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1994, 23:569-576Hypertension
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Francesco Portaluppi, Pietro Cortelli, Patrizia Avoni, Luciana Vergnani, Manuela Contin,Paolo Maltoni, Anna Pavani, Emilia Sforza, Ettore C. degli Uberti,
Pierluigi Gambetti, Elio Lugaresi
Abstract Fatal familial insomnia is a prion disease in which aselective thalamic degeneration leads to total sleep deprivation,hypertension, dysautonomia, adrenal overactivity, and impairedmotor functions. With patients under continuous recumbencyand potysomnographic control, we assessed the changes in the24-hour patterns of blood pressure, heart rate, plasma catechol-amines, corticotropin, and serum cortisol in three patients atdifferent stages of the disease. Six healthy volunteers were usedas control subjects. A dominant 24-hour component was detectedat rhythm analysis of all variables, both in patients and controlsubjects. In the patients, the amplitudes gradually decreased asthe disease progressed, leading to the obliteration of any signif-icant diurnal variation only in the preterminal stage. A shift inphase corresponded to the loss of the nocturnal fall in bloodpressure in an early stage of the disease, when nocturnal brady-
Fatal familial insomnia (FFI) is a rapidly progres-sive disease, with an autosomal dominant pat-tern of inheritance, pathologically characterized
by severe atrophy of the anterior ventral and mediodor-sal nuclei of the thalamus.17 The most prominentclinical features are progressive, untreatable loss of anysleep activity as well as impaired autonomic and motorfunctions. To date, FFI has been reported in fiveunrelated kindreds with identical clinical and patholog-ical features.2-67 Previous clinical studies have reportedthat hypertension is always present in these patients.17
These studies were based on casual sphygmomanomet-ric measurements, so incomplete data are available onthe extent and nature of the blood pressure (BP)elevation, particularly its time course within the disease.A pituitary-adrenal dysfunction has been reported intwo previous cases,1-5 with striking elevations in serumcortisol levels, normal plasma concentrations of corti-cotropin (ACTH), and loss of circadian rhythmicity.This pattern was attributed to adrenal overactivity as a
Received October 28, 1993; accepted in revised form February2, 1994.
From the Hypertension Unit, Institute of Internal Medicine,University of Ferrara (Italy) (F.P., L.V., E.C. degli U.); Neurolog-ical Institute (P.C., P.A., M.C., E.S., E.L.) and the CentralLaboratory, Endocrinology Unit (P.M., A.P.), S. Orsola Hospital,University of Bologna (Italy); and the Division of Neuropathology,Institute of Pathology, Case Western Reserve University, Cleve-land, Ohio (P.G.).
Correspondence to Francesco Portaluppi, MD, HypertensionUnit, Institute of Internal Medicine, University of Ferrara, viaSavonarola 9, 1-44100 Ferrara, Italy.
cardia was still preserved. Plasma cortisol was high and becameincreasingly elevated, whereas corticotropin remained withinnormal levels; abnormal nocturnal peaks appeared in theircircadian patterns. The disrupted patterns of cortisol and bloodpressure preceded the development of hypertension and severedysautonomia, which in turn were paralleled by increasing cate-cholamine and heart rate levels. Our data demonstrate that inpatients with fatal familial insomnia the changes detectable in therhythmic component of diurnal blood pressure variability resultin a pattern of secondary hypertension. Disturbances in thalamic,pituitary-adrenal, and autonomic functions seem to be involvedin mediating these changes. (Hypertension. 1994^23^69-576.)
consequence of a continuous stress syndrome.1-5 How-ever, no prospective data are available on this feature ofFFI.
Based on these studies, FFI appears to be a novel andrare cause of genetically determined secondary hyper-tension. Moreover, the cardinal feature of this condition(a total and sustained disappearance of sleep activity)constitutes a unique, albeit dramatic, opportunity inhumans to observe diurnal BP variability independentlyof a sleep/wake cycle. We studied three cases of FFI,each with complete loss of physiological sleep but withdifferent disease duration and severity of autonomicand motor impairment. Our aims were to observe thechanges in the 24-hour patterns of BP variation indifferent stages of FFI and to investigate the possiblerelation with the circadian patterns of pituitary-adrenaland autonomic nervous activity.
