Neurosurgical treatment of tourette's syndrome: A critical review

Neurosurgicai Treatment of Tourette's Syndrome: A Critical Review Scott L. Rauch, Lee Baer, G. Rees Cosgrove, and Michael A. Jenike Some patients with Tourette's syndrome (TS) remain disabled despite conventional treatment. Recently, neurosurgical procedures have been reported to be potentially effective interventions for such intractable cases. Clinicians are now being asked to make recommendations to patients about these candidate operations. This review explores the reported experience with neurosurgical treatment of TS to assess critically the evidence regarding risks and benefits. Toward that end, the rationale for the various procedures and the relevant neuroanatomy are outlined and recommendations for patient selection and management of future cases are discussed. We reviewed all available published reports on this subject and two unpublished cases, totaling 36 patients. Although a variety of operations have been used to treat TS, there is limited

evidence pertaining to the risks or benefits of any surgical procedure. Neurosurgical treatment of TS remains experimental, since there is only anecdotal experience with these operations. Furthermore, there is no compelling evidence that any neurosurgical procedure is superior to all others. If these experimental neurosurgeries are to continue, guidelines should be developed regarding patient and operation selection, and interdisciplinary assessment committees should implement such guidelines at institutions where these operations are performed. Moreover, future cases should be prospectively studied using contemporary technologies to assess lesion placement and size and validated clinical instruments to characterize patients and assess outcome, including adverse effects. Copyright © 1995 by W.B. Saunders Company

OURETTE'S SYNDROME (TS), or To-

experience with neurosurgical treatment of TS. Case report data are presented first, followed by discussion of relevant neuroanatomy and clinical considerations. Recommendations regarding future study of these controversial operations are presented, based in part on the authors' experience with neurosurgical treatment of obsessive-compulsive disorder (OCD). 9

T urette's disorder, is a neuropsychiatric con-

dition characterized by motor and vocal tics, lasting longer than 1 year and emerging before age 21. I The estimated prevalence of TS is approximately 0.5%, with a preponderance in males versus females of at least 3:1. 2,3 The motor movements and vocalizations can often be temporarily suppressed, although the occurrence of tics, especially in public, can be humiliating and socially and vocationally debilitating. Pharmacotherapy has been the mainstay of treatment. Antidopaminergic agents such as haloperidol and pimozide, 24 the e~2-adrenergic agonist clonidine, 3,6,7 and the benzodiazepine clonazepam 3,6 have all been demonstrated to be beneficial for some TS patients. One recent study suggested that the behavior-therapy technique of habit reversal can also be effective.8 Despite adequate trials of these conventional therapies, some TS patients have residual debilitating symptoms. Neurosurgical treatments have been attempted in a few treatment-refractory TS patients. Recently, patients and clinicians have become increasingly interested in these surgical procedures as anecdotal successes have been publicized. However, important unanswered questions remain regarding the scientific rationale, clinical evaluation, patient selection, safety, efficacy and ethics surrounding such surgical procedures. The present review examines the reported

NEUROSURGICAL PROCEDURES USED IN TS

A variety of neurosurgical procedures have been performed in attempts to treat TS (Fig 1). Reports to date have described (1) frontal lobe operations (i.e., frontal lobotomy and bimedial frontal leukotomy), (2) limbic system operations (i.e., anterior cingulotomy, limbic leukotomy), (3) a novel multisite operation (i.e., anterior cingulotomy combined with infrathalamic lesions), (4) thalamic operations (i.e., bilateral coagulation of rostral intralaminar and medial thalamic nuclei, and ventral-tier thalamic lesions), and (5) a cerebellar operation (i.e., bilateral cerebellar dentatotomy). From the Obsessive Compulsive Disorders Clinical and Research Unit, Department of Psychiatry, and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Address reprint requests to Scott L. Rauch, M.D., Department of Psychiatry, OCD Unit, 9th Floor, Massachusetts General Hospital-East, 149 Thirteenth St, Charlestown, MA 02129. Copyright © 1995 by W.B. Saunders Company 0010-440X/95/3602-0001503.00/0

ComprehensivePsychiatry, Vol. 36, No. 2 (March/April), 1995: pp 141-156

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Fig 1. Relevant neuroanatomy and approximate locations of different lesion target sites for the various neurosurgical procedures are depicted in a highly schematized illustration of the brain in parasagittal section. The exact method, size, and placement of lesions have evolved for a number of these surgeries. In particular, whereas bimedial frontal leukotomy and cingulotomy were at one time performed as freehand procedures, these are now performed with greater precision via stereotactic placement of lesions. Note that limbic leukotomy entails combining the stereotactic lesions of anterior cingulotomy and bimedial frontal leukotomy. D.E. Richardson's novel procedure entails combining infrathalamic lesions and anterior cingulotomy. The lesions of frontal Iobotomy (a gross freehand procedure) are not shown.

CASE

REPORTS:

NEUROSURGERY

FOR TS

Table 1 lists all cases of neurosurgery for TS reviewed herein (N = 36). Cases appearing in peer-reviewed literature were identified via a search conducted using Paper Chase (Paper Chase, Boston, MA). Non-peer-reviewed sources were identified by cross-referencing from the bibliographies of peer-reviewed sources, and well-known neurosurgical texts. Data from additional unpublished cases were communicated to us by colleagues with relevant experience. The case summaries that follow are organized according to the type of operation performed. The degree of detail provided in the case reviews reflects that available from the original reports. For some cases, only summary data are available.

Frontal Lobe Operations (two cases) In 1964, Stevens reported a case of transorbital (frontal) lobotomy performed in 1955 by Dr. James Watts on a 37-year-old man suffering from TS. 1° The patient was

educated through age 15, had no employment history, and remained dependent on his parents throughout adulthood. At age 8, he developed a motor tic followed by vocal tics, including coprolalia. His repertoire of tics varied, as did the intensity. Motor tics primarily consisted of rhythmic head movements, throwing out his arms, and "a violent generalized shudder" that was combined with copralalic utterances. Later, he developed echolalia and echopraxia. His tics occasionally led to bumping his head, and his barking kept his family awake at night. The tics were reported to occur at a frequency of five to seven per minute when he was relaxed. The severity and persistence of his symptoms left him debilitated. There was no other significant medical history. Family history was "negative." He had been examined by several renowned physicians of the era (including Adolph Meyer and Sir Henry Head) and had received psychotherapy and occupational therapy to no avail. He was noted to be pleasant and cooperative but "childish" on psychiatric examination. No other abnormalities were noted

