. Some consider this increase in CBV but whether increased adrenomedullary secretion precedes pulsatility to be indicative of a paradoxical increase in cere- neurocardiogenic syncope has been unknown. brovascular resistance (CVR) prior to syncope. We, in con- Methods. Eighteen patients referred for tilt table testing for trast, contend that mean CBV decreases much less than or frequent presyncope had plasma does mean BP implying that cerebral autoregulatory mecha- levels of catecholamines and forearm hemodynamics mea- nisms are intact and functioning at syncope. The decrease in sured before and after tilt-evoked neurocardiogenic syncope. CVR at syncope that is used as an index of intact cerebral Results" All of 11 patients with tilt-evoked syncope had autoregulation is normally calculated as (mean BP/mean marked increases in plasma epinephrine levels beforethe loss CBV). This calculation ignores the contribution of critical of consciousness (mean more than 10 times baseline, closing pressure (CCP), the pressure below which blood p<0.001). Simultaneously obtained plasma norepinephrine flow in a vessel ceases. The resistance area product (RAP) levels increased to a significantly lesser extent, so that the takes the contribution of CCP into account. We calculated proportionate increase in plasma epinephrine from baseline beat to beat profile of CCP and RAP from the minute exceeded that in norepinephrine ("sympathoadrenal imbal- preceding NMS until 30 sec after termination of HUT from ance"). Before syncope, forearm vascular resistance de- I1 (7_, 4_) patients aged 42.0 • 5.2 (SE) years (range creased, and the change in forearm vascular resistance 23-72 years). Heart rate (HR), BP (Finapres) middle cere- correlated negatively with the change in the epinephrine:no- bral artery (MCA) CBV and end tidal CO 2 were continu- repinephrine ratio. In marked contrast, all 7 patients with- ously recorded. MCA BP was estimated by subtracting the out syncope had forearm vasoconstriction throughout the hydrostatic pressure difference between the TCD probe site tilting and had about equal increments in plasma norepi- and the BP recording site (heart level). At syncope HR nephrine and epinephrine levels from baseline. decreased from 90.7 + 0.9 to 76.1 + 1.1 bpm, MCA systolic Conclusions: Adrenomedullary stimulation and relative BP decreased from 76.8 _+ 3.1 to 47.2 + 3.5 mmHg, dia- sympathoinhibition precede tilt-evoked neurocardiogenic stolic BP decreased from 33.7 + 2.1 to 13.8 + 2.0 mmHg, syncope. "Sympathoadrenal imbalance" correlates with skel- and diastolic CBV decreased from 25.1 + 0.6 to 14.5 _+ 1.2 etal vasodilation in neurocardiogenic syncope and might cm/sec. Systolic CBV did not change (65.3 + 1.1 to 65.1 _+ play a pathophysiologic role, by shunting blood away from 1.6 cm/sec). CVR decreased from 1.26 + 0.29 to 0.82 +_ the brain. 0.32 and RAP decreased from 1.29 + 0.03 to 0.90 + 0.03 mmHg/cm/sec. CCP (-0.79 + 5.1 mmHg) did not change Assessment of venous compliance in patients at syncope. We conclude that during HUT induced syn- with orthostatic intolerance cope the contribution of CCP is negligible so that CVR provides an accurate estimator of RAP. The reduction of R. Freeman, M.R. Risk, V.A. Lirofonis, W.B. Farquhar RAP at syncope indicates that cerebral autoregulation is Beth Israel Deaconess Medical Center, Harvard Medical School, intact in NMS. Boston, MA, USA Sympathoadrenal imbalance and skeletal Objectives: To characterize venous compliance in the fore- muscle vasodilation before tilt-evoked arm and calf in patients with orthostatic intolerance neurocardiogenic syncope Background: Increased venous pooling and venous dener- vation may contribute to symptoms of patients with ortho- D.S. Goldstein, C. Holmes, M. Naqibuddin, R. Dendi, static intolerance (OI). We hypothesized that patients with S. Btentzel, S.M. Frank OI would have greater venous compliance compared to NINDS, NIH, Bethesda, MD, USA controls. Background: Neurocardiogenic syncope is the most com- Methods: Forearm and calf venous compliance was assessed mon cause of acute loss of consciousness in the general in 11 patients diagnosed with OI and 11 age-matched con-

0959-9851 2001 Lippincott Williams & Wilkins 177 XIIth International Symposium on the Autonomic Nervous System: Abstracts trols. A venous collecting cuff on the upper arm and thigh Leg crossing combined with leg and abdominal was inflated to 60 mmHg for 4 minutes and cuff pressure muscles tensing can abort vasovagal fainting subsequently decreased 1 mmHg / sec; changes in venous C.T.P. Krediet, N. van Dijk, I. de Bruin, J.J. van Lieshout, volume were measured using a mercury-in-silastic strain W. Wieling gauge (cuff pressure was used as an estimate of venous pres- Academic Medical Center, Department of Medicine, sure). P-V curves were generated and fitted with a quadratic Amsterdam, The Netherlands regression; compliance was calculated as the derivative of the P-V curve. These curves were generated during basal con- ditions and during a sympathoexcitatory stimulus (static In patients with autonomic failure leg crossing combined handgrip with post-exercise ischemia). with tensing of leg and abdominal muscles is an effective Results: There was a significant difference in the pressure- physical countermaneuver to combat orthostatic hypoten- volume relationship between the OI and control groups in sion. Its effectiveness in otherwise healthy subjects prone to the upper and lower extremity in the basal state (both p vasovagal fainting is largely unknown. <0.0005). Sympathetic activation did not change the pres- We tested the hypothesis that leg crossing combined with sure volume relationship in patients or controls in the upper muscle tensing aborts an impending vasovagal faint. Eight or lower extremity (p=ns). A comparison of the pressure consecutive subjects aged 19-69 years (4 females) referred volume relationship in the upper extremity with that of the for the evaluation of transient loss of consciousness in whom lower extremity was not significantly different in patients a vasovagal reaction was observed during tilt-table testing and controls in both the basal and sympathetically activated were investigated. The patients were instructed how to per- state (all p=ns). form the countermaneuver prior to the test. Conclusion: Contrary to expectations, patients with OI The protocol consisted of a 60 degree head-up tilt for 20 have decreased compliance in upper and lower extremities. min duration, if negative followed by sublingual nitroglyc- These differences may reflect soft tissue or vascular wall erine (0.4 rag) and an additional 15 min tilt. Three patients changes in the patient group. Paradoxically, the reduced experienced presyncopal symptoms coinciding with a pro- venous compliance may limit the extent of the response to gressive fall in during head-up tilt alone. Five orthostatic stress and play a role in the symptoms of OI. patients developed a vasovagal response after additional ni- troglycerine administration. At the moment of the impend- ing vasovagal faint finger arterial pressure had fallen from Orthostasis fails to produce active limb 109/72 (range 96/60-125/80) mmHg just prior to the on- venoconstriction in adolescents set of the faint to 63/42 (range 50/35-80/65) mm Hg and heart rate from 93 (range 80-100) bpm to 57 (range 35-85) J.M. Stewart bpm. The subjects subsequently performed the physical New York Medical College, Valhalla, New York, USA countermaneuver. It raised blood pressure almost instanta- Orthostasis is characterized by translocation of blood from neously in all (p<0.05) and aborted presyncopal symptoms. the upper body and thorax into dependent venous struc- Within 1 minute blood pressure had increased to 102/61 tures. Although active splanchnic venoconstriction is known (range 80/45-125/75) mmHg and heart rate to 77 (range to occur, active limb venoconstriction remains controver- 35-85) bpm. After uncrossing of the legs blood pressure did sial. We investigated whether active venoconstriction occurs fall and again a faint was impending. in the arms and legs in eleven healthy volunteers aged 13-19 Conclusion: legcrossing in combination with tensing of leg years using venous occlusion strain gauge plethysmogtaphy and abdominal muscles effectively serves as a natural anti- to obtain the forearm and calf blood flows and to compute gravity suit in that it can abort an impending faint by re- the capacitance vessel volume-pressure compliance relation. infusion of blood pooled below the diaphraghma into the Heart rate and blood pressure changes and variability mea- chest. Patients with recurrent vasovagal syncope should be sures were used to assess the sympathetic activation and trained to apply this effective physical countermaneuver. vagal withdrawal. Subjects were studied supine and at -10 ~ +20 ~, +35 ~. Blood flow decreased (forearm: from 3.2_+0.4 to 2.0_+0.3; leg from 2.7_+0.4 to 1.9_+0.4 ml/100ml/min), and limb arterial resistance increased (forearm: from 26_+4 to Acetylcholinesterase inhibition as new 41+_4; leg: from 31+_6 to 50+_10 mmHg/ml/100ml/min), approach in the treatment of patients with with +20 ~ of tilt compared to supine while blood flow de- orthostatic intolerance creased (forearm: to 2.1+_0.3; leg: to 1.7-+0.4 ml/100ml/ min), limb arterial resistance increased (forearm: to 42+_5; W. Singer, T.L. Opfer-Gehrking, S.M. Hines, leg: to 60+_llmmHg/ml/lOOml/min), heart rate increased B.R. McPhee, H. Tani, P.A. Low (from 64_+2 to 79+_2), baroreceptor gain decreased (from Department of Neurology, Mayo Clinic, Rochester, MN, USA 29+_2 to 20_+2), and high frequency heart rate variability decreased (from 1747+_253 to 882+_227) with +35 ~ of tilt Objective: To evaluate the efficacy of acetylcholinesterase compared to supine indicating sympathetic activation, para- inhibition in patients with orthostatic intolerance (OI). sympathetic withdrawal and arterial vasoconstriction. The Background: Volume expansion, beta-adrenergic blockade, volume-pressure relation was unchanged by orthostatic ma- vasoconstrictive agents and many other approaches are cur- neuvers. The results suggest that, despite sympathetic acti- rently used in the treatment of OI but the efficacy shows vation, parasympathetic withdrawal and arterial vasocon- great variability among patients and is oftentimes not sat- striction, active venoconstriction in the limbs is not isfactory. New approaches to alleviate symptoms of OI are important to the orthostatic response. clearly needed. We have previously demonstrated the effec-

178 ClinicalAutonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts tiveness of acetylcholinesterase inhibition in the treatment alternating days, progressively increasing in resistance. Ten of orthostatic , presumably by enhancing sym- patients enrolled; 6 completed the protocol (4 male; age pathetic ganglionic transmission. 72.1• of normal weight (BMI 25.5-+2.5). Three Methods: We investigated 18 patients (15 female, 3 male, dropped out due to psychosocial reasons and one due to 18-44 years, mean-age 28.7 years) with OI defined as heart chronic sciatica. SBP (supine, standing, and the change rate (HR) increment of at least 30bpm within 5 minutes in from supine to standing) were similar at weeks 1 + 8. All the upright position associated with symptoms of cerebral indices of muscle strength increased (absolute weight lifted hypoperfusion and/or sympathetic overactivity. Autonomic and repetitions performed) and walking time was shortened failure was quantified by distribution and severity reaching during the TUG, though improvements did not reach sta- 2.4 + 1.3 on a composite autonomic severity scale (CASS) tistical significance. None of the subjects experienced a fall from 0 to 10. HR, blood pressure (BP) and indices for during the investigation period. We believe that a home- cardiac output (COI), enddiastolic volume (EDVI) and pe- based RT program is a safe and viable method to promote ripheral resistance (PRI) were continuously monitored dur- activity in elderly people with OH. ing supine rest and during 5 min of 70 degree head-up tilt Support= Life Fimess/Parabody, The Hygenic Corporation, before and one hour after oral application of 60 mg pyri- Vidda Foundation dostigmine (Mestinon~). All patients scored orthostatic symptoms during tilt on a symptom-scale from 0 to 10 for both tilts. Results: Pyridostigmine significantly decreased HR in both supine (78.9• vs 73.0• bpm, p<0.001) and upright Quality of life in patients with postural position (123.7-+17.8 vs 110.6 vs 17.0 bpm, p<0.001). The tachycardia syndrome HR-increase with tilt was also significantly blunted (44.8• vs 37.6-+10.1, p<0.05). These changes of HR L.M. Benrud-Larson, P.A. Low, M. Dewar, P. Sandroni, were associated with improvement in orthostatic symptoms: T. Rummans Symptom-score pre-drug: 5.6-+2.9, post-drug: 4.2• Mayo Clinic and Foundation, Rochester, MN, USA (p<0.01). No side effects were reported. Conclusions: Pyridostigmine improves orthostatic toler- Patients with postural syndrome (POTS) expe- ance in orthostatically intolerant patients without inducing rience many potentially distressing and disabling symptoms, significant side effects. The presumed mechanism is im- including fatigue, palpitations, visual blurring, nausea, provement of sympathetic ganglionic transmission along tremulousness, and weakness. Simple activities such as eat- with the known cholinergic properties of this drug. If pla- ing, showering, or low intensity exercise may profoundly cebo-controlled studies can confirm these findings pyrido- exacerbate these symptoms and significantly impair even the stigmine can be a new useful tool in the treatment of OI. most rudimentary activities of daily living. Despite this, [Supported by NIH (PO1 NS32352), Mayo GCRC (M01 research has failed to investigate the impact of POTS on RR00585), and Deutsche Forschungsgemeinschaft] quality of life. Thus, the present study examined quality of life in patients with POTS. Ninety-four patients recruited through the Mayo Clinic Autonomic Disorders Laboratory Safely training senior citizens with participated in the study. All patients completed a question- naire packet including measures of quality of life (SF-36 Health Survey) and symptom severity (Autonomic Symp- A.S. Zion, R.E. De Meersman, D.M. Bloomfield tom Profile). Results indicated that patients with POTS Columbia University, New York, NY, USA reported significant impairment (1-2 standard deviations below a healthy population) in multiple domains of quality Resistance training (RT) has been suggested to improve of life. Energy level and role functioning were particularly orthostatic tolerance in patients with . How- impaired and similar to that reported by patients with other ever, individuals with orthostatic hypotension (OH) gener- chronic, disabling conditions (e.g., chronic obstructive pul- ally do not exercise for fear of exacerbating the risk of falls monary disease). Hierarchical regression analyses examined associated with the precipitous decline in systolic blood the relationship of demographic and clinical characteristics pressure (SBP) and related symptoms upon maintaining a (symptom severity, duration) to quality of life. Results in- standing posture. Therefore, a pilot study was designed to dicated that symptom severity and disability status were test the safety and efficacy of an 8-week home-based RT significantly associated with the SF-36 physical health sum- program using elastic resistance exercise bands (Thera- mary scale, together accounting for approximately 44% of Band). We hypothesized the program would attenuate the the total variance IF (4, 82) = 20.9, p <.001]. None of the change in SBP from supine to standing; improve muscular clinical or demographic variables examined significantly strength, and decrease walking time during a functional test predicted scores on the SF-36 mental health summary scale of gait and balance, the Timed Up + Go (TUG). Patients (p> .05). In summary, patients with POTS experience sig- with diagnosed OH were referred for enrollment. Blood nificant limitations across several domains of quality of life, pressure measurements were recorded during supine and including physical, social, and role functioning. More re- standing intervals. Subjects then performed isometric and search is needed to determine factors, both disease-related isokinetic muscle strength tests, and the TUG. Total body and psychosocial, that predict functioning and adjustment strength exercises, particularly those that emphasized the in this population. Such knowledge is necessary for the lower body were assigned and individualized to each subject optimal care of persons with this potentially disabling for use at home. Exercises were performed for 8-weeks, illness.

Clinical Autonomic Research 2001, Vol 11 No 3 179 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Parasympathetic cardiac modulation increases addition, we derived the transfer function (DC gain) be- during exercise in chronic obstructive lung tween respiration as the input and RR interval spectra as the disease (COPD) output for both protocols and stages. The ANOVA revealed significant changes in RR interval spectra for both LF and M.N. Bartels, S. Jelic, P. Ngai, R.C. Basner, HF modulations between stages of the exercise protocol (p R.E. DeMeersman <0.05). No significant changes were seen between LF and Departments of Rehabilitation Medicine and Medicine, HF modulations for any of the SB stages. Preliminary trans- Columbia University College of Physicians and Surgeons, fer function analyses during exercise showed a significant New York, NY, USA loss of gain with increasing workloads (p <0.01). No Autonomic responses to exercise have not been well char- changes in DC gain were seen during the SB protocol. acterized in patients with chronic obstructive pulmonary These findings suggest that changes in respiratory rate and disease (COPD). Because their markedly abnormal pulmo- volume have little effect on RR interval spectra below the nary physiology should be expected to lead to marked VT. Some other factors beside rate and volume changes changes in autonomic function, we evaluated heart rate vari- during exercise mediate changes in RR interval spectra. ability in individuals with moderate to severe COPD. Acknowledgment" VIDDA foundation, NIH-1-K12- Subjects: Fifty three patients with COPD (age 46-78 years, HDD1097-01A1 FEV1 35• predicted, room air arterial blood gases: PaO2 68_+11 mmHg, PaCO2 40• mmHg) were studied at The neural mechanism for sudden cardiac death rest and at peak exercise using cycle ergometry (mean peak VO2 18• ml/kg/min; all subjects received 30% supple- D.L. Jardine, C.J. Charles, M.D. Forrester, mental oxygen). Cardiac autonomic modulation was as- M. Whitehead, H. Ikram sessed with time-frequency analyses of the electrocardio- Departments of Cardiology and Medicine, Christchurch gram derived heart rate variability. Hospital, Christchurch, New Zealand Results" Power in the low frequency (LF, 0.04-0.15 Hz) Although ventricular fibrillation [VF] is thought to be the and high frequency (HF, >0.15-0.4 Hz) bands were aver- most common form of sudden cardiac death, the mecha- aged over representative 3 minute periods of rest and peak nisms involved in the initiation of VF are uncertain. We exercise. For the group, mean (• In-transformed LF have recently developed a sheep model for the study of (msec2) was significantly increased from baseline (B) to conscious cardiac sympathetic activity [CSNA] and exercise (E): B=I 1.8(1.4); E=12.4(1.4) (p<0.02), as was HF: report the first recordings following acute myocardial in- B=10.8(1.4); E=11.6(1.4) (p<0.005). LF/HF was signifi- farction and during VF. A female Coopworth sheep under- cantly decreased from B to E: B=3.0(1.4); E=2.3(0.8) went thoracotomy under general anesthesia and electrodes (p<0.005). SaO2 remained >92% during E; mean respira- were positioned in the left thoracic cardiac . Seven tory rate increased from 17/min to 27/min. days later, the animal underwent acute myocardial infarc- Conclusions- The increase in the absolute HF component tion under pethidine and diazepam analgesia using a suture of heart rate variability along with a decrease in the LF to around a branch of the left anterior descending coronary HF ratio suggests an increased parasympathetic cardiac artery. Blood pressure [MBP], heart rate [HR] and CSNA modulation in these patients. These findings are suggestive were recorded continuously and at baseline were 97 mmHg, of a compensatory reflex to exercise form a variety of pos- 143 bpm and 76 bs/min respectively. During 30 minutes sible mechanisms. These may include a response to altered following occlusion, MBP gradually decreased from 91 to pulmonary mechanics or a response to increased CO2. 85 mmHg; HR from 138 to 100 bpm and CSNA increased from 91 to 108 bs/min. After 30 minutes, ventricular ec- The effects of respiration on R-R interval topics increased and baroreflex entrainment of CSNA was spectra during exercise still present. Three seconds before VF, there was a sudden crescendo of CSNA activity which did not appear to be R. De Meersman, M. Bartels, D. Newandee, S. Reisman baroreflex-modulated. Burst area increased by 260% and Columbia University, New York and New Jersey Institute of remained high for at least 20 seconds after VF became Technology, NJ, USA established. This is the first demonstration of VF during Although it is accepted that increased respiratory rate and CSNA monitoring in a conscious animal. Following acute volume during exercise mediate changes in RR interval myocardial infarction, VF may be triggered by a sudden spectra it has not been well studied. Therefore, our objective increase in CSNA. We suspect this has not been reported was to determine the contribution of increased respiratory before because CSNA is inhibited by anesthesia and is dif- rate and volume on power spectra of RR interval during ficult to record continuously in conscious animals. steady-state exercise up to the ventilatory threshold (VT). We studied 12 healthy subjects (7d' , 5 ~ ) during 1) cycle Sympathetically-mediated sodium retention ergometry (Ex) at 50, 75 and 100% of previously deter- does not contribute to the hypertension of mined VT and 2) while seated and breathing (SB) at autonomic failure matched respiratory rates and volumes as during the Ex T. Tellioglu, B. Black, V. Watkins, (3. Farley, protocol. Throughout the SB protocol carbon dioxide was R.M. Robertson, I. Biaggioni added to maintain normal gas homeostasis. Power spectra Autonomic Dysfunction Center, Vanderbilt University, for both protocols were derived from 3-minute epochs of Nashville, TN, USA stationary data using frequency domain analyses. These data were analyzed via a 2 (protocol) by 3 (stages) repeated mea- The sympathetic nervous system is thought to contribute to sures ANOVA followed by Scheffe' posthoc analyses. In essential hypertension (HTN), in part through its actions

180 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts on the kidney (sodium retention). We have previously SBP correlated with the decrease in LFsBe in MSA, HTN shown that 50% of patients with autonomic failure have and NTN, but not in PAF. Thus, LFsBP, coupled with severe supine hypertension, but the mechanism depends on ganglionic blockade, revealed human models of sympa- the underlying pathology. The ganglionic blocker tri- thetic-dependent (MSA) and independent (PAF) hyperten- metaphan produces dramatic decreases in blood pressure in sion. This approach can be used to assess the contribution patients with multiple system atrophy (MSA) but not in of the sympathetic nervous system in essential hypertension, patients with pure autonomic failure (PAF). We studied in which sympathetic dependence is variably increased. these human models of sympathetically-dependent (MSA) These results also highlight the usefulness of autonomic and -independent (PAF) hypertension to test the hypothesis failure patients as human models of sympathetically- that urinary sodium retention would be greater in MSA dependent hypertension. patients because of their residual sympathetic tone. We studied a total of 44 patients in a metabolic ward, on a A novel syndrome of familial 150-mEq sodium diet, and measured blood pressure and noradrenergic failure sodium excretion overnight. Patients were divided into 4 groups, MSA and PAF, with (HTN) and without (NTN) I. Biaggioni hypertension. Patients with HTN had greater sodium ex- Autonomic Dysfunction Center, Vanderbilt University, cretion (pressure natriuresis), but no differences were ob- Nashville, TN, USA served between MSA and PAF in either group with or with- out HTN (table). Furthermore, all four groups fell within We report a family with three out of seven siblings affected the same "pressure-natriuresis" line. In conclusion, we with isolated noradrenergic failure. Patients were two fe- found no evidence of sodium retention contributing to males, ages 39 and 38 at the time of evaluation, and a male HTN in autonomic failure patients. who died at age 16. Patients had episodes of severe hypogly- cemia during infancy and symptoms consistent with ortho- static hypotension, even though this was not recognized Supine SBP UNa mol/mg creatinine until later in life and were initially treated as a dis- order. Physical examination was otherwise normal, without MSA without NTN 130 • 3 100 • 20 ptosis or clinical evidence of neuropathy or parkinsonism. MSA with HTN 184 • 9 190 • 40 PAF without NTN 127 • 7 100 • 30 Autonomic function tests revealed selective noradrenergic PAF with HTN 174 • 4 170 • 40 failure with normal sweating and intact parasympathetic function. Plasma norepinephrine and DHPG were below limits of detection. Plasma dopamine was below limits of The sympathetic nervous system in essential detection and plasma dopamine-beta-hydroxylase (DBH) hypertension: lessons from autonomic failure activity was present, ruling out DBH deficiency. Further- more, treatment with DOPS (which is converted to norepi- A. Diedrich, J. Jordan, J. Tank, J.R. Shannon, nephrine by the ubiquitous L-Aminoacid Decarboxylase) R.M. Robertson, F. Luft, D. Robertson, I. Biaggioni increased blood pressure and restored plasma norepineph- Franz Volhard Clinic, Berlin, Germany; Autonomic rine (to 65 and 139 pg/ml in each patient) and the intra- Dysfunction Center, Vanderbilt University, Nashville, TN, USA neuronal NE metabolite DHPG (to 1742 and 771 pg/ml), suggesting that sympathetic terminals were intact. Patients The contribution of the sympathetic nervous system to es- were hypersensitive to the effects of phenylephrine and iso- sential hypertension (HTN) can be evidenced by an increase proterenol, ruling out a postsynaptic receptor defect. in vascular sympathetic modulation, as reflected in low fie- Baroreflex function was intact (6 msec/mm Hg), suggesting quency systolic blood pressure fluctuations (LFsBe), and an intact central autonomic pathways. Skin immunohisto- exaggerated decrease in blood pressure during sympathetic chemistry using specific antibodies was positive for DBH withdrawal. To validate this approach, we determined staining but no tirosine hydroxylase (TH) staining was LFsBe and the effect of ganglionic blockade in HTN pa- found. Both DBH and TH staining were present in control tients and normotensive subjects (NTN). Multiple system skin. A diagnosis of tyrosine hydroxylase deficiency, how- atrophy (MSA) patients, in whom supine hypertension is ever, is not certain, given the absence of CNS signs. Also, maintained by residual sympathetic tone, served as positive plasma levels of DOPA were normal (1455 and 1913 controls. Pure autonomic failure (PAF) patients, in whom pg/ml). DOPAC levels were decreased but present (587 and supine hypertension is largely independent of sympathetic 395 in patients, 1300_+60 in normals). Therefore, the etiol- tone, served as negative controls. Supine SBP was 203-+9, ogy of this novel syndrome remains to be determined. 186_+6, 176_+11 and 134_+4 mm Hg in MSA, PAF, HTN and NTN, respectively. LFsBp was higher in MSA and HTN (5.7_+1.5 and 5.8_+1.4 mm Hg 2) compared to NTN The genetic basis of and PAF (2.8_+0.6 and 1.1+0.5 mm Hg2). Trimethaphan dopamine-beta-hydroxylase deficiency 2-4 mg/min induced complete autonomic blockade, as de- C.H. Kim, C.P. Zabetian, J.F. Cubells, S. Cho, termine by loss of baroreflex function. Trimethaphan low- I. Biaggioni, B. Cohen, D. Robertson, K.S. Kim ered SBP below 125 mm Hg in all NTN andall but one Harvard Medical School, University of Tennessee, Yale MSA (mean SBP post trimethaphan: 110-+4 and 95-+10 mm University, Vanderbilt University Hg, respectively), but not in PAF (168-+6 mm Hg). Re- sponses in HTN were variable; SBP decreased below 125 Dopamine-beta-hydroxylase (DBH) deficiency is a congen- mm Hg in three and remained elevated in four (group mean ital disorder presenting as severe orthostatic hypotension. It SBP post trimethaphan, 130_+8 mm Hg). The reduction in is characterized by undetectable tissue and plasma levels of