Methods
Patients and VolunteersWe studied two members of the original family in which FFI
was first described and one member of another Italian kindred.The patients are identified according to the family pedigrees,which have been previously published with clinical and patho-logical details.2-6
Case IV-16 was a 58-year-old woman at the onset of thedisease, characterized by dysarthria and gait impairment. Atmonth 6, when she underwent the first study session, severeinsomnia with minimal signs of dysautonomia was present. Bythe time of the second study session at month 14, sporadic andevoked myoclonus was also present. Later, dysautonomia andmotor impairment became worse, and by month 25 enacted
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dreaming and stupor set in. Death occurred at month 35. Acomplete autopsy examination showed the typical neuropath-ological findings of selective thalamic atrophy, with only minorcerebellar and cerebral degeneration.
Case V-58 (female, 35 years old at disease onset) wasstudied in a more advanced stage (months 20 and 23), whentotal sleep loss was already accompanied by hypertension andother signs of dysautonomia, as well as enacted dreaming andmotor impairment. Death occurred at month 25, 40 days afterthe last session.
Patient IV-26 (male, 52 years old at disease onset) had aswift course of the disease and was studied in the terminalstage (months 8 and 9), when total sleep loss, hypertension,severe autonomic and motor impairment, hallucinations, and(at month 9) stupor with responsiveness only to intense stimuliwere present. The last study session was performed 20 daysbefore death. In addition, six normal volunteers (four men, 29to 50 years old) underwent a 24-hour study session with thesame protocol and were used as control subjects.
Twenty-four-Hour Study SessionsThe protocol was approved by the local ethics committee.
Before undergoing a 24-hour study session, each patient andvolunteer spent at least two nights in the hospital for habitu-ation. The sessions were performed in a sound-proofed roomat constant temperature (24° to 25°C), with continuous recum-bency audiovisually controlled through a closed-circuit TV set.For meals, at 8 to 9 AM, noon to 1 PM, and 5:30 to 6:30 PM, thehead of the bed was elevated 30°. Lights were on between 7 AMand 10 PM. The volunteers were not allowed to sleep during theday until the lights went off and were awakened at 7 AM.
Two hours before the beginning of each session, an intrave-nous cannula was inserted into an antecubital vein and keptopen with a slow infusion of 0.9% saline (15 mL/h). Venoussamples (8 mL) were drawn every 30 minutes. On the sameday, BP was monitored noninvasively by a fully automatedinstrument (Finapres 2300, Ohmeda Monitoring Systems) thatuses a volume-clamp method in the finger and also permits theassessment of heart rate (HR). To avoid discomfort to thesubjects and minimize possible interferences of finger vesselreactions, the finger cuff was disconnected for 10 minutes aftereach 2-hour interval of continuous operation. For furtherevaluation, the mean values of each 1-minute period wererecorded and then averaged for intervals of 10 minutes. Apolygraph (Grass Instruments) was used to simultaneouslymonitor an electroencephalograph (EEG), ocular movements,activity of antigravitary muscles (with surface electrodes),thoracic and abdominal respiration (by means of thermocou-ple and strain-gauge transducers, respectively), oxygen satura-tion (using an ear oxymeter), rectal temperature, andelectrocardiograph.
Laboratory ProceduresBlood samples were drawn for determination of plasma
catecholamines, plasma ACTH, and serum cortisol. They werepromptly centrifuged at 3000g for 15 minutes at 4°C, and thenthe plasma was frozen at -80°C until the assay was performed.All samples for each hormone were processed in duplicate inthe same assay. Plasma norepinephrine and epinephrine weremeasured by high-performance liquid chromatography withelectrochemical detection after extraction on alumina using aSeries 10 liquid chromatograph (Perkin-Elmer) equipped witha model 7125S injection valve (Rheodyne) and a Coulochem5100A electrochemical detection system (ESA). A reversed-phase Nucleosil C18 (5 fj.m) column (200x4 mm internaldiameter, Macherey and Nagel) was used. The intra-assay andinterassay coefficients of variation for norepinephrine were4.4% and 4.1%, respectively, and for epinephrine were 7.1%and 9%, respectively. Detection limits for norepinephrine andepinephrine were 0.029 nmol/L and 27 pmol/L, respectively. Acommercial radioimmunoassay kit (Diagnostic Products Corp)
was used for serum cortisol. The assay sensitivity was 5.5nmol/L, and the intra-assay and interassay variations were4.3% and 8.5%, respectively. An immunoradiometric assay kit(Nichols Institute Diagnostic) was used for ACTH. The assaysensitivity was 0.2 pmol/L, and the intra-assay and interassayvariations were 4% and 10%, respectively.