NEUROSURGERY FOR TOURETTE'S SYNDROME

on neurologic examination. An electroencephalogram (EEG) and a pneumoencephalogram were normal. Stevens noted, "He not only recognized the absurdity and impropriety of his verbal explosions but found it increasingly intolerable and was desperate for help . . . . In the light of the patient's incapacity, the prolonged duration and prospect of further progression, a transorbital lobotomy was performed...,,m By report, he became more relaxed in the postoperative period and continued to improve over the next several weeks, although these observations were confounded by the addition of chlorpromazine (100 mg/d) during this time. (No mention was made of preoperative pharmacologic interventions.) He was, for the first time, able to attend social events without being disruptive. Two years of follow-up evaluation found a marked decrease in frequency, duration, and amplitude of tics, and at 9 years these gains persisted. There were no reported adverse psychiatric or neurologic sequelae, although no formal testing was described. The researcher did allude to postoperative obesity, another observation confounded by addition of neuroleptic therapy. Stevens provided no theoretic justification for the potential efficacy of frontal lobotomy. This anecdotal report was uncontrolled, and most glaring is the confounding influence of neuroleptic treatment in the postoperative period. No formal preoperative or postoperative testing was performed to gauge clinical improvement or adverse effects. The potential adverse effects of frontal lobotomy have subsequently become well known. In 1962, Baker jl described a bimedial frontal leukotomy performed on a 22-year-old man with TS. The patient had suffered birth trauma in conjunction with a 3-day labor. Hypotonicity, a "deformed head," and an inability to cry or suckle were evident at birth. Developmental delays included slow motor development with "weakness and incoordination" and failure to speak until 30 months. He suffered grand mal seizures at 3 and 5 years of age. Motor and vocal tics were noted at age 9 and gradually worsened. He was also enuretic until age 12. At age 16, he was dismissed from school due to TS symptoms, despite otherwise good academic performance. Panic symptoms emerged at age 20, and he became progressively hopeless thereafter while suffering from intrusive violent and sexual fantasies. Neuropsychiatric treatment throughout childhood was of little benefit. Pharmacologic treatment with chlorpromazine (up to 700 mg/d) "afforded a slight reduction of the tic," but had no effect on panic. Preoperatively, his repertoire of tics consisted of a variety of motor tics and a frequent neck jerk accompanied by a cupping of his hand over one ear while shouting out "eh!". He also exhibited occasional coprolalia. His tic frequency during a teaching rounds was 14 per minute (although this was coincident with a period of chlorpromazine withdrawal). His mental status was otherwise unremarkable on examination. His 1Q was said to be 110, and "personality tests" were interpreted as suggestive of "obsessional personality." Physical examination showed pallor of the right optic disk (he had undergone surgery for a right esotropia) and left-sternocleidomastoid hypertrophy (attributed to his tor-

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ticollic tics). Spinal fluid analysis, EEG, air encephalogram, and right-carotid arteriogram were all normal. His operation was complicated by a staphylococcal frontal abscess with grand mal seizures, which was relieved by aspiration and treatment with antibiotics and (unspecified) anticonvulsants. Additional details pertaining to the operation were not provided. During the 14-month postoperative follow-up period, his tics and panic were reported to be "markedly reduced" and he was successfully attending night school. When he was again presented at teaching rounds, only two tics were observed during a 30-minute period. The medical regimen at the time of that assessment was not specified. He was discharged on treatment with chlorpromazine (up to 800 mg/d) and phenytoin (which when given preoperatively had no effect on his tics). The "destructive fantasies" abated, but he continued to exhibit a short attention span and avoidance of social situations. His IQ was subsequently measured at 115. Baker's TS patient suffered from concurrent symptoms reminiscent of depression, OCD, panic disorder, and attentional deficits, and all but the attentional deficits were observed to remit postoperatively. According to Baker, the indications for the frontal lobe procedure were the patient's hopelessness (possibly a depressive symptom), destructive thoughts (possibly obsessions), and panic; the response with regard to tics was to some extent unanticipated.

Limbic System Surgery (five cases) Robertson et al. 12 reported in 1990 the case of a 19-yearold man with TS and self-injurious behaviors who was treated by limbic leukotomy. A cesarean delivery precipitated by placenta previa complicated the patient's birth and necessitated a 4-day postpartum hospital stay. His development proceeded normally until age 5 and a half, when facial tics emerged. Over the subsequent 10 years he exhibited a wide variety of motor tics, and at age 15 he developed symptoms of OCD including repeating and checking compulsions and "distasteful" and "lurid" intrusive thoughts. At age 16 he developed grunts, which at 17 evolved into coprolalia and were accompanied by a variety of selfinjurious behaviors (e.g., lip-biting, head-banging, and selfburning with cigarettes). He became obsessed with the notion that he might jump off a building, developed an irresistible urge to touch the back of his eye, and caused repeated injury to his cornea. Preoperatively, his physical examination was otherwise normal. A brain computed tomography (CT) scan and EEG were normal. A magnetic resonance imaging (MRI) scan showed a high-signal focus in the region of the right globus pallidus. Neuropsychologic testing found a verbal IQ of 117 and performance IQ of 114. Initially, pharmacologic treatment with sulpride (200 mg twice daily) abolished the motor tics, but despite an increase in the dose (up to 1 g/d), the self-injurious behavior persisted. He was hospitalized due to increasing risk of self-enueleation, and at that time he evidenced symptoms of major depression. Additional interventions with chlorprothixene (a dopamine antagonist; 500 mg/d) and clomipramine (an antiobsessional/antidepressant; 200 mg/d) along with behavioral response-prevention techniques "led to

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minor improvements." Addition of L-tryptophan proved unsuccessful. He developed other self-injurious behaviors, causing damage to his nose, and also began to perform the Valsalva maneuver so violently that he caused "extensive" petechial hemorrhages (location not specified). After detailed discussion with the patient, his family, and two consultant psychiatrists, as well as consideration by an independent Mental Health Review Tribunal, he was referred for neurosurgical treatment. The procedure performed was a stereotactic bilateral limbic leukotomy, entailing bilateral lesions of the lower middle quadrants of the frontal lobes, as well as the anterior cingulum. Placement of lesions was confirmed by MRI postoperatively. The patient was reported to exhibit some agitation initially, which resolved spontaneously, resulting in an otherwise "uneventful" postoperative course. After the operation, he transiently displayed "mild apathy, a mild degree of intellectual impairment, and some minor organizational problems and difficulties in concentration." By 2 days postoperatively, compulsions had markedly decreased, and by 6 weeks had resolved entirely. Thereafter, he continued a course of behavioral therapy. His improvement in OCD symptom severity was quantified via the Leyton Obsessional Scale 13 from 17 to 8 and the Maudsley Compulsion Checklist 14 from unspecified preoperatively to 1. His Beck Depression Inventory (BDI) J5 score remained unchanged at 4. He was discharged from an inpatient setting 2 months after the surgery, and between 2 and 4 months postoperatively he continued to make functional progress, entered a training program, and later attained gainful employment. At 2 years' follow-up evaluation, while being maintained on sulpride (1,600 nag/d), the manifestations of his TS were limited to a single shoulder tic (improvement estimated at 75% from baseline). He was free of self-destructive behavior, but continued with "bouts of verbal aggression and periods of self-doubt and anxiety." Noting the overlap between OCD and TS, Robertson et al. 12suggested that self-injurious behaviors may represent a unique brand of compulsion, more common in TS than in primary OCD. Their rationale for choosing limbic leukotomy rested on the theoretic role of the cingulate cortex in modulating emotionally charged language and stereotyped movements, as well as its anatomic relationship with midbrain dopaminergic systems, which have been implicated in the pathophysiology of TS. 12,16They further cited positron-emission tomography (PET) studies 17 implicating metabolic abnormalities in the cingulate cortex of TS subjects. Robertson et al. also referenced an abstracted case report 18 that was later published as an original article by Kurlan et al. 19in 1990 reporting a series of two patients with TS and comorbid OCD treated with bilateral radiofrequency anterior cingulotomy. The first of their 19cases was a 28-year-old man who developed facial tics at age 5 that lasted several months and then spontaneously remitted, only to have recurrence at age 13 of symptoms consisting of truncal tics and violent obsessive thoughts. Since age 12, he had exhibited mood swings and was diagnosed with bipolar disorder. His affective symptoms were well controlled with lithium (2,100 mg/d). At 19, he developed echopraxia along