Clinical Autonomic Research 2001, Vol 11 No 3 181 XIIth International Symposium on the Autonomic Nervous System: Abstracts norepinephrine, DHPG and epinephrine and their metabo- the SNP of normal subjects, but has been noted in regen- lites, and elevated levels of dopamine and its metabolites. erating nerves of mouse footpad and in a few diabetic sub- The norepinephrine-synthesizing enzyme DBH is not de- jects. Some empty S-100 stained Schwann cell sheaths were tectable by antibody assay or functional assay. These pa- observed, suggesting active denervation. tients exhibit profound deficits in autonomic and cardio- Conclusion: Marked decrease in unmyelinated peripheral vascular function, but relatively subtle signs of CNS innervation was noted throughout epidermal and subepi- dysfunction. They have ptosis of the eyelids, normal sinus dermal layers which is consistent with previous reported , absent pressor response to the indirectly-acting peripheral neuropathology. Immunostaining indicated ma- sympathomimetic amine, tyramine, but a pressor response jor losses in Substance P and CGRP immunoreactive nerves to the 2 agonist, clonidine. There are frequent stillbirths and suggesting that the FD gene mutation may cause secondary perinatal deaths among siblings of affected patients. depletions in multiple neurotransmitters. The presence of We hypothesized that mutations in the Phox2A, Phox 2B (VIP)-ir nerves, as well as empty Schwann cell sheaths sug- or DBH gene would underlie the norepinephrine deficit in gests active denervation and regeneration and confirms these patients. No abnormality in the coding regions of clinical impressions of FD being a progressive neurological Phox 2A or Phox 2B was detected. However, we found disorder. seven novel polymorphisms in human DBH gene from analysis of two unrelated patients from the U.S. mid-South A human model of orthostatic intolerance: and their families. Both patients are compound heterozy- selective norepinephrine reuptake inhibition gotes for variants affecting expression of DBH protein. Each carries one copy of a T6 C transversion in the splice donor C. Schr6der, J. Tank, A.M. Sharma, F.C. Luft, J. Jordan site of DBH intron 1, creating a premature stop codon. In Clinical Research Center, Franz Volhard Clinic, CharitY, patient 1 there is a missense mutation in DBH exon 2. Berlin, Germany Patient 2 carries missense mutations in exons 1 and 6 re- Observations in patients with functional mutations of the siding in cis. Two of 88 normal individuals in the U.S. norepinephrine transporter (NET) gene suggest that im- mid-South were heterozygotes for the mutation creating the paired norepinephrine uptake may contribute to idiopathic stop codon, but no individuals among 150 patients with orthostatic intolerance. In 12 healthy subjects (8 female, age Alzheimer's disease had this mutation. 33+2, BMI 22+0.8 kg/m 2) we tested the effect of the selec- We conclude that DBH deficiency is a Mendelian reces- tive NET blocker reboxetine and placebo on cardiovascular sive disorder resulting from heterogeneous molecular lesions responses to cold pressor testing, handgrip testing, and a at DBH. DBH deficiency could be a significant cause of graded head-up tilt test (HUT). In a double-blind cross- stillbirths and perinatal mortality. over fashion, subjects ingested 8 mg reboxetine or placebo 12 hrs and 1 hr before testing. Heart rate (HR), finger blood Cutaneous innervation in familial dysautonomia pressure, impedance cardiography and blood flow velocity in the middle cerebral artery were monitored continuously. M.J. Hilz,1'2 W.R. Kennedy,3 B. Stemper, In the supine position, HR was 67+3 bpm with placebo and G. Wendelschafer-Crabb, 3 F.B. Axelrod 1 74+4 bpm with reboxetine. At 75 ~ HUT, HR was 87+4 and Departments of Neurology at LNYU Medical Center, USA; 122+5 bpm with placebo and reboxetine, respectively 2University of Erlangen-Niirnberg, Germany; 3University of (p<0.001). Mean arterial pressure was 89+3 with placebo Minnesota, Minneapolis, MN, USA and 97+2 mmHg with reboxetine while supine and 106+3 Introduction: Familial Dysautonomia is characterized by mmHg and 111+3 mmHg at 75 ~ HUT. Reboxetine reduced sensitivity to mechanical pain and thermal stimuli, blunted the increase in systemic vascular resistance with with reduced small dorsal root ganglia neurons and unmy- HUT, which was compensated by an increase in cardiac elinated peripheral nerves. output. Cerebral blood flow velocity was not altered by Objective To identify the type of unmyelinated nerves affected. reboxetine. During cold pressor testing, systolic blood pres- Methods: We performed punch skin biopsies on 10 FD sure increased by 26+2 mmHg with placebo and 6+3 patients (8 female). Skin biopsies from the calf and back (T mmHg with reboxetine (p<0.001). Similarly reboxetine 3-4) were immunostained and imaged with a CARV con- blunted the blood pressure increase on hand grip testing. focal microscope to assess density and fiber type. We conclude that selective NET blockade creates a pheno- Results" Epidermal nerve fibers (ENFs) were markedly re- type that resembles idiopathic orthostatic intolerance. This duced at both locations.The average density in calf was 0.25 observation supports the hypothesis that disordered norepi- ENFs/mm epidermal length (501am sections) (nor- nephrine uptake mechanisms can contribute to human car- ma1=15.94, n=25, S.D.=6.75). Back samples contained 9.3 diovascular disease. ENFs/mm (normal=70.09, n=12, S.D.=22.45). There was also severe nerve loss of nerves in the subepidermal neural Comparative biomonitoring of autonomic plexus (SNP) and of deep dermal nerves of some subjects. functions in patients treated with various Sweat glands and sweat ducts were infrequent and those psychotropic drugs sweat glands present had reduced innervation density. In M. Mueck-Weymann, R. Rauh, J. Acker, P. Joraschky those biopsies that contained sufficient SNP, there was Department of Psychosomatic Medicine, University of marked reduction of Substance P (SP) immunoreactive (-ir) Technology Dresden; Institute of Physiologyand Cardiology, and Calcitonin gene related peptide (CGRP)-ir nerves where SP-ir and CGRP-ir nerves would be expected, University of Erlangen; Germany whereas Vasoactive intestinal peptide (VIP)-ir nerves were Most antidepressant drugs lead to enhanced synaptic avail- noted in the majority of biopsies. VIP is rarely observed in ability of the neurotransmitters serotonine and/or norepi-

182 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts nephrine. However, affecting also other transmitters, e.g. acetyl- level sojourn and this is independent of CMS. We speculate choline, antidepressants cause peripheral autonomic dysfunction that the abnormal vasoreactivty is genetically determined (e.g. dry mouth, tachycardia or sudden cardiac death). Aim of our and an adaptation of cerebral vasoregulation to life at high study was to objectify these autonomic dysfunction. altitudes in the Andes. Therefore, we applied simultaneous recordings of ECG Support: Clinica Medica 1, IRCSS, S. Matteo, Pavia, Italy, for assessment of heart rate variability (HRV), as well as skin NMHEMC Research Foundation, Laboratorio de Trans- blood flow and skin conductance level - indicating periph- porte de Oxlgeno, Departamento de Ciencias Fisiol6gicas, Uni- eral autonomic responses like inspiratory gasp response versidad Peruana Cayetano Heredia, Lima, Peril (IGR) and skin conductance response (SCR) - to patients under treatment with psychotropic drugs (amitriptyline, Acute cardiovascular responses upon tilt in donzapine, fluoxetine, or hypericum extract; n=20 each). spinal cord-injured and control individuals We found that heart rate variability was reduced in all patients treated with ami, or do but not under treatment M.T.E. Hopman, J.T. Groothuis, S. Houtman, H. van Langen with flu, or hyp. Exclusively in ami-, do-treated patients 1) Department of Physiology and Vascular Laboratory, University redilation of IGR was prolonged, indicating inhibition of Medical Centre Nijmegen, The Netherlands norepinephrine re-uptake, and 2) in about 50% of these Despite the loss of centrally mediated sympathetic vasocon- patients SCR was blocked completely, or reduced in the striction in spinal cord injured (SCI) individuals, they cope other 50% (due to anticholinergic effects). surprisingly well with orthostatic challenges. In the patho- Assessing HRV, SCR, and IGR under treatment with physiology of this intriguing observation spinal and/or myo- psychotropic drugs, one can objectify autonomic dysfunc- genic reflexes may play a pivotal role. The purpose of the tion caused by side effects. Maybe, this non-invasive present study is to compare cardiovascular changes (blood biomonitoring will become a helpful diagnostic tool in the pressure, leg blood flow, leg volume) immediately upon tilt treatment of patients. between individuals with SCI (i) without centrally mediated motor and autonomic control (spastic paralyses: SP, n=8), Cerebrovascular reactivity to CO 2 at high (ii) without centrally mediated motor and autonomic con- altitude and sea level in Andean natives trol as well as without spinal reflexes (flaccid paralyses: FP, n=7) and ten healthy controls (C). All individuals were R. Roach, 1 C. Passino, 2 L. Bernardi, 3 J. Gamboa, 4 tilted to 30 ~ within 5 seconds. Red blood cell velocity of the A. Gamboa,40. AppenzellerS common femoral artery was measured beat by beat using 'Hypoxia net. Montezuma, NM, USA; 2Istituto di Fisiologia, Echo Doppler Ultrasound (ATL 5000 HDI). Blood pres- Clinica, CNR Pisa, Italy; ~Clinica Medica 1, IRCSS, S. Matteo, sure was measured continuously using portapres. Leg vol- Pavia, Italy; 4Laboratorio de Transporte de Ox~geno, ume changes were assessed by plethysmography. Within the Departamento de Ciencias Fisiol6gicas, Universidad Peruana first 10sec after tilt mean arterial pressure dropped in all Cayetano Heredia, Lima, Peril; 5NMHEMC Research three groups, with red blood cell velocity in the femoral Foundation, Albuquerque, NM, USA artery showing a clear decrease in C and a slight but tran- In Tibetans cerebrovascular reactivity to incremental in- sient increase in SP and FP. Around 30 sec after tilt, mean creases in blood pressure is attenuated. We report on the arterial pressure in all groups was back to baseline level or reactivity of cerebral vessels to CO 2 in Andeans (N=31) with even a bit above and mean velocity was decreased in all chronic mountain sickness (CMS, N=15) and in normal groups. Calf volume increased most rapidly in SP and FP. local subjects (C, N=16) in Cerro de Pasco (CP) (altitude This study demonstrates that in the first 10 sec after tilt 4338m), Peru and in the same subjects in Lima (L), (alti- blood flow to the legs in SCI increases despite a drop in tude 150m), restudied within 24 hours of arrival at sea level. blood pressure, most likely an effect of gravity and/or the We measured middle cerebral artery flow velocities by lack of increase in peripheral resistance. Interestingly, within Doppler ultrasound (TCD) and manipulated alveolar CO 2 30 sec after tilt all groups were able to increase peripheral partial pressure (PCO2) by rebreathing through a closed resistance and restore blood pressure despite the loss of cen- circuit until - 64% increase from baseline. All subjects were tral control and spinal reflexes. This seems to suggest that examined to assess a standard CMS-score (CMS-sc), hemat- the myogenic component may play a pivotal role in the ocrit (HTC) was also measured. CMS was defined by a adaptation in vascular resistance. CMS-sc of >12 and, separately, by HTC of >65%. TCD was adjusted for mean HTC of C in CP (53.4%), for mean Autonomic and cardiovascular response to PCO 2, before rebreathing, of C in L (41.2; equation of acute orthostatic challenge in subjects with Markwalder et al.) and for mean CMS-sc of C in CP (7). paraplegia and controls HTC did not change in L. CMS-sc in all subjects returned to normal in L concomitantly with remission of CMS J.M. Wecht, J.P. Weir, A.M. Spungen, symptoms. Using these adjustments (by ANOVA) and R.E. De Meersman, W.A. Bauman paired T-tests we found a paradoxical decrease in TCD Department of Medicine, Mount Sinai School of Medicine, New York, NY; Spinal Cord Damage Research Center, VA (P<0.001) in all subjects and in all locations at the end of rebreathing. There were no differences in the slopes between Medical Center, Bronx, NY; University of Osteopathic Medicine and Health Sciences, Des Moines, ID; Department of C and CMS but C's had higher TCD's in all locations (P<0.001) and the drop in TCD's at the end of rebreathing Rehabilitation Medicine, College of Physician & Surgeons, in CP was larger in both groups (P<0.001). Thus, paradoxi- Columbia University, New York, NY, USA cal vasoreactivity of cerebral vessels to increases in PCO 2 Previously, we demonstrated similar resting cardiovascular characterizes Andean natives at altitude and on short sea and autonomic function in subjects with paraplegia com-

Clinical Autonomic Research 2001, Vol 11 No 3 183 XIIth International Symposium on the Autonomic Nervous System: Abstracts pared to sedentary able-bodied controls (Wecht et al. 2000). at baseline and decreased to 96_+7.2/54+-2.8 mmHg during We are now reporting cardiac and autonomic response to gafiglionic blockade with trimethaphan, which is consistent acute orthostatic challenge in similar groups. Nineteen sub- with the presence of functioning sympathetic efferents. En- jects with paraplegia (P) below T-6 and nine age-, heigh-t, tacapone increased systolic blood pressure in a dose- weight- and gender-matched control (C) subjects were dependent fashion. Compared with baseline values, systolic tested. Three head-up tilt (HUT) positions, +10 ~ +35 ~ and blood pressure 120 minutes after drug ingestion was +70 ~, were randomized, and rest intervals of 15 minutes 0.7_+1.9 mmHg with placebo and 11+3.7 with entacapone were maintained between each maneuver. Autonomic data 400 mg (p<0.05). However, the pressor response to a mod- was acquired while the tilt-table was adjusting and for the erate dose of yohimbine was approximately 3.5 times greater initial 2-minute period at each tilt angle. Cardiovascular than the response to the maximal dose of entacapone. We data was then immediately collected. Heart rate (HR) and conclude that COMT inhibition elicits a moderate dose- blood pressure were measured beat-to-beat by use of lead II dependent pressor response in the setting of severely im- of the electrocardiograph and finger photoplethysmograph, paired baroreflex buffering and residual sympathetic func- respectively; data were digitized, recorded and stored on tion. Our findings suggest that multiple system atrophy hard disk. Cardiac output (CO) and stroke volume (SV) represents an ideal model to characterize the effect of subtle were assessed using noninvasive cardiac output (NICO) by manipulations of norepinephrine turnover on blood pres- the acetylene uptake technique. Mixed ANOVA, unpaired sure regulation in small numbers of subjects. t-tests and multiple regression analyzes were used to test for within and between group differences for autonomic and cardiac parameters, significance was set at 0.05. With pro- gressive HUT, no significant group differences were found Effect of acute unilateral high frequency for cardiac function; within groups, CO and SV were sig- nificantly reduced (P<0.0001) and HR significantly in- stimulation of the subthalamic nucleus on the creased (P<0.0001); the group by tilt interaction effect was heart rate and blood pressure in patients with not significant. Normalized cardiac sympathovagal balance Parkinson disease (LF/HF) increased from supine to 70 ~ in both groups (P: A. Voustianouk, K.F. Bhattacharya, J.-M. Gracies, P=0.03, C: P=0.01); however the change in LF/HF was M. Mata, H. Kaufmann significantly greater in the C compared to the P group at Department of Neurology, Mount Sinai School of Medicine, 35 ~ (7.1~ vs. 0.75~ msec2/Hz, respectively; P=0.02) New York, NY, USA and 70 ~ of HUT (13.3_+16.7 vs. 3.2_+6.2 msec2/Hz, respec- tively; P=0.03). There was a significant increase in periph- eral vasomotor tone (LFSBP) from supine to 70 ~ of HUT in Deep brain stimulation in the subthalamic nucleus (DBS- both groups (P: P=0.01, C: P=0.001); however the increase STN) ameliorates motor deficits in patients with Parkin- was significantly greater in the C vs. the P group at both 35 ~ son's disease (PD) but its effect, if any, on cardiovascular (-0.5+-19.7 vs. 17.7_+20.9 mmHgi/Hz, respectively; parameters is not known. To determine whether acute STN P=0.04) and 70 ~ (57.9_+60.2 vs. 16.9_+32.7 mmHgi/Hz, stimulation modifies blood pressure and heart rate we stud- respectively; P=0.03). Central cardiac function was main- ied three male patients with advanced PD (age 62_+11) who tained in subjects with chronic paraplegia below T-6 despite had chronically implanted stimulators in the STN (bilateral reduced sympathovagal response to HUT. in two and unilateral in one). Mean DBS-STN settings were 185Hz, 138E]s, 2.5V and configurations were unipolar in two patients and bipolar in one. R-R intervals and beat-to- beat blood pressure (Finapres) were monitored while pa- tients were resting supine, in the practically defined levo- Catechol-O-methyl-transferase inhibition in dopa "off" state, during 15 minutes after switching multiple system atrophy stimulation off and during 15 minutes after switching stimulation on again. During the last 10 beats with the J. Jordan, J. Tank, A. Lipp, C. Schr6der, A. Diedrich, stimulation off, R-R intervals were 934_+12 ms (heart rate G. Arnold, A.M. Sharma, F.C. Luft 64 b/min) and blood pressure was 132_+2/67_+2 mmHg Franz-Volhard-Clinic, Berlin, Germany; Dept. of Neurology, (systolic/diastolic, mean_+SD). When switching the stimu- Humboldt University, Berlin, Germany; Autonomic lator on, the initial ten RR intervals decreased to 892_+12 ms Dysfunction Center, Vanderbilt University, Nashville, TN, USA (heart rate 67 b/rain, p <0.001) while blood pressure in- creased to 133_+1/69+-0 mmHg (p = 0.056 for systolic, and Whether or not catechol-O-methyltransferase (COMT), p <0.05 for diastolic pressure). Heart rate and blood pres- the enzyme that metabolizes extraneuronal norepinephrine, sure increased rapidly and remained high for the following can contribute to blood pressure regulation in humans is fifteen minutes. RR intervals during this period were unknown. We studied the effect of placebo, incremental 885_+10 ms (heart rate 68 b/min, p <0.001), and blood doses of the COMT inhibitor entacapone (100, 200, and pressure was 131_+1/69_+1 (p <0.001 for diastolic pressure). 400 rag), and the sympathetic stimulant yohimbine (5.4 We conclude that deep brain stimulation in the STN rag) in seven patients with multiple system atrophy. The acutely increases heart rate and blood pressure likely autonomic regulation was carefully characterized using in- through stimulation of sympathetic outflow. As the STN is travenous phenylephrine, nitroprusside, and trimethaphan. involved in motor control, it is tempting to speculate that Patients were extremely hypersensitive to phenylephrine and this nucleus may be part of the central command pathways nitroprusside. Blood pressure was 147_+12/75+-4.3 mmHg that increase sympathetic outflow when initiating movement.

