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Gilles de la tourette syndrome: A new clinico-therapeutic approach
Prog.
Nezuv-Psychophamc.
Vol.
1, pp. 335-338,
1977.
.Pergamon Prese.
Printed
in Great
Britain.
GILLES DE LA TOURETTE SYNDROME: A NEW CLINICO-THERAPEUTIC APPROACH
North
J. A. YARYURA-TOBIAS and F. A. NEZIROGLU Division of Research Nassau Mental Health Center, Manhasset, L.I., New York, (Final
form,
July
U.S.A.
1977)
Abstract 1. 2. 3. 4.
This investigation has yielded aggression and obsessive-compulsiveness as additional psychiatric symptoms to the neurological Gilles de la Tourette syndrome. Obsessive-compulsive relatives, as well as other Tourette family members seemed affected, suggesting a role of the genetic factors. Clinical data obtained in fifteen patients showed that chlorimipramine (CLI) a potent serotonergic blocking agent appears to have a good efficacy, with the advantage over haloperido1 of having mild side effects. A serotonin disturbance as a causative factor was hypothesized.
Keywords:
Tourette
syndrome,
chlorimipramine,
serotonin,
obsessive-compulsive.
Introduction Itard (1825) and later, Gilles de la Tourette (1885) described a syndrome characterized by uncoordinated movements, noises and echolalia. Additional symptoms included obsessions, compulsions, aggressive behavior (Moldofsky et al., 1974) and self-mutilation (Van Woert et al., 1975). The usual onset is childhood, with a chronic course, and a cephalocaudal progression of changing tics. The bizarre and proteiform symptomatology suggest a psychological etiology, or a combination of psychological and organic factors (Challas et at., 1967; Lucas and Rodin, 1973; Shapiro et aZ., 1973c; Logue et al., 1973) while for others, the causation remains unknown (Fernando, 1967). Psychobiological treatments include: behavorial therapy (Yates, 19581, hypnosis (Erickson, 1962). mass negative practice (Teoh, 1974) and psychotherapy 19641, psychosurgery (Baker, 1961) seems to be the best (Shapiro (Ascher, 1948). Of'all therapies, haloperidol (Seignot, et al., 1973b). Further information and the International
can be obtained by reading a classic Registry of this maladie (Abuzzahab
on tics (Meige and Feindel, and Anderson, 1973).
1907)
Our interest in the Tourette's syndrome goes back to 1974 when we tried the tricyclical antifor the treatment depressant chlorimipramine (CLI) (Anafranil, Ciba-Geigy Labs., New Jersey) then, haloperidol was the only available drug in the of obsessive-compulsive symptoms. Until U.S.A. which had some therapeutic efficacy in obsessive-compulsive symptoms. Hence, as haloperidol was also the treatment of choice for Tourette's syndrome where obsessive-compulsive symptoms are present, syllogizing, CL1 was given to two cases of Tourette's with good results (Yaryura-Tobias, 1975). Accordingly, we hypothesized that the psychomotor symptoms could conmovement could be sist of two components: (1) ideational; and (2) motor. Thus, the involuntary thought a priori, its ideation becoming an urge to perform the movement. This paper reports data on clinical aspects of the Gilles de la Tourette syndrome and the chlorimipramine therapeutic efficacy. Methodology Thirteen male and seven female patients, ages ranging from 5 to 52 (2 = 23), were selected movefor this study. Self-rating scales to record Tourette symptoms: simple and complicated compulsions and aggressive behavments, sounds and words (Shapiro et al., 1973a) obsessions, 335
J.A.
336
ior (Yaryura-Tobias and Neziroglu, psychiatric evaluations, routine EEG and hair analysis for mineral
Yaryura-Tobias
and.F.A.
Neziroglu
1975) were utilized at regular.intervals. Psychological and blood chemistries, 5 hr oral glucose tolerance tests (50GTT), tracings were also performed.
