Jarrett Barnhill, MD Director, Developmental Neuropharmacology Clinic UNC School of Medicine
The overlap between Tourette Disorder (TD), obsessive-compulsive disorder (OCD), and pervasive developmental disorders (PDD) suggests a common neurobiological substrate for these neuropsychiatric disorders (Kerbeshian & Burd, 1992; Einfield & Aman, 1995). This paper will explore this complex interrelationship by using two very different clinical case examples. The clinical cases come from the Developmental Neuropharmacology Clinic, a tertiary referral center that specializes in the treatment of neurobehavioral disorders in people with developmental disabilities mental retardation, autism and PDDs, and TS.
Obsessive-Compulsive and Tourette Disorder: A Complicated Kinship
There is a significant overlap in symptoms, genetics, clinical course, and patterns of treatment responsiveness between obsessive compulsive spectrum disorders and Tourette disorder (Baer, 1994). As a result, the boundary between some forms of complex tics and compulsive rituals is often not an easy one to establish-especially since both disorders share a waxing-waning course and in some individuals tics may alternate with compulsions. There is also a developmental wrinkle to this relationship. Age of onset can play a major part in symptomatic expression. For example more than 20% of carefully screened male preschoolers who present with OCD will eventually develop tics (Cath, Hoodguin, van de Wetering, van Woerkom, Roos, & Rooymans, 1992). A different aspect of this developmental conundrum involves children who present with a tic disorder that eventually morphs into OC symptoms during adolescence-even as their tics are waning or, in many cases, have disappeared (Bruun & Budman, 1993; Lang 1993; Santangelo, Pauls, Goldstein, Farone, Tsuang, & Leckman, 1994; Robertson, 2000).
Neurobiologically, both OCD and Tourette Disorder also share an overlapping neuro-anatomical substrate (Iiada et al., 1996). Functional neuroimaging studies (PET scan and fMRI) provide the best evidence for these overlapping neurological substrates (Haber & Lylnd-Balta, 1993; Peterson & Klein, 1997), but these same studies also point out key differences in patterns of activation and lateralization within fronto-striatal and limbic regions (Haber & Lynd-Balta, 1993; Palumbo, Maughn, & Kurlan, 1997). Studies that focus on neurotransmitters reveal a similar pattern of variability. For example, neurotransmitter abnormalities associated with Tourette Disorder are similar to those reported in other hyperkinetic movement disorders-an imbalance in dopamine receptors. The earlier evidence focused on a tendency for tics to worsen following the use of indirect dopamine agonists (such as stimulants), and the efficacy of D2 antagonists such as haloperidol. This model suggested an etiopathogenic role for dopamine (Bruun & Budman, 1996). More recent research challenges this dopamine-centric view of tic disorders and points to a more complicated neurochemical anatomy (Eidelberg et al., 1997; Robertson, 2000).
Many hyperkinetic movement disorders also present with obsessive-compulsive symptoms. Even though most research in OCD suggest predominantly serotonergic mechanisms, two subgroups stand out as possible exceptions. OC symptoms associated with tics and impulsivity/low harm avoidance have a more complicated relationship to serotonin dysfunction. These differences suggest a dimensional aspect to obsessive-compulsive behaviors. This heterogeneity is the basis of the increasing use of the term "obsessive-compulsive spectrum disorders (Cohen, Simeon, Hollander, & Stein, 1997; Marazatti, 1999; Saxena, Bota, & Brody, 2001; Phillips, 2002).
Conclusions from these neuro-chemical relationships point to a basal ganglia area that is rich with interconnecting circuits between the frontal cortex and limbic systems (Lang 1993; Troster, 1994; Castellano, Ritchie, Marsh, & Rapoport, 1996). Pharmacological heterogeneity also suggests that tics and OC symptoms represent a mosaic of relatively discrete but interlocking pathways involving multiple dopamine, acetylcholine, norepinephrine, serotonin, GABA, glutamate, and several neuropeptides. Disturbances in the balance between these systems may be the crucial factor in the entire spectrum of movement and compulsive disorders (Cohen, Freidhoff, Leckman, & Chase, 1992; Saint-Cyr, Taylor, & Nicholson, 1995; Eidelberg et al., 1997).