184 ClinicalAutonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

The isolated spinal cord can generate may not be linearly related to sympathetic activity. We sympathetic adrenergic but not sympathetic hypothesize that direct analysis of the raw MSNA will give cholinergic activity a better representation of sympathetic activity. We studied 7 healthy subjects during baseline, -15 and, -30 mmHg of C.J. Mathias, 1 P. Cariga, ~'2,a M. Catley, 2 G. Savic, 4 lower body negative pressure suction (LBNP). The MSNA H.L. Frankel, 4 P.H. Ellaway ~'2 was recorded from the peroneal nerve. Automatic burst de- 1Neurovascular Medicine Unit and 2Department of tection in the integrated MSNA was manually verified and Sensorimotor Systems and Imperial College School of Medicine common parameters were calculated. Action potentials of and 3Autonomic Unit, NHNN, and Institute of Neurology, individual and group neurons in the raw MSNA were de- UCL, London, UK; 4National Spinal Injuries Centre, Stoke tected based on modified Wavelet denoising technique and Mandeville Hospital, Aylesbury,UK classification algorithm. Analyzed data have been compared The sympathetic skin response (SSR) is used to investigate with NE spillover for each level of LBNP. Number of bursts the integrity of sympathetic cholinergic sudomotor path- per minute and burst area per min, estimated from the ways. There are contrasting reports on whether the SSR can integrated MSNA, correlated poorly with NE spillover be generated within the spinal cord 1'2. Palmar and plantar (0.57 and 0.62 respectively). Total spike amplitude, deter- SSR electrical stimulation of supra orbital nerve, median mined from the raw MSNA showed a better correlation (r= and peroneal nerves were recorded in 29 spinal cord injury 0.80, fig). We conclude that analysis of the raw MSNA (SCI) with cervical and thoracic lesions and 10 normal con- based on Wavelet denoising techniques is a useful and stron- trols to investigate the relationship between generation of ger tool for the assessment of sympathetic activity. SSR and level of SCI. All controls had palmar (latency 1476+162 ms; amplitude 2.98+1.5 mV; values refer to 800 R = 0.80 mean+SD) and palmar SSR (latency 2231+305 ms; ampli- tude 1.77+1.11 mV). In physiologically complete SCI 600 above T6, the SSR below the lesion was absent with both == supra and infra lesional nerve stimulation. In incomplete SCI, SSR was dependent upon supraspinal connections; 400 palmar SSR was present below the lesion in 7 of 8 with some degree of motor function, whereas SCI only with sensory preservation did not have SSR. There was no dif- "~" 200 ference between recording from ipsi- and contralateral limbs. 0 , We conclude that supraspinal connections to spinal su- 0 100 200 300 domotor pathways is necessary for generation of palmar and plantar SSR. In complete SCI, activation of the isolated Total Spike Amplitude (au/min) spinal cord sympathetic adrenergic system causes cardiovas- cular autonomic dysreflexia. In keeping with clinical obser- Sympathetic dysfunction in early diabetes is vation (of lack of sweating below the lesion) our data with associated with increased nitric oxide the SSR indicate the inability to activate the spinal sympa- thetic cholinergic system. Thus, the spinal cord isolated R.D. Hoeldtke, K.D. Bryner, J.E. Riggs, G.R. Hobbs, from supraspinal pathways appears incapable of generating C. Baylis an SSR. West Virginia University Medical School, Morgantown, WV, USA References 1. Fuhrer MJ. JNNP 1975; 38:749-755. Endothelial dysfunction in diabetes is linked to deficient 2. Curt A, etaL JANS 1996; 6:175-180. nitric oxide (NO) activity. Despite this, recent studies in rats (Maree, ClinSci 90:379, 96) and man (Chiarelli, Dia- betes 49:1258, 2000) have revealed that in plasma the NO Does the integrated microneurogram provide a products, nitrite and nitrate (collectively NOx) are increased complete assessment of muscle sympathetic early in diabetes, before plasma creatinine has risen, sug- neural activity.'? gesting increased NO production. In states of oxidant stress A. Diedrich, 1 W. Charoensuk, 1 R. Shiavi, 1 R.J. Brychta, ~ (e.g. diabetes) NO reacts with the superoxide anion to form A. Ertl, ~ S. Paranjape, ~ L.D. Lane, ~ B.D. Levine, 2 peroxynitrite, a neurotoxic compound which might lead to J. Zuckerman, 2 J.F. Cox, 3 I. Biaggioni 1 peripheral nerve damage. We have examined the relation- IVanderbilt University, Nashville, TN; 2Institute for Exercise ship between NOx and peripheral nerve function in a co- and Environmental Medicine, Dallas, TX; 3Virginia hort of patients with recent onset type 1 diabetes. Thirty- Commonwealth University, Richmond, VA, USA seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which peripheral The integrated microneurogram is commonly used to assess nerve function was evaluated annually for three years. NOx muscle sympathetic nerve activity (MSNA). However, it was increased in the poorly controlled patients (with high correlates poorly (correlation coefficients between 0.48 to HgbA1) throughout the study.We categorized patients each 0.57 have been reported) with norepinephrine (NE) spill- year as to whether their NOx was above or below the me- over. The integrated MSNA may have lost some physiologi- dian for the group. We assessed sympathetic function by cal information during signal preprocessing and therefore it measuring sweat production following acetylcholine stimu-

Clinical Autonomic Research 2001, Vol 11 No 3 185 XIIth International Symposium on the Autonomic Nervous System: Abstracts lation. Patients with high NOx had lower sweat production Blood Resting Maximum than those with low NOx. glucose CVC CVC Regression analysis of NOx versus sweating confirmed a Trial (IJmol/mL) (LDU/mmHg) (LDU/mm Hg) negative association (p<.01). A similar relationship between NOx and somatosensory function was seen, but the changes 1--Baseline 5.75 + 0.39 0.27 • 0.03 2.17 + 0.15 were present less consistently. There was a negative corre- (time 0) 2--Peak glucose 11.22 • 0.45 0.25 • 0.03 2.14 • 0.13 lation between NOx and motor median response ampli- (60 min) tudes year 1 (p<.01) and year 2 (p<.05). 3 (180 min) 7.40• 0.26• 2.18• In summary, poor glycemic control stimulates NO pro- 4 (360 min) 5.08 • 0.11 0.35+0.03* 2.09 • 0.14 duction in early diabetes and the latter is associated with decreased peripheral nerve function. *p <0.05 versus trials 1, 2, and 3. Neuropathological diagnosis of enteric diabetic autonomic neuropathy Diabetic patients M. Selim, G. Wendelschafer-Crabb, W.R. Control subjects First evaluation Second Third Kennedy HgbA1 Low High Low High Low High Department of Neurology, University of Minnesota, NOxumoles/L 34• 48• 58• 41• 60• 38• 63• Minneapolis, MN, USA

*p <.01 different from controls, 1"p < .05 different from low HgbAl. This preliminary study shows a striking loss of enteric nerves in the mucosa of jejunum and colon of diabetic Diabetic patients patients. The method used has potential to provide mor- Control subjects First evaluation Second Third NOx Low Low High Low High Low High phological confirmation of autonomic neuropathy, now limited to interpretation of clinical and physiological test Total sweat(pl) 3.9• 5.7• 4.0• 4.6• 3.3• 5.3• 3.6• results. "p <.05 different from patients with low NOx. The gut is innervated by extrinsic nerves of vagus, spinal afferent and sympathetic origin and by intrinsic nerves with neuron cell bodies in the myenteric and submucosal plex- Local cutaneous vasodilation during acute uses within the gut wall. Immunostained thick sections of systemic hyperglycemia in humans bowel demonstrates that large numbers of unmyelinated nerve fibers from these plexuses stream into the lamina N. Charkoudian, A.S. Reed, A. Vella, P. Shah, propria ofsubmucosa, encircle the crypts of Lieberkuhn and R.A. Rizza, M.J. Joyner glands of Brunner, and ascend into the intestinal villi. Sev- Departments of Anesthesiology and Endocrinology, Mayo Clinic eral unmyelinated nerve fibers enter the villi and some pro- and Foundation, Rochester, MN, USA ceed to the tips of the villi. During their course these nerves interconnect and provide many side branches. The branches Whereas chronic hyperglycemia is known to adversely affect subdivide into small twigs that lie between the capillaries endothelial function and cutaneous vascular control, it is and the basement membrane that underlies the epithelium. unclear whether acute hyperglycemia contributes to the In bowel from long-term diabetic subjects a deficient inner- pathophysiology of endothelial dysfunction seen in diabetes. vation was immediately obvious at low magnification. As in Local warming of the skin in humans causes a marked, normal bowel, several nerve fibers projected into the villi nitric oxide-dependent cutaneous vasodilation, which is but most ended well short of the tip of the villi. Short villi maximal following prolonged local warming to 42 ~ To had a more normal appearing innervation. The nerves test the hypothesis that acute hyperglycemia causes a reduc- around the crypts and in villi often had a fuzzy appearance, tion in this endothelium-dependent vasodilation, we used which at higher magnification was found to be caused by an intravenous glucose infusion to mimic the systemic ap- many short side branches which we interpreted to be nerve pearance of a glucose meal in non-diabetic volunteers. Glu- sprouts, perhaps attempting to establish collateral reinner- cose was maintained at 95 mg/dL in a control group. Skin vation. It is now necessary to examine colon and jejunum blood flow was measured using laser Doppler flowmetry from subjects with different duration of diabetes and sever- (LDF), and local temperature was controlled at a 12 cm 2 ity of symptoms to determine the sensitivity of our meth- area around the LDF probe. We performed local warming ods. Nevertheless, it is already obvious that these methods of the skin at baseline, and at 60, 180 and 360 minutes of can be used to provide pathological confirmation of enteric glucose infusion. Each local warming trial consisted of a autonomic neuropathy in some patients. 10-minute baseline (local temperature = 33 ~ followed by 30 minutes of local warming to 42 ~ Maximal vasodila- Comparison of SSR and QSART in early tion was assessed by calculating cutaneous vascular conduc- diabetic neuropathy--the value of tance (CVC) over the last three minutes of local warming. length-dependent pattern in QSART Maximal CVC was not altered by hyperglycemia (see table). H. Shimada, M. Kihara, 1,2 S. Kosaka, H. Ikeda, 2 There was a small increase in resting CVC in Trial 4, which was likely due to a slight hyperthermia relative to other K. Kawabata, T. Tsutada, T. Miki trials, since it also occurred in the group maintained at 1Department of Geriatrics and Neurology, Osaka City euglycemia. We conclude that acute hyperglycemia does not University Medical School; 2Department of Neurology, Kinki alter resting skin blood flow or maximum cutaneous vasodi- University, Osaka, Japan lation in healthy non-diabetic individuals. We evaluated postganglionic sympathetic function using Supported by HL63328 and DK29953. the sympathetic skin response (SSR) and quantitative sudo-

186 Clinical Autonomic Research 2001, Vol 11 No 3 Xllth International Symposium on the Autonomic Nervous System: Abstracts motor axon reflex test (QSART) on the feet of 31 (18 men impaired BR and enhanced CR reflex sensitivity. The and 13 women) patients with early diabetic neuropathy and changes in reflex sensitivity may promote excessive sympa- 20 age-matched normal controls. Magnetic stimulation was thetic activation and vasoconstriction in AS. used to evoke the SSR with a magnetic stimulator. The QSART, according to Low et al, was measured using a Sudorometer with two multicompartmental sweat capsules Are all autonomic responses to hypoxia attached to the skin of dorsal feet and distal legs. The am- regulated through the peripheral plitude of SSR and the sweat volume of QSART were sig- chemoreflex arc? nificantly decreased in the diabetic patients. We evaluated the sensitivity of the tests in detecting autonomic failure. B.E. Hunt, ~ P. Kaushal, ~ W. Weiss, 2 J.A. Taylor1 Out of 31 patients, 14 (45%) had abnormal SSR (14 ab- 1Harvard Medical School; 2Beth-Israel Deaconess Medical sent; 17 present), while 16 of 31 patients (52%) had ab- Center; and Research and Training Institute, Boston, MA, USA normal QSART (1 absent; 5 absolutely reduced and 10 During acute exposure to hypoxia, vascular sympathetic showed a length-dependent pattern of reduction). More im- outflow increases, restricting local vasodilatation. It is pre- portant than differences in sensitivity is the specificity of sumed the chemoreflex mediates the increase in sympathetic QSART, which specifically evaluates the postganglionic activity. However, this appears paradoxical in that sympa- axon (instead of polysynaptic pathways in SSR) and pro- thetic activation restrains the ability to augment blood flow vides quantitative data on the severity and pattern of auto- and thus, oxygen delivery. The baroreflex is not believed to nomic deficit. In normal controls under 65 years of age, play a significant role during hypoxia because there are no there was a significant correlation between the amplitude of obvious changes in arterial pressure. Alternatively, the SSR and the sweat volume of QSART. However, there was baroreflex may indeed be engaged by the fall in vascular no significant relationship between these in diabetic pa- resistance associated with local vasodilatation, increasing tients. These results suggest that QSART can evaluate early sympathetic and decreased vagal outflow, resulting in the diabetic neuropathy more precisely than SSR. maintenance of arterial pressure. The purpose of this study was to test this alternative hypothesis. We measured heart Impaired baroreflex and enhanced chemoreflex rate (ECG), arterial pressure (photoplethysmography), and sensitivity in normotensive atherosclerotic mice calf blood flow (venous occlusion plethysmography) during W. Sun, X. Ma, F.M. Abboud, M.W. Chapleau 20 minutes of mild isocapnic hypoxia (SAO2=82_+1%) un- University of Iowa and Veterans Affairs Medical Center, der three conditions: 1) unblocked hypoxia, 2) hypoxia with Iowa City, IA, USA ~x-blockade (phentolamine), and 3) hypoxia with ci and cholinergic blockade (phentolamine and ). Prelimi- Patients with cardiovascular disease commonly exhibit both nary analysis of data from 5 young adults shows hypoxia hypertension (HT) and atherosclerosis (AS). HT and AS with c~-blockade, resulted in a greater fall in vascular resis- may alter cardiovascular reflexes through independent and tance compared to unblocked hypoxia (-26 vs 2%), pre- interacting mechanisms. While the effects of HT have been sumably due to unopposed local vasodilatation. However, studied extensively, few studies have examined the effects of mean arterial pressure was well maintained (-3.3 vs -3.4 AS on baroreceptor (BR) and chemoreceptor (CR) reflexes mmHg), likely a result of a greater tachycardia (11 vs 7 in the absence of HT. We hypothesized that AS alone leads bt/min). Hypoxia during cholinergic and or-blockade was to decreased BR and enhanced CR reflex sensitivity. Apo- associated with a similar fall in vascular resistance (-27%). lipoprotein E knockout (apoE KO) mice with AS and age- However, the decline in mean arterial pressure was more matched (9-12 months) control C57BL/6J mice were stud- than three times that seen during o~-blockade or hypoxia ied. Resting mean arterial blood pressure (BP) measured in alone (- 11 mmHg), due to the inability to produce a tachy- both conscious and anesthetized states was not significantly cardia (-5 bt/min). Thus, when input to the chemorecep- different in apoE KO and control mice. Reflex control of tors was comparable (82 vs 83 vs 82% SaO2), heart rate BP was assessed by measuring the BP response to bilateral responded differentially; apparently in order to maintain carotid occlusion (BCO) in anesthetized, vagotomized mice. arterial pressure, a function primarily under baroreflex con- Differences in the magnitude of the reflex during 21% and trol. Therefore, we believe these data provide strong infer- I00% oxygen (02) ventilation were used to calculate the ential data suggesting the baroreflex is intimately involved in relative contributions of BR and CR reflexes to the re- regulating autonomic outflow during mild hypoxia. sponse. The BR mediated increase in BP (during 100% 02 ventilation) was significantly impaired in apoE KO (+15-+4 mmHg, n=12) vs. control (§ mmHg, n=5) mice. In Hypoxic chemoreceptor stimulation induces contrast, the CR component of the BCO reflex was en- paradoxic cardiovascular responses in hanced in apoE KO (+18+3 mmHg) vs. control (+8-+4 mmHg) mice. BR-mediated changes in renal sympathetic familial dysautonomia nerve activity in response to nitroprusside and phenyleph- B. Stemper, 1 M.J. Hilz,1,2 L. Bemardi,3 G. Welsch,~ rine-induced changes in BP were significantly impaired in C. Passino,3 F.B. Axelro& anesthetized apoE KO mice (2.2-+0.3 %/mmHg, n=5) com- IDepartment of Neurology, NYU, New York, NY, USA; pared with control mice (3.8-+0.5 %/mmHg, n=7). CR- 2Department of Neurology University Erlangen-Nuremberg, mediated changes in respiration in response to 10% and Germany; 3IRCCS S. Matteo, University of Pavia, Italy 100% 02 ventilation were significantly enhanced in con- scious apoE KO (n=9) compared with control (n=10) mice. Familial Dysautonomia (FD) patients manifest with irregu- The results indicate that AS, in the absence of HT, leads to lar breathing patterns and inadequate responses to hypoxia

Clinical Autonomic Research 2001, Vol 11 No 3 187 XIIth International Symposium on the Autonomic Nervous System: Abstracts

or hypercapnia. They present with breath-holding spells se- thetic modulation on SBP, vagal and symapthetic on RR), vere enough to cause syncope. The purpose of this study was and at 0.2Hz (HF, vagal modulation on RR), in CP, before to evaluate the effects of hypoxia on cardiovascular regula- and during normoxia (CP+ox), and in Lima, sea-level, after tion of FD patients. one night sleeping in normoxia (SL) and during hypoxia. 22 FD patients (age 24.7• 11 men, 10 women) Subjects were divided according to CMS score (CMS§ =/> and 21 controls (age 26.0• 12 men, 10 women) 12, N=15, CMS-: <12, N=16). underwent hypoxic chemoreceptor stimulation by means of In CP, compared to CMS-, CMS+ showed reduced rest- a rebreathing technique. Participants breathed through a ing HF (p<0.05), reduced HF-NS modulation on RR closed circuit system into and from a 10 liter reservoir. (p<0.02), and reduced LF-NS on RR (p>0.02) but not on Inspiratory 02 levels decreased continuously. To ascertain SBP, indicating preserved sympathetic modulation but re- constancy of inspiratory carbon dioxide (CO2), the expira- duced cardiac baroreflex vagal modulation. CP+OX in- tory air was directed either through a standard anesthesiol- creased RR modulation in CMS-, so all differences became ogy CO 2 filter (Sodalime) or directly into the reservoir using more significant. At SL, CMS score dropped to 2.9 • a three-way valve. We monitored blood pressure (BP), elec- (p<0.0001); RR resting and NS-induced HF increased trocardiogram RR-intervals, plethysmographic 0 2, end- (p<0.01) in CMS§ attenuating the differences with respect tidal CO 2 (ColinVM), skin blood flow at the left index finger to CMS- (p<0.05 during both LF-NS and HF-NS). Hyp- pulp (SBF; Perimed) and respiration (RespitraceTM). oxic gas mixture administrated at SL restored the differences 02 levels decreased significantly in both groups (controls: seen at CP in the RR response to either LF-NS or HF NS 98.1• to 83.9+5.9; FD patients: 94.9• to 82.7• (both p<0.01). Resting HF (p<0.01) and HF-NS in RR Wilcoxon p<0.05). In controls RR intervals decreased correlated inversely with CMS score (p<0.0002) in CP. (865.3• to 714.4• and BP (systole: Vagal and baroreflex dysfunction may be implicated in ll7.1• to 122.1• diastole: the origin of CMS symptoms; this can partially reverse with 61.34• to 65.35• and ventilation in- improved oxygenation. creased significantly during hypoxic stimulation (Wilcoxon p<0.05). SBF decreased slightly from 205.1• to 194.4• FD patients had a slight bradycardia Arterial baroreflex function after (706.6• to 718.0• a decrease of systolic carotid endarterectomy BP (146.8• to 134.1-+28.9mmHg; Wilcoxon p<0.05) and an increase of SBF (166.4• to H.J.L.M. Timmers, 1 J.M. Karemaker, 2 W. Wieling, a 211.1• Wilcoxon p<0.05), and no change in F. Buskens, 4 J.W.M. Lenders 1 ventilation. Departments of 1'3General Internal Medicine, 2Physiologyand In controls hypoxic Stimulation induced physiologic re- 4Vascular Surgery, l'4University Medical Center Nijmegen and sponses with increase of ventilation, heart rate and blood 2'3Academic Medical Center Amsterdam, The Netherlands pressure increase and peripheral vasoconstriction. In con- trast, FD patients had paradoxic cardiovascular responses Background: Carotid endarterectomy (CE) may elicit post- with bradycardia, blood pressure decrease and increase of operative hyper- and hypotension as a consequence of acute skin blood flow. These results suggest that chemoreflex ac- baroreflex dysfunction. The effect of CE on the long-term tivation might lead to severe bradycardia or even asystole if reflex regulation of heart rate and blood pressure is unclear. it is not counteracted by other compensatory mechanisms. Objective: To assess arterial baroreflex function in non- selected CE patients. Patients and methods: We examined 14 patients (12m:2f, 64.8+6.5 years) 4.3 years (:median, range 0.3-11.2) after Improved oxygenation relieves baroreflex unilateral CE and 12 healthy controls (1 lm: lf, 60.9+7.9 dysfunction in Andean altitude natives years). Patients with pre-existing hypertension were ex- L. Bernardi, 1 C. Passino, 2 J. Gamboa, a M. Bonfichi,1 cluded. Blood pressure level and variability were estimated A. Gamboa, 3 M. Vargas, 3 L. Malcovati, ~ R. Roach, 4 from 24 hours ambulatory blood pressure measurements O. Appenzeller ~ (Spacelabs| and a 5 hours beat-to-beat registration (Por- ~Universita' di Pavia and IRCCS S. Matteo, Pavia, Italy; tapres| during standardised activities respectively. Barore- 2Istituto di Fisiologia Clinica CNR Pisa, Italy; 3Laboratorio de ceptor sensitivity was expressed as the o~-index at 0.1 Hz transporte de Oxigeno, Universidad Peruana Cayetano Heredia calculated from cross-spectral analysis (Fast-Fourier Trans- Lima, Peru; 4Division of Physiology, New Mexico Highlands form). Beat-to-beat blood pressure and heart rate responses University, Las Vegas, NM, USA; 5NMHEMC Res. (Finapres| to Valsalvas manoeuvre, standing up, forced Foundation, Albuquerque, NM, USA breathing, cold pressor test and mental arithmetic were assessed. Andean altitude natives with chronic mountain sickness Results: Averaged daytime blood pressure was not signifi- (CMS) have neurologic and autonomic symptoms at alti- cantly different between CE patients and controls tude, which disappear at sea-level. To test whether barore- (139.7+15.8/ 84.8+8.1 mmHg, 79.1+7.7 bpm versus flex abnormalities contribute to CMS, we measured RR 130.7+11.4/82.0+6.6 mmHg, 77.4+9.4 bpm, ns), nor was interval (RR), systolic blood pressure (SBP), and respiratory baroreflex gain (o~: 8.1• versus 11.8+4.9 ms/mmHg, variabilities, by spectral analysis, in 31 natives of Cerro de p=0.11). CE patients exhibited a broader (relative) blood Pasco (CP), (4338m, Peru), with variable degrees of CMS pressure distribution (coefficient of variance MAP: 15.2+3.5 (CMS score 4-26) at baseline and during carotid baroreflex versus 12.2+2.3%, p=0.033). During the initial phase of modulation by neck suction (NS) at 0.1Hz (LF, sympa- standing-up, CE patients showed a smaller maximal heart

188 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts rate increase (+36.7_+14.6 versus +53.6_+21.1 bpm, thetic nervous system regulating cardiovascular systems. We p=0.018). Valsalvas ratio was lower in CE patients assessed hemodynamics, plasma catecholamines, and (1.43_+0.34 versus 1.68_+0.29, p=0.022). Hemodynamic re- baroreflex and adrenoreceptor sensitivity during 5 critical sponses to both cold pressor test and mental arithmetic were points along one menstrual cycle. Two points at the follic- similar as were I-E differences during forced breathing ular phase (early and late) and 3 points at the luteal phase (12.9_+9.3 versus 13.7_+3.6 bpm). (early, mid and late) were investigated in 9 healthy eumen- Conclusion: Our findings in carotid endarterectomy pa- orrheic nuUipara young volunteers. tients of a higher blood pressure variability together with Normal ovarian-hormones pattern was confirmed in 8 attenuation of reflex adjustments to standing up and the volunteers. Plasma norepinephrine levels decreased signifi- Valsalva's manoeuvre may reflect chronic impairment of cantly during the late follicular phase and gradually return baroreflex function. to baseline values at the late luteal point (265+45, 185_+20, 219_+25, 233_+25 and 263_+45 pg/ml, rmANOVA, P<0.03 for each point respectively). The baroreflex sensitivity ex- Barofex control of sinus node during sleep trapolated from changes in systolic BP, induced by phenyl- J.M. Legramante, 1'2 F. Placidi,3 M.G. Marciani, 3 ephrine, against the corresponding changes in RR intervals A. Romiti,3 M. Tombini, a A. Galante, 1,2 S. Aquilani, ~'2 was significantly lower during the follicular time points as G. Raimondi, 1 M. Massaro, 1'2 F. lellamo ~,2 compared to the luteal phase (20_+7, 14_+3, 20_+2, 29_+6 and 1Departimento di Medicina Interna, 2Riabilitazione Cardiologica 38_+10 ms/mmHg, for each time point respectively, S. RaffaeleHospital, 3Clinica Neurologica, Universita "Tor rmANOVA, p<0.04). The ISO15 (a measure of ~-adreno- Vergata," Roma, Italy receptors, the dose required to increase the heart rate by 15 bpm) was 0.2+0.04 at early follicular point and gradually Sleep stages have been related to a variety of changes in increases to 0.4-+0.05 pg at late luteal point (rmANOVA, autonomic output. Less studied is the arterial baroreflex p<0.05). However, the blood pressure increasing effect of activity during sleep. In particular the arterial baroreflex phenylephrine (PHE15, a measure of ot-adrenoreceptor, the modulation of HR in response to both hypertensive and dose required to increase systolic BP by 15 mmHg) did not hypotensive stimuli during the different sleep stages has not change significantly during the studied points of the men- been performed previously. Therefore this study aimed at strual cycle. exploring the baroreflex control of sinus node in the differ- In conclusion" Ovarian hormones alterations that occur ent seep stages. We studied 10 healthy subjects. Polygraphic during the menstrual cycle are associated with significant sleep recordings were performed. Arterial pressure (AP) and [3-adrenoreceptors and baroreflex sensitivity, but not in RR interval were recorded by Finapres and by an ECG lead. c~-adrenoreceptor sensitivity. Baroreflex sensitivity (BRS) was calculated through the Sequence Method both for hypertensive (up) and for hy- potensive (down) sequences. The measurements were per- formed in the morning (baseline) and during ligjt (stage I Change of spontaneous baroreflex sensitivity and II), deep (stage III and IV) and REM sleep. by long-term use of an angiotensin II blocker Our results show that the overall baroreflex control of Losartan in mild to moderate essential hypertension sinus node is unaltered through the sleep stages and if com- pared with morning recordings. A novel finding is that if we S.-J. Yeh, 1 E.-Y. Tu, 1 C.-C. Chiu 2 consider separately the BRS in response to hypertensive and 1Department of Neurology, Cheng-Ching Hospital; 2Institute of hypotensive stimuli the BRS up during REM is significantly Automatic Control Engineering, Feng-Chia University, increased as compared both to baseline and to III + IV sleep Taichung, Taiwan stage. Our results suggest that the baroreflex control of sinus node is more active in buffering AP increases possibly oc- The aim of this study was to evaluate the spontaneous curring in REM stage in which a sympathoexcitation has baroreflex sensitivity (BRS) in patients with mild to mod- been largely reported. erate hypertension before and after effective antihyperten- sive treatment with Losartan, an AII blocker. BRS was