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with vocal tics in the form of echolalia and palilalia, as well as additional symptoms of OCD (e.g., repetitive standing and sitting, touching of door frames, and preoccupation with odd and even numbers). The OCD symptoms were debilitating: he had difficulty with daily activities and was socially isolated and unemployed. Pharmacologic treatments, including imipramine, tranylcypromine, clonidine, trazodone, several neuroleptics, and carbamazepine, were ineffective. The combination of haloperidol (3 mg/d) and benztropine (4 mg/d) led to mild improvement. At age 21, he had a psychotic episode that responded to treatment with lithium and trifluoperazine. At 24, motor and vocal tics returned, with variable repertoire (including coprolalia) and intensity. Preoperative physical examination was unremarkable, other than the multiple tics observed. EEG was "mildly abnormal" with "bursts of high-voltage sharp theta waves posteriorly without clinical accompaniment," and a CT scan of the brain was noncontributory. The decision to proceed with the operation was apparently based on the patient's severe disability and failure to respond to an extensive array of other treatments. The operation and immediate postoperative period were uncomplicated. No postoperative neuroimaging was performed to confirm lesion placement or size. At the 2-year follow-up evaluation, the patient was noted to have "persistent although modest improvement in his ritualistic activities, obsessions, and functional abilities." These gains were not quantified by validated rating scales, but were globally estimated at "25% to 30% improved." The progress in OCD symptoms was confounded by postoperative addition of clomipramine (225 mg/d) and clonazepam (1 mg/d) to his previous maintenance regimen of haloperidol and lithium. Kurlan et al. stated clearly that "no effects on tics or coprolalia were noted following surgery." Case no. 2 of their series 19 was a 22-year°old man with a history of developmental speech and motor delays who developed vocal tics and ritualistic behaviors (e.g., a preoccupation with the color green, wearing and using items only of that color). At age 10, motor tics emerged and the diagnosis of TS was made. A trial of haloperidol (2 mg/d) resulted in "mild improvement" of the tics. Since some facial movements were correlated with right-temporal sharpwave activity on EEG, a trial of mephobarbital (300 mg/d) was also begun. From age 13 to 16, he developed a broad repertoire of motor and vocal tics. Treatment with haloperidol eventually precipitated a catatonic state, which resolved within 1 month in response to medication discontinuation. After medication withdrawal, his tics gradually improved, only to worsen again after a few months. At age 16, he required hospitalization and suffered weight loss (other symptoms of depression are not mentioned). During the ensuing 15 months, he underwent a variety of medication trials (i.e., haloperidol, imipramine, clonidine, clonazepam, and tranylcypromine), as well as a course of electroconvulsive therapy (details not available). Due to his degree of debility and failure to respond to an exhaustive array of conventional therapies, a bilateral radiofrequency stereotactic anterior cingulotomy was performed. A 10-day postoperative period was marked by "improvement in spontaneous movements and ability to perform

NEUROSURGERY FOR TOURETTE'S SYNDROME

daily activities." However, by 2 months' follow-up, symptoms had returned to preoperative severity. Eight months postoperatively, he continued to exhibit motor and vocal tics. A second cingulotomy procedure was performed to enlarge the lesions. No neuroimaging procedures were performed postoperatively to document lesion size or location, nor were formal rating scales used to quantify changes in clinical severity. Two months after the second cingulotomy, he was noted to show "moderate improvement in ritualistic behavior but continued to need assistance with daily activities." Subsequent pharmacologic trials included trazodone, trihexyphenidyl hydrochloride, and lithium, without benefit. Three months after the operation, a trial of reserpine (2.5 mg/d) led to "moderate functional improvement" and increasing independence. By 1 year postoperatively, he was attending school and living independently in a residential facility. Motor and vocal tics persisted postoperatively, although their character, variety, and severity were neither quantified nor explicitly compared with the preoperative state. However, in their summary, Kurlan et al. pointed out that "tics were not alleviated by cingulotomy in our patients or in the case reports by Robertson et al." Subsequently, Baer et al.2° reported an additional case of anterior cingulotomy for OCD in a 35-year-old man with concomitant TS. This patient's experience is instructive because OCD symptoms improved after cingulotomy, whereas tics were unchanged or slightly worse. He had onset of both OCD and TS symptoms at age 5, characterized by a wide variety of counting, repeating, and touching rituals along with urges to blurt out obscenities and numerous motor and vocal tics numbering in the hundreds per day. These symptoms persisted into adulthood. Interestingly, he reported that he was easily able to distinguish between his OCD and TS symptoms based on his subjective experience. When assessed via structured clinical interview, he met criteria for OCD, TS, major depression, dysthymia, and alcohol abuse (which he reported was the only treatment that helped control his tics), with an axis II diagnosis of mixed personality disorder. His OCD symptoms had failed to respond to trials of behavioral therapy and adequate trials of clomipramine, fluoxetine, haloperidol, pimozide, and clonidine. Therefore, in the context of severe and treatment-refractory OCD, he was referred for cingulotomy. Immediately before his first cingulotomy, while taking fluoxetine (60 mg/d), the patient's score on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) 21 was 26 and his score on the BDI was 28. (The YBOCS is a validated measure of OCD symptom severity. Obsessions and compulsions are each rated along five separate dimensions on a 0 to 4-point scale, yielding a maximum score of 20 for obsessions, 20 for compulsions, and 40 total. Entry criteria for OCD treatment studies, for example, typically require a total YBOCS score > 15, which is equated with at least moderate symptom severity.) He underwent a bilateral thermal radiofrequency stereotactic cingulotomy via bur holes in 1989 with an uncomplicated postoperative course. At 3 months' follow-up evaluation, on the same medication, he reported a decrease in urges to touch and break things, but his tics were minimally

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increased (with reported emergence of a new vocal tic). His YBOCS score was 12 and BDI score was 15, and Clinical Global Improvement (CGI) 9reflected that his OCD, depression, and anxiety were "slightly better." At 18 months after the first operation, he returned for evaluation before a second cingulotomy. His YBOCS score was 22 and BDI score was 10. Compared with baseline, on CG1 he reported that his depression and anxiety were "much improved," but that his OCD and tics were "not improved." In 1991, he underwent a second bilateral anterior cingulotomy to extend the original lesions. Again, the immediate postoperative course was unremarkable. At the most recent follow-up evaluation, 13 months after the second operation, his YBOCS score was 1I, and on CGI, his OCD and anxiety were "much improved," depression was "very much improved," and tics were "minimally worse." This patient apparently experienced improvement in OCD, anxiety, and depression after cingulotomy, whereas his tics were minimally worse. Although this patient was evaluated prospectively, the follow-up evaluation emphasized OCD symptoms because OCD was the indication for his procedure and TS had not been the focus of the team's prospective research effort. Finally, Sawle et al.22 reported the case of a 45-year-old man with comorbid TS and OCD who underwent a limbic leukotomy. The patient had developed motor tics at age 7 years, with emergence at age 10 of "urges" to break things, expose himself, burn money, and destroy clothes. At 35, in addition to persisting motor tics, he developed echolalia, coprolalia, self-injurious compulsions, contamination obsessions, hoarding, and obsessional slowness. This constellation of symptoms led to legal difficulties and loss of employment. Psychiatric and neurologic evaluations at that time showed no abnormalities other than TS and OCD. Specifically, a brain MRI scan was normal and neuropsychologic testing yielded a verbal IQ of 108 and performance IQ of 104. The patient underwent a broad array of conventional treatments for OCD and TS. Behavioral therapy met with initial success, but within 2 months his condition had relapsed to pretreatment levels of symptom severity. Pharmacologic trials included carbamazepine, chlorpromazine, clomipramine, clonazepam, fluvoxamine, haloperidol, pimozide, procyclidine, propranolol, and sulpride "without sustained benefit." Doses and durations of treatment were not specified. The patient was deemed totally disabled by his OCD and TS symptoms. In the face of his treatment refractoriness, he was approved for neurosurgical treatment by the Mental Health Commission and referred for surgery. Of note, in the original report the operation was correctly termed a limbic leukotomy, but was described as entailing anterior cingulotomy plus anterior hypothalamic lesions.22 Subsequently, it has been confirmed that the actual targets were those of conventional limbic leukotomy, i.e., anterior cingulate plus frontothalamic fibers (personal communication, G.V. Sawle, July 1994). Postoperatively, the patient exhibited a striking and progressive improvement in both TS and OCD symptoms. There is no mention of postoperative complications or adverse effects. Specifically, at the 1-month follow-up evaluation, repeat neuropsychologic testing demonstrated a verbal IQ of 114 and performance IQ of 97. At 3 months postoperatively, reduction of OCD symptoms was