Gender also plays a role in Tourette and Obsessive-compulsive disorders. The pattern of distribution of tic disorders in general (greater likelihood of tic disorder in males versus compulsive symptoms in females) suggests gender dimorphic differences in the sensitivity or vulnerability of the neuroanatomical and chemical substrates. Gender dimorphism also suggests differences in the expression of related genes, different thresholds of expression, or divergent developmental Effects of gonadal hormones on symptom expression (Santangelo et al., 1994). Families with genetic loading for tics or OCD provide an example of gene-gender interactions. Within these affected families, there is a trend towards a male predominance for tic disorders while female relatives are apt to develop OCD (Bruun & Budman, 1993; Robertson, 2000). As noted earlier, the age of onset also influences the gene-gender relationship-early onset OCD is associated with greater genetic loading (more affected family members) but also increases the likelihood that males in this group will develop tics. As we have seen, puberty also changes the clinical expression of both disorders (Cohen et al. 1997; Santangelo et al., 1994).
From this brief review it is apparent that neurochemical models that separate OCD (serotonin-focused) from tic disorders (dopamine-focused) are woefully oversimplified. In spite of the success of selective serotonin re-uptake inhibitors (SSRIs) in the treatment of OCD, there are a substantial number of patients who fail to substantially improve on the class of agents. The SSRIs appear less effective for patients with OCD associated with comorbid impulse control disorders and tic disorders (Baer, 1994). Additionally, there are many with tic disorders who improve while taking SSRIs. Both groups of patients frequently eventually may require a combination of treatments such as clonazepam or second generation antipsychotic drugs (Hollander & Rosen, 1999).
PDD versus OCD
Pervasive Developmental Disorders are a collection of syndromes characterized by deficits in social relatedness, communication and language, behavioral flexibility, and adaptive behaviors. In PDD, the broad range of clinical presentations is influenced age of onset, level of tested intelligence, and associated neurological complications (Ozonoff, Strayer, McMahon, & Filloux, 1994). Symptomatically autism represents the severe end of the PDD spectrum. Asperger syndrome, on the other hand, appears to be a milder variant that differs from autism in terms of lower levels of functional impairments in language-communication skills, social relatedness and cognitive abilities. As a rule, people with Asperger syndrome and milder forms of PDD spectrum disorders lack severe comorbid intellectual disabilities, and seizure/neurological/metabolic disorders. There are also more significant gender differences (greater male predominance) in Asperger syndrome when compared to autism (Bodfish & Madison 1993; Leboyer et al., 1994; Willemsen-Swinkels, & Buitelaar, 2002).
Clinically, many people with high functioning autism are referred for OCD, anxiety/mood disorders, ADHD, and occasionally for tic disorders. On closer clinical scrutiny, those presenting with obsessive-compulsive or repetitive behaviors frequently differ from classic OCD. For example, rather than obsessions, contamination fears, cleaning/washing and checking rituals, these individuals with PDD frequently present with compulsions that include arranging, organizing, and touching behaviors, and need for balancing or symmetry. A similar pattern of compulsive behaviors without extensive obsessions is also seen in persons with TS, other movement disorders, and some impulse control disorders (Baer, 1994; Leary, 1996; Rapin 2001; Willemsen-Swinkels & Buitelaar, 2002). Among people with severe/profound intellectual disability, referrals often focus on SIB, stereotypies, abnormal movements, and explosive behaviors. The considerable overlap in target symptoms suggests the idea of a shared neurobiology between a subset of clients with TS, OCD, and PDD/autistic spectrum disorders (Rapin, 2001).
Case 1: H.S. is a 27 year old nonverbal autistic male with severe mental retardation who was referred secondary to explosive outbursts, SIB, and suspected tardive dyskinesia. His aggression tends to occur when unexpected or unpredictable events occur, there is less structure, or the group home staff try to redirect his stereotypic arranging and organizing furniture, newspapers and magazines, and place mats on the kitchen table. H.S. is a diligent worker, but is unable to tolerate any "down time" or change in his work routine. His SIB takes on 2 forms. The first is his incessant picking at sores, picking his nose, and rearranging his pants. Although intensity and severity are minor, these high frequency repetitive behaviors eventually can produce tissue damage. Because of his constant picking at wounds, these rarely heal spontaneously. Head slapping and repetitive pounding on his left leg characterize his severe SIB. Although these behaviors are dramatic, they do not coincide with tantrums. H.S. shows no pain insensitivity. By the time of his referral, H.S. had failed 2 behavior programs that changed social contingencies (assuming social contact reinforced his behavior), DRO/DRI protocols, and restraint programs to minimize tissue injury. H.S. had also failed trials of high dose haloperidol (15 mg/d); fluoxetine 40 mg/d; buspirone (60 mg/d); and is currently taking Anafranil 75 mg/d and Luvox 50 mg/d. Interestingly, H.S. responded within "hours" to each regimen, but over the span of several weeks became increasingly hyperactive and irritable.