Baseline I + II III + IV REM evaluated in 20 hypertensive patients before and after the use of Losartan. BRS was derived from beat-to-beat SBP MAP 86.4 • 3.8 80.6 • 2.0 73.1 • 2.4*:[: 80.9 • 3.3 R-R interval 1,017.3 • 64.2 1,152.4 • 64.2* 1,079.9 • 42.8 1,100.6 • 41.6 and RR interval data acquired by Finapres. A 50-minute BRS 23.2 • 4.9 24.1 • 2.7 20.7 • 3.3 25.2 • 2.6 continuous monitoring of BP and RR data from dynamic BRS up 18.3 • 3.4 22.3 • 3.5 19.5 • 3.0 27.6 • 3.3"1" BRS down 24.3 • 5.0 26.3 • 2.4 23.0 • 3.7 23.7 • 2.5 activation of autonomic function by tilting, deep breathing and cold pressor test was used in this analysis. The index of "p <0.05 versus base; IP <0.05 versus Ill-IV; :l:p <0.05 versus I + I1: BRS (BRS-I) was estimated from the slope of linear regres- sion of RR duration to the change in SBP sequences tech- Menstrual cycle affects I~-adrenoreceptor and nique. The average BRS sequences per minute (BRS-C, baroreflex sensititivity c/min) was counted. After a baseline evaluation, the evalu- G. Jacob, N. Hirshom, I. Zoran, Y. Itzkovitz ation was repeated 60 days (M2) of treatment. At baseline, Jacob Recanati Autonomic Dysfunction Center, Rambam SBP= 147.6+-14.8, DBP= 97.4+-6.5mmHg by sphygmo- Medical Center, IIT-Technion, Haifa, Israel manometer and BRS-I= 6.82 +- 2.96 ms/mmHg. After treatment, SBP and DBP significantly decreased (SBP= Profound gonadal hormone changes occur along the men- 134.7+-14.3; DBP=87.7+-7.5 mmHg at M2 ). BRS-I = strual cycle. These hormonal alterations can affect sympa- 8.05 +-3.16 ms/mmHg significantly increased with respect

Clinical Autonomic Research 2001, Vol 11 No 3 189 XIIth International Symposium on the Autonomic Nervous System: Abstracts to baseline evaluation. On the contrary, BRS-C = 2.08 +- at 0.1 Hz. , applied at the right side (A), left side (B), 1.50 c/min at M2 decreased significantly from BRS-C = concomitant right and left sides in phase concordance (C) 2.35 +- 1.39 c/min. The increase of BRS index with de- and in phase opposition (D). Respiration was controlled at creased response rate suggests that BRS is more effective 0.25 Hz. Power spectrum analysis assessed the changes in after Losartan treatment. Whether the improvement of BRS the 0.1 Hz oscillatory component of RR interval and contributes to the lowering of hypertension needs further MSNA variability induced by the rhythmic baroreceptor investigation. loading. Mean RR interval and MSNA were unchanged during each neck suction procedures as compared to baseline Homogeneous response of post-ganglionic (925• ms and 16_+1.7 bursts/rain, respectively). During neural sympathetic activity (MSNA) following A, B, C and D sinusoidal neck suction increased the power mono- and bi-lateral carotid of the 0.1 Hz oscillatory component of RR variability in C baroreceptor stimulation (1563_+417 ms, p<0.05), and, to a lower extent, in A R. Furlan, 1 A. Diedrich,2 A. Rimoldi,1 L. Palazzolo, 1 (791_+160 ms) and D (826_+204 ms), as compared to B C. Porta, 3 L. Vasquez, 2 D. Robertson, 2 L. Bernardi 3 (550_+83 ms). The 0.1 Hz oscillatory component of MSNA 1Unit~ Sincopi, Centro Innervazione Cardiovascolare, CNR, increased and reached similar values in A (1.75_+0.28 log Med. Interna 2, Osp. "L. Sacco," Univ. Milano, Italy; 2CRC, a.u.2), B (1.77_+0.3 log a.u.2), C (1.82_+0.28 log a.u. 2) and D Vanderbilt University, Nashville, TN, USA; 3Dipartimento (1.88_+0.31 log a.u. 2) during the neck suction procedures. Medicina Interna, IRCCS S. Matteo, Univ. Pavia, Italy Thus, external sinusoidal stimulation of carotid barore- ceptors at 0.1 Hz is accompanied by an increase of the 0.1 Post-ganglionic neural sympathetic discharge activity to the Hz oscillatory components of RR and MSNA variability. vessels (muscle sympathetic nerve activity, MSNA) is modu- Right side and combined right and left sides stimulation lated by carotid baroreceptors. However, it is unclear both in phase and in opposition of phase are more effective whether MSNA may present a functional asymmetry in in modulating RR variability than the left side stimulation response to right versus left carotid baroreceptor stimula- alone. Conversely, asymmetrical carotid baroreceptor stimu- tion. To address this issue, 12 healthy volunteers underwent lation does not seem to elicit functional asymmetry in the a sinusoidal neck suction procedure (from 0 to -50 mmHg) neural sympathetic modulation of vasomotor tone.

190 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Poster Session I

Analysis of raw microneurographic recordings Wavelet denoising and classification technique allows the based on wavelet denoising technique and study of discharge behavior of individual and group neurons classification algorithm and provides more detailed physiological information.

A. Diedrich, 1 W. Charoensuk, 2 R. Shiavi, 2 R.J. Brychta, ~ A. Ertl, ~ I. Biaggioni ~ ~Autonomic Dysfunction Center; 2Biomedical Engineering, Vanderbilt University, Nashville, TN, USA Exercise and manipulated breathing affect peripheral blood flow, blood pressure, and Sympathetic outflow is commonly estimated by the inte- heart rate in synchronized manner grated microneurogram of muscle sympathetic nerve activ- ity (MSNA), but this approach has its limitations. It de- D.M. Cataldo, 1 R. Cataldo, 2 J.K. Prentice, 1 pends on the number of recorded units, and signal R.A. Robergs ~ preprocessing may distort physiological information. We IUniversity of New Mexico, Albuquerque, NM; 2Arizona Heart Institute, Phoenix, AZ, USA e- 100- Wavelet i .o Purpose: Investigate the synchronous relationship between peripheral blood flow (PBF), systolic blood pressure (SBP), o ii I (D diastolic blood pressure (DBP), heart rate (HR) at rest com- a 1 I pared with exercise and manipulated breathing (MB). Syn- 4-J chronism identifies central control mechanisms rather than o 50- i t .= i I peripheral controls. Deviation from synchronicity during i I Classical Discriminator o l exercise versus rest implies additional control mechanisms. 0 i I S Methods- Twenty-two subjects performed three five- $ is" minute trials: rest, MB alone (15 breaths/minute) and O_ ~s exercise/manipulated breathing (EMB) (30 repetitions/minute; 15 breaths/minute). HR, SBP, DBP and PBF were continu- ously recorded and digitized using discrete Fourier Trans- form (DFT). Synchronism of PBF with HR, SBP, DBP in Signal to Noise Ratio low frequency (LF) (0.1 Hz) and high frequency (HF) (-0.25 Hz) spectra were determined by squared coherence. One factor MANOVA determined stable relationships be- detected and analyzed action potential trains of individual tween hemodynamic variables and between conditions. and group neurons in the original raw MSNA by developing Phase delays between signals were calculated to determine a modified Wavelet denoising technique and classification time delay between oscillations of two signals. One factor algorithm. We compared these results with those obtained MANOVA determined whether individual signals (SBP, with the classical discriminator method. The test and ap- DBP, HR) preceded or lagged in comparison to PBF be- plication signal sets were simulated signals with different tween conditions. noise content and recordings of 7 healthy subjects during Results" Fluctuations in PBF were coherent with those of baseline, -15 and, -30 mmHg of lower body negative pres- SBP, DBP and HR in LF and HF components and with all sure suction (LBNP) respectively. Wavelet denoising tech- treatment conditions (p <. 05). PBF fluctuations preceded nique improved the number of correct detection of action changes in HR and BP in LF and HF bands (p <. 05). potentials (figure) and diminished the number of false de- Fluctuations during MB preceded those at rest and during tection in simulated signals as compared with the classical EMB, suggesting parasympathetic effect and rapid vagal discriminator method. The number of spikes and total spike changes (p <. 05). Fluctuations during EMB lagged behind amplitude detected from the raw MSNA showed good cor- both rest and MB, suggesting sympathetic effect and slow relations with the number of bursts per min detected from changes compared to parasympathetic. the integrated MSNA (0.79 and 0.88). Seventy nine percent Conclusions" PBF is synchronized with SBP, DBP and of detected action potential can be classified into eight HR, in both LF and HF spectral bands suggesting predom- classes, which are similar in each subject and LBNP level. inance of central control mechanisms. Furthermore, MB

0959-9851 2001 Lippincott Williams & Wilkins 191 XIIth International Symposium on the Autonomic Nervous System: Abstracts

exerts a predominant parasympathetic effect preceding sym- had a mean age of 14 yrs (range 0.5 - 18). Referrals came pathetic effect. from gastroenterology (39%), neurology (28%), orthope- dics (7%), autonomic disorders (6%), cardiology (5%), gen- eral pediatrics (5%), and genetics (4%). Referral complaints included: abdominal pain, nausea/vomiting (34%), syn- Manipulated breathing enhances cope, dizziness (26%); limb pain, fibromyalgia (20%). No parasympathetic tone during exercise by heart complications occurred. Deep breathing response (DB) was rate and blood pressure variability normal in 58%, Valsalva (VM) in 45%, and both normal in 32%. The response to DB was exaggerated (> 2 times nor- D.M. Cataldofl R. Cataldo, 2 R.A. Robergs 1 mal) in 9%, and that to VM (> 0.5 over normal) in 19%. ~University of New Mexico, Albuquerque, NM, USA; 2Arizona Tilt showed a heart rate increase of > 35 bpm in 45%. 20% Heart Institute, Phoenix, AZ, USA had OH (BP drop > 20 mmHg). Axon reflex sweating was abnormal in 39% (> 20% of tested sites abnormal). Three Purpose: Examine the effects of exercise and manipulated of ten thermoregulatory sweat tests were normal. All 6 pa- breathing on heart rate variability (HRV) and systolic blood tients assessed for reflex sympathetic dystrophy (RSD) had pressure variability (SBPV) in humans. it. No patient had a normal battery, and 58% had 2 or more Methods: Twenty-four subjects completed seven separate abnormal results. Chart review revealed that autonomic test- protocols each five minutes in duration. The protocols in- ing altered diagnostic thinking in 60%, affected manage- cluded rest, manipulated breathing (MB) at six ment in 30% and produced no action in 5%. breaths/minute (MB6), 15 breaths/minute (MB15) com- Conclusion: Autonomic testing appears useful in the pedi- bined with leg extension/flexion protocols. These included atric population. The main referral diagnoses were gastro- 10% of maximal voluntary contraction at 15 intestinal symptoms, syncope, dizziness, and RSD. POTS repetitions/minute (15 reps/min) and 30 reps/min com- was the most common interpretation. The large number of bined with both MB protocols (MB6115repslmin, abnormal results suggests either that (1) only the most ab- MB613Orepslmin, MB 15/15reps/min, MB 15/30reps/min). normal children are being referred, and many ate going Beat by beat analysis of heart rate (HR) and systolic blood undiagnosed, or (2) the pediatric norms are set too tightly, pressure (SBP) was performed by Fast Fourier Transform and more rigorous norms are required. A large normal pe- (FFT) into frequency domain components. HR and SBP diatric series is desperately needed. spectral components were separated into very low frequency (VLF), low frequency (LF) and high frequency (HF). Au- tonomic influences were determined by LF: HF ratios. Re- peated measures MANOVA was used to evaluate the effects Heart rate variability and autonomic nervous of manipulated breathing, exercise and their combination system: an experimental approach on autonomic control of HR and SBP. Results: A decrease in the LF: HF ratio was observed in J.M. Legramante, ~ G. Raimondi, ~ F. lellamofl HRV during manipulated breathing compared to rest A. Gatante, 1 S. Sacco, 1 M. Massaro, 1 C. Michelassi, 2 (p< .05), indicating a parasympathetic effect. At rest LF: HF S. Chillemi,3 R. Baiocchi2 ratio was 1.022 ( .187 compared with MB6 (.212 (.187) 1Oipartimento di Medicina Interna, Universit~ "Tor Vergata," and MB15 (.469 (.125). Exercise and the combined pro- Roma; 2Istituto di Fisiologia Clinica C.N.R.; 3Istituto di tocols did not significantly alter the LF: HF ratio. As hy- Biofisica C.N.R. Pisa, Italy pothesized no significant differences were observed for SBPV during all treatments. RR interval variations represent a fine tuning of the beat- Condusions" Manipulated breathing exerts a significant to-beat control mechanisms mediated by autonomic activity parasympathetic effect compared to baseline measured by directed to the sinus node. Heart rate variability (HRV) has heart rate variability but not by systolic blood pressure vari- been investigated by means of a number of mathematical ability. This effect was offset by exercise during this study. methods. To our knowledge, how and in what extent the autonomic nervous system modulate the time domain in- dexes of HRV have not been directly investigated. The aim of our study was to evaluate the role played by the auto- Is pediatric autonomic testing valuable? nomic nervous system in modulating the oscillations of heart rate as measured by different methods exploring the G. Chelimsky, T. Chelimsky time domain. We evaluated in 13 slightly anesthetized rab- Departments of Pediatrics and Neurology, University Hospitals bits the effects of complete autonomic pharmacological of Cleveland and Case Western Reserve University blockade (guanethidine plus propranolol plus atropine, CAB) on the heart rate oscillations measured with different Background= Pediatricians infrequently utilize autonomic indexes: 1) mean; 2) standard deviation 3) average of the testing. root squared magnitude of the beat-to-beat oscillations Methods- We reviewed autonomic tests performed since (AvMag). Arterial Pressure was continuously recorded from 1994 in children (age < 18 years, or pediatrician referred) the femoral artery and heart rate (HR) was monitored by for referring service, referral complaint, and test result. We the electrocardiogram. From the RR time series the new also reviewed the clinical chart, when available (76%), for series representing the magnitude of the beat-to-beat oscil- the impact on clinical management. Results: 74 children lations was derived by computing the absolute differences of

192 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts successive RR intervals. We monitored heart rate time series rated into three parts: A) Normal range: from 212 healthy in baseline condition and after CAB. subjects (20 to 80 years old), in three sites; B) intra-subject reproducibility: 45 subjects were selected for same-day re- testing, three times for each test; C) inter-site reproducibil- R-R interval SdRR AvMag ity: results of the three tests were compared by age decade, and in the case of VT, additionally by gender; D) database Baseline 215.7 • 29.57 2.5 • 1.40 0.89 • 0.26 screening: a total of 3516 diabetics were classified by dura- CAB 290.6 • 43.1 * 3.5 • 2.11 1.76 • 0.61 * tion of diabetes (DD) and number of abnormal tests. Re- p <0.05 versus baseline by paired t test. sults: A) The 5th percentile was chosen as the lower limit of normal for all tests; B) intra-subject reproducibility results, expressed as the mean coefficient of variation (CV%): 4.3% Our results show that the information on the autonomic for MT, 6.26% for VT and 6.66% for ST; Kruskal-Wallis cardiac modulation obtained by investigating the heart beat test for reproducibility was calculated: P=0.77 for MT, oscillations may differ according to the different index used. P=0.98 for both VT and ST; C) inter-site reproducibility: The autonomic nervous system seems to restrain the mag- there was no significant difference among the three sites, nitude of heartbeat excursion leaving unaltered the scatter- except for MT at 60-70 years old decade; D) P<0.001 for ing of heart rate values around the mean value. independency of diagnostic classification and DD. Conclu- sions: 1) our NR was consistent with those reported by previous studies (O'Brien 1985, Low 1997, Piha 1991); 2) A case of chorea-acanthocytosis with high P-values and low CV% suggest high intra-subject re- dysautonomia: quantitative autonomic deficits producibility; 3) no significant differences among three sites using CASS for each decade suggests high inter-site reproducibility; 4) the clinical database analysis demonstrates the system can M. Kihara, 1 H. Nakashima, 2 M. Taki, 2 M. Takahashi, 1 discriminate three stages of AN in diabetics. Y. Kawamura 2 I Department of Neurology, Kinki University, Osaka; 2Department of Neurology, Kawamura Hospital, Gifu, Japan

The purpose of this study was to quantitatively assess car- The role of the vagus in vasovagal syncope diovagal, adrenergic and postganglionic sudomotor func- D.L. Jardine, J. Sutherland, M.D. Forrester, S.I. Bennett, tions in a patient with chorea-acanthocytosis. We describe a H. Ikram 25-year-old woman with acanthocytosis, lip and tongue bit- Department of Cardiology, Christchurch Hospital, ing, chorea like movements and increased levels of serum Christchurch, New Zealand creatine phosphokinase. The patient presented with ortho- static hypotension. The heart period response to deep breathing was moderately decreased and the quantitative Efferent vagal activity is responsible for many of the symp- sudomotor axon reflex test (QSART) was mildly abnormal toms associated with vasovagal syncope and may be in- in the lower extremities. The composite autonomic score creased in patients predisposed to this condition. We com- (CASS) for this patient was 6 points which indicates mod- pared normal subjects [mean age 52(7 years, n=10] to erate autonomic failure. Although a few previous reports has patients with vasovagal syncope [mean age 51 (5 years, n=20, described autonomic dysfunction associated with chorea- mean time to tilt-induced syncope= 16.5 (2 mini by measur- acanthocytosis and have indicated that impairments is pri- ing parasympathetic baroreflex control of heart rate. Carotid marily sympathetic, our case study suggests that there is also baroreflex sensitivity was assessed by measuring increases in parasympathetic dysfunction. We conclude that there is RR intervals during different levels of negative pressure ap- widespread autonomic involvement in chorea-acanthocy- plied to the neck. Arterial baroreflex sensitivity lABS] was tosis and that autonomic studies are useful in monitoring assessed by: [a] correlating increases in RR intervals with their course. systolic blood pressure during phase IV of the Valsalva ma- neuver, and [b] correlating RR responses to spontaneous changes in systolic blood pressure. In patients with vasovagal syncope, carotid baroreflex A new system for autonomic tests: feasibility to sensitivity [between -10 and -70 mmHg distending pres- perform multicenter clinical studies sure] was 0.42 nu/mmHg [R2=0.7] versus 0.39 [R2=0.9] in M. Risk, C. Broadbridge, A. Cohen normals [p=0.5]. Valsalva ABS was 4.8(0.3 ms/mmHg in Boston Medical Technologies, Wakefield, MA, USA patients versus 3.6(0.2 in controls [p=0.009]. Spontaneous ABS was 8.5(0.5 ms/mmHg in patients versus 8.6(0.5 in Autonomic testing has proven to be useful in diagnosis of controls [p=0.9]. autonomic dysfunction in patients, but its use in multi- In response to major increases in arterial distending pres- center clinical studies has been hampered by large inter-site sure, patients with vasovagal syncope have increased arterial variation in results. The aim of this work is to determine the but normal carotid baroreflex sensitivity. Arterial baroreflex feasibility of using Anscore, a new system for autonomic reponses to minor changes in blood pressure are normal. testing, in multicenter clinical studies. The Anscore system Increased sensitivity of the aortic baroreflexes may predis- allows for good control over metronomic breathing (MT), pose to vasovagal syncope by slowing heart rate in response Valsalva (VT), and stand (ST) tests. This study was sepa- to changes in blood pressure.

Clinical Autonomic Research 2001, Vol 11 No 3 193 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Cardiovascular and cerebrovascular response and 12 control subjects. Test was stopped at the imminence to combined heat and orthostatic stress: a of syncope and time to presyncope was taken as a measure model of postural tachycardia of orthostatic tolerance. Supine time series of R-R period syndrome (POTS)? (ECG) and systolic pressure (Finapres) were recorded before the beginning of the test. The power of the high (respira- F. Huang, R. Stein, J. Benoit, R. Schondorf tory) and low (LF " 0.1 Hz) frequency oscillations were SMBD Jewish General Hospital, McGill University, quantified by spectral analysis. Cross-spectral analysis pro- Montreal, QC, Canada vided, at the point of maximal coherence, the LF central frequency (LF_freq), phase shift, and transfer function gain During head-up tilt (HUT) some patients with POTS have between RR and systolic pressure fluctuations. been found to have an excessive decrease in cerebral blood According to reference values, patients were divided into velocity (CBV) whereas many other patients with POTS 35 with normal (NT), and 38 with poor (PT) orthostatic have normal CBV changes during HUT. Whether these tolerance. None of the control subjects displayed poor or- discrepancies reflect different pathologies in patients with thostatic tolerance. POTS is presently unknown. Although the cardiovascular Main results, the LF_freq in NT and in controls was and cerebrovascular response to HUT have been well de- significantly higher than that in PT (0.104 ( 0.003 Hz in scribed, there are few data concerning the response to higher NT; 0.105 ( 0.004 Hz in controls; 0.087 ( 0.002 Hz in PT, levels of orthostatic stress. We tested the responses of 10 p<0.001). 31138 of PT subjects (true positives) and 7/35 of women aged 22.7 + 1.6 years to 5 minutes of HUT alone NT subjects (false positives) had values of LF_freq lower and in combination with heat stress achieved by perfusing a than 0.095 Hz. At higher values we found 7/38 of PT tube-lined suit with warm water. Heart rate (HR), blood subjects (false negatives) and 28135 of NT subjects (true pressure (BP) middle cerebral artery CBV, end tidal CO2, negatives). Only 1 control subject showed a LF_freq lower skin blood flow (SKBF), oral and skin temperatures were than 0.095 Hz. The discriminant analysis based on the continuously recorded. Heat stress increased oral tempera- LF_freq allows the classification of PT from NT up to 80% ture an average of 0.650C and SKBF by approximately sensitivity and 82% specificity. 400%. Heat stress increased baseline HR from 65.5 + 2.0 These remarkable results suggest that LF central fre- to 82.0 + 3.6 bpm. HR during HUT without heat stress quency in supine may be proposed as a simple clinical index increased to 93.8 + 4.9 while HR increased to 123.0 + in the diagnose of orthostatic intolerance. 4.0 bpm during combined heat-HUT. Heat-HUT caused a further decline in systolic BP (112.4 + 5.1 to 104.1 + 6.5 mmHg), systolic CBV (85.3 + 4.1 to 75.1 + 4.8 cm/sec) and diastolic CBV (43.9 + 3.9 to 32.8 + 3.4 cm/sec).The decline in calculated cerebrovascular resistance (CVR) was Unaltered peripheral capacitance vessel greater during HUT (75.4 + 3.5%) than during heat-HUT volume-pressure compliance relation in (85.0 + 4.7%). End tidal CO2 decreased from 4.6 + 0.1% postural tachycardia of adolescents to 4.1 + 0.1% during initial HUT and from 4.5 + 0.1 to 3.9 J.M. Stewart + 0.1% during heat-HUT. These differences in CO2 were New York Medical College, Valhalla, NY, USA not significant. Dynamic cerebral autoregulation during HUT as assessed with standard linear transfer function analysis was not affected by heat stress. We conclude that Increased venous compliance has been proposed as a pos- heat-HUT mimics the reported cardiovascular and cerebro- sible cause of pooling in POTS. Previous data indicated vascular responses of patients with POTS. A decrease in increased venous pressure, Pv, >20mmHg in some patients cerebral perfusien during heat-HUT occurred without evi- (high Pv) but not others (normal Pv). We hypothesized that dence of hyperventilation. Given the strong similarities be- venous compliance and orthostatic venoconstriction is im- tween the responses of normal subjects to heat-HUT and of paired in those with high Pv. We compared 14 patients aged patients with POTS to HUT it is unlikely these patients 12-18 years (6 high Pv, 8 low Pv) to 11 normal controls have a primary disorder of cerebral autoregulation. using venous occlusion plethysmography to obtain the fore- arm and calf blood flows and to compute the capacitance vessel volume-pressure compliance relation. Heart rate and BP changes and variability measures were used to assess the Easy identification of subjects with poor sympathetic activation and vagal withdrawal. Subjects were orthostatic tolerance through cross-spectral studied supine and at -10 ~ +20 ~ +35 ~ waiting 15 minutes analysis of cardiovascular parameters in supine at each angle to reach a steady state. Forearm and calf re- G. Gulli, 1 V. Cooper, 2 M.J. Hilz, 1 R. Hainsworth 2 sistance, and flow were unchanged by tilt in POTS patients; Department of Neurology, University of Erlangen-Nuremberg, forearm and calf resistance increased and flow decreased in Germany; 2Institute of Cardiovascular Research, University of controls. Heart rate and blood pressure variability data were Leeds, UK consistent with a decrease in overall variability and vagoly- sis. High frequency power was decreased in low Pv patients An easy examination for the identification of sUbjects with in whom POTS criteria (HR increase >30 b/min) were orthostatic intolerance, thus potentially prone to syncope, is fulfilled even at 35 ~ Curvilinear regression showed no sig- not yet available. nificant difference among the groups. We conclude that A stepwise orthostatic test with 60 deg head-up-tilt, and there is no difference in venous compliance in POTS -20 and -40 mmHg lower-body-negative-pressure was per- compared to control nor evidence for orthostatic formed on 73 patients with history of unexplained syncope venoconstriction.