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"considerable"; at 6 months, he showed "overall 70% improvement"; and at 19 months, "he was living independently with no clinical signs of [TS]" and his OCD continued "substantially improved." The case reported by Sawle et al.22is most valuable in that the investigators present the results of PET studies performed before and after surgery. Normalized cerebral metabolic rates of oxygen consumption decreased substantially from preoperative to postoperative studies in the caudate, anterior cingulate, medial frontal cortex, and thalamus. These findings, although anecdotal, are convergent with recent PET studies of OCD symptom provocation 23 and OCD symptom improvement,z4,25 Implications of PET data with respect to TS are difficult to interpret, given the confounding factor of OCD comorbidity. Nonetheless, the apparent changes in brain oxygen metabolism that accompany symptomatic improvement of OCD and TS in conjunction with limbic leukotomy are intriguing.

Novel Multisite Surgery: Cingulotomy Plus Infrathalamic Lesions (three cases) There have been three cases of a novel combined surgery for TS entailing anterior cingulotomy plus infrathalamic lesions, performed by Dr. Donald E. Richardson,26 (personal communication, December 1991 and November 1992). First, Dr. Richardson provided us with a videotape including preoperative, intraoperative, and postoperative excerpts illustrating the progress of a 34-year-old woman with severe TS, OCD, and bipolar disorder, treated with bilateral anterior cingulotomy in combination with lesioning of the left infrathalamic area. This patient displayed numerous motor and vocal tics (including coprolalia). Upon reviewing the preoperative segment, we counted 18 tics per minute during a randomly selected 5-minute epoch. Intraoperatively, the video showed the neurosurgeon stimulating the left infrathalamic area, during which the patient's tics increased in intensity and frequency. In fact, the patient requested that the stimulation be discontinued because of the feeling that it caused. Subsequently, a lesion of the infrathalamic area was made and the patient's tics rapidly subsided. A 10-minute excerpt from a postoperative interview showed the patient to be more relaxed and nearly free of tics (timing of follow-up period from operative date not specified). We counted a total of only 18 tics in 10 minutes of videotape and only two tics per minute during a random 5-minute epoch. She stated that the intraoperative stimulation of her infrathalamic area had re-created the same feeling of tension that typically preceded her tics. Furthermore, she reported that postoperatively she was much improved without complications or new complaints. She had been maintained on lithium throughout the course chronicled by the videotape (dose and duration not specified), and no other treatments were described. Although these videotaped interviews are compelling, they are excerpts and include no assessment of symptom severity with accepted clinical rating scales. Much crucial information was lacking. Fluctuation in the severity of her symptoms preoperatively was not documented. Nor was there any information suggesting that preoperative and postoperative examinations (e.g., neuropsychologic testing)

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had been performed to assess whether changes in other functions had occurred as a consequence of the operation. Dr. Richardson further reported to us that two other patients undergoing this same procedure had far poorer outcomes (personal communication, November 1992). The second case, a 40-year-old man with forceful, self-injurious motor tics, coprolalia, and OCD, has been described in detail via a published case report. 26The patient had a broad array of motor tics that first developed at age 3 and vocal tics that emerged at age 11 and progressed to include coprolalia. He had an extended period of mild symptom severity during his twenties, with reemergence of more severe illness by age 29, when he presented to the Yale Child Study Center for care. At that time, clinical evaluation showed that in addition to numerous motor and vocal tics (including coprolalia), he had developed self-injurious tics that entailed striking the side of his face with his fist and biting his hand, as well as OCD (characterized by repetitive touching, checking, and cleaning). His past history was remarkable for attention deficit hyperactivity disorder and major depression. The family history was positive for tic disorders (father and sister) and OCD (father). During the subsequent decade, he underwent an exhaustive array of pharmacologic trials, including haloperidol, pimozide, clonidine, naltrexone, nifedipine, fluoxetine, and desipramine. Although some of these trials resulted in symptomatic improvement, his self-injurious tics remained refractory and led to left-retinal detachment. Preoperatively in 1991, without neuroleptic therapy, his tics were considered "severe" to "extremely severe." His Yale Global Tic Severity Scale (YGTSS) 27 scores were 22 for motor tics and 20 for phonic tics, with a global severity score of 90; his OCD symptoms were "moderate" to "marked," with a YBOCS score of 22. (The YGTSS is an instrument for quantification of tic severity. The severities of motor and phonic tics are rated along five separate dimensions on a 0 to 5-point scale, and overall impairment is rated on a 0 to 50-point scale. Thus, the maximum scores, denoting maximal symptom severity, are 25 points for each of the motor and phonic scales and 50 points for the overall impairment scale, yielding a combined maximum of 100.27) In the summer of 1991, bilateral anterior cingulotomy and bilateral lesions of the infrathalamic region were performed. OCD and some of the patient's motor tics were said to be improved postoperatively. A repeat procedure was performed less than 3 weeks later to extend the lesions on the left because of severe residual tics. Immediately after the surgery, the patient was noted to be dysarthric, with difficulty swallowing. The immediate postoperative course was further complicated by "sepsis of unknown etiology," which responded to antibiotics and corticosteroids. The patient was evaluated at 4 and 8 months and found to be in similar clinical condition at both time points: At the 8-month evaluation, YGTSS scores were 15 for motor tics and 9 for phonic tics, with a global severity score of 69; the YBOCS score was 7. Despite this estimated 30% to 45% improvement in tics and 68% improvement in OCD, selfinjurious behaviors persisted and the patient was left with severe residual neurologic deficits. He suffered apparently irreversible damage affecting his speech, phonation, swallow-

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ing, handwriting (with micrographia), extraocular movements, and gait. At 16 months' follow-up evaluation, the patient remained severely debilitated by these neurologic sequelae to the surgery. Despite moderate OCD and TS symptom improvement, the intervention failed to alleviate the self-injurious tics for which the procedure had been deemed indicated and produced a catastrophic constellation of adverse effects. There is scant information available to us regarding a third case (D.E. Richardson, personal communication, November 1992) involving a young man with TS and comorbid polysubstance abuse who underwent this same neurosurgical intervention without improvement of his TS. His course was further complicated by a serious postoperative motor vehicle accident of uncertain cause, in the context of continued substance abuse.

