An Evaluation of Autonomic Nervous System Function in Patients With Prader-Willi Syndrome

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An

Evaluation

of

Autonomic

Nervous

System

Function

in

Patients

With

Prader-Willi

Syndrome

Francis

J.

DiMario, Jr. MD*; Barbara Dunham, RN*; Joseph A. Burleson, PhD4;

Jay Moskovitz, MS; and Suzanne B. Cassidy,

MDII

ABSTRACT. Objective. Prader-Willi syndrome (PWS)

is a complex multisystem genetic disorder in which many

cardinal features may have a neurologically based

patho-physiology involving both the central and peripheral

components of the autonomic nervous system. Autonomic

nervous system function was studied noninvasively in a

group of subjects with PWS and control subjects to

de-termine whether autonomic nervous system dysfunction

exists as part of the PWS.

Design/setting. This cross-sectional study was

per-formed in the neurophysiology laboratory at a tertiary care facility.

Methods. Evaluation included anthropometric mea-surements and calculation of a body mass index (BMI). Simultaneous electrocardiography and serial recordings of pulse rate and systolic/diastolic mean arterial blood pressures during orthostatic maneuvers were taken.

Pu-pillary response to the instillation of dilute pilocarpine

and measurements of plasma norepinephrine at rest and after standing were also obtained. Results were analyzed using two-tailed t tests, Fisher exact test, analysis of vari-ance, and analysis of covariance adjusting for age, gender, and BMI.

Patients. There were 14 subjects with PWS (8 female,

6male; aged 4 to 40 years, mean age 16 years) and 8 control subjects (4 female, 4 male; aged 5 to 37 years, mean age 19

years).

Results. Abnormal findings were obtained only in subjects with PWS. Analysis of covariance adjusting for age, gender, and BMI revealed a trend for subjects with PWS to have lower resting diastolic blood pressure (P < .09) and significantly less change in diastolic blood pres-sure after standing (P < .02). Subjects with PWS had sig-nificantly greater BMI than did control subjects (P < .001), which correlated significantly with all pulse rate measure-ments where the greater the BMI the higher the pulse rate at rest (r = .25, P < .04) and the lower the pulse rate after arising from lying to standing at both 15 and 30 seconds (r = .17, P < .1; r = .55, P < .08 respectively). Pupillary

constriction of 2 mm or more was seen in 7 of 14 subjects

with PWS and in no control subjects (P < .004). The 30:15 R-R interval ratio was abnormal in 6 of 14 subjects with PWS and in no control subjects (P < .03).

Conclusions. These results suggest that patients with PWS have a detectable underlying autonomic dysfunction characterized principally by diminished parasympathetic

nervous system activity. Pediatrics 1994;93:76-81;

Prader-From the Department of Pediatrics, Divisions of *pediatuc Neurology,

Be-havioral Science and Community Health, and §Human Genetics, University

of Connecticut, Farmington; ljDepartment of Pediatrics, Division of

Genetics/Dysmorphology Genetics, University of Arizona, Tuscon. Received for publication Dec 18, 1992; accepted Jun 9, 1993.

Reprint requests to (F.J.D.) Dept. of Pediatrics, Bldg. 12, University of Con-necticut Health Center, 263 Farmington Ave., Farmington, CT 06030.

Acad-emy of Pediatrics.

Willi syndrome, autonomicfunction, parasympathetic ner-vous system, dysautonomia, chromosome 15.

ABBREVIATIONS. PWS, Prader-Willi syndrome; CNS, central

ner-vous system; ANS, autonomic nervous system; BMI, body mass

index; SBP, systolic blood pressure; DBP, diastolic blood pressure;

MAP, mean arterial pressure; ECG, electrocardiographic.