Data Analyses
In each patient, analysis of rhythmicity was performed onthe individual data of each recording session. Individual datafrom the control group of six subjects were averaged over10-minute (for BP and HR) or 30-minute (for hormones)intervals to obtain reference values of the calculated parame-ters. A Fourier series with four harmonics (periods of 24,12, 8,and 6 hours) was fitted to the data by means of the nonlinearleast-squares fitting program PHARMFTT.8 The following equa-tion was used:
with i being the number of the overlapping harmonics andMESOR the midline estimating statistic of rhythm (ie, therhythm-adjusted 24-hour mean). With the program, estimatesof the amplitude (half of peak to trough of rhythmic change)and acrophase (peak time of rhythmic change) of each har-monic were calculated. In addition, the MESOR, amplitude(half the distance between the absolute maximum and mini-mum of the fitted curve), and acrophase (time of occurrence ofthe absolute maximum of the fitted curve) of the overall fit ofthe Fourier model were obtained. The percentage of rhythmand a probability value to reject the hypothesis of zeroamplitude were also calculated for each harmonic and theoverall fitted function. A value of P<.05 was consideredsignificant in all tests. Values are reported as mean±SD.
ResultsPolysomnographic Data
Polysomnographic tracings revealed the disappear-ance of physiological sleep activity in all patients in allrecording sessions. Short-lasting episodes of EEG de-synchronization were recorded, associated with muscu-lar jerks of the upper limbs intermixed with moreorganized and complex motor activities in the electro-myogram of limb muscles. Breathing irregularities withvarious degrees of oxygen desaturation were also pres-ent in case IV-26, who was studied in an advanced stageof the disease. These episodes were interspersedthroughout the 24 hours so that no temporal pattern intheir occurrence was detectable.
No sleep disturbance was found in the control group.The mean time from sleep onset to morning awakening,detected at EEG, was 489±28 minutes (range, 459 to526 minutes), and the total duration of all nocturnalawakenings averaged 25±8 minutes (range, 16 to 37minutes).
Blood Pressure and Heart Rate Patterns
Nonlinear rhythm analysis identified significant time-dependent variations in systolic and diastolic BP as wellas HR in all recording sessions except the preterminalone of case IV-26 at month 9 of the disease course(Table 1). In all sessions and variables, the 24-hourperiod was the dominant one.
In healthy control subjects, the BP and HR profilesshowed two peaks around 10 AM and 8 PM, respectively,and a nocturnal fall. The mean amplitudes of therhythms (Table 1), expressed as a percentage of the
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Portaluppi et al Secondary Hypertension in Fatal Familial Insomnia 571
TABLE 1. Blood Pressure and Heart Rate Rhythms In Fatal Familial Insomnia
Case
IV-16
V-58
IV-26
Volunteers
Month FromOnset
6
14
20
23
8
9
Parameter
SBP
DBP
HR
SBP
DBP
HR
SBP
DBP
HR
SBP
DBP
HR
SBP
DBP
HR
SBP
DBP
HR
SBP
DBP
HR
Rhythm, %
18.1
32.6
39.7
23.8
24.5
48.6
18.5
23.4
19.5
16.5
10.5
12.7
8.4
10.8
28.0
2.5
1.7
2.7
60.3
62.5
79.1
P
<.OO1
<.001
<.001
<.O01
<.O01
<.001
<.001
<.001
<.001
<.001
.036
.005
.013
.003
<.001
.187
.099
.095
<.001
<.001
<.001
MESOR
139.3+1.0
78.6±0.5
75.2±0.5
130.6±0.7
74.2±0.5
79.2±0.4
169.7±1.4
97.9±0.9
94.7±0.5
167.0±1.1
99.6±0.8
97.6±0.7
159.1 ±0.7
90.7±0.5
77.1 ±0.3
161.3±0.7
87.4±0.3
85.9±0.3
122.2+8.4
70.8±4.9
62.5±3.5
Amplitude
9.2±1.5
6.8±0.8
6.5+0.7
7.7+0.9
5.9±0.7
6.5±0.5
9.9±2.3
8.3±1.3
3.8±0.8
7.9±1.6
3.1±1.2
3.1 ±0.9
3.2±1.0
2.2±0.6
3.6±0.6
1.6±1.0
1.0±0.5
1.0±0.4
9.8±1.5
8.3±0.9
9.0±0.7
Acrophase,24-Hour
Clock Hours
05.42±0.34
04.38±0.25
14.30±0.23
20.20±0.27
21.29±0.28
15.06±0.17