His other referral complaint, tardive dyskinesia, proved to be the most intriguing facet of H.S.'s history. According to his parents, H.S. had facial grimacing, eye blinking, and a shoulder shrug as a 7-year-old. The movements had disappeared for extended periods only to recur abruptly- often in the fall and winter. H.S. also developed a chronic "cough", and a "hiatal hernia", but no GERD or reflux disease.
H.S. had no history or clinical evidence of seizures, head injury, or signs of a neurodegenerative disorder. He was subsequently referred to the local mental health center at nine for growling, and snorting. The psychiatrist thought his behavior was a part of his autism, and started him on haloperidol 0.5-mg tid. The abnormal movements disappeared within several days, but cogentin was needed for secondary EPS and restlessness. H.S. remained on this regimen for the next 6 years. Over the ensuing years several attempts to reduce haloperidol resulted in a flare-up in his movement disorder. Several clinical trials with alternative neuroleptics, mood stabilizer, and buspirone were ineffective. On examination, H.S. did not have the characteristic buccolingual dyskinesia nor choreiform movements. His growling had returned and he spent much of the consultation, rocking, pacing, and rubbing his forehead. His neurological examination was significant for abnormal movements; mild left sided clumsiness, and multiple scabs and oozing wounds due to compulsive skin picking.
When referred E.F. was 18 year old white male with a two year history of sniffing, eye blinking, shoulder shrugging, and inattention. The tics and inattention waxed and waned with intensification in the fall, and a gradual improvement in the late spring. Due to a possible connection between flare-ups in tics and strep pharyngitis, PANDAS had been suspected, but antistreptococcal (ASA) and antiDNA-ase B antibodies were negative. E.F. had responded to low dose guanfacine for about one year.
At the time of referral several new complex tics and obsessive compulsive symptoms had surfaced. The new tics involved a series of hand movements, and the compulsions consisted of arranging objects and books in his room, a high need to keep everything organized in his room and severe rage outbursts if anyone disrupted his routines or disturbed his things. These difficulties were less apparent at school, although E.F. remained relatively aloof from most of his peers. He did make several friends, sporadically dated, but never felt comfortable with his peers. Although quite bright (IQ-135), E.F. had trouble with literature, social studies, and written assignments. His strengths were in the sciences and mathematics. Like many people with tics, E.F. had trouble with written work, and could not accelerate the pace of his work for standardized timed tests.
His tics and OC symptoms improved on fluvoxamine, 150 mg/d. His aloofness, difficulty with emotional perception, relative dysprosodic speech, cognitive deficits (concrete literal thought), and social skill deficits became more apparent over time. He was eventually diagnosed with high functioning autism (HFA) in addition to Tourette Disorder. His inability to tolerate disruptions in routine or his compulsive organizing persisted but the extent of his rage outbursts abated with fluvoxamine and aging. At present E.F. lives in an apartment, maintains peer actives (mainly computer related activities), but he returns to his apartment after social events to "rejuvenate ."
These two cases illustrate the overlapping spectra of autism, obsessive-compulsive symptoms, and tic disorders. The first case involves a severely impaired young man whose autism is readily apparent, but whose tic disorder required some dissection. The second case presents a bright adolescent with obvious tics, ADHD, and OC traits whose autism became apparent during the work-up for his tic disorder. Both were eventually diagnosed with autistic spectrum and tic disorder, rather than OCD. The exclusion of OCD in such individuals requires a careful review of clinical symptoms (typology) (Barnhill & Horrigan, 2002).