Of the twenty patients, ten that improved on haloperidol but had severe side effects (N=4) and/or did not improve (N=6) were placed on CLI, in addition to five new cases. The other five only participated for clinical data collection but never underwent therapy due to personal reasons. Of the fifteen patients that were given CLI, ten were selected for a 6 month double blind placebo (PBO) study, where medication was given for 5 months, followed by PBO for 2 weeks, ending with 2 weeks .of medication. CL1 was given in capsule form (25mg, 5Omg, and IOOmg). Placebo capsules contained lactose. Each patient was kept on his optimum dose administered three times per day. Patients were evaluated through self assessment, clinical observations In addition, return to school, job placement, better performance in their family integration gave us an index of therapeutic response.
and family interviews. milieu and better
Results Clinical data indicated child onset, where tics started in a head down progression,varying in A high incidence of obsessive-compulsive symptoms (89%) was also type, location and intensity. demonstrated, as well as aggressive and destructive behavior (75%). One patient suffered from anorexia nervosa, self destructive behavior and hypervitaminosis A. Sixty-two percent of the patients stated that they thought about their tics and had an urge to perform them at least 50% of the time. Abnormal 50GfT were reported in 54% of the cases and EEG dysrhythmias in 25%. Table Characteristical
J.T. L.W. S.K. B.M. D.C. A.S. R.P. A.K. J.C. A.H. D.F. S.W. F.P. R.B. J.F. R.K. G.D. S.U. J.L. A.S.
information
on twenty
AGE
50 GTT
EEG
27 22 22 19 41 9 24 30 27 52 12 27 22 IO 24 12 23 26 26 5
N N NA N NA NA H N N Ii NA P.D. N H NA NA P.D. P.D. P.D. NA
N NA AB N N NA N NA N AB NA NA NA N NA AB N AB NA NA
Key: N = Normal; AB = Abnormal; H = Hypoglycemia.
I Gilles
Urge to tic
de la Tourette Obsessive compulsive behavior
+ + + + + + + + + + + +
+ + + + + NA + NA NA NA NA
Aggressive behavior
+ + + + + + + + +
NA +
+ + + + + +
+ NA NA NA = Not applicable;
CL1 was given in a range of 25 to 350 mg. (x = 113.33) between two to three weeks from the onset of treatment
patients
P.D. = Pre-Diabetic;
and its therapeutic effect was noticed if not less than 50 mg. o.d. was given.
Gilles
de la Tourette
syndrome
Side effects were usually tolerable and mainly consisting mouth (N=3) sleepiness (N=3) perspiration (N=l) dizziness (N=4).
337
of mild hypotension (N=Z) dry (N-I) sleep walking (N=l) and nausea
Blood chemistries and urine remained within normal limits. Bait analysis in seven tested cases revealed high Cu (N=l) high PB (N=2) high Hg (N=l) high Zn (N=2) and low l& (N-6). Toxic effects were not observed. From our sample population, four parents had obsessive-compulsive symptoms, two parents suffered from facial, neck and shoulder tics and three pairs of siblings had Tourette's. In the open study, CL1 administration controlled 80% to 90% of the symptoms, as evidenced by family reports, clinical evaluations and the self-rating scale. In the double blind study, patients verbally reported recurrences of Tourette's symptoms and the investigator was able to diagnose four out of five cases put on PBO. liowever, the self-rating scale was unable to detect changes during this period. Discussion Our data suggest already mentioned.
an organic
physiopathology
for
this
syndrome,
corroborating
previous
work
Obsessive-compulsive symptoms and the urge to tic places Tourette's within the group of obsessive-compulsive disorders. In these disorders, the therapeutic efficacy of CLI, a potent a 5HI involvement (Yaryura-Tobias, 1976). Contrariwise, serotonin blocking agent, indicates a dopamine blocking agent, implies a catecholamine disturbance (Snyder et at., haloperidol, 1970; Meyerhoff and Snyder, 1973). Furthermore, haloperidol is usually given in high doses in conjunction with anti-parkinsonian medication thereby introducing an anti-cholinergic element in Tourette's therapy. The possibility that haloperidol acts by causing muscular rigidity is difficult to accept because of the concomitant use of anti-parkinsonian agents, yet it should be considered. A review of the pharmacology of the syndrome shows much contradiction (Sweet et at., 1976). Consequently, a conciliatory position seems unlikely. As we know today, different structures of the central nervous system (cerebellum, basal ganglia, thalamus and cortex) interact to control movements. Therefore, biochemical explanations for this syndrome should be entertained in the light of physioanatomical knowledge as well. brain physiological hierarchical levels are interdependent, as are pyramidal and Moreover, the discovery that motor and thalamic regions discharge extrapyramidal systems. Consequently, 1971) may support the observation that Tourette patients may think prior to movements (Evarts, its involuntary nature. Present morphological concept change their movements, thus challenging infer that similar changes might occur in neuro-histochemistry. Low manganese
level
found
in hair
analysis
may suggest
basal
ganglia
pathology.