21.07±0.48
22.38+0.38
15.18±0.46
22.47±0.44
04.08±1.26
11.12±1.11
20.02 + 1.13
22.28±1.09
11.28+0.30
21.47±0.43
20.08±2.25
09.38±1.51
14.58±0.26
14.16±0.31
14.39±0.44
Overall %Rhythm
56.5
62.6
61.7
48.3
54.1
71.9
30.8
45.7
38.8
30.4
22.6
27.7
18.9
17.4
61.1
9.1
5.8
8.5
83.9
82.4
91.2
SBP indicates systolic blood pressure; DBP, diastolic blood pressure; and HR, heart rate. A Fourier series with four harmonics (periodsof 24, 12, 8, and 6 hours) was fitted to the individual data of three patients with fatal familial insomnia and to the data averaged over10-mlnute intervals of a group of six healthy volunteers. Shown are rhythm-adjusted mean (midline estimating statistic of rhythm[MESOR]), percentage of rhythm, probability of zero amplitude (P), amplitude, and acrophase (peak time of rhythm) of the dominant24-hour period, together with improvement of fit (overall % rhythm) by adding the harmonics. Values are mean±SD. MESOR andamplitude values of blood pressure are in millimeters of mercury; heart rate in beats per minute.
24-hour mean, were 8%, 11.7%, and 14.4% for systolicand diastolic BP and HR, respectively. A close synchro-nism was evident in the 24-hour BP and HR patterns.
In patients with FFI, the amplitudes of the 24-hourcomponents were already reduced in the early phase ofthe disease (in the first session of case IV-16, they were6.6%, 8.7%, and 8.6% for systolic and diastolic BP andHR, respectively). As the disease progressed, the circa-dian variation of BP and HR decreased further, asdemonstrated by the progressive reduction of the am-plitudes (Table 1), which caused complete obliterationof the BP and HR rhythms in the preterminal stage ofcase IV-26. Two daytime peaks were still present in theBP profile, but at night a marked reduction or completeloss in BP fall was apparent in all recording sessions (Fig1). This finding was reflected in a shift of the acrophasesof the 24-hour components of BP toward the late
evening or early morning hours (Table 1). On the otherhand, the 24-hour profile of HR was essentially un-changed until the more advanced stages of the disease,although with reduced amplitude (Fig 2), and no phaseshift was present in its 24-hour component (Table 1).Hence, in these patients the changes in BP did notcorrelate with those in HR, as reflected by the asynchro-nism between the HR and BP rhythms.
In case IV-16, in whom the studies were performed inan early stage of the disease, the mean 24-hour levels ofBP and HR were only slightly increased. In patientsV-58 and IV-26, who were studied in more advancedstages of the disease, more severe hypertension andtachycardia were documented.
FIG 1. Plots show 24-hour profiles of systolic and diastolicblood pressures in different stages of fatal familial insomnia.Increasing severity (top to bottom and left to right) of autonomicand motor impairment was present, whereas simultaneous elec-troencephalogram always demonstrated total loss of any phys-iological sleep activity. Data points are mean values of 10-minuteIntervals. When significant (P<.05 in the zero-amplitude test),the nonlinear fit of a Fourier series with four harmonics is givenby the solid curve. Rhythm-adjusted 24-hour mean is repre-sented by the horizontal line.
except for case FV-26, in whom no rhythms were de-tected in the preterminal session of month 9 for cate-cholamines and serum cortisol and in both sessions forACTH (Table 2). In both healthy control subjects andpatients with FFI, the 24-hour period was dominant.The three additional harmonics accounted for onlyminor proportions of the hormonal variances.
Two daytime peaks and a nocturnal nadir were foundin all of the hormonal profiles of the control group, with
120
100
80
ISO
40
20
o^ '»1 100
1
to40
20
Manh6 [CaseIV-16] a m i *
Maah 20 [Case V-58) Moah 23
A.. .......^...