194 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

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Biphasic assessment of venous compliance phase in the forearm decreased (0.123(0.096 to before and after sympathetic stress 0.075(0.05 ml/dl/mmHg, P=0.043), while in the calf was not different (0.064(0.036 and 0.065(0.04 ml/dl/mmHg). M.R. Risk, V.A. Lirofonis, W.B. Farquhar, R. Freeman Conclusions" The P-V can be described with a biphasic Beth Israel Deaconess Medical Center, Harvard Medical School, model. This model characterizes a consistent linear phase Boston, MA, USA for both forearm and calf at pressures lower than 35 mmHg Objectives" To characterize venous compliance in the fore- and a non-linear phase at higher pressures. Sympathetic arm and calf with a biphasic analysis of the pressure-volume activation decreased compliance in the forearm, but did not (P-V) relationship in basal condition and under sympathetic do so in the calf. stress. Background: There is evidence that vascular compliance is not linear within the physiological range of pressures. Stan- Comparison of the effects of water and dard modeling of the P-V relationship do not adequately carbohydrate ingestion on blood pressure describe this non linearity. responses to rising from the squatting position Material and methods: Forearm and calf venous compli- M.S. Pitt, R. Hainsworth ance was assessed in 5 healthy subjects. A venous collecting Institute for Cardiovascular Research, University of Leeds, UK cuff on the upper arm and thigh was inflated to 60 mmHg for 4 minutes and cuff pressure subsequently decreased Squatting and subsequently standing induces large increases 1 mmHg/sec; changes in venous volume were measured and decreases, respectively, in blood pressure. In the fasted using a mercury-in-silastic strain gauge. P-V curves were state, there were no differences between the responses of generated. These curves were generated during basal condi- asymptomatic controls and patients with posturally related tions and sympathoexcitatory stimulus (static handgrip with syncope. Following a carbohydrate 'meal', however, in the post-exercise ischemia). Biphasic analysis was calculated patients, blood pressure variations increased, whereas in the separating a linear phase at low pressures starting at 10 controls they were smaller. In this study we compared the mmHg, from a second nonlinear phase at high pressures. effects of ingestion of a similar quantity of water with the The pressure at the end of the linear phase was determined responses to carbohydrate. for the segment with the highest linear coefficient of corre- In 6 healthy control subjects (aged 24-62) and 6 patients lation. Compliance for the linear phase was calculated as the (16-61) with poor orthostatic tolerance, we recorded the mean value of the derivative of the P-V curve within the effects on finger arterial blood pressure (Portapres) of stand- phase. Compliance for the nonlinear phase is characterized ing upright, squatting and subsequently standing for 1 rain as the derivative of the P-V relationship. each before and 30 rain after consuming a high carbohy- Results: Pressures at the end of the linear phase was drate meal (2.5 MJ) and, on a separate occasion, of a similar not different between basal and sympathetic stress in (500 ml) volume of water. forearm (27.2(8.9 and 33(9.1 mmHg) and calf In confirmation of our previous study, following the car- (32.2(6.8 and 34.8(4.8 mmHg). Compliance of the linear bohydrate meal in the patients there were significantly larger

Clinical Autonomic Research 2001, Vol 11 No 3 195 XIIth International Symposium on the Autonomic Nervous System: Abstracts increases and decreases in blood pressure during the ma- Background: To learn more about the true prevalence of noeuvres (p<0.01) but the variations during the manoeuvres syncope in a young healthy population we performed a were smaller. Water on the other hand, had no effect on the descriptive study among the medical students in the Aca- controls, whereas in patients it resulted in a significant demic Medical Centre. Our first study objective was to (p<0.05) increase in the minimum pressure reached during determine the prevalence of syncope in a young population, the standing following the crouch. including the recurrence-rate. Other study-objectives in- The larger pressure fluctuations after carbohydrate and cluded the evaluation of the gender-difference in syncope the improved stability after water that we observed in our and the evaluation of the triggers provoking syncope in patient group does raise the possibility of the existence of young adults. The main part of the questionnaire we devel- some minor impairment of autonomic control. oped consisted of questions about the history of syncope, the frequency of syncope and triggers of syncope. References 1. Mathias CJ. J Neurol Neurosurg Psychiatry 1991 ; 54:726-729. Results: The questionnaire was handed out to 395 students. 2. Jordan J. Circulation 2000; 101:504-509. Seventeen students did not fill in their gender. The remain- ing group consisted of 254 (64%) women and 124 (31%) men. The gender distribution is in accordance with the Risk stratification in syncope overall ratio of female and male students in our curriculum. N. Colman, 1 J. Reitsma, 1 M. Linzer, 2 W. Wieling ~ The median age for female and male students was 21 years. IAcademic Medical Centre, Amsterdam, the Netherlands; Of all 395 students 154 (39%;95%CI 34-44%) reported 2University of Wisconsin, Madison, WI, USA that they had experienced at least one (episode of) syncope. The prevalence of syncope was almost twice as high in In the diagnostic work up following syncope excess testing women compared to men (47% vs. 24%; RR 1.9, 95%CI should be avoided, without missing diagnoses in patients at 1,4-2,7%). The mean age at which the first syncope oc- high risk for cardiac death. We hypothesized that a stan- curred was not significantly different between women and dardized history, physical exam and a resting-ECG would men (14.3 and 14.8 years respectively). Female as well as provide a correct working diagnosis in at least 50% of pa- male students mentioned a diverse range of triggers. Being tients and that in the remaining patients an accurate risk in a warm environment and prolonged standing were men- stratification could be made. tioned by respectively 47 (12%) and 41 (10%) students. A first risk stratification was done based on information Other frequent triggers were pain, illness, alcohol and drugs, from the history (e.g. cardiac disease, age >70 years) and a emotion, seeing blood, standing up, insufficient food intake resting-ECG. After additional testing (echocardiography, and tiredness. Many students marked a combination of trig- 24hr-ECG and exercise ECG) a second risk stratification gers as the cause of an episode of syncope. was done based on all the test results. Both the second risk Conclusions: Syncope is common in young adults. The stratification and follow up are used as gold standard for the majority of triggers involved in syncope in young adults are initial stratification. common daily activities and circumstances. Attending physicians evaluated 152 consecutive patients. History, physical exam, and ECG yielded a certain diagnosis in 47 patients (31%). Of the remaining 105 patients 47 (31% of 152) had a highly likely (>80% certainty) diagnosis An unusual case of situational syncope according to the attending physician and 58 patients (38% of 152) had no diagnosis. Forty-three patients without a R.K. Khurana certain diagnosis (41%) were initially stratified as high-risk. Baltimore, MD, USA After additional testing and a second risk stratification, only 10 patients remained at high-risk. None of the patients who Background: Situational syncope has been attributed to were labeled low risk after the first stratification became activation of a vasovagal response by afferent impulses from high risk after additional testing. The initial stratification in a particular organ, such as the esophagus in cases of swallow low risk was correct in 100% of the cases (95%CI 69- syncope. 100%). In the patients who were labeled as high risk the risk Aim: To investigate the role of trigeminal afferents in a stratification was correct in 58% of the cases (95%CI 47- patient who consistently developed syncope during exami- 69%). Until now, no serious cardiac events have been iden- nation of the eyes. tified in the total patient group (follow-up ranging from Case study: A 51-year-old woman experienced episodes of 4-14 months). fainting since the age of twelve. These were precipitated by Conclusions: Our data indicate that after a risk stratifi- venipuncture, and eye examination. She developed transient cation based on history, physical examination and ECG, lightheadedness, loss of vision, pale face, loss of conscious- patients at low-risk for acute cardiac events are unlikely to ness, and occasional donic movements, followed by dia- need further cardiac testing. phoresis and urgency of bowel movement. General physical and somatic neurological examination, including function of trigeminal nerves, were normal as were laboratory data Prevalence and triggers of syncope in young including routine blood chemistry and electrocardiogram. adults: a questionnaire Autonomic investigations revealed normal cardiovagal func- N. Colman, 1 K. Ganzeboom, 1 J. Reitsma, 1 W. Shen, 2 tions (Valsalva ratio, 1.62; heart rate response to deep W. Wieling ~ breathing, 14.3 beats per minute). A head-up tilt produced IAcademic Medical Centre, Amsterdam, the Netherlands; presyncope and reduced blood pressure from 180/90 mm Hg 2Mayo Clinic, Rochester, Minnesota, USA to 80/60 mm Hg after eight minutes.

196 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

On a separate day, the contribution of trigeminal stimu- Acute human pharmacological model of lus to vasovagal response was studied, and application of norepinephrine transporter (NET) deficiency Schirmer's test strips in each conjunctival sac reduced her T. Tellioglu, B. Black, V. Watkins, S. Lonce, blood pressure from 1701100 mm Hg to 100/70 mm Hg in D. Robertson 2.5 minutes. Topical administration of 0.5% proparacaine Autonomic Dysfunction Center, Vanderbilt University, hydrochloride produced ocular anaesthesia and loss of Nashville, TN, USA corneal reflexes. Schirmer's test following anaesthesia again caused a drop in blood pressure from 200/120 to Orthostatic intolerance (OI) is a syndrome mainly charac- 90/50 mm Hg. The supramaximal stimulus to a supraor- terized by symptoms of inadequate cerebral infusion on bital nerve before and after topical anaesthesia did not affect standing usually associated with tachycardia, but not ortho- blood pressure or heart rate. Conclusions: 1. Trigeminal afferents did not induce va- Orthostatic changes in HR with DMI sodepressive syncope in this patient. Instead, corticohypo- thalamic centers may have played an important role. 2. A 5o conditioned cardiovascular response may be the actual trig- ~ 40 ger mechanism in patients with situational syncope. ~,~ 30 ~2o =~(.} 10 The relationship between tilt-table testing and 0 physiological plasma volume loss 0 2 Time'hour) 6 8 T. Ketch, H. Snyder, A. Diedrich, A. Ertl, D. Robertson Autonomic Dysfunction Center, Vanderbilt University, Nashville, TN, USA static hypotension. We recently identified a gene mutation causing impaired neuronal reuptake of norepinephrine (NE), which could explain some of the symptoms and find- Introduction: Assumption of upright posture leads to rapid ings in OI patients. In this study, we investigated if a drug- pooling of blood in the lower extremities due to gravita- induced NET deficiency can give rise to the clinical features tional forces. This change in posture from the supine posi- of OI in normal human volunteers. Supine and upright tion to standing leads to fluid shifts across the capillary blood pressures (BP) and heart rates (HR) were measured, endothelium into the extravascular compartment, thus re- and venous blood samples were withdrawn while supine and sulting in marked alterations in the concentration of blood after 10-minute standing in 6 healthy male and female sub- components, including hematocrit and plasma volume. Al- jects between the ages of 25-35. Then, subjects were given ready demonstrated is that active standing leads to a mean a single dose of desipramine (DMI) 50mg orally. Postural plasma volume shift of-16.5% and a mean hematocrit neurodynamic measurements and blood sampling were re- increase of 4.7% in about 20 minutes, with plasma volume peated every 2 hours for 8 hours. DMI significantly in- loss equilibrating after 20 minutes. The objective of this creased upright HR and plasma catecholamines without a study was to determine the magnitude of posture-related significant effect on BP. Acute blockade of the NET by changes in blood components versus time using a standard- DMI caused orthostatic tachycardia similar to that seen in ized 75-degree head-up-tilt. OI patients. Pharmacological blockade of the NET may be Methods: Fifteen subjects, seven healthy, seven patients used as a model to better understand the pathophysiology of with orthostatic intolerance (OI: a common syndrome char- OI and other diseases that are related to NE dysregulation. acterized by frequent orthostatic symptoms) and one patient with pure autonomic failure were studied. Supine and up- right plasma volume (PV) and hematocrit were determined Postural sway behavior in control subjects with for each patient. good and poor orthostatic tolerance Results- The mean plasma volume decrease upon 75-degree V.E. Bush, R. Soames, R. Hainsworth head-up-tilt was -9.4% ( 1.1%, with a range from -4.2% to Institute for Cardiovascular Research, University of Leeds, UK -17.0%. The mean hematocrit change was 2.6% ( .3%, with a range from 1.1% to 5.2%. The total time that sub- Some asymptomatic volunteers, when subjected to a pro- jects were able to tolerate this standardized tilt-table proto- gressive orthostatic stress test, show early presyncope, simi- col ranged from 5 to 30 minutes, with a mean of 14.9 ( 2.5 lar to patients with frequent fainting attacks. We hypoth- minutes. There was a statistically significant correlation be- esised that the reason that the normal subjects with poor tween the total time of tilt and plasma volume change. tolerance to the orthostatic stress do not usually faint was Conclusion: Tilt-table testing is a prevalently used diagnos- because they adopted a strategy of increased lower limb tic modality for autonomic disorders. A rapid reduction in movement, which would maintain venous return. We, plasma volume occurs during 75-degree upright tilt. This therefore, compared postural sway in control subjects with plasma volume shift ranged from 4.2% to 17% in our study good (n=6) and poor (n=9) orthostatic tolerance (OT) as subjects, with plasma volume shifts increasing as tilt time assessed by the Leeds technique of combined head-up tilting increased. Interindividual differences in orthostatic plasma and lower body suction [1]. volume shift are substantial and could contribute to indi- Postural sway was recorded using a computerised biome- vidual differences in tolerance to head-up-tilt. chanics measuring system. Foot position was standardised,

Clinical Autonomic Research 2001, Vol 11 No 3 197 XIIth International Symposium on the Autonomic Nervous System: Abstracts and subjects stood with their feet together and parallel either ment were derived from the ASP using the Composite Au- side of the midline, arms hanging loosely at the side. Con- tonomic Symptom Scale (COMPASS). A Composite Au- tinuous recordings were made for 30-second periods first tonomic Severity Scale (CASS) and cardiovascular with the eyes open, and then the eyes closed. parameters were derived from the Autonomic Reflex Screen. With the eyes open, no differences were observed in the Results: 148 patients with OI (117 female, 31 male, distance or velocity moved in anteroposterior or mediolat- 27.1+10.2 years) were included. 71 patients (48%) ful- eral directions, or the mean centre of pressure between the filled the criteria for POTS, 77 (52%) those for MOI, 40 two groups. With the eyes closed, subjects with good OT (27%) had a history of antecedent viral illness. The total showed no significant changes in the estimates of sway. COMPASS score was higher in POTS compared to MOI When subjects with poor OT dosed their eyes however, (57.6+19.1 vs 47.4+19.7) as was the orthostatic, vasomotor there were significant increases in distance moved, and ve- and pupillomotor subscore. COMPASS was not different locity of movement in the mediolateral plane (p<0.05). between VIR and N_VIR except for the urinary subscore These experiments have demonstrated that, in normal which was higher in the N_VIR group. The CASS score was subjects with poor OT as assessed by an orthostatic stress not different between POTS and MOI or between VIR and test, their leg movements tend to be greater when standing. N_VIR. HR was higher in POTS compared to MOI at These movements are likely to enhance venous return and supine rest (87.7+12.8 vs 66.9+9.2 bpm) and during tilt explain why, despite their poor test results, they do not (134.5+15.0 vs 103.9+8.9 bpm). BP was also higher in normally faint. POTS supine and upright. The VIR group had higher HR We propose that further studies of leg movement could and higher diastolic BP supine and upright. There was a be of help in understanding the susceptibility of some sub- tendency for an antecedent viral illness to be more likely in jects to syncope. POTS than MOI. Conclusions: Our data demonstrate that POTS is not only Reference associated with higher orthostatic HR but also with a higher 1. EI-Bedawi KM, Hainsworth R. Combined head-up tilt and lower autonomic symptom score than MOI. HR and BP in POTS body suction--atest of orthostatic tolerance. Clin Auton Res 1994; 4:41-47. is not only elevated with standing but also supine suggesting the presence of a hyperadrenergic state in this patient group. An antecedent viral illness seems to have only a marginal influence on autonomic impairment in OI and may be Are the clinical features of patients with more common in POTS than MOI. (Supported by NIH orthostatic intolerance influenced by the [PO1 NS32352], Mayo GCRC [M01 RR00585] and severity of postural tachycardia or a history of Deutsche Forschungsgemeinschaft.) antecedent viral illness? W. Singer, G. Paul, T.L. Opfer-Gehrking, M. Camilleri, P.A. Low Vascular resistance of the upper extremity in Department of Neurology and Gastroenterology,Mayo Clinic, orthostatic hypotension and the postural Rochester, MN, USA tachycardia syndrome Background: The pathophysiology of orthostatic intoler- W. Singer, S.M. Hines, T.L. Opfer-Gehrking, P.A. Low ance (OI) remains poorly understood and appears to be Department of Neurology, Mayo Clinic, Rochester, MN, USA heterogeneous. A limited, autoimmune autonomic neurop- athy is thought to be the underlying mechanism in patients Objective: To evaluate vascular resistance of the upper ex- with a viral illness prior to the onset of symptoms. Patients tremity and its response to head-up tilt in orthostatic hy- without such a history are more likely to have a family potension (OH) and the Postural Tachycardia Syndrome history of OI and to suffer from a constitutional form of OI. (POTS). On the other hand, the orthostatic heart rate (HR) varies Background: The normal response of systemic vascular re- greatly among patients with OI. A group with an orthostatic sistance (SVR) to orthostatic stress is a moderate and sus- HR of at least 120 bpm, known as 'Postural Tachycardia tained increase. SVR has been shown to fail to increment Syndrome' (POTS) has been separated from patients whose upon head-up tilt in POTS and to decrease in OH. The HR does not exceed this limit, called 'Mild Orthostatic contribution of local vascular beds to the change of SVR has Intolerance' (MOI). only been sparsely investigated. We have demonstrated a Objective: We therefore sought to evaluate how the se- normal orthostatic increase of leg vascular resistance in verity of postural tachycardia and an antecedent viral illness POTS and a reduced but present increase in OH. We have influence autonomic function and symptoms of patients also shown that mesenteric vasoconstriction in response to with OI. orthostatic stress is essentially intact in POTS and clearly Methods: Among all patients who were referred to our impaired in OH. In this prospective study we evaluated Autonomic Laboratory between January 1995 and March vascular resistance of the upper extremity and its response to 2000 we selected all cases who met the criteria for OI and head-up tilt in these disorders. had completed the Autonomic Symptom Profile (ASP), a Methods: We investigated 9 patients with neurogenic OH validated questionnaire evaluating autonomic symptoms. (66.0(8 years), 9 patients with POTS (31.7(9 years), 7 older Based on the history and the response to head-up tilt, pa- controls (OC, 62.4(10 years) and 8 younger controls (YC, tients were divided into POTS and MOI and patients with 29.1(9 years). Heart rate (HR), blood pressure (BP, Fi- (VIR) and without (N-VIR) precedent viral illness. A total napres) and systemic resistance index (SRI, Bomed) were score and several subscores of autonomic function impair- continuously monitored during 10min supine rest and

198 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

10min 60 degree head-up tilt. Blood flow velocity and di- PHE15 (oq-AR sensitivity, the dose of phenylephrine re- ameter of the brachial artery were measured supine and quired to increase the systolic BP by 15 mmHg), 120_+11 vs during tilt using Duplex ultrasound. Limb vascular resis- 185_+27 lag (p=0.03). Plasma norepinephrine concentrations tance (LVR) was calculated using an improved algorithm were similar in both group. based on limb blood flow and BP. Patients with OH were Conclusions: The autonomic nervous system related symp- compared with OC, patients with POTS with YC using toms of HMS patients have a pathophysiological basis, two-tailed student t-test. which suggest that dysautonomia is part of the syndrome. Results" There was an exaggerated HR response to tilt in POTS and a significant BP-drop in patients with OH. SRI increased with orthostatic stress in both control groups (YC Distinguishing clinical and laboratory features +26(6%, OC +31(11%), remained essentially unchanged in in patients with pure autonomic failure (PAF) or POTS (-2(7%, p<0.01) and decreased in OH (-23(5%, idiopathic autonomic neuropathy (IAN) p<0.01). LVR increased in both control groups (YC +36(17%, OC +65(15%). There was also an increase of C.M. Klein, P. Sandroni, L. Benrud-Larson, S. Vernino, LVR in POTS which tended to be exaggerated (+102(32%, P.A. Low p=0.09). The increase of LVR in the upright position in Mayo Clinic, Rochester, MN, USA OH was preserved but tended to be lower than in controls (+25(13%, p=0.06). Pure Autonomic Failure (PAF) and Idiopathic Autonomic Conclusions: The response of LVR to orthostatic stress did Neuropathy (IAN) are 2 recognized causes of generalized not reflect the changes of SRI in both OH and POTS. The autonomic failure. The purpose of this study was to analyze exaggerated response in the forearm in POTS along with the clinical features and laboratory findings in a group of pa- excessive HR increment and a relatively normal response of tients with these diagnoses to determine key distinguishing leg and mesenteric resistance vessels might reflect a com- diagnostic parameters. We reviewed the medical records of pensatory hyperadrenergic response to a partially denervated patients seen at Mayo Clinic-Rochester from 1991-2000 lower extremity and splanchnic-mesenteric bed. Limb vas- who were found to have orthostatic hypotension during cular responses appear to be only moderately impaired routine clinical autonomic studies (N = 823). A total of in OH suggesting a major contribution of the splanchnic 171 patients were identified as having diagnoses of either bed and possibly other vascular beds to the observed definite PAF (N = 33), definite IAN (N =50), possible PAF decrease of systemic resistance (Supported by NIH [PO1 (N = 57) or possible IAN (N = 31) by consensus review of specific clinical data extracted from their medical records by NS32352], Mayo GCRC [M01 RR00585] and Deutsche Forschungsgemeinschafr.) 3 authors (CMK, PS, PAL). Chi-square analyses and logistic regression tested whether patients in the 2 definite diagnos- tic categories differed in terms of their clinical characteris- tics. Univariate analyses revealed significant differences in the following parameters: total Composite Autonomic Scor- Dysautonomia in the hypermobility syndrome ing Scale (CASS), supine serum norepinephrine level, his- Y. Gazit, A.M. Nahir, G. Jacob tory of preceding illness or surgery, timing of symptom onset, history of initial gastrointestinal symptoms, disease course and positive ganglionic acetylcholine receptor anti- Introduction: Symptoms related to the autonomic nervous bodies (all p's < 0.01). Due to missing data, only selected system found to be frequent among patients with hypermo- diagnostic parameters were included in a logistic (multivari- bility syndrome (HMS). The aim of this study was to in- ate) regression model predicting diagnosis. A history of vestigate the pathophysiology of the autonomic nervous sys- preceding illness or surgery (odds ratio = 25.9, p < 0.01) tem regulating the cardiovascular system in HMS patients. or initial gastrointestinal symptoms (odds ratio = 11.4, Methods- Twenty-seven HMS patients, who fulfilled the p < 0.01) were more likely in patients with the diagnosis of Brighton criteria, and 21 healthy controls, went through IAN. These clinical features may be helpful in making a autonomic evaluation. Orthostatic test, cardiovascular vagal specific diagnosis in patients with generalized autonomic and sympathetic functions, catecholamines, and evaluations failure. of adrenoreceptors responsiveness were compared between HMS patients and controls. Results: Upright AHR and ASBP were 22+2 vs 15_+2 bpm, and -8.5_+1.8 vs -1.2_+1.2 mmHg, p=0.04 and p=0.005 for Orthostatic hypotension and mortality: patients and controls respectively. HMS patients presented a meta-analysis different sympathetic and vagal control of the cardiovascular J.L. Izzo, Q.Q. Fu system. Valsalva ratio was significantly higher in HMS pa- Buffalo, NY, USA tients 1.7_+0.09 vs 1.31_+0.02, p=0.002. Sympathetic in- dices showed a major drop and a higher increase systol- Orthostatic hypotension (OH) is a major cause of syncope ic BP during hyperventilation and after cold pressor test in and may be both cause and consequence of cerebrovascular HMS patients as compared to controls: -11.5_+1.6 vs disease. Accordingly, we performed a meta-analysis of exist- -5.5+1.4 mmHg, p=0.02 and 18.5_+2.5 vs 11+3.5 mmHg, ing literature to confirm whether orthostatic hypotension is p=0.06. Also, patients presented adrenoreceptor (AR) hy- associated with increased mortality. The MEDLINE data- perresponsiveness, as assessed by ISO15 (a measure of [3 t-AR base from 1966-2001 was searched using "orthostatic hy- sensitivity, the dose of isoproterenol required to increase potension", "mortality", and "prognosis" as the Main Medi- HR by 15 bpm), 0.13_+0.03 vs 0.25_+0.05 lag (p=0.04), and cal Subject Headings (MESH) search terms. Bibliographies