Let us begin the discussion with autistic spectrum disorders. In most circumstances, the diagnosis of autism is affected by both quantitative and qualitative differences in the level of intellectual disability and associated neurological/metabolic disorders (severity of symptoms) (Ozonoff et al., 1994; Willemsen-Swinkels & Buitelaar, 2002). H.S. presents with both severe autistic and profound intellectually disability. The combination of developmental disorders probably contributed to the delays in diagnosing his tic disorder (Kerbeshian & Burd, 1992; Leary & Hill, 1996). At the time of his referral, H.S. was treated with low doses of haloperidol for aggressive and disruptive behaviors. His abnormal movements and vocalizations were misattributed to tardive dyskinesia (a hyperkinetic movement disorder). Later access to older records revealed the presence of movements and vocalizations prior to the introduction of haloperidol. Without such historical records, it is often exceedingly difficult to distinguish primary Tourette Disorder (TS) from Tardive Tourette, a variant of tardive dyskinesia, or uncomplicated TD (Leary & Hill, 1996; Rapin, 2002).
For H.S., the overlap between stereotypies and other ritualistic behaviors, tantrums and explosive/aggressive behaviors and SIB and his tic disorder can be quite confusing. SIB and aggression are not uncommonly seen in individuals with Tourette Disorder (Robertson, 1992; 2000) and autism with severe ID as well (Robertson, 1992; Buitelaar, 1993; Schroeder et al., 2001). The presence of intense SIB (high intensity-tissue damaging) frequently suggests a chronic and severe form of Tourette disorder-more commonly associated with complex tics, sensory phenomena, and other repetitive-intrusive behaviors (Robertson, 1992; Brasic et al., 1994). For H.S., the absence of movements during sleep, waxing and waning course, and relative absence during volitional movements, decreased the likelihood of myoclonus (Palumbo et al., 1997; Schroeder et al., 2001; Robertson, 2000).
Low intensity-high frequency SIB may not necessarily vary with tic severity. Nail biting, cuticle picking can be associated with simple motor and phonic tics. The connection between mild SIB and Tourette disorder is often overlooked. One problem arises because of the similarities between many forms of high frequency-low intensity repetitive behaviors and complex tic-like behaviors. Another problem arises because tics are overlooked as the clinician misattributes the abnormal movements or vocalizations to sinus infections, attempts to verbally communicate pain or distress, or in rare circumstances myoclonic seizures (Robertson, 1992; Troster, 1994; Castellanos et al., 1996)
H.S. brings another problem to the table. Both his movements and behaviors worsened during multiple attempts to reduce his haloperidol. Was this tardive dyskinesia and breakthrough of his SIB-aggression (nonspecific troublesome behaviors)? A better explanation focuses on the behavioral changes associated with worsening tics (Budman, Bruun, Park, & Olson, 1998; Horrigan & Barnhill, 1997). As a result, and because of the real risk for TD, the author selected risperidone to replace haloperidol. Risperidone proved quite helpful, reducing both target behaviors and tics by approximately 90% from baseline.
Risperidone and other second generation anti-psychotic drugs (APDs) are helpful for aggressive behaviors in Tourette disorder (Bruun & Budman, 1996); as adjuncts to SSRIs in OCD in individuals with comorbid tics (Brasic et al., 1994; Robertson, 2000); and for treatment of severe tics (Bruun & Budman, 1996). Most individuals can tolerate low doses of risperidone but can experience akathisia in spite of diminished risk for EPS. Unfortunately, weight gain can be significant, especially in clients with free access to unlimited quantities of carbohydrates (Bruun & Budman 1996).
E.F. represents the other end of the spectrum. E.F. was referred because of his tic and OC disorders. From this case study it is apparent that E.F. is a bright, but verbally dysfluent young man. His speech remains clearly dysprosodic (lacks affective or gestural expressiveness), and he continues to struggle to grasp the emotional content of social interactions. He also has difficulty understanding the social intrigues of his peers, especially emotionally laden interactions. Although a participant in selected school activities, E.F. had considerable difficulty communicating and understanding nonverbal and emotional nuances of relating to his adolescent peers. Although fluvoxamine reduced the intensity of his anxiety and social avoidance, he continued to have difficulty initiating and sustaining a conversation, or would act in regressive or socially inappropriate fashion in unstructured or novel settings.