120
100
SO
60
40
20
0
120
100
SO
0120
100
to
to
40
08 12 16 20 00 04 09 12 16 20 00 04 OS
Time (Clock Hoar)
FIG 2. Plots show 24-hour profiles of heart rate in fatal familialinsomnia. Same study sessions as in Fig 1. Data points aremean values of 10-minute intervals. When significant (P<.05 inthe zero-amplitude test), the nonlinear fit of a Fourier series withfour harmonics Is given by the solid curve. Rhythm-adjusted24-hour mean is represented by the horizontal line.
a remarkable coincidence between the catecholaminesand BP and HR profiles and only a slight anticipation inthe daytime peaks of ACTH and cortisol.
In the early stages of FFI (case IV-16), the 24-hourhormonal profiles were essentially unchanged, with theexception of serum cortisol, which was already markedlyincreased (Fig 3). In the two patients studied in laterstages, further elevations in serum cortisol with normalACTH levels were documented, together with the ap-pearance of a distinct nocturnal peak in the patterns ofboth hormones (Fig 3A and 3B). Plasma catecholamineswere also elevated in these two patients, and their24-hour patterns (Fig 3C and 3D) showed a consider-able synchronism with HR. Rhythm obliteration in allhormonal patterns was reached in the preterminal stage(Table 2).
DiscussionThe present study was the first to monitor changes in
the 24-hour patterns of BP and HR of patients with FFIstudied in continuous recumbency and no physicalactivity except meal taking. A major finding is that adominant 24-hour rhythm is detectable in both BP andHR patterns of these patients. However, as a combinedresult of a decreased amplitude and shift in phase, thenocturnal BP fall is lost in an early stage of the disease,when nocturnal bradycardia is still preserved. Thisrhythmic component persisted, although with reducedamplitude and shifted phase, for months after the totaldisappearance of sleep. Only in the preterminal stage ofFFI was complete obliteration of any significant 24-hourvariation found. In addition, no association could bedetected with the pattern of motor activity or meals.
The pattern of changes over the 24-hour period werequantified in controlled and reproducible conditions,independently of the more rapid fluctuations that areknown to affect BP, HR, and plasma catecholamines ina sporadic way and ACTH and cortisol secretion in apulsatile fashion. The possible alternative of increasingthe number of recording days9 was not practical forethical reasons. We applied a Fourier model with fourharmonics to our data, as it has been recommended foruse with all subjects to standardize the degree ofsmoothing of input data.9'10 Adding higher harmonicsmay improve the model only in a small minority ofsubjects and does not significantly affect the statisticalparameters and shape of the fitted curve.9 In addition,equidistant and dense data points were used, as re-quired for an accurate and reproducible assessment ofthe parameters calculated.911 Finally, the Finapres in-strument that we used has been validated as a reliablealternative to the intra-arterial method, even in thepresence of marked instantaneous BP changes.1214
The lowering effect of sleep and bed rest on BP andHR is a well-known phenomenon in normotensive andhypertensive subjects who follow different activityschedules or remain recumbent throughout 24hours.1526 However, a dissociation of the 24-hour ac-rophases of BP from any specific behavioral event, as wefound in our patients, has been previously observed inhealthy subjects,26 and a recent study in transgenic ratshas also demonstrated dissociated BP and HR patterns,with BP in opposition of phase with the rest-activity andlight-dark cycles.27
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Portaluppi et al Secondary Hypertension in Fatal Familial Insomnia 573
TABLE 2. Hormonal Rhythms In Fatal Familial Insomnia
Case
IV-16
V-58
IV-26
Volunteers
Month FromOnset
6
14
20
23
8
9
Hormone
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
PNE
PE
ACTH
SC
Rhythm, %
70.0
61.7
59.2
74.1
59.3
58.2
36.3
58.7
61.8
31.8
31.9
23.7
31.2
28.4
28.2
24.8
35.7
41.1
10.1
25.5
2.2
5.5
7.0
7.7
81.9
77.7
83.2
72.3
P
<.001
<.001
<.OO1
<.001
<.001
<.001
<.OO1
<.0O1
<.001
<.001
<.001
.008
<.001
.007
.006
.017
<.OO1
.002
.275
.003
.589
.423
.416
.410
<.001
<.001
<.001
<.OO1
MESOR
1.99±0.06
172±6 .
