32
Elsevier Scientific Publishers Ireland, Ltd.
Short communication
SLEEP DISTURBANCES IN A CASE OF BRAIN-STEM LESIONS; PHARMACOLOGICAL STUDY
F. L A F F O N T *, H.P. C A T H A L A *, A. ERNST **, M. B O R M E R ***, D. S C H N E I D E R - H E L M E R T ***
and G.A. S C H O E N E N B E R G E R **
* Explorations Fonctionnelles Neurologie, Groupe Hospitalier Piti~-Salp~tri~re, 75651 Paris Cedex 13 (France), ** Research Department,
Psychiatric Clinic, 5200 Koenigsfelden (Switzerland) and *** Research Division, Department of Surgery/Research Department, Kantons-
spital, University of Basel, 4031 Basel (Switzerland)
(Accepted for'publi~cation: October 13, 1983)
Disorganization of sleep patterns and reduction of total
sleep duration have been observed in patients with bilateral
lesions of the brain-stem (Fetdman 1971; Wilkus et al. 1971;
Markand and Dyken 1976).
It is also known that delta-sleep-inducing peptide (DSIP)
given to people with chronic insomnia greatly improves sleep
(Schneider-Helmert and Schoenenberger 1981). Our aim was to
test DSIP in a patient with insomnia due to brain-stem lesions.
Material and Method
The patient, a 45-year-old man, had a brain-stem haemor-
rhage 8 months prior to the beginning of the study. Conscious-
ness was normal but he had severe insomnia. Clinical examina-
tion showed a left hemianaesthesia and hemiparesis, with im-
pairment of right cranial nerves (3rd, 5th, 6th, 9th, 10th) and a
bilateral cerebellar syndrome. There was tremor of the upper
limbs, left hemiface, and both eyelids; the tremor was slow (2.5
c / s e c ) and occurred whether the patient was standing, resting
or active.
During our study psychoactive drugs were suppressed, ex-
cept for Calciparine. Long polygraphic recordings (36 h) were
performed to clarify the patient's problems. Two reference
records were carried out during a period of 1 m o n t h before the
beginning of the test. DSlP was administered by slow in-
travenous injection over a period of 3 weeks as follows:
First week: every day, for 5 days: 30 nmol ( -- 25 ng)/kg, 1
h before bedtime.
Second week: during the day: 5 injections of 30 n m o l / k g on
the first day, then 3 injections of 30 n m o l / k g on the following
4 days.
Third week: every day, for 5 days, 70 n m o l / k g , 1 h before
lights off.
NO DSIP was administered at the weekends.
The 36 h polygraphic records were made each week from
the beginning of the 4th night until the end of the 5th night. In
addition, 36 h records were made 1 and 2 weeks after the end
of DSIP treatment.
Three other drugs, given for 8 days, were also tested; 15
drug-free days intervened between each test: (1) 5-HTP: 50
mg x 1 5 / d a y +benzerazide: 50 m g x 8 / d a y . In this case the
0013-4649/84/$03.00 Q 1984 Elsevier Scientific Publishers Ireland, Ltd.
Electroencephalography and clinwal Neurophysiology, t984, 57:32--34
patient was given clomipramine (Anafranil): 10 mg x 3 / d a y by
mistake; (2) levodopa 200 m g + benzerazide 50 nag (Modopar)
= 250 nag x 3 / d a y ; (3) clonazepam (Rivotril): 2 mg x 3/day.
Polygraphic records included: 7 EEG channels (FI-Cz, C 1-
T 3, T3-O 1, Fz-C 2, C2-T4, T4-O2, Fz-T4); E M G of chin muscles
and subhyoid muscles, EOG of horizontal and vertical move-
ments, ECG and respiration (buccal air flow, nasal flow and
thoracic movement). The plasma DSlP level, measured before
the test, was high (6.6 n g / m l ) to normal ( 2 - 4 n g / m l ) .
Results
(1) Symptomatic aspect
Before the beginning of treatment the patient's EEG was
normal whether he was asleep or awake. Whatever the level of
watchfulness, there was periodic breathing with apnoeas of
central origin, and a fragmentation of the sleep EEG due to less
profound sleep when the apnoea ended.
The tremor was present during 47% of waking time, 13% of
stage 1 sleep, 3% of stage 2 sleep, 1% of stage 4 sleep and 16%
of paradoxical sleep (PS), but in the last case it was slight and
limited to the chin.
(2) Quantitative aspect (Table 1 and Fig. 1)
Before treatment the patient slept a total of 4 h / d a y and
the total PS for each night lasted only 60 min (mean). The
R E M / N R E M ratio was high (0.6) and the PS latency short
(mean: 38 rain). During the day there was no drowsiness (14
rain and 1 rain of stage 1 for the 2 registered days).
Over the 3 week period of the pilot treatment with DSIP,
the total duration of sleep increased step by step. The effects of
DSIP were: the duration of sleep increased, there were fewer
nocturnal awakenings and the R E M / N R E M ratio returned to
normal. This improvement cannot be related to a decrease of
the apnoeas since they were not modified, nor to lessening of
the tremor which was, in fact, enhanced with DSIP.
The increased levels of endogenous DSIP and the relatively
large dose of DSIP needed for noticeable effects suggest, in
accordance with animal studies, that the midbrain and brain-
stem might be the predominant sites of action for this peptide.
The total insomnia observed with 5-HTP is more difficult to
SLEEP DISTURBANCES IN BRAIN-STEM LESIONS 33