The failure in the PBO study to detect symptoms recurrence by the use of the self-rating scale could be due to its lack of sensitivity to denote changes within a 2 week period. Fur-. thermore, 2 weeks without medication may not be enough for the reappearance of gross symptoms, relatives and investigators. while fine worsening of the symptoms were observed by patients, The use of CL1 in Gilles de la Tourette offers an alternative to haloperidol. Good efficacy, lack of toxicity and mild side effects of CL1 therapy contrast with partly good results of sometimes irreversible (Shields and haloperidol therapy and the severity of untoward effects, Bray, 1976) the need to associate anticholinergic drugs. Conclusion The high incidence of obsessive-compulsive and aggressive symptoms indicates a psychiatric having Tourette and obparticipation in this neurological syndrome. The presence of siblings sessive-compulsive symptoms and/or tics in family members points to the genetic trait. Chkor with the advantage over haliperidol of having mild imipramine appears to be a good medication, Low manganese and CL1 action on serotonin metabolism, suggest basal ganglia ad side effects.
338
J.A.. Y%yura-Tobias
and .F.A. Nesiroglu
serotonin involvement, respectively. Inquiries wui reprint requests should be addressed to: Dr. J.A. Yaryura-Tobias, North Nassau Mental Health Center, 1691 Northern Boulevard, Manhaaset, L.I., N.Y.
11030,
U.S.A.
References Gilles de la Tourette's syndrome, international ABUZZAIIAB, F.E., SR. and ANDERSON, F.O. (1973). registry. Minxesota Medicine. 56: 492-496. ASCHER, E. (1948). Psychodynamic consideration in Gilles De La Tourette's disease (maladie des tics). Am. J. Psych&t. 105: 267-276. BAKER, E.F.W. (1962). Gillesx La Tourette's disease treated by biomedial frontal leucotomy. Can. Med. Ass. J. 86: 746-747. CHALLAS, G., CHAPEL,?.L. and JENKINS, R.L. (1967). Tourette's disease: Control of symptoms and its clinical course. Int. J. Neuropsychiat. 3: 95-109. ERICKSON, M.B. (1964). Experimental hypnotherapy ii Tourette's disease. Am. J. Clin. Hypnoeis. 7: 325-331. EVGTS, E.V. (1971). Activity of thalamic and cortical neurons in relation to learned movement in the monkey. Int. J. Neml. 8: 321-326. FERNANDO, S.J.M. (1967). Gilles DT La Tourette's Syndrome: A report on four cases and a review of published case reports. BP. J. Psych&t. 113: 607-617. ITARD, J.M.G. (1825). Memoire sur quelques fonxons involuntairee,des appareils de la locomotion, de la pr6hension et de la voix. Arch. Gen. Med. 8: 385-407. LOGUE, P.E., PLATZEK, D. and HUTZELL, R. (1973). NeurologiFal, neuropsychological and behavioral Perceptual hnd Motor Skills. 37: aspects of Gilles De La Tourette's syndrome: A case. 855-861. LUCAS, A.R. and RODIN, E.A. (1973). Electroencephalogram in Gilles De La Tourette's disease. Dis. Nerv. Syst. 34: 85-89. MEIGE, H. and FFINDX, E. (1907). Tic8 and their Treatment, pp. 349. William Wood, New York. MEYERHOFF, J.L. and SNYDER, S.H. (1973). Gilles De La Tourette's disease and minimal brain dysfunction: Amphetamine isomers reveal catecholamine correlates in an affected patient. Psychophazvuc. IBerl.1 20: 211-220. MOLDOFSKY, Il., TULLIS, C. Gd LAMON, R. (1974). Multiple tic syndrome (Gilles De La Tourette's Syndrome). Clinical, biological and psychosocial variables and their influence with haloperidol. J. Nerv. Ment. Di.9. 