Although his tics have waned over time, his OC symptoms continue-especially his arranging, organizing, symmetry and balancing actions. There are no contamination fears and cleaning-grooming rituals, or doubting-checking rituals. He acknowledges rare obsessions, mostly repeating words and numbers in his head, or after the fact, rehearsing what he should have said in an unsuccessful social contact. These "rituals" are soothing to E.F., and he becomes easily upset if anyone attempts to interrupt his repetitive behaviors.
The symptoms of E.F.'s pervasive developmental disorder (PDD) are subtle. As a result, it is often difficult to differentiate OCD, OC spectrum, complex tics and Asperger syndrome (Rapin, 2000; Phillips, 2002). Several features warrant further exploration. In contrast to patients with classic OCD, E.F. has little desire to inhibit these rituals/compulsions, and seem largely unaware of the impact of these rituals on others (diminished insight). He would frequently interrupt a conversation with a peer to carry out his repetitive behaviors. On closer analysis, E.F.'s repetitive behaviors share common features with those seen in Tourette disorder or autism. Phenomenologically, his compulsions lack antecedent obsessions. E.F. describes the sensory experience (discomfort over his hands and lower extremities) and a growing urge to move that drives his rituals. From this perspective his "compulsions" would continue until they felt right. Anxiety and insight are minimal.
Although of limited significance in a differential diagnosis, both his compulsions and tics improved with modest doses of fluvoxamine (100 mg/d). His pattern of improvement was not typical of the usual anti-OCD response to fluvoxamine. In contrast to the clinical course of improvement in classic OCD, E.F. responded in several days of initiating the fluvoxamine-rather than the 6-12 weeks latency to response in many people with OCD. In addition, he was unable to tolerate the higher doses of fluvoxamine usually required for OCD (Bodfish & Madison, 1993; Mazarratti, 1999) (no evidence of cytochrome p450 1A2 problem). In fact, doses above 100 mg/d produced significant increases in irritability and behavioral disinhibition. Lowering the dose below 100 mg/d led to a resurgence of severe social avoidance, increase in repetitive behaviors, and a flare-up in aggressive responses to frustration and interruption of ritualistic behavior. This exquisite sensitivity to a narrow range of effective SSRI doses is a common clinical observation in patients with autism but is also observed in many individuals with tic disorders with or without comorbid ID (Rothernberger, 1992; Campbell, Anderson, Small, Adams, Gonzalez, & Ernst, 1993; Brasic et al., 1994; Gillborg, 1995).
These cases exemplify the neurobiological relationship between certain symptoms of TS and autism. These cases also suggest that OC symptoms and some repetitive behaviors (including SIB) represent the common ground between Tourette and pervasive developmental disorders (Kerbeshian & Burd 1992; Palumbo et al., 1997; Rapin, 2000). These findings also support the need to accurately describe repetitive behaviors-specific symptoms such as hand-washing with contamination obsessions or arranging shoes. It appears that the key to understanding these clinical phenomena lies in both phenomenology and the need to repeat apparently meaningless behaviors. Differentiating tics from compulsions and other repetitive behaviors requires fine-tuning and subtype analysis (Troster, 1994; Phillips, 2002).
These cases also suggest that there is no single anatomic lesion or single neurochemical pathway for TS or autistic spectrum disorders. Both syndromes represent disruptions in a complex array of interconnecting systems. As such, repetitive behaviors represent a final common pathway for expressing a range of developmental brain disorders. Although not reviewed in this paper, the scope of effective treatments includes opiate antagonists (Campbell et al 1993; Rothenberger, 1992) SSRIs, benzodiazepines, and low doses of newer APDs (Gilborg, 1995; Marazatti 1999, Robertson, 2000; Rapin 2001). This treatment diversity also reflects the complex pathophysiology for tics and compulsions. These observations also supports the concept of a developmental basal ganglia disorder that manifests as movement disorders, affect disorders, repetitive and compulsive/ritualistic behaviors, as well as impairments in executive and social functioning (Ozonoff, Strayer et al 1994; Patterson, Klein 1997; Saxena et l 2001). The combination of these deficits along with underlying language-communication disorders, disturbances in social perception and social behaviors, and drive for social relatedness represent the expanded behavioral phenotype for the autistic spectrum disorders. Perhaps this convergence explains the relationship between tic disorders and autism.
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For further information: Jarrett_Barnhill@med.unc.edu.