Prader-Willi syndrome (PWS) is a genetically

de-termined multisystem disorder with an incidence of

1 per 10 000 to 15 000 individuals.’-3 Hallmarks of

PWS include central hypotonia, cognitive

dysfunc-tion, dysmorphic appearance, behavioral

distur-bances, hypothalamic hypogonadism, short stature,

and obesity.1 Aside from these core features,

pa-tients with PWS have been studied and found to

ex-hibit abnormal temperature regulation,7 an increased

tolerance to pain,8’9 and diminished salivation9; there

is a subset with hypopigmentation.8”#{176} These latter

fea-tures in particular, when coupled with the core

fea-tures, suggest a neurologically based

pathophysiol-ogy involving both central (CNS) and peripheral

nervous systems. Hypothalamic involvement in PWS

has special relevance here because in addition to its

neuroendocrine function, it also serves a key role in

the CNS integration of autonomic activity and

veg-etative functioning.6” This link of peripheral nervous

system and CNS disturbance is best unified through

functional aberrations involving the autonomic

ner-vous system (ANS).1”2

An ANS “lesion” can be conceptualized when one

considers the nature of the clinical observations made

in patients with PWS. A “higher pain threshold” may

be attributed in part to an altered central perception

of pain, but also to an anatomic paucity of both

pe-ripheral cutaneous nerve plexi and pain receptors.8’9

Diminished salivation in patients with PWS is likely

a consequence of faulty peripheral autonomic

inner-vation to the salivary glands themselves since there

exists no morphologic evidence of gland

abnormali-ties9 and since salivary secretion can be reliably

increased with oral pilocarpine (Cassidy SB,

un-published observations, 1992). Abnormal

tempera-ture regulation as evidenced by a reduction in body

core temperature in response to cold stress,7 poor

sa-tiety recognition and diminished metabolic rate,7 and

altered sleep control (eg, excessive daytime

sleepi-ness, sleep-onset rapid eye movement)” emphasize

disturbances in hypothalamic-ANS regulation

exhib-ited by patients with PWS. The observation of

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PWS may stem from a reduction in

melanin-producing cells or their products.8”4 Since these cells

are embryologically derived from the neural crest,

they bear common ancestry to the precursor cells of

the autonomic ganglia.14 From these observations we

developed and tested the hypothesis that evidence of

autonomic dysfunction can be observed in patients

with PWS by using noninvasive tests of autonomic

function.’5”6

METHODS

Patients with PWS and control subjects were recruited from the

PWS clinic at the University of Connecticut Health Center. All

subjects with PWS had a definitive diagnosis established by one of

the authors (S.B.C.) using accepted clinical criteria with supportive

cytogenetic evidence of deletions in chromosome 15 noted in Ii

(78%) of 14 cases. Control subjects included six normal siblings of

patients with PWS and two unaffected/unrelated clinic staff

vol-unteers. The only entry criterion was the ability to attain an

un-supported standing posture from supine position. No subject was

receiving medication at time of study or had cardiac structural

anomaly or arrhythmia, CNS tumor, pheochromocytoma,

neuro-blastoma, or familial dysautonomia. Each subject and his or her

parent gave written informed consent to be in a protocol approved

by the Institutional Review Board. All evaluations took place

dur-ing the day at least 2 hours after eating a meal. Each subject was

examined. Weight (in kilograms), height (in meters), and skin-fold

thickness (in millimeters) measurements from four areas (left

bi-cep, tricep, infrascapula, and suprailiac crest) were obtained. A

body mass index (BMI) was calculated using the formula weight

(kg)/height (m)2. Each underwent the insertion of a heparin lock

for subsequent blood drawing and then had two drops of 0.0625%

pilocarpine ophthalmic solution instilled into one conjunctival sac.

A positive pupillary response was defined as 2 mm or more of

pupil constriction in the tested eye relative to the nonexposed eye

at 30 minutes after instillation. The subjects rested in supine

po-sition in a sound-dampened, dimly lighted room for 30 minutes.

At the termination of quiet resting, pupil sizes were recorded by

an observer blinded to the instilled eye and a resting blood

speci-men was obtained through the heparin lock by syringe. A second

blood specimen was obtained by the same manner 2 minutes after

the subject had attained a standing position from supine. Plasma

was extracted from the blood and frozen pending subsequent

fractionated catecholamine determination by high-pressure liquid

chromatography.