Thalamic Surgery (25 cases) In 1962, Cooper reported a series of 50 cases characterized by various forms of dystonia, which were treated with a number of different kinds of operations targeting the basal ganglia. 28 Of these, one case involved bilateral chemothalamectomy of a 16-year-old girl with TS. The patient was neurologically normal until age 9, when she developed facial motor and simple phonic tics. The motor tics gradually migrated to include all her extremities and much of her torso. The tics were worse in the company of others and she became progressively anxious, although no anxiety disorder diagnosis was noted. From ages 12 to 16, she underwent psychotherapy, as well as hypnosis, and sedative medication trials (dose, duration, and compound unspecified) without benefit. By age 16, she had become a recluse and "virtually incapacitated," with constant involuntary muscle movements and loud, explosive grunts. In the autumn of 1960, she underwent a left chemothalamectomy, targeting the ventrolateral nucleus. Postoperatively, there was immediate cessation of vocal tics and motor tics on the right side of the body and face. Left-sided tics persisted, but the postoperative course was otherwise uncomplicated. Two months later, remission of right motor tics continued, with 50% resurgence of the vocal tic and persistent left-sided motor tics. Four months after the original surgery, a right chemothalamectomy was performed. This time, there was immediate improvement of right-sided motor tics. At discharge, the patient was essentially without motor or phonic tics. Six years after the second operation, reevaluation showed a mild return of right-sided motor tics involving the face, extremities, and trunk, as well as complaints of a right-sided sensation of tightness (akin to a premonitory sensation). Therefore, she underwent an additional left cryothalamectomy, which was tolerated without sequelae but did not yield any additional benefit. In summary, this patient sustained an estimated 90% improvement in motor tics and complete irradication of vocal tics without adverse sequelae. As a consequence of her symptomatic improvement, she was able to graduate high school and establish gainful employment in a secretarial capacity. In 1969, in Dr. Cooper's textbook on involuntary movement disorders, he again described the above-mentioned case and alluded to five others.29Although he noted that the

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former was typical of the six cases his group had seen and treated in this manner, we have been unable to locate any detailed published account of the other five cases. In 1970, Hassler and Dieckmann3° reported three TS patients who were treated with bilateral coagulation of the rostral intralaminar and medial thalamic nuclei. These three patients' tics were noted to improve by 70%, 90%, and 100% (including irradication of coprolalia), respectively. Their rationale for selecting this procedure was based on their previous positive experience in patients suffering from OCD, as well as their understanding of the relevant neuroanatomy. 31,32 They concluded that "this therapeutic effect confirms the hypothesis that the symptoms of generalized tic disease are motor compulsions," and that the obsessive component is eliminated by lesioning the medial nuclei and the compulsive component responds to intralaminar lesions. Via book chapters on related topics,31,32they summarized their updated experience with this operation for TS. In all, they have reported on 15 cases. Although detailed case reports were not furnished for the majority of these cases, outcome in terms of efficacy was tabulated for nine of the cases as follows: four patients improved 90% to 100% and five patients improved 50% to 80%, whereas two patients (both from the 50%- to 80%-improved group) suffered unspecified adverse effects. They acknowledged that this procedure, when performed for other indications, has resulted in psychomotor akinesia and amnesia. A review of their contributions also reveals an evolving and complicated theory regarding the functional anatomy involving substructures within the thalamus. 31,32 In 1977, Divitiis et al. 33 reported the cases of three patients with "multiple tics, motor compulsions, and coprolalia," consistent with a TS diagnosis, who were likewise treated with thalamotomy. Each had previously undergone psychotherapy without benefit, although no mention is made of prior medication trials. Radiofrequency-coagulation lesions of the dorsal medial and intralaminar nuclei of the thalamus were performed unilaterally on the right, with no complications noted. Postoperatively, Divitiis et al. observed "complete remission in two patients, while the third had a small reduction in symptomatology." The third patient returned after 9 months with no clinical change from his preoperative status. He then underwent a second, contralateral procedure, again without benefit. The other two patients had remission of their symptoms for over 1 year, but in both cases TS symptoms returned. In one case, the reemergence of tics occurred after "a prolonged period of mental confusion"; in the other, tics recurred gradually. Both patients refused the contralateral procedure. Based on these three patients, Divitiis et al. concluded that "this procedure is not successful in treating the Gilles de la Tourette syndrome.33'' Finally, in 1991, Korzen et al. 34 reported a case of a 19-year-old man with TS who underwent bilateral cryodestruction of the ventrolateral thalamic nuclei. The patient developed motor tics at age 5, as well as phobic anxiety symptoms. At 10 years of age, vocal tics emerged and progressed to coprolalia. His condition worsened during puberty. A trial of pimozide was initially helpful in reducing tics, but TS symptoms returned to their full severity while

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the patient was still being maintained on a neuroleptic. His symptoms waxed and waned, with a severe exacerbation occurring at age 18. OCD symptoms became prominent in addition to tics, aggressiveness, and social isolation, prompting hospitalization. Neurologic evaluation at that time included a normal CT scan of the brain and abnormalities on EEG that consisted of mild left temporal and occipital slowing. In preparation for the proposed thalamic lesioning procedure, the patient was studied via a series of intraoperative electrical stimulations in the vicinity of the thalamus. This surgery culminated in the cryodestruction of the patient's right ventrolateral thalamic nucleus. The postoperative period was remarkable for a transient loss of speech, which lasted 4 days. Three months later, cryodestructive lesions of the ventrolateral thalamic nuclei were made without complication. Three weeks postoperatively, he was discharged to home, showing "definite improvement" in his

TS. The patient returned for follow-up evaluation 1 year later to be considered as a candidate for additional surgery. It was determined at that time that his motor and vocal tics, including coprolalia, had practically disappeared. He had been maintained on a consistent dose (unspecified) of pimozide, which had been ineffective preoperatively. Since the operation, he was no longer socially isolated, could enjoy traveling on vacations, had established full-time employment, and experienced "normalization of affect." No enduring adverse sequelae of the surgery were noted.

Cerebellar Surgery (one case) In 1972, Nadvornik et al. 35 reported a series of seven patients with a variety of spastic or myoclonic symptoms treated with stereotactic dentatotomy; the investigators' focus was the description of a new surgical approach. One

Table 1. Neurosurgical Procedures for TS Type of Operation

Frontal Surgery Bimedial frontal leukotomy

Primary Diagnosis TS

Frontal Iobotomy TS Limbic System surgery Bilateral anterior OCD cingulotomy

Secondary Diagnoses

No. of Patients

Panic attacks, birth trauma, hopelessness

1

None mentioned

1

TS: 1 with psychotic episode

2

Bilateral anterior cingulotomy

OCD

TS, dysthymia, MDD, alcohol abuse, mixed personality disorder

1

Limbic leukotomy

TS

Severe self-injurious behaviors, MDD

1

Limbic leukotomy

OCD

TS

1

Novel Multisite Surgery Bilateral anterior TS cingulotomy plus infrathalamic lesion

Bilateral anterior cingulotomy plus infrathalamic lesion

TS

Attention deficit hyperactivity disorder, MDD, OCD symptoms

1 with bipolar disorder 1with polysubstance abuse

Clinical Response

Adverse Effects

Tics and panic Frontal abscess with attacks were markgrand real seizures edly reduced, relieved by medisocially acceptable cation Improved Obesity Rituals improved in 1 Slowness improved in1 No mention of improvement in tics OCD much improved, MDD very much improved, tics minimally worse Complete and sustained resolution of destructive behavior, 75% reduction in tics No signs of TS, OCD substantially improved 30%-45% improvement in motor and phonic tics, 68% improvement in OCD symptoms