2.4±0.2
409±19
2.46±0.06
172±5
2.0±0.1
401±16
3.82±0.08
343±21
2.4±0.1
472±21
3.89±0.09
813±17
2.1 ±0.1
504+22
4.08±0.11
385±12
2.3+0.3
492±23
4.60±0.07
588±14
2.0±0.1
532±20
2.11 ±0.29
156±35
2.9+0.5
247±45
Amplitude
0.84+0.06
53±7
1.1+0.2
202±21
0.43±0.07
38+5
0.2±0.1
141 ±18
0.64±0.09
100±24
0.6±0.2
91 ±32
0.42±0.10
64±23
0.5±0.2
68±24
0.46±0.11
72±20
0.5±0.4
90±28
0.11±0.12
33+25
0.2±0.1
37±31
0.86±0.10
98±10
1.3±0.2
124±13
Acrophase,24-Hour
Clock Hours
13.04±0.28
14.35±0.36
10.01 ±0.53
10.38±0.36
14.15±0.51
13.39±0.54
09.04±1.04
10.23±0.42
14.01 ±0.34
13.55±1.15
09.15±1.09
08.25±1.09
12.22±1.32
14.14±1.32
09.09±1.20
10.36±2.01
13.07±1.29
19.35±0.44
14.45±2.58
09.47±1.28
19.05±2.23
18.13+1.35
15.45±2.41
07.51 ±2.20
13.51 ±0.31
13.58±0.21
09.54±0.29
10.12±0.38
Overall %Rhythm
90.5
78.7
62.2
81.6
75.5
80.9
64.9
80.3
76.0
52.6
67.1
65.7
58.1
36.3
48.8
38.7
46.7
44.7
21.1
36.9
17.4
23.1
20.4
19.4
88.2
88.3
94.1
96.7
PNE indicates plasma norepinephrine; PE, plasma epinephrine; ACTH, cortlcotropin; and SC, serum cortlsol. A Fourier series withfour harmonics (periods of 24, 12, 8, and 6 hours) was fitted to the Individual data of three patients with fatal familial insomnia and tothe data averaged over 30-minute intervals of a group of six healthy volunteers (controls). Shown are rhythm-adjusted mean (MESOR),percentage of rhythm, probability of zero amplitude (P), amplitude, and acrophase (peak time of rhythm) of the dominant 24-hour period,together with improvement of fit (overall % rhythm) by adding the harmonics. Values are mean±SD. MESOR and amplitude values ofPNE and SC are in nanomoles per liter; PE and ACTH in picomoles per liter.
At a stage when nocturnal bradycardia was still pre-served, the sleep deprivation of FFI was accompanied bya total loss of the nocturnal fall in BP. This finding bringsfurther evidence not only to the concept that the 24-hourvariation in HR reflects modulatory influences that aredifferent from those controlling the BP pattern28 but alsoto the notion that sleep seems to account for only a minorpart of the nocturnal decline in HR.26
The dissociation of BP and HR patterns that we ob-served closely resembles the situation described in second-ary forms of human hypertension, as in Cushing's syn-drome,29 pheochromocytoma,30 chronic renal disease,31-32
diabetes,33-34 preeclamptic toxemia,35 and sleep apneasyndrome,36 or in some hypotensive diseases such asautonomic failure,37 Shy-Drager syndrome,38 and conges-tive heart failure.39-40 In our patients, serum cortisol was
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FIG 3. Plots show 24-hour profiles of serum cortisol (A), corticotropin (ACTH) (B), norepinephrine (C), and epinephrine (D) levelssampled at 30-minute intervals In fatal familial insomnia. Same study sessions as in previous figures. When significant (P<.05 in thezero-amplitude test), the nonlinear fit of a Fourier series with four harmonics is given by the solid curve. Rhythm-adjusted 24-hour meanis represented by the horizontal line.