Sequential recordings of pulse rate, systolic/diastolic (SBP/

DBP) blood pressure, and mean arterial pressure (MAP) with

concurrent electrocardiographic (ECG) recordings using standard

limb leads were made while the subject was seated, supine, and

upon standing from a lying position; a Dinemap monitor was used

as described elsewhere)4 Measurements made during sequential

position changes were taken after a 2-minute adjustment period

for each posture. The blood pressure cuff was applied to the right

arm and maintained parallel to the floor during all positions and

recordings. The percent change in pulse rate (% P) was

calcu-lated from the difference in mean supine pulse rate to mean

stand-ing pulse rate. The percent changes in pulse rate at 15 and 30

seconds of standing (% P @ 15 s and 30 s) were calculated from

the differences in mean supine pulse rate to the pulse rate at 15

seconds and 30 seconds after the assumption of an upright posture

from lying. Similarly, the percent changes in MAP, DBP, and SBP

(% L MAP, % SBP, and % DBP) were calculated from the

differences in mean supine MAP, DBP, and SBP to mean standing

MAP, DBP, and SBP, respectively, at 15 and 30 seconds of

attain-ing a standing position from lying supine.

Electrocardiographic recordings were analyzed and

measure-ments in millimeters were made of the longest and shortest R-R

intervals during quiet supine breathing, which corresponded to

expiration and inspiration, respectively. The expiration:inspiration

ratio (longest R-R interval during expiration divided by the

short-est R-R interval during inspiration) was calculated. The R-R

inter-vals appearing at the 15th and immediately succeeding QRS

com-plex (beat) as well as at the 30th and immediately succeeding QRS

complex (beat) after the assumption of a standing posture from

supine position were also measured. The 30:15 ratio (30th R-R

interval divided by the 15th R-R interval) was then also calculated.

Data were analyzed with a statistical software package

(SPSS/PC + V2.0) using two-tailed t tests, Fisher exact test,

analy-sis of variance, and analysis of covariance adjusted for age,

gen-der, and BMI. Raw data were analyzed as well as the percent

change measures as delineated in the tables.

RESULTS

Of 27 eligible subjects with PWS, 14 agreed to

par-ticipate. They included 8 females and 6 males aged 4

to 40 years, with a mean age of 16 years. The 8

vol-unteer control subjects included 4 females and 4 males

aged 5 to 37 years, with a mean age of 19 years.

Con-trol subjects were not matched to subjects with PWS.

There was no statistically significant difference in

mean age between subjects with PWS and control

subjects. All participants had normal results on

gen-eral and neurologic examinations, except for the

fea-tures consistent with PWS in the study group.

No participant had an abnormal resting pulse rate,

blood pressure, MAP, or ECG rhythm for age. Results

are presented as percent change measures in Tables 1

and 2, although analysis of both raw data and percent

change measures were undertaken separately.

Analy-ses are summarized in Table 3.

Anthropometric measures revealed significantly

greater bicep, infrascapular, and total skin-fold

thick-nesses in subjects with PWS compared with control

subjects after adjustment for age and gender. In

addition, study subjects had a greater BMI than did

control subjects.

After adjustment for age, gender, and BMI, subjects

with PWS displayed a trend toward having a lower

resting DBP (P < .09) and significantly less change in

DBP after arising from supine position (P < .04). We

found no differences in SBP or MAP measurements at

rest or after position changes in either absolute or

per-cent change measures between groups. However,

there was a positive trend (P < .06) between BMI and

MAP. Pulse rate measurements were significantly

correlated to BMI at all measurement intervals. After

we adjusted for age and gender, participants with

higher BMI had higher lying pulse rates at rest (r =

.25, P < .04). After we adjusted for lying pulse rate at

rest in addition to age and gender, a positive

corre-lation existed between higher BMI and lower pulse

rates upon arising from supine at 15 seconds and 30

seconds of standing (r = .17, P < .1; r = .55, P < .08,

respectively). This association was strongest in

sub-jects with PWS since they had the highest BMI and

correspondingly lowest pulse rate measures at each of

these intervals.