15: 282-292. SEIGNOT, M.J.N. (1961). A ca8e of the syndrome of tics of Gilles De La Tourette controlled by R 1625. Am. Med. Psychol. 119: 578-579. SHAPIRO, A.K., SHAPIRO, E. an=AYNE, H.L. (1973a). The symptomatology and diagnosis of Gilles De La Tourette's syndrome. J. Am. Acad. child Psych. 12: 702-723. SHAPIRO, A.K., SHAPIRO, E. and WAYNE, H.L. (1973b). Treatment of Tourette's syndrome with haloperidol, Review of 34 cases. Arch. Gen. Psychiat. 28: 92-97. SHAPIRO, A.K., SHAPIRO, E. and WAYNE, H.L. (1973c). Orga& factors in Gilles De La Tourette's syndrome. BP. J. Psychiat. 122: 659-664. SHIELDS, W.D. and BRAY, P.F. (1976). A danger of haloperidol therapy in children. J. Pediat. 88: 301-303. SEER, S.H., TAYLOR, K.M., COYLE, J.T. and MEYERHOFF, J.L. (1970). The role of brain dopamine in behavioral regulation and the actions of psychotropic drugs. Am. J. Psychiat. 127: 199-207 SWEET, R.D., BRUUN, R.D., SHAPIRO, A.K. and SHAPIRO, E. (1976). The pharmacology of Gilles De In: Clinical NeuroQhamnacology, Klawans, H.L. La Tourette's syndrome (chronic multiple tic). (ed.) pp. 81-105. Raven Press, New York. TEOH, J.I. (1974). Gilles De La Tourette's Syndrome: A study of the treatment of six cases by mass negative practice and with haloperidol. Singapore Med. J. 15: 139-146. DE LA TOUBETTE, G. (1885). Etude sur une affection nerveuse caracterisee par l'incoordination motrice accompagnee d'echolalie et de coprolalie. Arch. Neural. 9: 158-200. Gilles De La Tourette's VAN WOERT, M.H., JUTKOWITZ, R., ROSENBAUM, D. and BOWERS, M.G. (1975). syndrome: Biochemical approaches. Presented at Association for Research in Nervous and Mental Diseases, New York, December. YARYURA-TOBIAS, J.A. (1975). Chlorimipramine in Gilles De La Tourette's disease. Am. J. Psych&t. 132: 11, 1221. YARYURA-TmS, J.A. (1976). Obsessive-compulsive disorders: A serotonergic hypothesis. Presented at Society of Biological Psych., San Francisco. YARYURA-TOBIAS, J.A. and NEZIROGLU, F.A. (1975). The action of chlorimipramine in obsessivecompulsive neurosis: a pilot study. Curr. Ther. Res. 17: 111-116. YATES, A.J. (1958). The application of learning theory z the treatment of tics. J. Abnon. Sot. Psychol. -52: 175-182.
Nezuv-Psychophamc.
Vol.
1, pp. 335-338,
1977.
.Pergamon Prese.
Printed
in Great
Britain.
GILLES DE LA TOURETTE SYNDROME: A NEW CLINICO-THERAPEUTIC APPROACH
North
J. A. YARYURA-TOBIAS and F. A. NEZIROGLU Division of Research Nassau Mental Health Center, Manhasset, L.I., New York, (Final
form,
July
U.S.A.
1977)
Abstract 1. 2. 3. 4.
This investigation has yielded aggression and obsessive-compulsiveness as additional psychiatric symptoms to the neurological Gilles de la Tourette syndrome. Obsessive-compulsive relatives, as well as other Tourette family members seemed affected, suggesting a role of the genetic factors. Clinical data obtained in fifteen patients showed that chlorimipramine (CLI) a potent serotonergic blocking agent appears to have a good efficacy, with the advantage over haloperido1 of having mild side effects. A serotonin disturbance as a causative factor was hypothesized.
Keywords:
Tourette
syndrome,
chlorimipramine,
serotonin,
obsessive-compulsive.