Clinical Autonomic Research 2001, Vol 11 No 3 199 XIIth International Symposium on the Autonomic Nervous System: Abstracts of the articles identified were then scanned to find any Hypersensitivity of sympathetic receptors and additional pertinent studies. Included were prospective hypertrophy of left ventricle in patients with mortality studies of community dwelling patients in which diabetes mellitus and autonomic neuropathy OH was defined as a decrease in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least B. Milovanovic, M. Krotin, A. Milovanovic, V. Bisenic, 10 mmHg after 3 minutes of upright posture. Statistical S. Simikic, S. Markovic, L.J. Vusovic analysis generally followed the method of Yusuf (1985), B. Kosa Department of Cardiology, University of Belgrade, which calculates pooled risk by combining data from con- Belgrade, Yugoslavia tingency table analyses of each study included. Four pro- Introduction: It is a well-known fact that sympathicus can spective cohort studies were identified that met criteria. play an important role in the pathogenesis of myocardial Over 15,000 individuals were followed for 4 or more years hypertrophy. According to canon law of denervation in pa- with a mean mortality rate of about 50 per 1,000 person- tients with diabetes mellitus, there is a very often the ap- years for those with OH. The pooled risk ratio was 2.0 pearance of vagal and sympatho-vagal denervation with hy- (95% C.I. 1.60, 2.51. p<0.01). We conclude that OH s a persensitivity of receptors. major risk factor, with premature death, which occurs twice Aim: To establish connection with sympatho-vagal dener- as frequently in OH as in subjects without OH. We suggest vation with increasing activity of sympathicus and hyper- that measurement of orthostatic blood pressures should be- trophy of the left ventricle. come a routine part of risk assessment in middle-aged and Methodology: 102 (64/M,38/F) diabetics are examined older patients. and divided into 2 groups: 1) Diabetics with hypertrophy of myocard (n=25,13/M,12/F); and 2) Diabetics without hy- pertrophy of myocard (n=77, 51/M, 26/F). Evidence for denervation hypersensitivity to norepinephrine in patients with familial Autonomic neuropathy (AN) is diagnosed with applying dysautonomiama microdialysis study of cardiovascular reflex tests after Ewing. AN was considered to exist if at least 2 tests were positive. Vagal denervation is A. Bickel, 1 F. Axelrod, 2 H. Marthol, 2 B. Stemper, 2 examined with applying of 3 tests: Valsalva maneuver, deep B. NeundSrfer, 1 M.J. Hilz 2 breathing test, response to standing test. The denervation of INeurologische Klinik mit Poliklinik, sympathicus is examined with applying of 2 tests: blood Friedrich-Alexander-Universit~itErlangen-Niirnberg, Erlangen, pressure response to standing, hand grip test. Peripheral Germany; 2Department of Pediatrics and Department of neuropathy is diagnosed by neurological examination. Hy- Neurology, New York University Medical Center, pertrophy of the left ventricle of myocard is diagnosed by New York, NY, USA echosonographic examination of heart (Acuson 128). Results: Valsalva maneuver was positive in 10 (45,45%) Objective: Patients with Familial Dysautonomia (FD) suf- diabetics (D.) with hypertrophy of left ventricle (HLV) and fer from autonomic crises with excessive rises of blood pres- 13 (28,88%) D. without HLV p<,05.Test of deep breathing sure despite having a serious autonomic neuropathy. De- was positive in 13 (54,16%) D. with HLV and 16 (31,37%) nervation hypersensitivity to catecholamines at peripheral D. without HLV p<,05.Response to standing test was posi- blood vessels may contribute to this phenomenon. tive in 17 (70,83%) D. with HLV and 26 (50,91%) D. Methods: Single hollow microdialysis fibers (outer diameter without HLV p<,05.Blood pressure response to standing 0.4mm, cutoff3000 kDA) were inserted intracutaneously at was positive in 6 (25%) D. with HLV and 9 (17,64%) D. a length of 0.5cm in the lower leg in 14 FD-patients and 12 without HLV p<,05.Hand grip test was positive in 15 age-matched healthy controls. The fibers were perfused with (62,50%) D. with HLV and 32 (62,71%) D. without HLV Ringer's solution at a flow rate of 0.41al/min and dialysate p<,05. was collected after skin passage. After 30 min Ringer's so- Conclusions: Hypertrophy of left is with statistically sig- lution was changed for a solution containing 10-6M nor- nificance more present in patients with diabetic complete epinephrine (NE) for 30 min. Local vasoconstriction was sympatho-vagal denervation. Diabetics with vagal denerva- assessed by measuring the zone of vasoconstriction (blanch- tion have more often hypertrophy of left ventricle, but with- ing) around the membrane and local laser Doppler flux out statistical importance. All cardiovascular reflex tests for above the microdialysis membrane. The dialysate was analy- vagal function and postural hypotension are more often sed for total protein content. positive in diabetics with HLV. Results: Skin perfusion at rest was slightly lower in FD patients (n.s.). During application of NE, total decrease in local blood flow was similar in both groups, but vasocon- striction was induced earlier with lower doses of NE in the The significance of hand grip in diagnosis of FD group. Additionally, the diameter of the zone of vaso- sympathetic denervation and coronary constriction around the microdialysis membrane was sig- insufficiency in patients with diabetes mellitus nificantly larger than in the controls, giving evidence for and autonomic neuropathy lower tissue concentrations of NE to be effective in FD B. Milovanovic, M. Krotin, V. Bisenic, S. Markovic, patients. After termination of NE application in the patient S. Simikic, A. Milovanovic, L.J. Vusovic group, protein content in the dialysate showed a lower and B. Kosa Department of Cardiology, University of Belgrade, slower increase compared to controls. Belgrade, Yugoslavia Conclusion: All tested parameters support the hypothesis of a hypersensitivity of peripheral blood vessels to exoge- Introduction: Hand grip test is based on use of static ef- neously applied NE in FD patients. fort of voluntary contraction of the hand in diagnostics of

200 Clinical Autonomic Research 2001, Vol 11 No 3 XIhh International Symposium on the Autonomic Nervous System: Abstracts coronary insufficiency, but also of denervation ofsympathi- orthostatic intolerance, urinary incontinence, bloating, cus. The normal reaction is increase of heart frequency and truncal cutaneous hypersensitivity, and weakness and sen- diastolic blood pressure, which is missing in case of damage sory abnormalities in the legs. Examination showed ortho- of innervation of sympathicus. Under the influence of effort static hypotension (OH) and signs of diabetic truncal neu- (50% of maximal muscle contraction of the hand) ot comes ropathy, proximal motor neuropathy, and polyneuropathy. to increasing requirement of myocard for oxygen, which can Treatment of OH with fludrocortisone and midodrine was lead to appearance of ischemia and pain, which is very relatively ineffective; gastroparesis improved with domperi- important in diagnostics of coronary insufficiency. done. Other symptoms worsened. Prednisone 60 mg q.d. Aim= To establish if sympathetic denervation diagnosed and an insulin pump were started. Within a month all with Hand grip test is followed with ischaemia and distur- neuropathies were remarkably better. bance in rhythm. Patient 2: 24-year-old woman with DM for 11 years de- Methodology= 83 (44\M,39\F) diabetics are being exam- veloped subacutely severe foot burning and postural light- ined and divided into 3 groups in dependence of results of headedness. Examination showed OH, excessive tachycardia Hand grip test: 1) Diabetics with negative test (n=24, on standing, and polyneuropathy. OH symptoms were re- 13\M,11\F); 2) Diabetics with borderline test (n=7, fractory to treatment with fludrocortisone and midodrine. 4\M,3\F); and 3) Diabetics with positive test (n=57, Pain was not controllable with nortriptyline and carbamaz- 27\M,25\F). epine. One year later she had a pancreas transplant and All diabetics had Hand grip test and cardiovascular reflex within three weeks all symptoms were remarkably better. tests (after Ewing): Valsalva maneuver, deep breathing, 30\5 Discussion: These two diabetics developed subacute DAN ratio test, blood pressure response to standing test. Diagno- and other somatic neuropathies. Treatment with corticoste- sis of autonomic neuropathy was established, if at least two roids and tight glucose control in one, and with pancreas tests were positive. The most patients had 24h Holter EKG transplantation (and concomitant immunosuppression) in Monitoring (with parameters: ischemia-ST depression > the other, resulted in dramatic improvements. 1ram, disorder of rhythm: Lown>II,Lown,05 Difficult disturbances of rhythm (Lown > II) had 8 T. Hattori (42,10%) patients with autonomic neuropatiiy and noone Department of Neurology, Chiba University School of without AN p<,05 Ischemia had 15 (40,54%) patients with Medicine, Chiba, Japan AN and 5 (27,77%) without AN p>,05 Disturbances of rhythm had 16 (47,05%) patients with positive test, 2 Objective: To compare autonomic dysfunction in acute (33,33%) borderline and 8 (50%) with negative test. p>,05 inflammatory demyelinating polyneuropathy (AIDP) and Difficult disturbances of rhythm (Lown>II) had 4 (25%) chronic inflammatory demyelinating polyneuropathy with positive test, 2 (100%) with borderline and 2 (CIDP). (22,22%) with negative test. p>,05 Supraventricular distur- Subjects and methods: We examined 7 AIDP patients, 8 bances of rhythm had 8 (50%) with positive and 5 CIDP patients and 10 healthy control subjects. To evaluate (55,55%) with negative test. p>,05Ischemia had 12 cardiovascular function, all patients underwent a head-up (35,29%) patients with positive, 2(40%) with borderline tilt test and CVR-R. Plasma noradrenaline concentrations and 6 (37,15%) with negative test. p>,05 were measured in the 4 AIDP patients and 7 CIDP patients. Conclusions= Diabetics with complete autonomic denerva- Sympathetic sweat responses (SSwR) and sympathetic skin tion have more often coronary ischemia and disturbances of blood flow (SFR), as indexes of cutaneous sympathetic rhythm, especially more difficult forms ofarrhythmia (Low- function, were examined in all of the patients and in the 10 nII). Diabetics with positive Hand grip test have almost control subjects. equal often ischemia and disturbances of rhythm in com- Results: In the AIDP group, none of the patients had or- parison to diabetics without sympathic denervation (nega- thostatic hypotension, but 4 patients showed sinus tachy- tive test). cardia (HR > 90 beats/rain), and 3 patients had elevated plasma noradrenaline concentrations. Only 1 patient showed a slightly reduced CVR-R value. SSwRs were not evoked in 3 patients who had severe motor disability, while Subacute diabetic autonomic neuropathy: all patients showed normal SFRs. In the CIDP group, none recovery following treatment of the 7 patients showed orthostatic hypotension, tachycar- J.D. Stewart, R. Schondorf dia or abnormal CVR-R values. Only 1 patient showed an McGill University, Montreal, QC, Canada elevated plasma noradrenaline concentration. 2 patient did not present SSwRs, and 4 patients showed reduced SFR Background: Diabetic autonomic neuropathy (DAN) is amplitudes. usually chronic and irreversible. We describe two patients Conclusion: Sympathetic cardiovascular hyperfunction was with subacute DAN in whom treatment induced remark- seen in the AIDP patients. Although neither the AIDP nor able improvements. the CIDP patients showed marked cardiovascular hypo- Patient 1: This 19-year-old woman with diabetes mellitus function, cutaneous sympathetic function was hypoactive, (DM) for 14 years developed over 6 weeks weight loss, particularly in the CIDP patients.

Clinical Autonomic Research 2001, Vol 11 No 3 201 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Sympathetic sudomotor and sensory small the incidence or perception of headaches has not been fiber function in familial dysautonomia studied. Objective: To study the incidence, frequency and type of M. Brys, l'a M.J. Hilz, ~'2 B. Stemper, ~'2 A. Bickel, 2 headaches in FD patients. H. Marthol, 1 F.B. Axelrod ~ Methods: We surveyed 95 FD patients (44 female) who IDepartment of Neurology, New York University Medical were diagnosed by standard criteria including genetic test- Center, New York, NY, USA; 2Department of Neurology, ing. Using a standardized questionnaire, we gathered infor- University Erlangen-Nuremberg, Erlangen, Germany; mation on: age of onset, frequency, location, duration, se- 3Department of Neurology, Jagiellonian University, verity, associated symptoms, triggers and medication. Cracow, Poland Headache types were classified according to the IHS criteria. Familial dysautonomia (FD) is a rare autosomal recessive Results: 68195 patients (71.6%) reported a history of head- disorder with vasomotor and sudomotor instability possibly aches (36 females). 56168 (82.4%) patients fulfilled criteria resulting from small fiber dysfunction. The purpose of this for tension-type headache, 8168 patients (11.7%) could not study was to evaluate sympathetic sudomotor and sensory be classified and 4/68 (5.9%) patients reported migraine- small fiber function in FD patients. like symptoms. The age of onset was before 10 years in Fifteen FD patients (age 29.4+-9.9) underwent evaluation 26168 (38.2%) and between 10 and 15 years of age in of warm (WT) and cold perception thresholds (CT) at the 23/68(33.8%). The most common frequency was one distal medial calf and the shoulder using a Marstock ther- attack/week to one attack/month (29168=42.6%). Tension- motest (Somedic, Sweden) and the method-of-limits. Post- type headache patients had predominantly frontal head- ganglionic sweat output (WR Medical, Stillwater, MN) at aches (49156 =87.5%). In most patients, the headaches the forearm was quantified following 5 minutes iontophore- lasted less than an hour (51168=75.0%) None of the ses of 10% acetylcholine. CT and WT as well as sweat patients had to restrict his activities of daily living. The output were compared to the results of age-matched healthy most commonly associated symptoms were nausea controls. (24168=35.3%), phonophobia (17168=25.0%) and sweat- Five FD patients were insensitive for cold and seven for ing (13/68=19.1%). Identifiable triggers were tension warm stimulation. Mean CT in FD patients was (57/68=83.8%), lack of sleep (33/68=48.5%) and change of 12.43_+4.2_+C at the calf and 11.41_+4.5+_C at the shoulder. weather (24/68=35.3%). 58/68 (85.3%) patients needed CT of FD patients was higher than in controls: at the calf medication; 51/58 (87.9%) took NSAID. by 6.13_+4.2+C and at the shoulder by 8.91+4.5_+C. Mean Conclusion: Most FD patients experience headaches. The WT in FD patients was 8.32+3.0-+C at he calf and high frequency of tension-type headaches suggests that the 9.04-+3.8-+C at the shoulder. Again, thresholds exceeded trigeminal neurons innervating the meninges are functional those of controls: at the calf by 0.82_+3.0+C and at the in FD patients. Migraine-like headaches occur very rarely. shoulder by 5.44_+3.8-+C. FD patients had a significantly As changed vascular reagibility of brain vessels is involved in higher baseline sweat rate (5.79+l.6_+mol/min) than did the pathophysiology of migraine, the low frequency of mi- controls (4.44+0.5-+mol/min; p

202 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts fingertip of dig. II of the non-dominant hand. A micro- flow reduction more than 70% led up to fourfold decrease lightguide of EMPHO II SSK was applied to the fingertip of hemoglobin oxygenation. of dig. III beside. After baseline measurements (3 min.) Simultaneous measurement of blood flow and oxy- three deep inspirations were performed with a time distance gen saturation may provide additional information about of 15 seconds each. oxygen supply, consumption, and related regulatory pro- Regression between IGR (parameter of flow change) and cesses. This can be useful especially under pathophy- AHbO 2 (indicator of tissue oxygen supply) fit best with an siological conditions with reduced blood flow (e.g. exponential model (p>,001). Reduction down to 70% of peripheral arteriosclerosis), increased oxygen need (e.g. in- baseline flow during vasoconstrictive episodes was accom- flammatory diseases) or dysregulation (e.g. diabetic neurop- panied only by small deoxygenation (AHbO2 < 2%), while athies).

Clinical Autonomic Research 2001, Vol 11 No 3 203 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Poster Session II

Transnasal iontophoresis, a new non-invasive involvement of the autonomic nervous system. In order to drug delivery system for the brain that investigate whether the ANS is affected in these patients, an circumvents the blood-brain barrier Electroautonomogram was recorded of CFS patients and compared with that of healthy subjects. E. van Zanten, ~ E.N. Lerner, ~ G.R. Stewart 2 Methods: The present study include 58 patients diagnosed 1Lerner Medical Technology Ltd., Amsterdam, The with CFS and a group of 20 healthy subjects. The following Netherlands; 2Genzyme Corporation, Framingham, USA signals were recorded simultaneously: skin potentials from Introduction: Many autonomic nervous system disorders the palmar and plantar sides, the electrocardiogram, the have a central origin and pharmacological treatment is electrogastrogram and the respiration. After 10 minutes of mostly inefficient due to the presence of the blood brain baseline recording, the subject was subjected to the follow- barrier that effectively restricts the brain uptake of many ing stimuli: electric stimulation on the median nerve (n=3), substances. The olfactory pathway has been suggested as an audio (n=3), Valsalva manoeuvre and deep breathing. attractive drug administration route to the brain, because it Results: In contrast to healthy subjects, the Electroautono- provides a direct route to the brain that circumvents the mogram of CFS patients showed a number of deviations. blood brain barrier. However, brain uptake of large, hydro- Most prominent abnormality that was found was the oc- philic compounds such as peptides via this route is limited. currence of contra phases in either evoked or spontaneous The present study examined whether transnasal iontophore- skin potentials. The contraphase may occur between palmar sis can be used as enhancement technique to increase brain skin potentials, or between plantar skin potentials or be- transport of the test peptide Octreotide acetate. In order to tween palmar and plantar potentials. Next to deviations in exclude systemic drug transport to the brain, the study was synchronization of skin potentials also abnormally high performed in exsanguinated rabbits. spontaneous plantar skin potentials (up to 10 mV) were Methods: Octreotide acetate was administered in four rab- observed in the patient group. Recovery time of evoked bits by transnasal anodal iontophoresis using a total current responses were longer in CFS patients as well. No differ- strength of 3,0 mA during 60 minutes. In three control ences were found in heart rate variability and respiration animals the drug was administered by transnasal delivery rate between the two groups. with 0 mA during 60 minutes. Immediately after exsangui- Conclusion: The presence of synchronization abnormalities nation, two electrodes comprising each 250 lal of drug for- in simultaneously recorded spontaneous and evoked skin mulation that contained 3,0 mg/ml of Octreotide acetate potentials from palmar and plantar sides strongly suggest were inserted deep in the rabbit's nasal cavities. After 60 that there is dysregulation of the ANS in CFS patients. The minutes the treatment was stopped and the animal's brain results further show that electroautonomography can be was collected and sectioned for drug analysis. In addition to used as a diagnostic method in the assessment of CFS. brain samples also a sample of cerebrospinal fluid, the lum- bar spinal cord and a piece of muscle were collected for analysis. Results: A significant difference (P < 0.05) in Octreotide brain levels was obtained following transnasal iontophoresis. The effect of diabetes on the central autonomic Brain samples and of iontophoretically treated animals con- nervous system assessed by tained at least 10 times more peptide than control animals. electroautonomography Drug levels in spinal cord and muscle samples were negli- gible in both treatment groups. E.N. Lerner, 1 H.F. Dankmeijer, 2 H. Rollman, 1 Conclusion: From the results it can be concluded that E. van Zanten 1 transnasal iontophoresis is a potentially powerful drug de- 1Lerner Medical Technology Ltd., Amsterdam, The livery technique to the brain. Netherlands; 2Gezondheidscentrum Bunnik, The Netherlands

Is chronic fatigue syndrome a disorder of the Introduction: Diabetes (I or II) is known to affect the autonomic nervous system? peripheral autonomic nervous system (ANS), but its effect on the central part of the ANS is not fully understood. The E. Lemer present study was conducted to examine to what extent the Lerner Medical Technology Ltd., Amsterdam, The Netherlands central autonomic nervous system is affected in diabetes Introduction: Chronic fatigue syndrome (CFS) is associ- type I and II patients. For this purpose, an Electroautono- ated with a large number of symptoms that suggest the mogram (EAG) was recorded of two patient groups.