Electrocardiographic analysis revealed all

partici-pants to have normal expiration-inspiration ratios. By

Fisher exact test, there was a statistically significant

difference between subjects with PWS and control

subjects with respect to abnormal 30:15 R-R interval

ratios (normal ratio is greater than 1.03), where 6 of 14

subjects with PWS had abnormal ratios vs none of the

control subjects (P < .03).

Seven of 14 subjects with PWS experienced 2 mm

or more of pupillary constriction in response to

pi-locarpine instillation compared with none of the

con-trol subjects (P < .004).

There were no statistically significant differences in

mean plasma norepinephrine levels between groups

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at rest or after standing. A positive correlation was

found between the resting and the standing plasma

norepinephnne levels for all subjects (r = .57, P < .07),

where the greater the resting level the greater the

standing level. A negative correlation between BMI

and standing plasma norepinephnne levels was

found for all subjects (see Figure). We could not

de-termine a difference between PWS subjects with

chro-mosomal deletions vs those without as regards the

clinical/study parameters measured.

DISCUSSION

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Prior to undertaking this study, we reasoned that a

number of clinical manifestations exhibited by

pa-tients with PWS could, in part, be related to a common

neurologic substrate, the ANS. Measures of

parasym-pathetic and sympathetic activity were obtained and

compared to both a control group and accepted

nor-mative data. We found that patients with PWS

dem-onstrated several abnormalities in autonomic system

activity.

Our subjects with PWS exhibited typical and

rec-ognizable signs of the syndrome, with approximately

80% carrying a cytogenetic abnormality consistent

with the diagnosis. Sibling control subjects were

se-lected to emphasize the genetic homogeneity of the

compared groups. More specifically, the control

sub-jects were paired so that inherited genetic influences

exerted over autonomic function would be similar in

each group, thereby highlighting the group

differ-ences to be associated with PWS itself and its

cyto-genetic cause (ie, chromosome 15). This implies that

abnormalities and differences noted between subjects

with PWS and the control group are correlated with

and perhaps etiologically determined by cytogenetic

abnormalities related to chromosome 15. Statistical

analysis incorporated mathematical adjustment for

age and gender as well as BMI to eliminate these

po-tential sources of bias.

Examination of the anthropometric measures

re-vealed, as expected, striking differences between

groups for BMI and total, bicep, and infrascapular

skin-fold thicknesses. The difference in BMI increased

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Figure. Correlation between standing plasma norepinephrine

E (PNor) level and body mass index BMI in subjects with

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TABLE 3. Summary: Means and Statistical Differences Between Subjects With Prader-Willi

Syn-drome and Control Subjects*

PWS Subjects Controls P Value

(n=14) (n=8)

* Abbreviations: PWS, Prader-Willi syndrome; DBP, diastolic blood pressure; NS, not significant.

t Means adjusted for baseline variable, age, gender, and body mass index where differences are

dependent on body mass index.