Transient aseptic meningitis in 1

References Baker, 11 1962

Stevens, 1° 1964

Kurlan et al, ls,19 1988, 1990

Tics minimally worse Baer et al,2° 1994

Mild apathy, intellectual impairment, and difficulty concentrating

Robertson et al, 12 1990

None mentioned

Sawle et al,=2 1993

Reemergence of self- Leckman et al,2e 1993 injurious tics, plus dysarthria, dysphonia, dysphagia, ataxia, micro9raphia, supranuclear palsy 90% reduction of tics None in 1 case Richardson (personal in 1 case 1 case continued communication, No improvement in 1 substance abuse December 1991 and had serious and November auto accident 1992)

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patient in this series was a 12-year-old boy diagnosed with TS who suffered from "myoclonic movements in the face and diaphragm followed by bark-like sounds." In this patient's case, a bilateral dentatotomy was performed transtentorially via a single right-sided parieto-occipital bur hole, and no operative complications were documented. After the operation, they noted that his "movements decreased" and the "bark-like sounds disappeared." This report contains no discussion of preoperative or postoperative treatment with medications or behavioral techniques, no mention of preoperative or postoperative assessment with validated clinical rating scales, and no attempt to quantify the improvement described. Nadvornik et al. provided no theoretic justification for the use of this procedure on patients with TS. CRITICAL

REVIEW

OF REPORTED

CASES

The few case reports and personal communications involving 36 patients herein described illustrate that there are very limited data pertaining to neurosurgical treatment of TS. A variety of operations have been used, and fewer than 20 patients have received any single procedure

(Table 1). None of the published reports used a prospective design that allowed for valid quantitative assessment of clinical improvement in tics or adverse effects over a sizeable cohort. Moreover, there is limited information pertaining to the nature of pharmacologic and behavioral treatments provided during preoperative and postoperative periods. Consequently, there is at present no substantial scientific evidence to support the effectiveness of any of these procedures in the treatment of TS. Furthermore, there is no compelling evidence to suggest that any one of these candidate procedures is superior to the others, although these anecdotal cases suggest that cingulotomy alone may be particularly ineffective for alleviating tic symptoms t9,2° and that combined cingulotomy plus infrathalamic lesions may be particularly dangerous. 26 Consequently, all these procedures must be considered experimental treatments for TS.

Table 1. Neurosurgical Procedures for TS (Cont'd) Type of Operation

Primary Diagnosis

Secondary Diagnoses

No. of Patients

Clinical Response

Adverse Effects

References

Thalamic Surgery Bilateral chemothalamectomy of ventrolateral nuclei

TS

None mentioned

6

1 was 90% relieved None mentioned of tics, "typical" of other 5 cases (only 1 reported in detail) 4 were 90%-100% 2 with unspecified improved adverse effects 5 were 50%-80% (possibly akinesia improved for and/or amnesia) copralalia and motor tics 6 others not described in detail, with comparable outcome Complete remission Prolonged period of in 2, with relapse mental confusion in both after 1 year in 1 No improvement in 1

Cooper, 2s.2e 1962, 1969

Bilateral coagulation of rostral intralaminar and medial nuclei of thalamus

TS

None mentioned

15

Bilateral coagulation of rostral intralaminar and medial nuclei of thalamus Bilateral cryodestruction of ventrolateral thalamic nuclei

TS

None mentioned

3

TS

OCD symptoms

1

Near resolution of all tics and copralalia, improved social life, employed for 1st time

Transient speech deficit (resolved after 4 days)

Korzen et al, 34 1991

TS

None mentioned

1

Movements decreased, barklike sounds disappeared

None mentioned

Nadvornik et al, 35 1972

Hassler and Dieckmann, 30,311970, 1973; Hassler, 32 1982

Devitiis et al, 33 1977

Cerebellar Surgery Bilateral cerebellar dentatotomy

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THEORETIC RATIONALE FOR CANDIDATE OPERATIONS

Because of the invasiveness of neurosurgical intervention and the checkered history of neurosurgical treatments for neuropsychiatric conditions, there are necessary concerns about the rationale behind these procedures. Little has been written about the mechanisms by which any of these surgical procedures should alleviate TS. In contrast, there are numerous publications about the use of neurosurgical treatment for other neuropsychiatric conditions including OCD, major affective illness, schizophrenia, and chronic pain. 36-46 Of the extensive clinical experience with limbic system operations for other neuropsychiatric indications, most relevant to TS is the experience with limbic system surgery for OCD, because of the apparent link between OCD and TS (description follows).

Pathophysiology of TS The pathophysiology of TS remains poorly understood. Several lines of evidence suggest that tics are mediated via midbrain dopaminergic systems and their interactions with the basal ganglia. 3,47 Dopamine antagonists are effective therapies for TS, 3-6 and dopamine agonists reliably exacerbate TS. 3,48-5°Functionally excessive dopaminergic transmission, perhaps via receptor supersensitivity, has been hypothesized in the pathobiology of TS. 3,51 Dopaminergic involvement may not be limited to the nigrostriatal tracts, but may also include influences from mesolimbic and mesocortical projections. Dopaminergic projections to limbic striatum have typically been associated with affective illness and psychosis, and may be involved in OCD as well. Furthermore, the efficacy of nondopaminergic agents in the treatment of TS, and a growing appreciation for the neurochemical complexity of the basal ganglia suggest that other neurotransmitters also play some role in mediating symptoms. The role of the basal ganglia in mediating cognitive, affective, and especially motor functions is consistent with the notion that it could be a site of pathology in TS. 52 Basal ganglia pathology has been established in a variety of other movement disorders such as Parkinson's disease, Huntington's disorder, and encephalitis lethargica. One study using PET to measure

regional glucose utilization in TS patients showed hypermetabolism in basal ganglia, frontal cortex, and temporal lobes bilaterally. 17Subsequent PET studies have provided data supporting theories that corticostriatal circuits, including sensorimotor cortex, putamen, and ventral striatum, play a role in the pathophysiology of TS. 53-55Recent morphometric MRI studies of TS converge to suggest abnormal symmetry of the lenticular nuclei. 56-58 In addition, animal studies suggest that the cingulate cortex plays a central role in the neuroanatomy of vocalization. 47 The most comprehensive published model of OCD acknowledges involvement of many of these structures. 59-61If TS and OCD represent a spectrum disorder, as has been suggested, the underlying pathology may parallel that spectrum topographically. Baxter et al. 6° have hypothesized that patients with TS alone have relative dorsolateral involvement of the striatum, whereas patients with OCD alone have relative ventromedial involvement of the striatum. Indeed, contemporary neurobiologic models of TS focus on the relevant corticostriato-thalamo-cortical circuits. 55 In summary, the roles of the basal ganglia and the nigrostriatal dopaminergic system have long been central to models of TS pathophysiology. Involvement of frontal cortex, cingulum, and thalamus is now also suspected. The influences of mesolimbic and mesocortical dopaminergic systems, as well as other transmitter systems, require further study.