0959-9851 2001 Lippincott Williams & Wilkins 205 XIhh International Symposium on the Autonomic Nervous System: Abstracts

Methods: The study included 10 diabetes patients with patients respectively. All the patients (8) with a FAI score type II (4 males, 6 females) and 5 patients diagnosed with ranging more than 130, presented also an impairment of diabetes mellitus type I (2 males, 3 females). Palmar and parasympathetic cholinergic functions. No patient pre- plantar skin potentials were recorded simultaneously. A 15 sented orthostatic hypotension. minutes baseline recording was made of the spontaneous Conclusion: The most interesting result of this study is the skin potentials followed by the application of a series of the linear correlation between the FAI scores and the heart rate following stimuli: electric stimulation on the median nerve changes at different tests. These data suggest a relationship (n=3), audio (n=3), and a Valsalva manoeuvre. between parasympathetic dysfunction and severity of MSF. Results: An abnormal EAG was observed in 80% of DM The SSRs were pathological in all our patients; however this type I patients. Spontaneous skin potentials were low in result, according with previous studies, is common in MS amplitude (< 100 laA) and showed a low degree of synchro- patients and it seems not related with the MSF. nization. Contra phases were observed in both spontaneous and evoked potentials between hands and legs. The baseline EAG of all diabetes type II patients was abnormal, the sig- Depletion of cholinergic neurons in the nals were either of low amplitude (< 100 laA) or displayed a mesopontine tegmentum in multiple pattern of fast oscillating waves with frequencies of 0.3 - 0.5 system atrophy Hz, whereas the evoked response was abnormal in 60 % of the patients. Clinical status, age and duration of the disorder E.E. Benarroch, A.M. Schmeichel did not appear to be indicators for the occurrence of an Mayo Foundation, Rochester, MN, USA abnormal EAG or evoked skin response. Rapid eye movement (REM) sleep behavior disorder (RBD) Conclusion: Spontaneous palmar and plantar skin poten- tials show an abnormal signal pattern with a low degree is a prominent feature of multiple system atrophy (MSA), and occurs early in the disease. RBD also occurs in other of synchronization with the presence of contra phases be- synucleinopathies, such as Parkinson's disease and dementia tween hands and legs. The results indicate a central ANS with Lewy bodies. The cholinergic neurons of the meso- dysregulation. pontine tegmentum, particularly the laterodorsal tegmental group (LDT) is thought to play a critical role in REM sleep Relationship between autonomic dysfunction control. We sought to determine whether cholinergic neu- and fatigue in multiple sclerosis patients: an rons of the LDT were affected in patients with MSA. Brains exploratory study were obtained at autopsy from four control subjects, and four with clinical diagnosis of MSA, confirmed neuropath- A. Merico, F. Piccione, G. Levedianos, F. Giorgi, ologically. Serial 50 mm cryostat sections were obtained P. Tonin throughout the rostral half of the pons. Every eighth section Hospital S. Camillo, Department of Neurorehabilitation, was processed for choline acetyl transferase (CAT) immu- Lido-Venice, Italy nocytochemistry (goat polyclonal, Chemicon, Temecula, CA.) Some sections were also stained for nicotinamide ad- Introduction: Fatigue is recognized as one of the most enine dinucleotide phosphate diaphorase (NADPH-d), an- common symptoms in patients with Multiple Sclerosis other marker of LDT neurons. Neurons of the locus ceru- (MS). Nevertheless, the pathophysiologic basis of MS- leus were identified by their neuromelanin content. In all related fatigue (MSF) remains obscure. Objective of this MSA cases, there was a severe depletion of CAT immuno- study is to investigate the relationship between MSF and reactive neurons, as well as neuromelanin containing neu- autonomic system. rons of the locus ceruleus. These findings, which are con- Patients and method: Fifteen MS patients (10 males, 5 sistent with those in Parkinson's disease and LBD, indicate females; mean age 42 _+ 10), entered the study. All the that in MDS, like in other synudeinopathies, involvement patients were gait independent (The Expanded Disability of cholinergic LDT neurons may contribute to RBD. Status Scale ranged from 3.0 to 5.5). The patients under- went a cycle of physiotherapy lasting four weeks; after the rehabilitative treatment, fatigue has been assessed by a self- report measure, the Fatigue Assessment Instrument (FAI). Depression and The autonomic activity has been explored by a non invasive hyperautonomic dysfunctioning group of quantitative examinations: the heart rate changes J.-J. Shen, Y.-T. Lin (R-R interval) during normal and deep breathing, standing Center for Mental Health Care, Wel-Gon Memorial Hospital, (30:15 ratio) and Valsalva test to investigate the parasym- Mio-Li, Taiwan, ROC pathetic cholinergic (cardiovagal) function; the sympathetic skin response (SSR) to investigate the sympathetic cholin- "Depression has become a fashionable term to the public ergic activity; the blood pressure changes to tilt-table test to since mental health professionals and related workers started investigate the sympathetic adrenergic activity. to alert people as the suicide figure raised. People were able No subjects were on medication likely to influence to get information regarding depression from TV program, autonomic nervous system (ANS). No heart disease has Internet, bookshop, and &-I 1..etc., different forms of self- been detected by clinical, ECG and Echocardiographic rating scales for depression were available from street cor- examination. ners. Several famous entertaining stars declared that they got Results: All the patients presented SSR abnormalities: a depression. However, as new cases of depression were pathological SSRs have been detected in both upper and increasingly diagnosed nowadays, depressive patients tended lower limbs and in lower limbs only in thirteen and in two to look for medical check-up for their physical symptoms

206 Clinical Autonomic Research 2001, Vol 11 No 3 XIlth International Symposium on the Autonomic Nervous System: Abstracts before they were referred to a psychiatric clinic. We studied second, that the cyclic exercise protocol produces significant the depressive cases from a consecutive out-patient popula- changes in subjects with Parkinson's disease during con- tion and analyzing the types and frequency of autonomic trolled breathing. symptoms and examined the related variables. We found a tentative conclusion that :32 out of 37 depressive patient (87%) tended to have at least one autonomic symptoms and Blood pressure changes during hypoxic 21 of them (68%) sought help initially at departments other stimulation are altered in ALS patients than psychiatry. For them, it took an average of 7 weeks (from 3 weeks to 4 months) before they sought a psychiatric M.J. Hecht, C.M. Brown, F. Mittelhamm, B. Neund6rfer, evaluation. Those with older age, male, no apparent psy- M.J. Hilz chosocial stress, and higher depressive rating score tended to Department of Neurology, University of have more autonomic symptoms, and tended to spend more Erlangen-Nuremberg, Germany weeks before they come to a psychiatric OPD. Those who Sympathetic overactivity has been demonstrated in amyo- were younger, female, with prominent precipitating stress, trophic lateral sclerosis (ALS). Reports of fatal sudden bra- and lower depressive rating score tended to have less auto- dycardia and arterial hypotension in mechanically ventilated nomic symptoms. The autonomic symptoms had an order ALS patients and reduced baroreflex sensitivity in early ALS of priority as the following: GI)NEURO)CV. More cases patients suggest that autonomic dysfunction might contrib- would be recruited to our study and so advanced result will ute to sudden death even in early stages of ALS. Baroreflex be presented accordingly. dysfunction might account for abnormal cardiovascular re- sponses to chemoreflex activation, e.g. by nocturnal hyper- capnia or hypoxia, as counterregulation of bradycardia Controlled breathing in Parkinson's disease might be compromised. This study evaluated hypercapnia during cyclic exercise and hypoxia induced cardiovascular responses in non- respirator dependent ALS patients. S. Reisman, 1 I. Dardik, 2 S. Hagberg, 2 M. Rymer, 2 Patients and methods: In 14 non-respirator-dependent A. Petrock, 1 A. Stuckey 2 ALS patients and 15 controls heart rate and blood pressure I NJ Institute of Technology, Newark, NJ; 2Lifewaves were continuously monitored. After baseline recording, International, Califon, NJ, USA end-tidal CO2 was selectively increased to 55 mmHg, and, after 20 minutes of breathing room air, 02 saturation was A novel cyclic exercise protocol was tested on a group of 18 decreased (>10%) using a closed rebreathing system. We subjects with Parkinson's disease. Subjects performed a se- analysed the mean heart rate (RR interval) and mean systolic ries of 5 cyclic increases and decreases in heart rate 3 times blood pressure during 100 heart beats of the baseline and per week for 12 weeks. Controlled breathing was performed the rebreathing periods. Results were compared by t-test. once per week to assess resting heart rate variability. Subjects Results: The heart rate of the ALS patients was significantly breathed at 12 breaths per minute for 5 minutes by follow- higher than of the controls during the baseline, hypercapnia ing a rising and falling bar on a computer screen. The and hypoxia (all p< 0.05). Heart rate increased significantly interbeat intervals between heartbeats were recorded and during hypoxia and hypercapnia without a significant dif- stored in a PC. The data were then analyzed for spectral ference between ALS patients and controls. Systolic blood power in the LF (0.05-0.15 Hz) and HF (0.05-0.4 Hz) pressure during baseline and hypercapnia did not differ. ranges by first interpolating the data using a backward step However, during hypoxia we found a significant increase of interpolation, and then taking the Fourier transform. the systolic blood pressure in the ALS patients (133mmHg The mean HF power increased by 32 percent from pre to to 140mmHg, p= 0.02), but not in the controls (135mmHg post testing, but the change was not significant. However, to 134mmHg, n.s.). two non-traditional measures were examined which showed Conclusion: The higher heart rate in the ALS patients again significant results for this population. It was first observed indicates sympathetic hyperactivity in ALS. The increase of that the time interval during which the subjects maintained the blood pressure during hypoxia in ALS patients is similar the pacing increased as the study progressed. Results show a to findings in patients with obstructive sleep apnea, known mean change from 0.626 minutes (pre) to 0.979 minutes to be related to cardiac arrhythmia. (post) which is significant with p=0.034 (t-test, one tail). The second measure was the shape of the interbeat interval curve over time. An interbeat interval curve for a normal subject during controlled breathing shows an almost sinu- Carbamazepine attenuates parasympathetic heart rate modulation in chronic temporal soidal shape, whereas for these subjects, the shape tended to be more triangular, indicating an abnormal pattern of res- lobe epilepsy piration. It was also noted that as the study progressed, the A. Druschky, 1 M.J. Hilz, 1 G. Platsch, 2 P. Hopp, ~ shape tended to become more sinusoidal. A numerical mea- K. Druschky, ~ T. Kuwert, 2 H. Stefan, ~ B. Neund6rfer ~ sure was developed where "0" represented a purely triangu- Departments of 1Neurology and 2Nuclear Medicine, University lar shape and "10" a purely sinusoidal shape. The "shape of Erlangen-Nuernberg, Germany factor" increased from 3.28 (pre) to 4.72 (post) which is significant with p=0.0039 (t-test, one tail). Temporal lobe epilepsy (TLE) is associated with dysfunc- We have therefore shown that, first, non-traditional mea- tion of the autonomic nervous system which might contrib- sures provide important results when evaluating subjects ute to unexplained sudden death in epilepsy. Anticonvulsive with Parkinson's disease during controlled breathing and medication, particularly carbamazepine (CBZ), might also

Clinical Autonomic Research 2001, Vol 11 No 3 207 XIIth International Symposium on the Autonomic Nervous System: Abstracts infuence autonomic cardiovascular modulation. MIBG- jects exhibited more variance compared to younger subjects. SPET quantifies postganglionic cardiac sympathetic inner- Discussion: Dry ice stimulation appears to be an effective, vation (CSI), while heart rate variability (HRV) testing only non-invasive and reasonably tolerable means to investigate provides functional parameters of autonomic modulation. mucosal blood flow at different mucosal sites. The data To assess the influence of CBZ on cardiac sympathetic already indicate different responsitivity to painful cold and parasympathetic innervation in chronic TLE patients. stimulation at different sites on the oral and perioral mu- In 12 women and 10 men (median age 34.5 yrs.) with a cosa; in particular, mBF response at the tongue was least history of TLE for 7-41 years (median 20 yrs.), we deter- pronounced. In conclusion, assessment of stimulated mBF mined the index of cardiac MIBG uptake and assessed HRV appears to be a promising tool to further investigate the at rest, during metronomic breathing and Valsalva maneu- pathophysiology of a number of neurological entities, e.g. ver. To evaluate the influence of CBZ on autonomic func- the burning mouth syndrome. tion, we compared MIBG uptake and HRV in 11 patients with and 11 patients without CBZ medication and in 16 healthy controls. Perfusion scintigram was performed to identify MIBG uptake defects due to myocardial ischemia. Effects of bathing in carbonated water on skin blood flow, sympathetic skin responses, and Cardiac MIBG uptake was significantly smaller in the sympathetic nerve activity in the skin TLE patients (1.75) than the controls (2.14; p = 0.001), but did not differ between subgroups with and without CBZ. H. Tanaka, H. lida, H. Watanabe, T. Nagasaka, Perfusion scintigram was normal in all patients. HRV pa- K. Shindo, Z. Shiozawa rameters showed predominance of parasympathetic cardiac Yamanashi Medical University, Yamanashi, Japan activity, but less parasympathetic modulation in the patients with CBZ than without CBZ (p <0.05). We examined the effects of bathing in carbonated water on In the TLE patients, MIBG-SPET demonstrates deficient sympathetic flow response(SFR) , sympathetic skin re- postganglionic CSI resulting in a predominance of parasym- sponse(SSR) and sympathetic nerve activity in the skin- pathetic HRV modulation. The sympathetic innervation (SSNA) at rest and during electrical stimulation. deficit might bear an increased cardiac risk. CBZ seems to Sixteen patients (6 men and 10 women), aged 21-78 be particulaty suited for the treatment of chronic TLE pa- with diseases other than neurological disorders, were in- tients as it counterregulates the observed findings of post- cluded in the study. Each subject was laid on a bed in an ganglionic sympathetic neuron decrease and enhanced para- examination room after bathing in plain water at 35 for 20 sympathetic activity. minutes and after bathing in carbonated water at 35 for 20 minutes. Blood flow in the dorsal surface of the right forth toe and SSRs were measured while electrically stimulating the right foot in a resting state. In 4 of the 16 cases, SSNA The dry ice test for the assessment of oral was also monitored simultaneously at the peroneal nerve in mucosal blood flow the contralateral popliteal region. J.G. Heckmann, 1 S.M. Heckmann, 2 T. Hummel, 3 Larger decreases in the rate of the SFR as a result of M. Popp, 2 H. Marthol, 1 B. NeundSrfer, ~ M.d. Hilz ~ electrical stimulation, a tendency towards a lower SSR fre- Departments of 1Neurologyand ZProsthodontics, University of quency, and a tendency towards a larger SSNA amplitude Erlangen-Nuremberg; 3Department of Otorhinolaryngology, were found after bathing in both plain water and carbonated Technical University of Dresden, Germany water at 35. The effects tended to be stronger after bathing in carbonated water, suggesting that bathing in water may Background: The aim of the study was to establish a pro- effect the autonomic nervous system. cedure for the investigation of microcirculatory changes in Key words: carbonated water, sympathetic skin re- the oral cavity. To this end, we studied effects of painful sponse(SSR), sympathetic flow response(SFR), skin sympa- stimulation using dry ice (CO2). To investigate potential thetic nerve activity(SSNA) regional differences in the change of blood flow recordings were made at the mucosa of the tongue, the hard palate, the lip and oral vestibule. Autonomic cardiovascular reflexes in Material and methods: We investigated a total of 26 sub- Wilson's disease jects which were divided in groups of younger (10 m, 3 f; age range 21-31 years) and older subjects (2 m, 11 f; range K.F. Bhattacharya, M. Velickovic, A. Wang, M. Schilsky, 54-74 years). Mucosal blood flow (mBF) was obtained by H. Kaufrnann laser Doppler flowmetry. Measurements were made at rest Department of Neurology, Mount Sinai School of Medicine, and over 2 min following dry ice application of 10 s dura- New York, NY, USA tion using a pencil shaped apparatus. In addition, blood pressure (BP), heart rate (HR), cutaneous blood flow (cBF), Wilson's disease is an autosomal recessive disorder charac- transcutaneous pCO 2 and pO 2 were recorded. terized by neurological and hepatic dysfunction secondary Results: mBF increased at all sites in response to dry ice to copper deposition in the liver and in the central nervous application (p<0.001) with peak flow at 0.5-1.5 min after system, but whether the disorder affects autonomic neurons stimulation onset. During the following 1.5-2 rain blood is not known. We studied heart rate and blood pressure flow decreased at all measurement sites with a tendency to variability during supine rest and deep paced breathing, return to baseline. HR, BP, pCO 2, pO2, and cBF did not Valsalva maneuver and ten minutes sixty-degree passive exhibit significant changes. Overall, responses in older sub- head-up tilt in fourteen patients with Wilson's disease (age

208 Clinical Autonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

35• mean_+SD, range 14 to 58 years, disease duration SaO2 (r= .63, p<0.0005) and correlated inversely with rest- 16_+14, range 4 months to 14 years, male to female ratio ing HVR (p<0.05) and Ht (p=0.05): i.e. more compro- 6:8). They also completed an autonomic symptom ques- mised subjets improved more. During CP+ox the same pat- tionnaire and had neurological assessment, complete blood tern was observed, despite an increase in VE and SaO2 count and liver function tests. (p<0.0001) during SBr in all subjects. Immediately after Twenty-six per cent of patients had decreased heart rate CP+ox, HVR was no longer depressed in Ht+ subjects. variability during deep breathing and 25% of these also had Thus: 1) a functional (rather than lung organic) alteration, decreased Valsalva ratio. Eighty-six per cent of patients had likely due to abnormal breathing pattern, may cause the neurological findings on examination; 26% had severe par- association between low SaO2 and high Ht; 2) slow breath- kinsonism, cerebellar ataxia or pseudobulbar palsy and 50% ing improves ventilator'/efficiency and may potentially re- had mild dysarthria, minimal bradykinesia, and minimally verse the abnormalities seen in Andean altitude natives. decreased voluntary saccades. Twenty-one per cent had ab- normal liver function tests and fourteen per cent were cur- rently taking penicillamine with pyridoxine while 71% had taken penicillamine in the past. All patients with abnormal autonomic function had neurological deficits, severe in 75% Effects of hot and warm water immersion in and mild in 25%. In addition, 50% had abnormal liver Japanese bathtub on autonomic function and 25% were taking penicillamine. Fourteen per functional parameters cent of patients reported orthostatic lightheadedness on the M. Suzuki, S. Hod, I. Nakamura, K. Yamaguchi, questionnaire but no abnormalities on testing. N. Aikawa We conclude that mild impairment of parasympathetic cardiac function occurs in almost one third of patients with Department of Emergency Medicine, Keio University, Wilson's disease, most frequently in patients with other Tokyo, Japan neurological deficits. Parasympathetic neurons could be af- fected either centrally or peripherally due to copper depo- Background: Fourteen thousand elders suddenly die annu- sition, liver abnormality or penicillamine treatment. ally during bathing in Japan. The mechanisms are rarely known. Recent studies have suggested that stroke and VF are negligible causes. Japanese style bathing is characterized by the deep bathtub and hot water (40-44 Celsius degree) Slow breathing, chemoreflex, and oxygen immersion. Accordingly, it is suspected that heat stress by saturation in Andean altitude natives hot water immersion may contribute to the events. Purpose: Aim was to study whether responses of autonomic L. Bernardi, 1 M. Bonfichi M, 1 A. Gamboa, 2 J. Gamboa, 2 parameters were different between hot and warm water im- C. Passino, 3 Tapia Ramirez, 2 L. Malcovati, 1 R. Roach, 4 mersion in a setting of Japanese style bathing. O. Appenzeller5 Methods: Nine male healthy subjects (age: 20-22 y/o, 1Universita' di Pavia and IRCCS S. Matteo, Pavia, Italy; BMI: 21.3) who gave written informed consent, partici- 2Laboratorio de transporte de Oxigeno, Universidad Peruana pated in this study. Following control condition (Control), Cayetano Heredia Lima, Peru; 3Istituto di Fisiologia Clinica each subject was immersed in hot water (44-Celsius degrees) CNR Pisa, Italy; aDivision of Physiology, New Mexico for 7 rain (Phase-I). Then, after 5 rain interval, they were Highlands University, Las Vegas, NM, USA; 5NMHEMC Res. immersed again as long as they tolerated (6-14 rain) (Phase- Foundation, Albuquerque, NM, USA 2). On another day, each subject was immersed in warm water (40-Celsius degrees) in the same manner. Sublingual Slow respiration improves oxygen saturation (SaO2) and temperature (BT), RR interval, systolic blood pressure ventilatory efficiency in chronic or acute hypoxia. We tested (SBP), and plasma noradrenalin level were examined. Heart whether 1) polycitemia could be associated to ventilatory rate variability (HF) was assessed using wavelet transform inefficiency 2) changes in breathing pattern could benefit (Fludet). subjects with different levels of polycitemia. In 31 natives of Results: BT significantly increased (Warm: Control Cerro de Pasco, (4338m, Peru), with variable degrees of 36.8+0.3; Phase-1 37.4+0.3; Phase-2 38.0+0.5, Hot: polycitemia (hematocrit, Ht, from 44 to 76%), during 37.0+0.8; 38.6+0.4; 40.1_+0.6, repeated ANOVA: spontaneous breathing (SBr), controlled breathing at slow P<0.0001). Both HR and NA significantly increased (HR: (6/min) and normal (15/min) rates, we measured ventila- Warm 68+9bpm; 87_+7; 100+6, Hot: 70+14; 116+16; tion (VE), end-tidal carbon dioxide (CO2), SaO2, hypoxic 127-+16, P<0.0001, NA: Warm 0.35• and hypercapnic ventilatory responses (HVR, HCVR, at 0.45-+0.17; 0.50_+0.14, Hot 0.36_+0.12; 0.59+0.19; SBr only), before and after 45 rain. of normoxia (CP+ox). 0.79_+0.24, P=0.002), while SBP was not affected by the During SBr, SaO2 correlated inversely, and CO2 corre- bathing (P=0.39). HF significantly reduced by bathing lated directly with Ht (p<0.0001), whereas VE and HCVR (Warm 71+53; 10_+12; 4_+4, Hot 107_+72; 2_+1; 1_+1, did not; HVR showed lower (inverse) correlation with Ht P<0.0001). However, there were no differences of HF be- (p<0.01). During controlled breathing SaO2 increased tween warm and hot water immersion (P=0.15). Regression (p<0.0001) in all subjects, but, at 15/rain this was aassoci- analyses between BT and HF, and NA, showed significant ated to increased VE (p<0.0001) and reduced CO2; at correlations (BT vs. HF: r=-0.73 P<0.0001, vs. NA: r=0.68 6/min an even greater SaO2 increase occurred without P<0.0001). changes in VE and CO2. The extent of increase in SaO2 Conclusion: Sympathetic responses (HR, NA) are more during 6/min (reaching even 17%) depended on baseline augmented in hot water immersion than those in warm

Clinical Autonomic Research 2001, Vol 11 No 3 209 XiIth International Symposium on the Autonomic Nervous System: Abstracts water immersion. However, response of HF does not differ Tabasco as well as the spontaneous thermal sweating in the between hot water immersion and warm water immersion. ipsilateral side of the forehead and the perioral region. No laterality in the sweat response was observed when Tabasco was applied to the left or the right side of the tongue. When o~-, I~-Methylene ATP elicits the muscle the unilateral stellate ganglion was blocked with local anes- chemoreflex in decerebrate cats thesia, Tabasco failed to elicit the sweating on the ipsilateral side of the forehead and perioral region. These results sug- R.L. Hanna, S.G. Hayes, M.P. Kaufman gest that the taste stimulus might reflexly cause the sweating University of California, Davis, CA, USA in the forehead possibly through a nociceptive mechanism whereas it might cause the sweating in the perioral regions Recently, adenosine-3',5'-triphosphate (ATP) has been due to the taste stimulus, as a gustatory sweating. It was shown to stimulate visceral afferent C-fibers transducing the concluded that the gustatory sweating reflex utilizes the ef- sensation of pain. Somatic C-fibers, along with thinly- ferent sudomotor systems for the thermal sweating that de- myelinated A-delta fibers, comprise the afferent limb of the scend the spinal cord, ascend the cervical sympathetic trunk muscle reflex arc that causes the cardiovascular and respira- and reach the face skin. tory adaptations to exercise. We tested the hypothesis that ATP injection into the arterial blood supply of the triceps surae muscles of decerebrate cats elicits reflex cardiovascular Cardiac vagal function is impaired in and respiratory changes similar to those seen during exer- amyotrophic lateral sclerosis cise. Alpha, beta methylene ATP (5, 20 and 50 ug/kg) was C.M. Brown, M.J. Hecht, F. Mittelhamm, B. Neund6rfer, injected into the popliteal artery and subsequently trapped M.J. Hilz in the vasculature of the triceps surae muscles. Blood pres- Department of Neurology, University of sure (BP), heart rate (HR) and phrenic nerve activity (PNA) Erlangen-Nuremberg, Germany were monitored. Injections were carried out before and after cutting the sciatic nerve. Significant increases in MAP and Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative PNA were evoked by all three doses of alpha, beta methy- disorder primarily affecting the motor neurons, but there is lene ATP. For example, at 20 ug/kg, MAP increased by 18.1 increasing evidence of autonomic nervous system involve- + 1.7 mmHg (n=15, P <0.001) and PNA increased by 21.2 ment that might contribute to early fatalities. This study + 9.8 units/min (n=15, P<0.05) Thechanges in heart rate was undertaken to assess baroreflex-mediated autonomic with ATP injection were not significant for any of the doses. cardiovascular control of the heart and blood vessels in ALS The increases in MAP and PNA were significantly attenu- patients. ated by cutting the sciatic nerve. At 20 ug/kg, the increase In 12 ALS patients (age 54_+4 years) and 12 controls (age in MAP was 9.3 _+ 2.4 mmHg and there was, on average, a 55+3 years) we stimulated the carotid baroreflex by sinu- decrease in PNA of 8.7 -+ 7.5 units/minute. No pressor soidal neck suction (0 to -30 mmHg) at 0.1 Hz to assess the response was elicited by injection of 100lag of 2-chloro- sympathetic modulation of the heart and blood vessels and adenosine into the arterial blood supply of the triceps surae at 0.2 Hz to assess the effect of parasympathetic stimulation muscles using the same protocol as that used for the ATP on the heart. Breathing was maintained at 0.25 Hz. Blood injections (n=7). These results suggest that ATP is a poten- pressure (BP), electrocardiographic RR-intervals and respi- tial chemical activator of the thin fiber afferents whose end- ration were recorded continuously. Spectral analysis was ings arise from muscle. This work was supported by NIH used to evaluate the magnitude of the oscillations in RR- HL30710. interval and BP in response to sinusoidal baroreceptor ac- tivation. Stimulation at 0.2 Hz induced an oscillation in RR- The mechanism of the physiological interval at 0.2 Hz. The power of this oscillation was signifi- gustatory sweating cantly smaller (p<0.05) in ALS patients (12.15_+5.62 ms 2) than in controls (186.40_+88.22 ms2). Baroreceptor stimu- Y. Inukai, J. Sugenoya, T. Matsumoto, N. Nishimura, lation at 0.1 Hz significantly increased the magnitude of M. Kato oscillations in RR-interval and BP at 0.1 Hz. RR-interval Department of Physiology, Aichi Medical University, responses to 0.1 Hz stimulation were significantly (p<0.01) Nagakute, Aichi, Japan reduced in ALS ~patients (69.24_+11.75 ms 2 [baseline] to 167.95_+30.59 ms [neck suction]) compared to the controls Under a hot environment (30~ 40%) the effects of taste (99.61_+34.79 to 1363-+413.13 ms2). Responses of blood stimulation (Tabasco of 0.25 ml applied to the tongue for a vessels to 0.1 Hz stimulation did not differ significantly minute) on sweating in the face involving the forehead, between the groups. cheek and perioral (oral angle) regions were examined. Five The reduced response of RR-interval to 0.2 Hz barore- healthy males with an average age of 22.0 (_+2.1 [SD]) years ceptor activation in the ALS patients indicates impaired were used for the subject. Tabasco elicited sweating on the vagal control. The reduced RR-interval responses to 0.1 Hz forehead and the perioral region, but not on the cheek. stimulation in ALS patients suggests cardiac vagal or sym- Mental arithmetic increased the sweating equally in the pathetic impairment, or both. The normal BP response in forehead and the perioral region, whereas Tabasco tended to the ALS patients suggests that they have intact baroreflex increase the sweating more in the perioral region than in the control of the blood vessels. The cardiovagal baroreflex im- forehead. Skin pressure applied to the unilateral side of the pairment might contribute to cardiovascular crises in ALS axilla produced a suppression of the sweating elicited by patients.