<.03 <.004

NS NS

Parameter

Body mass index

Biceps skin-fold, mm

Infrascapular skin-fold, mm

Total skin-fold thickness, mm

Greater resting pulse,t beats

Lesser orthostatic rise in pulse

@ 30 s,t beats

Blunted orthostatic change in DBP,t

mm Hg

Abnormal 30:15 ratio

Hypersensitive pupil

Plasma norepinephrine.-resting, pg/mL

Plasma norepinephrine-standing, pg/mL

28.6 ± 7.6 21.4 ± 4.8 <.001

20.5 ± 8.2 10.0 ± 6.3 <.02 38.1 ± 19.6 13.6 ± 5.0 <.01

128.6 ± 43.4 82.8 ± 37.4 <.03

81 ± 20.2 73 ± 20.2 <.04

82.8 ± 21.4 90 ± 21.4 <.08

57.3 ± 9.3 58.4 ± 9.3 <.04

1.07 ± 0.14 1.11 ± 0.07

7/14 0/8

101±58 119±58

229 ± 130 316 ± 130

with age as would also be expected inasmuch as

sub-jects with PWS become increasingly obese in the face

of decelerated linear growth with age.’7”8 We chose to

analyze the remainder of autonomic indexes relative

to BMI rather than skin-fold thickness or percentage

body fat calculations because BMI is a more

conser-vative and accurately reproducible index.’9

Several measures of cardiovascular reflex activity

were assessed. The assumption of a standing position

from lying supine normally triggers a bimodal

in-crease in heart rate for I to 15 seconds associated with

first an increase of systolic pressure for several

sec-onds followed by a fluctuating decline thereafter.20’2’

The diastolic pressure follows a similar course;

how-ever, by 10 to 15 seconds after standing, the heart rate

has maximized and diastolic pressure reverts to

rest-ing supine measure with systolic pressure below

rest-ing Each of these parameters then

nor-malize to resting baseline gradually thereafter. The

effects of standing from a supine position are

aug-mented by a preceding rest and are minimally

influ-enced by physical training.20 The immediate rise in

blood pressure is caused by the compression of

ar-teries in proximity to contracting postural muscles.2’

The immediate rise in heart rate, however, is due to

the “exercise reflex,” whereby active muscle

contrac-tion enhances vasoconstrictor (sympathetic) tone and

inhibits vagal (parasympathetic) influence, resulting

in cardiac acceleration.20’ Both peripheral and central

control of this reflex are postulated.20’ Baroreceptor

reflexes then become active in response to the rise in

systemic blood pressure, resulting in an augmented

vagal (parasympathetic) cardioinhibition and

dimin-ished sympathetic vasoconstriction and cardiac

contractility.2#{176}’

Subjects with PWS exhibited both higher resting

pulse rates and lower incremental pulse rises after

standing compared with control subjects. This was

most notable in subjects with the highest BMI, for

whom diastolic and MAP measures were

signifi-cantly low. This finding supports a faulty

barorecep-tor reflex principally affecting the parasympathetic

branch of the reflex arc. Peterson et a!24 examined

au-tonomic activity in obese men. They found that

depressions of sympathetic and parasympathetic

activity were weakly correlated with increasing

per-centages of body fat? Both resting heart rate and DBP

showed positive correlations to increasing body fat

percentage but were not related to BMI? Therefore,

we believe that this parasympathetic deficiency is

more specifically related to PWS than to the

individu-al’s degree of obesity per se.

The ECG recordings and abnormal 30:15 R-R

in-terval ratios in our subjects with PWS also support

diminished parasympathetic activity. This ratio is a

numeric value representing the degree of normally

provoked immediate tachycardia (15th R-R interval)

and relative delayed bradycardia (30th R-R interval)

after standing.’3 Ratios of 1 .03 are reflective of an

absent or deficient vagally mediated parasympathetic

cardioinhibition.’5 This response can also be seen in

patients with sympathetic vasomotor failure;

how-ever, in those patients one observes a concomitant

un-interrupted decline in blood pressure.25

Pupil response to piocarpine instillation is a

rea-sonable means of assessing “denervation”

hypersen-sitivity. Since the pupil is under the tonic influence of

sympathetic (dilator) and parasympathetic

(constric-tor) input, exposure to a weak

parasympathetomi-metic agent would evoke constriction of a

hypersen-sitive “denervated” pupil.’5 Subjects with PWS

demonstrated significant sensitivity to this agent,

again

suggesting

depression

of parasympathetic tone.

A similar finding was noted by Peterson et al,24 who

found a positive correlation between pupillary

la-tency period and BMI in obese men.

These results support our hypothesis of an

under-lying detectable disturbance of autonomic

function-ing in patients with PWS. These results suggest that

the disturbance is primarily one of parasympathetic

deficiency. We could not correlate all measures with

the degree of obesity (BMI) in our subjects, although

these trends were apparent. Statistical analysis

ad-justed for the difference in BMI among subjects

and controls, and therefore our results emphasize

the unique group differences of patients with

PWS. Our findings support the notion that

auto-nomic disturbances-parasympathetic deficiencies

in particular-may be important in human obesity.