Introduction Itard (1825) and later, Gilles de la Tourette (1885) described a syndrome characterized by uncoordinated movements, noises and echolalia. Additional symptoms included obsessions, compulsions, aggressive behavior (Moldofsky et al., 1974) and self-mutilation (Van Woert et al., 1975). The usual onset is childhood, with a chronic course, and a cephalocaudal progression of changing tics. The bizarre and proteiform symptomatology suggest a psychological etiology, or a combination of psychological and organic factors (Challas et at., 1967; Lucas and Rodin, 1973; Shapiro et aZ., 1973c; Logue et al., 1973) while for others, the causation remains unknown (Fernando, 1967). Psychobiological treatments include: behavorial therapy (Yates, 19581, hypnosis (Erickson, 1962). mass negative practice (Teoh, 1974) and psychotherapy 19641, psychosurgery (Baker, 1961) seems to be the best (Shapiro (Ascher, 1948). Of'all therapies, haloperidol (Seignot, et al., 1973b). Further information and the International
can be obtained by reading a classic Registry of this maladie (Abuzzahab
on tics (Meige and Feindel, and Anderson, 1973).
1907)
Our interest in the Tourette's syndrome goes back to 1974 when we tried the tricyclical antifor the treatment depressant chlorimipramine (CLI) (Anafranil, Ciba-Geigy Labs., New Jersey) then, haloperidol was the only available drug in the of obsessive-compulsive symptoms. Until U.S.A. which had some therapeutic efficacy in obsessive-compulsive symptoms. Hence, as haloperidol was also the treatment of choice for Tourette's syndrome where obsessive-compulsive symptoms are present, syllogizing, CL1 was given to two cases of Tourette's with good results (Yaryura-Tobias, 1975). Accordingly, we hypothesized that the psychomotor symptoms could conmovement could be sist of two components: (1) ideational; and (2) motor. Thus, the involuntary thought a priori, its ideation becoming an urge to perform the movement. This paper reports data on clinical aspects of the Gilles de la Tourette syndrome and the chlorimipramine therapeutic efficacy. Methodology Thirteen male and seven female patients, ages ranging from 5 to 52 (2 = 23), were selected movefor this study. Self-rating scales to record Tourette symptoms: simple and complicated compulsions and aggressive behavments, sounds and words (Shapiro et al., 1973a) obsessions, 335
J.A.
336
ior (Yaryura-Tobias and Neziroglu, psychiatric evaluations, routine EEG and hair analysis for mineral
Yaryura-Tobias
and.F.A.
Neziroglu
1975) were utilized at regular.intervals. Psychological and blood chemistries, 5 hr oral glucose tolerance tests (50GTT), tracings were also performed.
Of the twenty patients, ten that improved on haloperidol but had severe side effects (N=4) and/or did not improve (N=6) were placed on CLI, in addition to five new cases. The other five only participated for clinical data collection but never underwent therapy due to personal reasons. Of the fifteen patients that were given CLI, ten were selected for a 6 month double blind placebo (PBO) study, where medication was given for 5 months, followed by PBO for 2 weeks, ending with 2 weeks .of medication. CL1 was given in capsule form (25mg, 5Omg, and IOOmg). Placebo capsules contained lactose. Each patient was kept on his optimum dose administered three times per day. Patients were evaluated through self assessment, clinical observations In addition, return to school, job placement, better performance in their family integration gave us an index of therapeutic response.
and family interviews. milieu and better
Results Clinical data indicated child onset, where tics started in a head down progression,varying in A high incidence of obsessive-compulsive symptoms (89%) was also type, location and intensity. demonstrated, as well as aggressive and destructive behavior (75%). One patient suffered from anorexia nervosa, self destructive behavior and hypervitaminosis A. Sixty-two percent of the patients stated that they thought about their tics and had an urge to perform them at least 50% of the time. Abnormal 50GfT were reported in 54% of the cases and EEG dysrhythmias in 25%. Table Characteristical
J.T. L.W. S.K. B.M. D.C. A.S. R.P. A.K. J.C. A.H. D.F. S.W. F.P. R.B. J.F. R.K. G.D. S.U. J.L. A.S.
information
on twenty
AGE
50 GTT
EEG
27 22 22 19 41 9 24 30 27 52 12 27 22 IO 24 12 23 26 26 5
N N NA N NA NA H N N Ii NA P.D. N H NA NA P.D. P.D. P.D. NA
N NA AB N N NA N NA N AB NA NA NA N NA AB N AB NA NA
Key: N = Normal; AB = Abnormal; H = Hypoglycemia.