Relationship Between TS and OCD TS and OCD are clinically related in several ways: First, there is a high rate of symptom overlap; it has been estimated that 30% to 90% of patients with TS exhibit OCD symptoms. 3,6z,63 Second, there are some symptoms (i.e., repetitive rubbing, tapping, and touching behaviors) that lie on the border between tics and compulsions. 64Third, family studies have found that TS and OCD may be genetically related, 65,66and a series of studies have led to the conclusion that in some cases TS and OCD represent different phenotypic expressions of the same genetic abnormality. 65-68 Genetic transmission appears to follow the pattern of an autosomal dominant gene with incomplete penetrance; in the case of

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TS, its expression is sex-influenced with male preponderance. 65-6s Clinical and genetic relationships between TS and OCD may also extend to models of pathophysiology. In both cases, the basal ganglia have been implicated as potential sites of abnormality, although current theories of pathophysiology in OCD emphasize the role of the frontostriato-pallido-thalamo-ffontal (FSPTF) loop and the Papez circuit. 4°,59-61,69 Investigations of neurotransmitter dysregulation in OCD have focused on serotonergic systems, because of the clinical efficacy of serotonergic medications in treating O C D . 61 Antidopaminergic agents that are efficacious for TS are typically not beneficial for OCD, although they may be effective as augmenting agents in the face of concurrent tics. 7° Conversely, the serotonergic agents that represent the first line of therapy for OCD are not typically helpful in treatment of the tics of TS. Thus, despite clinical similarities in the two disorders, this disparity in treatment response exemplifies the fact that effective treatments for OCD are not necessarily effective for TS, or vica versa.

Neuroanatomy Relevant to TS and OCD Although a comprehensive review of neuroanatomy is beyond the scope of this article, detailed accounts are available elsewhere. 52,71,72 Neurosurgical lesions may be conceptualized as influencing neural systems, rather than as simply ablating target structures. There are several relevant circuits whose functional neuroanatomy must be appreciated to comprehend the potential impact of the candidate neurosurgeries. The frontal cortex sends projections via white matter tracts (1) to cingulate cortex and other limbic structures, (2) directly to thalamic nuclei, and (3) indirectly to thalamic nuclei via integrative relays at the level of the striatum and globus pallidus. Sensorimotor cortex also has projections to the thalamus via the striatum (predominately the putamen) to ventral-tier thalamic nuclei. The thalamus sends reciprocal projections to frontal cortex, as well as to other cortical regions including cingulate, sensorimotor, and premotor cortex. It is suspected that the frontothalamic axis is a mutually excitatory reverberating loop modulated by inputs from

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the cingulate cortex and the basal ganglia (i.e., the striatum and globus pallidus). The sensorimotor corticothalamic circuit represents a segregated parallel pathway mediated via the putamen. Modulatory influences on these corticostriatal systems may include (1) connections from the subthalamus to the thalamus via the globus pallidus; (2) dopaminergic projections from the substantia nigra to the striatum; (3) dopaminergic projections from the ventral tegmentum to frontal cortex and limbic structures, including the limbic striatum (i.e., nucleus accumbens); and (4) diffuse serotonergic projections from the raphe nuclei. The respective roles of the different structures in these circuits are not fully understood. One theory suggests that the frontothalamic positive-feedback circuit mediates behavioral drives (i.e., urges associated with tics or compulsions), whereas the FSPTF pathway provides modulatory feedback, which functionally inhibits or "controls" those drives. 59 Presumably, limbic circuits, including inputs from cingulate cortex and limbic striatum, mediate the affective valence of drives and behaviors. Corticostriato-thalamic pathways originating in sensorimotor cortex may be of unique importance in TS by mediating the fundamental motor component of tics or associated sensory premonitory u r g e s . 55,73

All the reported candidate neurosurgeries impact the circuits described above.

Pathophysiology and Neurosurgical Treatment of OCD The rationale for limbic system operations (i.e., anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leukotomy) and thalamotomy for OCD has been reviewed elsewhere. 4° In short, the FSPTF circuit and its connections with the Papez circuit 69 have been hypothesized to mediate OCD symptoms. 4°,59 The lesions of limbic system surgery theoretically interrupt those circuits, thereby disrupting cyclic feedback and alleviating unwanted symptoms. Although this theory remains crude and poorly tested, an impressive body of data has accumulated that demonstrates the relative safety of limbic system surgeries. 36,37,40'74 Their efficacy in the treatment of OCD, although supported by many case reports

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and open trials, remains incompletely studied, since few prospective and no double-blind studies with sham operations and random assignment have been conducted.9,4°

Functional Neuroanatomy of Candidate Surgeriesfor TS Frontal lobotomy entails a crude severing of connections between prefrontal cortex and the rest of the brain. Not only are the frontothalamic axis, FSPTF loop, and the frontocingulate connections severed, but also communication between frontal cortex and other areas of association cortex. Consequently, frontal lobotomy not only interrupts the frontothalamic axisassociated drives, it also blocks the inhibitoryfeedback circuit and results in a well-documented frontal syndrome.75,76 Bimedial frontal leukotomy entails a more limited and precise interruption of the medial white matter tracts that primarily carry frontothalamic connections, specifically from orbitofrontal cortex to the medial thalamic nuclei (Fig 1). This distinction is important, since these medial orbitothalamic tracts have been implicated in the pathophysiology of OCD.59 Anterior cingulotomy entails lesioning of anterior cingulate cortex, as well as the anterior cingulate bundle, which consists of white matter tracts intrinsic to the Papez circuit coursing adjacent to cingulate cortex. Limbic leukotomy entails combined lesions of the orbitothalamic tracts with bilateral anterior cingulotomy. Anterior capsulotomy and subcaudate tractotomy (neurosurgical procedures for OCD that have not, to date, been applied in the treatment of TS) sever frontothalamic connections further downstream, as well as frontostriatal projections. All these limbic system surgeries have been reported to reduce the symptoms of OCD. 4° Anterior cingulotomy plus infrathalamic lesioning combines cingulotomy with a lesion of the infrathalamic area. This infrathalamic region is adjacent to the ventral tier of thalamic nuclei and encompasses fibers of passage between thalamus, subthalamic nucleus, and pallidum. Lesions of the infrathalamic region can influence ventral-tier thalamic input and output. It is not clear, based on the functional neuroanatomy of this region, whether the net

RAUCH ET AL

effects of such a lesion should improve or exacerbate symptoms of a movement disorder. The thalamus is a complex structure with several discrete divisions, each with its unique input and output profile. The medial thalamic nucleus, also known as the dorsal medial nucleus, receives input from other thalamic nuclei, limbic structures, and prefrontal (including orbitofrontal) cortex. The medial thalamic nucleus sends its projections primarily to prefrontal cortex in a reciprocal manner. The intralaminar nuclei are several small nuclei scattered throughout the intralaminar connective tissue, which separates the various subdivisions of the thalamus. The intralaminar nuclei receive input diffusely from the other thalamic nuclei, as well as the reticular formation and the basal ganglia. The intralaminar nuclei send their output diffusely to cortex, including frontal, motor, and premotor cortex. In this way, the medial thalamic nucleus and the intralaminar nuclei correspond to the thalamic relay sites of the hypothesized FSPTF circuit.59 Therefore, operations that lesion the medial thalamic and intralaminar nuclei bilaterally can be conceptualized as interrupting the frontothalamic axis within the thalamus while leaving other thalamic nuclei relatively intact. The ventral-tier nuclei of the thalamus serve as the principal relay nuclei for the sensory and motor systems. In this manner, lesions of ventraltier nuclei can be conceptualized as interrupting the sensorimotor cortico-striato-thalamocortical circuit within the thalamus. The cerebellum also influences the motor system via communication with the thalamus. The dentate nucleus, one of the deep nuclei of the cerebellum, sends its projections via the superior cerebeUar peduncle to the ventral-tier nuclei of the thalamus. These efferents contribute to the thalamic fasciculus, which courses through the infrathalamic region. The ventraltier nuclei of the thalamus also integrate input from the basal ganglia and in turn send projections to motor and premotor cortex. This pathway is theorized to play a role in preparation, learning, and execution of motor movements. Consequently, lesions of the dentate nuclei of the cerebellum would be expected to interrupt this contribution to motor movement. As discussed earlier, dentatotomy has also been re-