210 ClinicalAutonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts

Paroxysmal hypertension during a complex trations did not change. MSNA (bursts/100 heart beats) was partial seizure Significantly correlated with bound leptin concentration (r2=0.48, P<0.05) but not with free leptin levels (r2=0.00, D.L. Jardine, I.G. Crozier, T.J. Anderson, H. Ikram n.s.). Bound rather than free leptin levels are correlated with Departments of Cardiology and Neurology, Christchurch basal sympathetic outflow in normotensive, non obese sub- Hospital, Christchurch, New Zealand jects. However, acute changes in sympathetic tone do not A 50-year-old man with recurrent absence attacks under- change plasma leptin concentration. Thus, bound leptin went tilt testing to exclude vasovagal syncope. Continuous may be an important modulator of sympathetic activity blood pressure [BP], heart rate [HR] and muscle sympa- even in normal weight subjects. thetic nerve activity [MSNA] were recorded. After 10 min- utes of tilt, the patient had a typical absence attack. He became pale, sweaty and withdrawn for about 30 seconds. Carotid artery distensibility and baroreflex No loss of muscle tone was observed. Coinciding with the sensitivity are reduced in young normotensives onset of his symptoms, MSNA increased briefly for 3 sec- with a parental history of hypertension onds associated with a sudden increase in BP from 138/95 M. Kollai, Z. Kovats, P. Studinger, Z. Lenard to 2201150 mmHg over 10 seconds. HR also increased Semmelweis University, Budapest, Hungary from 65 to 98 bpm. Over the next 20 seconds, BP and HR decreased and there was a major burst of MSNA followed A family history of hypertension represents increased risk by reciprocal oscillation of BP with MSNA [0.1 Hz] as BP for the development of arterial hypertension. Hypertensive returned to normal levels. During recovery, he complained subjects exhibit impairment at baroreflex function, and of his usual transitory headache. Venous noradrenaline lev- baroreflex sensitivity (BRS) was shown to be related to ca- els were increased before and after tilt [1650 and 5250 rotid artery distensibility (CAD). We aimed to determine if pmol/L, normal values: 456+-50 and 705+-74 pmol/L]. The CAD and BRS were altered in normotensive children with symptoms could not be reproduced by increasing BP to a family history of hypertension. 220/150 mmHg with iv bolused norepinephrine. Further Thirteen young subjects with at least one hyperten- monitoring demonstrated similar paroxysms of BP coincid- sive parent (HP group: 21.5 • 1.9 yrs) were compared ing with symptomatic focal EEG changes and hippocampal to 11 subjects with normotensive parents (NP group: atrophy was present on magnetic resonance imaging. Com- 21.6 + 1.2 yrs). plex partial seizure disorder was diagnosed and he remains Arterial pressure was measured with sphygmomanometry asymptomatic 2 years later on carbamazepine 400mg daily. and Finapres. CAD was determined using an ultrasound This is the first demonstration of seizure activity transiently wall-tracking system (Pie Medical, The Netherlands). BRS overriding the arterial baroreflexes, allowing an increase in was determined from spontaneous fluctuations in heart rate MSNA and HR simultaneously. and systolic pressure. Result are given as mean +_ 1 SD, differences were consideral significant at p <0.05. Plasma leptin levels and sympathetic outflow in Arterial pressure and heart rate did not differ in the two non-obese subjects groups. Body mass index, blood sugar, serum total and HDL cholesterol level were not different, whereas serum J. Tank, ~ G. Brabant, 2 A. Diedrich, 3 C. Schroeder, ~ triglyceride level was higher in HP than in NP (0.91 +- 0.27 A.M. Sharma, ~ F.C. Luft, 1 J. Jordan 1 vs 0.63 +- 0.17 mmol/1). CAD and BRS were reduced in HP lClinical Research Center, F*'anz Volhard Clinic, Humboldt as compared to NP (4.6 • 0.9 vs 6.1 • 1.2" 10 -3 mmHg q University, Berlin, Germany; 2Department of Endocrinology, and 11.8 • 4.2 vs 21.6 +- 6.2 ms'mmHg -1, respectively). MH-Hannover, Germany; 3General Clinical Research Center, BRS was directly related to DC across HP and NP subjects Vanderbilt University, Nashville, TN, USA (r = 0.53, p <0.05). It is concluded that in young normotensives with a family Animal studies suggest a strong interaction between leptin history of hypertension carotid distensibility is reduced in- and sympathetic nervous system activity. We tested the hy- dependently of arterial pressure and stiffening of the carotid pothesis that plasma leptin levels are correlated with basal artery wall contributes to the impairment of baroreflex sympathetic activity in 14 healthy subjects (10 male, 4 fe- function. male 27• yrs, 23+-3 kg/m2). In addition we determined the effect of acute sympathetic stimulation on leptin concentra- tion. ECG, blood pressure, muscle sympathetic nerve activ- ity (MSNA), and respiration were measured continuously. Baroreflex sensitivity in fibromyalgia Subjects underwent hand grip testing (3 min, 30 % maxi- S. Colombo, 1 P. Sarzi Puttini,2 G. Randisi, 2 A. Malliani, 1 mum voluntary contraction), cold pressor testing (1 min), R. Furlan ~ and incremental sodium nitroprusside infusions (snp; 0.2, 1Unit~ Sincopi e Disturbi della Postura, Centro Innervazione 0.4, 0.8, and 1.6 lag/kg/min). Total, flee, and bound plasma Cardiovascolare, CNR, Universitfi degli Studi di Milano, leptin levels were measured at baseline, before and imme- Medicina Interna II; e 2Divisione di Reumatologia, Osp. Luigi diately after handgrip testing, 10 min after handgrip testing, Sacco, Milan, Italy and after snp infusion. The R-R interval decreased from 984+-125 ms at baseline to 689+-69 ms during snp Unpublished observations from our laboratory suggest that (P<0.001). Blood pressure was 113• mmHg at base- patients suffering from fibromyalgia are characterized by an line and 104•177 mmHg during snp. MSNA increased increased cardiac sympathetic activity compared to healthy to 210+-77 % during snp infusion. Plasma leptin concen- controls, on the basis of higher heart rate and LFRR

Clinical Autonomic Research 2001, Vol 11 No 3 211 XIIth International Symposium on the Autonomic Nervous System: Abstracts component of RR variability. This might be accompanied either avoidance or other alternative means could help mini- by abnormalities in the baroreflex inhibitory function con- mize the degree of blood pressure variation in baroreflex trolling heart rate. To address this issue, we studied 10 failure. patients with fibromyalgia (FM) and 10 healthy controls(C) in recumbent position. Baroreflex function was assessed by the [-]LF index, obtained using cross-spectral analysis of RR interval and systolic arterial pressure variability and by the Effects of negative pressure breathing on the SAP/RR spontaneous sequences technique (BRS). carotid baroreceptor-vascular resistance reflex At rest, RR interval was lower in FM (828_+30 ms) than V.L. Cooper, 1 C. Bowker, 2 P. Kanthapallai,2 in C (937_+41 ms) while blood pressure was similar in both S. Pearson,2 R. Hainsworth1 groups. The spectral index of cardiac sympathetic modula- 1Academic Unit of Cardiovascular Medicine, University of tion (LFR~) was higher and the marker of vagal activity to Leeds, Leeds; 2Department of Respiratory Medicine, Leeds the heart (HF/~) was lower in FM (68.4_+4.9 and 23.9_+4.8 General Infirmary, Leeds, UK nu, respectively) than in C (47.7_+6.7 and 48.8_+6.3 nu, respectively). V1LF was similar in the two groups (FM: 14.2_+2,5, C: 19,4_+3 mmHg/msec) as well as BRS Obstructive sleep apnea (OSA) has been associated with (FM:21.17_+4.39, C: 23.53_+4.26 mmHg/msec). hypertension independently of factors such as obesity. How- These data suggest that the increase of sympathetic ever, the mechanisms by which OSA leads to hypertension modulation to the heart observed in patients with fibromy- are unknown. We hypothesised that changes in intratho- algia is not accompanied by abnormalities in the baroreflex racic pressure, such that occur during apnoeic events may function. We hypothesize that central integration is primar- result in resetting of baroreceptors or alter baroreceptor gain ily responsible for increased sympathetic activity, possibly leading to a maintenance of arterial pressure at a higher reinforced by peripheral sympatho-sympathetic reflex level. mechanisms. In this preliminary study we assessed vascular responses to carotid baroreceptor stimulation (neck suction NS, -20, -40 mmHg) and unloading (neck pressure NP, +20, +40 mmHg) with and without an inspiratory resistance of-10 mmHg in 8 healthy control subjects, aged 25-62 years. Potent pressor effect of ambient light in Vascular resistance was calculated by dividing mean arterial baroreflex failure pressure (Finapres) by blood flow velocity (Doppler ultra- T. Ketch, T. Oeltmann, B.K. Black, D. Robertson sound) of the brachial artery. Responses to each level of Autonomic Dysfunction Center, Vanderbilt University, neck pressure were calculated as the maximum percentage Nashville, TN, USA change from an average of 5 beats before the onset of stimu- lation. A linear regression function was performed on the responses to NS and NP. Background- Loss of the ability to buffer blood pressure Breathing with an inspiratory resistance caused a small and heart rate against wide excursions is the hallmark of but insignificant decrease in mean arterial pressure baroreflex failure. Factors that have been clearly demon- (99.5_+1.9 mmHg versus 103.2_+4.8 mmHg, control). There strated to profoundly affect baroreflex failure patients in- was no effect on end tidal CO2. Neck suction did not result clude pain, emotion, and mental or physical stress. The in any significant change in vascular resistance with or with- purpose of this study was to determine if differing degrees of out inspiratory resistance. Neck pressure increased vascular light exposure affect blood pressure and heart rate in barore- resistance by similar amounts independent of negative pres- flex failure. sure breathing; the gains of the reflex were -2.1_+1.0 and Methods: Response to differing degrees of light exposure -2.1_+0.4 percent.mmHg-:. was studied in a 51 year-old white female with baroreflex These results show that negative pressure breathing does failure. Continuous heart rate and blood pressure were de- not alter the gain of the carotid baroreceptor-vascular resis- termined by Finapres measurement. The subject was ex- tance reflex. Further studies are required to examine wheth- posed to 0.1 lux, 6.6 lux and 9.1 lux. er the reflex is reset. Results: With exposure to 0.1 lux, baseline blood pressure was 110/65 with a heart rate of 88 beats per minute. Blood pressure increased to 275/165 with a heart rate of 112 within 1.75 minutes of exposure to 6.6 lux. Exposure to 9.1 Circadian rhythm abnormalities of gastric lux prompted an increase in blood pressure to 310/195 with myoelectrical activity in patients with multiple a heart rate of 120 within one minute; system atrophy Conclusion: Wide excursions of blood pressure and heart rate in baroreflex failure patients produce symptoms that A. Suzuki, M. Asahina, C. Ishikawa, T. Fukutake, affect activities of daily life. Exposure to light in this subject T. Hattori is one factor that produced hypertension, accompanied by Chiba University, Chiba, Japan headache and flushing. Recognition that presence or ab- sence of light affects blood pressure is clinically important Objective: To evaluate the circadian rhythm of gastric myo- for this patient population. Spontaneous increase in blood electrical activity in patients with multiple system atrophy pressure with symptoms could possibly be acutely treated (MSA). with the combination of a dark room and biofeedback Material and method; We measured the cutaneous elec- measures. Also, prevention of excessive light exposure by trogastrogram (EGG) for twenty-four hours in 15 MSA

212 ClinicalAutonomic Research 2001, Vol 11 No 3 XIIth International Symposium on the Autonomic Nervous System: Abstracts patients (7 males; 8 females; mean age 59.7+-8.4) and 9 The assessment of autonomic dysfunction healthy controls (6 males; 3 females; mean age 59.3-+11.0) using R-R interval spectral analysis in diabetic with handy EGG recorder (EG Nipro Co. Japan). We ana- patients with increased urine albumin lyzed the seven segments of the twenty-four-hour EGG; six excretion rate segments of ten-minute EGG before and after each Y. Zhang, 1 L.A.H. Critchley, 2 J.A.J.H. Critchley, 1 meal, and a segment of twenty-minute EGG during sleep. Y.H. Tam, 2 C.K. Chung, 2 W.B. Chan, 1 B. Tomlinson, ~ We used three parameters to examine the seven seg- C.S. Cockram, ~ J.C.N. Chan 1 ments - dominant frequency (DF), instability coefficient 1Division of Clinical Pharmacology, Department of Medicine & (IC)((standard deviation of DF/mean DF)xl00%), and Therapeutics, 2Department of Anaesthesia and Intensive Care, amplitude. Chinese University of Hong Kong, Prince of Wales Hospital, Results: The mean DF of the seven segments were Hong Kong, China 3.28+-0.26 cycles per minute (cpm) in the MSA patients and 3.19+-0.25 cpm in the controls respectively. The DFs in- Purpose: To assess autonomic dysfunction in diabetics with creased during daytime and decreased during sleep in the renal impairment defined by the increased urinary albumin controls, while the DFs increased during daytime but did excretion rates (UAER). not fall much during sleep in the MSA patients. The DF Methods= Fifty-six diabetic (4 groups) and 14 healthy sub- during sleep in the MSA patients (3.20+0.08cpm) was sig- jects (N) were matched for age and gender. They were nificantly higher than that in the controls (3.02-+0.08cpm). divided into groups (D1) - DM with normal UAER, (D2) Although it was not significant, the mean IC of the seven - DM with UAER over 20 but less than 200 lag/min, (D3) segments in the MSA patients (5.42+-12.4%) was lower than - DM with UAER over 200 lag/min and (AN) - DM with that of the controls (8.05-+15.3%). There was no difference known autonomic neuropathy. Their electrocardiogram was in the mean amplitude of the seven segments between the recorded whilst supine (10-minutes) and during a head-up MSA patients and the controls. The ICs and amplitudes did tilt to 55 degrees (10-minutes). Spectral analysis of the RR not fluctuate all day in both the MSA patients and the intervals were performed and the (LF) low frequency (0.04- controls. 0.15 Hz) and (HF) high frequency (0.15-0.40 Hz) band Conclusions: The DF increased during daytime and de- contents (msec 2) measured. creased during sleep. The circadian rhythm of gastric myo- Results: The spectral analysis of the resting data revealed a electrical activity disappeared in the MSA patients. progressive decrease in the LF content (1138649 and 4814, P<0.001, Kruskal-Wallis H test) for the healthy subjects followed by the diabetic patient groups stratified for increas- ing UAER and evidence of autonomic neuropathy (i.e. N, D1 & D2, and D3 & AN). A similar trend was seen with Dysfunction in peripheral sympathetic mediated HF content (257>82>24 and 59>9, respectively, P<0.001). neurovascular transmission in complex Interestingly, although the LF component rose during head- regional pain syndrome type I (CRPS I) as up tilt in the healthy subjects, it fell in the diabetics, again shown by 123-1- metaiodobenzylguanidine related to the degree of albuminuria and neuropathy (122, uptake of the forearm 66, 29 & 5 for N, D1, D2 & AN, respectively, P<0.001). C.A. Haensch, 1 H. Lerch,2 J. dSrg~ Head-up tilt consistently decreased HF content in all sub- Departments of 1Neurologyand 2Nuclear Medicine, University jects but the extent ranged from 98 in the healthy subjects of Witten/Herdecke, Wuppertal, Germany to 28-36 in the diabetics with varying degrees of albumin- uria, to only 5 in the autonomic neuropathy subjects (N vs diabetics, P<0.001). Vascular abnormalities are a characteristic feature of CRPS Conclusion= DM patients with nephropathy and auto- I. The sympathetic nervous system is suggested to be in- nomic neuropathy show diminished resting spectral con- volved in these disturbances. At present, CRPS I is a pure tent, reflecting reduced modulation of heart rate by both clinical diagnosis and no objective laboratory test exist to para- and sympathetic adjustment. Normal response pattern diagnose. Further studies showed mostly lower Noradrena- to head-up tilting is also lost in diabetics with known au- lin levels on the affected side, but the role of postganglionic tonomic neuropathy. sympathetic innervation is still unclear and controversially discussed. Scintigraphy with 123-I-metaiodobenzylguani- dine (MIBG) visualizes and quantifies sympathetic innerva- tion in vivo. Possible mechanisms of degeneration of We report a 44-years old patient with for 12 month preganglionic neurons in acetylcholinesterase existing chronic CRPS I of the left hand after wrist fracture antibody-injected rats 6 month before. , electroneurography, so- H. Tang, S. Brimijoin matosensory evoked potentials and sympathetic skin re- Department of Pharmacology, Mayo Foundation, sponse of the upper limbs turned out unremarkable. Scin- Rochester, MN, USA tigraphic shows a congruent reduction in perfusion and MIBG uptake in the left forearm and hand. The loss of Three months after systemic injection of acetylcholinester- perfusion and postganglionic sympathetic innervation can ase (ACHE) antibody, the population of preganglionic sym- be explained as a consequence of a peripheral lesion of pathetic neurons expressing choline acetyltransferase sympathetic fibres with vasoconstriction due to denervation (CHAT) in the intermediolateral (IML) nucleus of the hypersensitivity. rat spinal cord is markedly decreased. In principle, the

Clinical Autonomic Research 2001, Vol 11 No 3 213 XIlth International Symposium on the Autonomic Nervous System: Abstracts

disappearance of identifiable cholinergic neurons might re- 14 • 1 beats/min, and RR expiratory:inspiratory ratio of flect either outright cell death or severe atrophy with down- 1.00 • .03 , QTC of 411 • 4 mm. Evaluation by disease regulation of cholinergic markers. To distinguish between state revealed newly diagnosed NOH in 3.3 % of DM and these possibilities, preganglionic neurons were labeled with 6 % of thyroid disorders with a total prevalence of 10.5% the retrograde tracer dye, Fast Blue, one week before anti- among all of the patients. In conclusion, NOH is a more body injection or surgical transection of the cervical sym- common disorder than previously suspected in patients with pathetic trunk. Three months after either treatment, Fast- Endocrine disorders, as well as an explanation for many Blue labeled neurons in the thoracic IML were 40-60% referrals for suspected, but not verified, hormonal disorders. fewer than in controls, showing that preganglionic sympa- Therefore, it is important to screen all patients for auto- thetic neurons do degenerate after antibody injection or nomic dysfunction who present with symptoms suggestive . To clarify the importance ofaxonal damage in this of orthostatic hypotension. process, three different mechanical lesions were compared. A lumbar designed to interrupt most sym- pathetic axons emanating from L2 IML caused 92% loss of Heterogeneity of hemodynamic responses in ChAT positive cells observed 10 weeks later at that site. In patients with neurogenic comparison, transection of the cervical sympathetic trunk, orthostatic hypotension which spared some distally directed axonal branches from the thoracic IML, caused only a 46% loss of ChAT positive J.L. Gilden, D. Ramirez, P. Urn, H. Ha, A. Tartakover, I. Garcia, E. Mensah neurons at T1. Still smaller effects were seen after the same Diabetes/Endocrinology Section, Finch University of Health nerve was crushed, a lesion that is less disruptive to regen- Sciences/The Chicago Medical School, North Chicago, IL, USA eration. Thus, the ability of central sympathetic neurons to survive a peripheral lesion is probably related to the degree Evaluation of patients with neurogenic orthostatic hypoten- of axonal damage and to the opportunity for axonal sion (NOH) has been controversial. Therefore, we com- regrowth. pared the hemodynamic responses to 10 minutes of upright posture in 100 patients with newly diagnosed and untreated NOH due to various etiologies : Diabetes Mellitus (DM), The prevalence of neurogenic orthostatic n=lh; Autoimmune (AI), n =22; Mitral Valve Prolapse hypotension in patients with endocrinologic (MVP), n= 10, Pure Autonomic Failure (PAF), n=20; Mul- disorders tiple System Atrophy (MSA), n =4, Anxiety (A), n=10, J.L. Gilden, D. Ramirez, I. Garcia, A. Tartakover, P. Um, Postural Orthostatic Tacchycardia or Orthostatic Intoler- H. Ha, E. Mensah ance (POTS/OI), n= 7; or 12=other etiologies [(mean age= Diabetes/Endocrinology Section, Finch University of Health 51 • 2 ; range of 23-86 yrs) (79 female: 21 male) (duration Sciences/The Chicago Medical School, North Chicago, IL, USA NOH= 6 + 1 ; range=l-30 yrs)(most common key symp- toms= 58% dizziness, 20%lightheadedness, 8% tiredness, The prevalence of neurogenic orthostatic hypotension 6% syncope)]. The average systolic blood pressure decrease (NOH) has not been well studied. Since symptoms of vari- was 26 • 2 mm Hg by 2.6 • min of upright posture with ous endocrinologic disorders are often similar to those of maximal heart rate increase of 14 _+ 1 beats/min, and RR orthostatic hypotension, and it is not common to perform expiratory:inspiratory ratio of 1.00 • .03,30:15 ratio= 1.1 • routine upright blood pressure measurements in a clinical 0.3, QTC interval of 411 • 4 mm with resting EKG HR= setting, many of these patients remain undiagnosed. There- 72 * 2 (46-133). Comparison of groups revealed that in fore, a retrospective chart review of 952 patients enrolled in response to standing, DM, MSA, and PAF had significantly a Community-based teaching Adult Endocrinology Clinic greater decreases in SBP/DBP than the other diagnostic was conducted over a 3 year period of time [(mean age= 51 groups and were more likely to be older. DM were also • 2 ; range of 23-86 yrs) (689 female: 263 male)(dis- more likely to have greater PP, longest QTC, and more ease=450 diabetes mellitus (DM) , 344 thyroid, 58 other)]. symptoms of peripheral neuropathy. AI demonstrated great- 100 patients, all referred for other reasons and not previ- est decreases in DBP by 10 min. MVP had the greatest ously diagnosed , were identified with NOH. Referral rea- increase in HR which was sustained at 10 minutes. Symp- sons included: 12% for possible hypoglycemia, 13% for tom duration was longest in MSA, PAF, and A groups. diabetes mellitus, 21% for thyroid disorders, and 13% for Patients with more autonomic dysfunction had greater de- possible hormonal disorders. In no case was NOH previ- creases in SBP/DBP with a shorter time to maximal decrease ously suspected as an explanation for symptoms of dizziness, and less change in HR after upright posture (R=-.4, p<.01; lightheadedness, tiredness, or syncope. Furthermore, none R=-.5, p<.01; R=.3, p<.05; and R=-.3, p<.05 respectively). of the patients with possible hypoglycemia or hormonal In conclusion: Hemodynamic responses to upright posture dysfunctions had these diagnoses verified. The average sys- and other measures of autonomic function differ among tolic blood pressure decrease was 26 • 2 mm Hg by 2.6 _+0.3 the various diagnostic groups for neurogenic orthostatic min of upright posture with maximal heart rate increase of hypotension.

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