I
,q. ,q.

x x / -,. /e~
x/

,q. .__6 ..... ~i. ~ ~/, ~ o ........

t m ~
t"q
x--x ~.L~ .R:ao
~V"t ~ a i : ,NONm I~,,lel aNg2,,e~t n , m l m ~ : t GS, Lp ~'~Nm~
- - R[-u/s=, sj .s ~
C : cNm~

Fig. 1. Effects of DSIP on night sleep.

understand. The lack of PS could be ascribed to clomipramine

(Anafranil). Nevertheless the 5-HTP treatment significantly
decreased the tremor even though the percentage of apnoeas
,q. ,q.
was higher. This might explain the exclusive presence of stage 1
sleep during the night. A high percentage of stage 1 sleep was
also observed with clonazepam (Rivotril), associated with a
high percentage of apnoeas. L-DOPA + benzerazide (Modopar)
did not affect sleep, although the tremor was enhanced and the
apnoeas decreased.

Conclusion

The slow injection of DSIP reversibly improved the condi-

tion of a patient suffering from severe insomnia following a
brain-stem lesion, sequential and quantitative aspects of the
,q ,~. ,.,.k
sleep were reversibly improved: the patient slept more and
m.
e-
I
woke up fewer times during the night, and the R E M / N R E M
ll ratio was decreased. The effects confirm previous findings in
c-
O insomniacs without organic brain lesions: step-by-step im-
provement of sleep with repeated administration of DSIP,
O
improvement of sleeping/waking rhythms and higher daytime
alertness These effects persisted after the end of treatment
.,.., Since both respiratory problems and tremor were enhanced by
+
DSIP, these favourable effects must be attributed to the drug's
+ activity on other parameters. These results appear to support
O the concept of this neuropeptide as a modulating or program-
.9,o ming substance.
~r Sleep improved only with DSIP, whereas clonazepam im-
proved only light slow sleep, i.e., stages 1 and 2.
e-~

~2
Summary
~oo
A pharmacological study was carried out of a case of severe
insomnia following brain-stem lesions: several polygraphic con-
o : : trois were used.
34
Initially total duration of sleep was brief ( < 4 h) with a
high R E M / N R E M ratio and a short paradoxical sleep (PS)
latency. In addition, periodic breathing and tremor were ob-
served.
Slow injection of delta-sleep-inducing peptide (DSIP) im-
proved sleep both quantitatively and qualitatively, although PS
latency remained short. These effects were reversible.
The effects of 5 - H T P + benzerazide, of L-DOPA + benzera-
zide (Modopar) and of clonazepam (Rivotril) were compared.
R~sum~
Troubles du s o m m e i l en cas des l~sions du front c~r~bral," btude
pharmacologique
Une 6tude pharmacologique a 6t6 effectuee dans un cas
d'insomnie due h des h~sions du tronc c,~r,~bral. Un contr61e
polygraphique a permi d'6valuer l'insomnie et d'en suivre
l'6volution sous traitement.
L'insomnie +tait r~elte (DTS < 4 h), avec un rapport
R E M / N R E M important et une latence de sommeil paradoxal
courte. De plus certaines particularit~s +talent observ~es: pre-
sence d'une respiration p6riodique et existence de tremblement.
F. L A F F O N T ET AL.
Le DSIP en injection lente provoque une am61ioration
r6versible des aspects quantitatifs et s+quentiels du sommeil,
avec cependant une latence du sommeil paradoxal qui demeure
br+ve.
Les effets du 5-HTP + benserazide, du L-DOPA +
bens,brazide (Modopar) et du c l o n a z ~ a m (Rivotril) ont ,~t6
+tudi6s.
References
Feldman, M.H. Physiological observations in a chronic case of
'locked in' syndrome: Neurology (Minneap.), 1971, 21:
459-478.
Markand, O.N. and Dyken. M.L. Sleep abnormalities in pa-
tients with brain stem lesions. Neurology (Minneap.), 1976,
26: 769-776.
Schneider-Helmert, D. and Schoenenberger, G.A. The in-
fluence of synthetic DSIP (delta sleep inducing peptide) on
disturbed human sleep. Experientia (Basel), 1981, 37:
913-917.
Wilkus, R.J., Harvey, F.. Moretti-Ojemann, L. and Lettich, E.
Electroencephalogram and sensory evoked potentials. Arch.
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