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ported to be effective in eliminating certain other sudden involuntary movements similar to the tics of TS. 35 RECOMMENDATIONS REGARDING FUTURE EXPERIMENTAL NEUROSURGERY FOR TS

Although controversial, the use of experimental neurosurgery for TS should not necessarily present ethical concerns different from those for intractable pain or seizures. As long as a patient is capable of rendering informed consent, such procedures are analogous to any experimental surgical intervention. Unfortunately, guidelines for conducting experimental operations are not well established. There are serious uncertainties regarding any experimental neurosurgical procedure to the extent that such procedures produce irreversible changes, unknown adverse consequences, and questionable benefits. However, in the case of severe, intractable TS, these appropriate concerns must be juxtaposed against the risks of conventional therapies, including tardive dyskinesia from long-term treatment with neuroleptics 77'78 and the morbidity, or in the most extreme cases mortality, associated with treatment refractoriness. Patients who suffer from severe TS, are debilitated by their symptoms, and have failed an exhaustive array of conventional pharmacologic and behavioral therapies might reasonably arrive at a decision to proceed with an experimental treatment. However, in addition to informed consent, experimental operations should also require careful patient screening and thoughtful selection of the procedure to be performed. Based on our experience with OCD, we are of the opinion that the appropriateness of a TS patient's candidacy for such a procedure is best assessed by an experienced interdisciplinary committee, taking into account such issues as accuracy of diagnosis, severity of illness, complicating influences of comorbid diagnoses, adequacy of previous conventional therapies, and ability to render informed consent. Such interdisciplinary committees already exist for the assessment of candidates seeking neurosurgical interventions for other neuropsychiatric illnesses such as intractable cases of OCD, chronic pain, and major affective illness. 37,38 To date, criteria have not been established

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regarding appropriate candidacy for neurosurgical treatment of TS. In the case of OCD, our institutional Cingulotomy Assessment Committee has generated criteria for cingulotomy that include standards for "adequate trials of other conventional therapies," as well as contraindications to cingulotomy (e.g., ongoing substance abuse or severe comorbid personality disorder). We suggest that if these experimental surgeries are to continue, such patient criteria for neurosurgical treatment of TS are essential. Ideally, guidelines pertaining to adequacy of trials using conventional pharmacologic and behavioral therapies, as well as other clinical considerations, could be established by a panel of scientific and clinical experts in TS (e.g., the Clinical and Scientific Advisory Boards of the Tourette Syndrome Association). Likewise, the process of selecting candidate operations should proceed thoughtfully. Moreover, if experimental operations for TS continue to be performed, then it is essential that patients be managed in a manner that enhances the opportunity to learn from the experience and so contribute to the knowledge base from which important future clinical decisions can be made. Ideally, case management should begin with comprehensive preoperative screening, including clinical assessment by a psychiatrist and a neurologist, as well as by the neurosurgeon. A detailed review of the candidate's history is necessary to confirm the primary diagnosis and severity of illness, as well as to document carefully the adequacy of pharmacologic and behavioral treatment. A validated structured clinical interview instrument should be administered to confirm the clinical impression of the primary diagnosis, as well as comorbid diagnoses. Validated clinical instruments should be used to characterize quantitatively the severity and repertoire of tics, as well as anxiety, depression, OCD symptoms, and level of social and vocational functioning. Other studies performed preoperatively should include EEG, MRI, and neuropsychologic testing. Postoperatively, quantitative clinical instruments and special studies should be repeated to document interval changes associated with the operation. In particular, postoperative neuroimaging studies are essential to ascertain the actual location

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and extent of the neurosurgical lesions. Clinical assessments should be repeated periodically to gauge long-term efficacy and adverse consequences. CONCLUSIONS

Case reports in the literature provide only anecdotal evidence supporting the efficacy and safety of neurosurgical treatment of TS. Consequently, neurosurgical treatment of TS must be considered experimental. There is no compelling evidence that any particular neurosurgical procedure is best for TS. Cingulotomy may be particularly ineffective at ameliorating tics, and infrathalamic lesions may be particularly dangerous. If experimental neurosurgery for TS is to continue, then guidelines should be developed regarding patient and operation selection, and interdisciplinary assessment committees should implement such guidelines. Future cases of neurosurgery for TS should be studied prospectively using neuroimaging techniques to assess

placement and extent of surgical lesions, and validated clinical instruments should be administered preoperatively and postoperatively to monitor long-term outcome. Innovative techniques that allow neurosurgeons to make lesions without opening the cranium (e.g., gamma knife, proton beam, and linear accelerator) increase the potential for performing ethical, controlled studies using randomization to sham versus active operations. Results from such studies would be necessary to determine definitively which, if any, of these procedures are effective treatments for TS. ACKNOWLEDGMENT

The authors wish to acknowledge the assistance of Dmitry Berdichevsky, M.S., in translating the study reported by Korzen et al. in 1991 from Russian to English. We thank Linda Leahy for clerical assistance in processing the manuscript. We also wish to acknowledge the cooperation of Dr. Donald E. Richardson in communicating to us information regarding his experience with the novel multisite neurosurgical procedure described.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Ed. 3. Rev. Washington, DC: American Psychiatric Association, 1987. 2. Shapiro AK, Shapiro ES, Young JG, Feinberg TE. Gilles de la Tourette Syndrome. Ed. 2. New York, NY: Raven, 1988. 3. Singer HS, Walkup JT. Tourette syndrome and other tic disorders: diagnosis, pathophysiology, and treatment. Medicine 1991;70:15-32. 4. Shapiro AK, Shapiro E. Controlled study of pimozide vs placebo in Tourette's syndrome. J Am Acad Child Psychiatry 1984;23:161-173. 5. Shapiro AK, Shapiro E, Fulop G. Pimozide treatment of tic and Tourette disorders. Pediatrics 1987;79:1032-1039. 6. Truong DD, Bressman S, Shale H, Fahn S. Clonazepam, haloperidol, and clonidine in tic disorders. South Med J 1988;81:1103-1105. 7. Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Gilles de la Tourette's syndrome. Arch Gen Psychiatry 1991;48:324-328. 8. Azrin NH, Peterson AL. Treatment of Tourette syndrome by habit reversal: a waiting-list control group comparison. Behav Ther 1990;21:305-318. 9. Jenike MA, Baer L, Ballantine HT, Martuza RL, Tynes S, Giriunas I, et al. Cingulotomy for refractory obsessive-compulsive disorder: a long-term follow-up of 33 patients. Arch Gen Psychiatry 1991;48:548-555. 10. Stevens H. The syndrome of Gilles de la Tourette and its treatment. Med Ann DC 1964;33:277-279. 11. Baker EFW. Gilles de la Tourette syndrome treated by bimedial frontal leucotomy. Can Med Assoc J 1962;86:746747.

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