We speculate that a genetic influence over ANS

(6)

function and factors influencing body fat

homeosta-sis may reside in part on chromosome 15.

Further-more, ANS activity itself may affect certain of the

underlying manifestations of PWS.

Currently we are evaluating spectral analysis of

respiratory sinus arrhythmia in subjects with PWS in

comparison with age- and sex-matched control

sub-jects. Preliminary results show differences between

these groups, with subjects with PWS demonstrating

less heart rate variability.26 This further supports

de-ficient parasympathetic autonomic tone. Taken

to-gether, the findings of our investigations support the

potential use of parasympathetomimetic agents (eg,

piocarpine) as a treatment modality. One can only

speculate about whether a therapeutic increase in

parasympathetic tone can ameliorate some of the

as-sociated symptoms in PWS. It is logical that this could

improve salivary function, gastric motility, and

p0-tentially improve fat homeostasis among other

mani-festations.

ACKNOWLEDGMENTS

This work was supported, in part, by a grant from the Clinical

Research Center at The University of Connecticut Health Center.

We thank William Shoemaker, PhD, for catecholamme analysis

and Ms Kathleen Hamm for manuscript preparation.

REFERENCES

I. Cassidy SB, Ledbetter DH. Prader-Willi syndrome. In: Neurogenetic

Diseases. Neurol Clin. 1989;7:37-54

2. Butler MG. Prader-Willi syndrome: current understanding of cause and

diagnosis. Am I Med Genet. 1990;35:319-332

3. Burd L, Vesely B, Martsolf J, Kerbeshian J. Prevalence study of

Prader-Willi syndrome in North Dakota. Am I Med Genet. 1990;37:97-99

4. Cassidy SB. Prader-Willi syndrome. Curr Prob! Pediatr. 1984;14:1-55

5. Laurance BM, Brito A, Wilkinson J. Prader-Willi syndrome after age 15 years. Arch Dis Child. 1981;51:181-186

6. Hamilton CR, Scully RE, Kliman B. Hypogonadotropmism in

Prader-Willi syndrome. Am I Med. 1972;52:322-329

7. Bray GA, Dahms WT, Swerdloff PS, Fisher RH, Atkinson RL, Carrel RE.

The Prader-Wiffi syndrome: a study of 40 patients and a review of the

literature. Medicine (Ba!timore). 1983;62:59-80

8. Hittner HM, King RA, Riccardi VM, et al. Oculocutaneous albinoidism

as a manifestation of reduced neural crest derivatives in the

Prader-Willi syndrome. Am I Opthalmo!. 1982;94:328-337

9. Hoefnagel D, Costello PJ, Hatoum K. Prader-Willi syndrome. I Meat

Defic Res. 1967;11:1-11

10. Butler MG. Hypopigmentation: a common feature of

Prader-Labhart-Willi syndrome. Am

I

Hum Genet. 1989;45:140-146

11. Loewy AD. Central autonomic pathways. In: Loewy AD, Spyer KM.

eds. Central Regulation of Autonomic Functions. New York, NY: Oxford

University Press; 1990:83-103

12. McLeod JG, Tuck RR. Disorders of the autonomic nervous system, part

1 : pathophysiology and clinical features. Ann Neuro!. 1987;21 :419-430

13. Vela-Bueno A, Kales A, Soldatos CR, et al. Sleep in the Prader-Willi

syndrome. Arch Neurol. 1984;41 :294-296

14. Hall BK. The Neural Crest. New York, NY: Oxford University Press;

1988:3-24

15. McLeod JC, Tuck RR. Disorders of the autonomic nervous system, part

2: investigation and treatment. Ann Neurol. 1987;21:519-529

16. DiMario FJ, Chee CM, Berman PH. Pallid breath-holding spells:

evalu-ation of the autonomic nervous system. Clin Pediatr (Phila). 1990;29:

17-24

17. Butler MG, Meaney FJ. Standards for selected anthropometric

measure-ments in Prader-Willi syndrome. Pediatrics. 1991;88:853-860

18. Meaney if, Butler MG. The developing role of anthropologists in

medi-cal genetics: anthropometric measurement of the Prader-Labhart-Willi

syndrome as an illustration. Med Anthropol. 1989;10:247-253

19. Obesity in America: an overview. In: Bray GA, ed. Obesity in America.

Bethesda, MD: National Institutes of Health; 1980:1-19. US Dept of

Health, Education, and Welfare publication (NIH) 80-359

20. Borst C, Weiling W, van BrederodeJFM, Hond A, de Rijk LG, Dunnings

AJ. Mechanisms of initial heart rate response to postural change. Am J

Physiol. 1982;243H:676-681

21. Borst C, van Brederode JFM, Weiling W, van Montframs GA, Dunnings

AJ. Mechanisms of initial blood pressure response to postural change.

Cliii Sci. 1984;67:321-327

22. Hollander AP, Bouman LN. Cardiac acceleration in man elicited by a

muscle-heart reflex. JApp! Physiol. 1975;38:272-278

23. Spyer KM. The central nervous organization of reflex circulatory con-trol. In: Loewy AD, Spyer KM. ads. Central Regulation of Autonomic

Functions. New York, NY: Oxford University Press; 1990:168-188

24. Peterson HR. Rothschild M, Weinberg CR, Fell RD, McLeish KR, Pfeifer

MA. Body fat and the activity of the autonomic nervous system. N EngI

I Med. 1988;318:1077-1083

25. van Lieshout JJ, Weilings W, Wesseling KH, Karemaker JM. Pitfalls on

the assessment of cardiovascular reflexes in patients with sympathetic

failure but intact vagal control. Clin Sci. 1989;76:523-528

26. DiMario FJ, Bauer L, Volpe J, Cassidy SB. Vagal tone measured via

respiratory sinus arrhythmia in Prader-Willi syndrome. Ann Neural.

1993;34:487.

WATCH

THAT

CIRCUMLOCUTION

“We have no evidence” is a tricky phrase. It says “no,” but guards against the

consequences of being wrong; it leaves open the possibility for a switch to “yes” if

somebody else comes up with evidence to the contrary. Listen for it.

Safire W. On language. The New York Times Magazine. September 27, 1992.

Submitted by Student

(7)

1994;93;76

Pediatrics

B. Cassidy

Francis J. DiMario, Jr, Barbara Dunham, Joseph A. Burleson, Jay Moskovitz and Suzanne

Syndrome

An Evaluation of Autonomic Nervous System Function in Patients With Prader-Willi

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1994;93;76

Pediatrics

B. Cassidy

Francis J. DiMario, Jr, Barbara Dunham, Joseph A. Burleson, Jay Moskovitz and Suzanne

Syndrome

An Evaluation of Autonomic Nervous System Function in Patients With Prader-Willi

the World Wide Web at:

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An Evaluation of Autonomic Nervous System Function in Patients With Prader-Willi Syndrome

Evaluation

ABSTRACT. Objective. Prader-Willi syndrome (PWS)

exists as part of the PWS.

and measurements of plasma norepinephrine at rest and after standing were also obtained. Results were analyzed using two-tailed t tests, Fisher exact test, analysis of vari-ance, and analysis of covariance adjusting for age, gender, and BMI.

with PWS and in no control subjects (P < .004). The 30:15 R-R interval ratio was abnormal in 6 of 14 subjects with PWS and in no control subjects (P < .03).

Willi syndrome, autonomicfunction, parasympathetic ner-vous system, dysautonomia, chromosome 15.

METHODS

RESULTS

-‘1 rJ r- - Lfl . C O . L- .

DISCUSSION

to BMI rather than skin-fold thickness or percentage

The diastolic pressure follows a similar course;

the “exercise reflex,” whereby active muscle

barorecep-tor reflex principally affecting the parasympathetic

again

ACKNOWLEDGMENTS

WATCH

Pediatrics

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