I Gilles
Urge to tic
de la Tourette Obsessive compulsive behavior
+ + + + + + + + + + + +
+ + + + + NA + NA NA NA NA
Aggressive behavior
+ + + + + + + + +
NA +
+ + + + + +
+ NA NA NA = Not applicable;
CL1 was given in a range of 25 to 350 mg. (x = 113.33) between two to three weeks from the onset of treatment
patients
P.D. = Pre-Diabetic;
and its therapeutic effect was noticed if not less than 50 mg. o.d. was given.
Gilles
de la Tourette
syndrome
Side effects were usually tolerable and mainly consisting mouth (N=3) sleepiness (N=3) perspiration (N=l) dizziness (N=4).
337
of mild hypotension (N=Z) dry (N-I) sleep walking (N=l) and nausea
Blood chemistries and urine remained within normal limits. Bait analysis in seven tested cases revealed high Cu (N=l) high PB (N=2) high Hg (N=l) high Zn (N=2) and low l& (N-6). Toxic effects were not observed. From our sample population, four parents had obsessive-compulsive symptoms, two parents suffered from facial, neck and shoulder tics and three pairs of siblings had Tourette's. In the open study, CL1 administration controlled 80% to 90% of the symptoms, as evidenced by family reports, clinical evaluations and the self-rating scale. In the double blind study, patients verbally reported recurrences of Tourette's symptoms and the investigator was able to diagnose four out of five cases put on PBO. liowever, the self-rating scale was unable to detect changes during this period. Discussion Our data suggest already mentioned.
an organic
physiopathology
for
this
syndrome,
corroborating
previous
work
Obsessive-compulsive symptoms and the urge to tic places Tourette's within the group of obsessive-compulsive disorders. In these disorders, the therapeutic efficacy of CLI, a potent a 5HI involvement (Yaryura-Tobias, 1976). Contrariwise, serotonin blocking agent, indicates a dopamine blocking agent, implies a catecholamine disturbance (Snyder et at., haloperidol, 1970; Meyerhoff and Snyder, 1973). Furthermore, haloperidol is usually given in high doses in conjunction with anti-parkinsonian medication thereby introducing an anti-cholinergic element in Tourette's therapy. The possibility that haloperidol acts by causing muscular rigidity is difficult to accept because of the concomitant use of anti-parkinsonian agents, yet it should be considered. A review of the pharmacology of the syndrome shows much contradiction (Sweet et at., 1976). Consequently, a conciliatory position seems unlikely. As we know today, different structures of the central nervous system (cerebellum, basal ganglia, thalamus and cortex) interact to control movements. Therefore, biochemical explanations for this syndrome should be entertained in the light of physioanatomical knowledge as well. brain physiological hierarchical levels are interdependent, as are pyramidal and Moreover, the discovery that motor and thalamic regions discharge extrapyramidal systems. Consequently, 1971) may support the observation that Tourette patients may think prior to movements (Evarts, its involuntary nature. Present morphological concept change their movements, thus challenging infer that similar changes might occur in neuro-histochemistry. Low manganese
level
found
in hair
analysis
may suggest
basal
ganglia
pathology.
The failure in the PBO study to detect symptoms recurrence by the use of the self-rating scale could be due to its lack of sensitivity to denote changes within a 2 week period. Fur-. thermore, 2 weeks without medication may not be enough for the reappearance of gross symptoms, relatives and investigators. while fine worsening of the symptoms were observed by patients, The use of CL1 in Gilles de la Tourette offers an alternative to haloperidol. Good efficacy, lack of toxicity and mild side effects of CL1 therapy contrast with partly good results of sometimes irreversible (Shields and haloperidol therapy and the severity of untoward effects, Bray, 1976) the need to associate anticholinergic drugs. Conclusion The high incidence of obsessive-compulsive and aggressive symptoms indicates a psychiatric having Tourette and obparticipation in this neurological syndrome. The presence of siblings sessive-compulsive symptoms and/or tics in family members points to the genetic trait. Chkor with the advantage over haliperidol of having mild imipramine appears to be a good medication, Low manganese and CL1 action on serotonin metabolism, suggest basal ganglia ad side effects.
338
J.A.. Y%yura-Tobias
and .F.A. Nesiroglu
serotonin involvement, respectively. Inquiries wui reprint requests should be addressed to: Dr. J.A. Yaryura-Tobias, North Nassau Mental Health Center, 1691 Northern Boulevard, Manhaaset, L.I., N.Y.
11030,
U.S.A.
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