high and became increasingly elevated, whereas ACTHremained at normal levels. This finding clearly suggests acondition of hypercortisolism added to a functional dys-regulation of the hypothalamic-pituitary-adrenal axis,probably caused by an excessive and prolonged activationin severely and chronically stressed subjects, which resultsin adrenal overactrvity.1-5 Moreover, abnormal nocturnalpeaks were detected in the circadian rhythm of thesehormones. This, together with the reversal in the BPpattern, preceded the development of hypertension andthe clinical and instrumental signs of severe dysautono-mia, which in turn were paralleled by the catecholamineand HR changes. It has been shown that elevation ofplasma catecholamines alone, as in pheochromocytoma,30
causes only a minor decrease in the nocturnal BP fall,indicating that other mechanisms may be more importantin modulating the 24-hour fluctuations in BP. Instead,
disturbances of BP variability are particularly evident inCushing's syndrome, particularly the adrenal variant, inwhich the loss and frequent reversal of the nocturnal BPfall is accompanied by an essentially normal HR rhythm,29
as in our patients. In addition, it has been demonstratedthat exogenous glucocorticoid administration eliminatesthe nocturnal BP fall without affecting the HR profile.29
Altogether, these findings point to the role of serumcortisol and ACTH in the modulation of the circadianvariability of BP. It would be tempting to infer that serumcortisol more than ACTH is a major determinant of sucha modulatory mechanism, because ACTH was neverincreased in our patients. However, our sampling andanalytic techniques do not allow resolution of the finestructure of ACTH secretory profiles, preventing identi-fication of changes in the amplitude or frequency ofpulsatile activity that serve to modulate adrenal re-
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Portaluppi et al Secondary Hypertension in Fatal Familial Insomnia 575
sponse.41 ACTH levels were not increased in our patients,but neither were they suppressed, as would be expected ifprimary hypercortisolism had produced mean cortisollevels of approximately 500 nmol/L, as we found in ourpatients. This strongly suggests that in FFI there is someabnormality of feedback suppression of ACTH. Hence,the contribution of ACTH to the sequence of eventsleading to elevated cortisol levels and secondary hyperten-sion cannot be excluded.
A significant nocturnal hypersecretion of both ACTHand serum cortisol was documented in our patients, asdemonstrated by the appearance of distinct nocturnalpeaks in the patterns of both hormones. This hyperse-cretion occurred at a time when, in normal conditions,sleep is known to maximally affect ACTH and serumcortisol secretion.4244 Similar nocturnal peaks, repre-senting the reversal of the normal sleep-related inhibi-tion, have been produced in healthy subjects with acutesleep deprivation.4244 In such experimental conditionsmean serum cortisol concentrations do not rise, but theeffects of a chronic disinhibition of the hypothalamic-pituitary-adrenal axis over months of sleep deprivation,as happens in FFI, are not known.
Glucocorticoid-induced hypertension seems to bedue to alterations in vascular responsiveness to pressoragents.45 There is evidence that serum cortisol modu-lates the vascular response to catecholamines46 and actscentrally to increase sympathetic nerve activity,47
whereas hydrocortisone in the isolated perfused adrenalgland releases adrenomedullary catecholamines.48 Alead-in phase of the circadiari ACTH and serum cortisolrhythms (which peak in the morning hours) over thenorepinephrine and epinephrine rhythms (which peakaround midday) is well known and was maintained inour patients, suggesting an entrapment of the latter.49
These data suggest a relation between the altered pitu-itary-adrenal function and the disturbance of the auto-nomic function found in FFI, which consists of an unbal-anced autonomic control with preserved parasympatheticand higher background and stimulated sympathetic activ-ity.4 Sleep bradycardia is due more to parasympatheticactivation than to sympathetic withdrawal,22-50 so its pres-ervation in FFI patients seems justified.
Finally, a striking trend in all the 24-hour patternsthat we assessed in FFI is the gradual decrease in theamplitudes of their rhythmic components, showing thatcomplete rhythm obliteration requires a long diseasecourse to intervene. The primary and selective thalamiclesions of FFI determine the suppression of the sleep-wake cycle and, through the close connections of themediodorsal thalamic nucleus with the hypothalamusand basal prosencephalon, multiple endocrine, auto-nomic, and cardiovascular dysfunctions.1"7 The diseaseprocess spreads according to a consistent pattern, al-though at a variable pace in different patients, and thisis reflected in the gradualness of the modifications inthe 24-hour fluctuations of many physiologicalvariables.
In conclusion, we have demonstrated that the 24-hour BP and HR patterns in FFI patients show alter-ations that closely resemble those previously found inother secondary forms of hypertension in which asleep-wake cycle is maintained. It may be inferred fromour study that among the control systems involved inmediating the above changes, the thalamic nuclei, hy-
pothalamic-pituitary-adrenal axis, and autonomic ner-vous system may play a role. Finally, our data confirmthat a rhythmic 24-hour component in the 24-hourpattern of BP variability may exist independently ofsleep-wake and activity cycles.
AcknowledgmentsSupported by grants from the Italian National Research
Council (CNR, Rome, Italy) — "Prevention and Control ofDisease Factors, sub-project Stress (No. 93.0071.PF41)"-andfrom the Italian Ministry of University and Scientific andTechnological Research (40% to 60%).
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