Article

George Gilles de la Tourette, Charcot's pupil at the Salpétrière Hospital, Paris, defined Tourette's Syndrome, the pathological condition that has carried his name since 1885. Characterized by multiple tics of diverse nature, the disease had already been described by Dr. Itard in 1825

The syndrome is diagnostic (as per the DSM IV) when the patient presents:
• motor tics varying in intensity and involving diverse regions;
• vocal and/or sound tics;
• fixed ideas leading to related tics (repetitive ideas with the impulse to carry them out or the obsession to perform certain unjustified behavioural patterns).

Epidemiologically speaking Tourette's Syndrome prevails in 4-5 individuals on 10,000 in the population at large. The disease's motor symptoms can generally be noticed within the first 7 years of life, while vocal tics set in around the age of 11. The disorder's incidence is three times higher in males than in females. From an aetiopathogenetic viewpoint genetic factors no doubt play a decisive role in the development of Tourette's Syndrome, though details have still to be defined. Tourette's Syndrome and the Obsessive-Compulsive Disorder are closely related; the latter was in fact noticed in 40% of Tourette patients. But the syndrome's relations with the Attention Deficit Hyperactivity Disorder is even more interesting as about 50% of patients suffering from the latter present both problems. The dopaminergic system's involvement in tic disorders has been ascertained, and this explains how dopamine antagonist drugs (i.e. haloperidol, pimozide and flufenazine) diminish tic intensity, while agents that increase central dopaminergic activity (i.e. methylphenidate, amphetamines, pemoline and cocaine) instead tend to aggravate them. But anomalies in the noradrenergic system, such as diminished tic intensity resulting from the administration of clonidine (an alpha-adrenergic agonist that reduces the release of noradrenaline in the CNS), have been noticed, thus confirming the theory of neurotransmitter alterations in the disorder's aetiopathogenesis. Organic lesions in basal ganglia cause many movement disorders like Huntington's Disease, the Obsessive-Compulsive Disorder and the Attention Deficit Hyperactivity Disorder. From an organic viewpoint Tourette's Syndrome seems to originate at this level. Recent studies suggest that certain forms of Tourette's Disease are caused by an autoimmune response directed against basal ganglia and triggered by Streptococcus beta-haemolyticus group A infections. Other clinical evidence has proved relations between Tourette's Syndrome and Borrelia burgdorferi infections (Lyme's disease). A proper diagnosis requires the disease to appear before the patient is 18 years old (generally around 5-6 years) and it must neither result from the direct physiological effects of a substance (i.e. stimulants) nor from a general medical condition (i.e. Huntington's disease or viral encephalitis). The most frequent initial symptom is a blinking tic (blepharospasm), followed at a later date by abnormal head movements, such as grimaces. Tics tend to present a rostro-caudal progression in time, involving other body regions too. Three forms of Tourette's Syndrome are currently classified: 1. the pure form, which only presents motor and vocal tics; 2. the complex form, which, besides motor and vocal tics, also involves copropraxia, coprolalia, echolalia, etc.; 3. the plus form, which combines the above described symptoms with the Attention Deficit Hyperactivity Disorder, or rather with obsessive-compulsive disorders. Treatment is chiefly pharmacological, though the medication (in a broad sense) of Tourette patients presents quite a few problems, mainly the answers to questions concerning which patients must be treated, the treatment method and its duration. The syndrome in question is too diversified concerning both the clinical picture and compromised physiopathology. Hence the therapeutic problem cannot be 'summarily' solved. Every patient is a case in itself and the clinical picture, by definition based on syndromes, is changeable! We must consider that in the DSM IV classification Tourette's Syndrome also involves social embarrassment and this factor, before all else and beyond diagnostic aspects, should motivate us to begin any medication whatsoever once the disease has been recognized with its subsequent embarrassment. It is understood that the mildest TS pictures require no treatment whatsoever. Those associated with ADHD that could present educational and working difficulties are an exception. OCD pictures are often inadequately compensated and are a factor of disorder in daily life. However, as already mentioned, neurological drugs remain the basic medication for Tourette's Syndrome. Drugs that are effective on the dopaminergic systems are the core of the therapeutic approach. In fact neuroleptics play a leading role in the treatment of Tourette patients' symptoms: haloperidol is successfully combined with pimozide, which, like other D2 receptor specific neuroleptics, presents more or less acceptable collateral effects that must however be monitored. Patients treated with pimozide can in fact present ECG alterations; accurate cardiologic follow ups are hence required. Sulpiride, tiapride and, recently, risperidone (atypical neuroleptics) are used with fair results. Table 3 reports the receptor profile and D2 receptor bonds formed in the striated muscle with neuroleptics that can be used in Tourette's Syndrome. Results are variable and at times unforeseeable; worse still, these drugs have a limited duration as they lose their effectiveness in time. To date there are neither papers nor predictive clinical signs that advice the clinician to use a certain neuroleptic drug instead of another. Besides no currently available controlled clinical studies have systematically faced this issue.

Olanzapine (an atypical neuroleptic marketed quite recently in Italy) is frequently resorted to for clinical use. Data concerning the use of tetrabenazine, a powerful dopaminergic depleter, is no doubt interesting, though the drug is hard to find in Italy as it is not registered in our country. Dopamine agonists (34) such as pergolide and similar drugs have an entirely opposite use in terms of pathogenetic assumptions, compared to neuroleptics, but this only confirms the complex systems involved in the disease's progress. Clonidine's, an alpha-2 adrenergic agonist, recent use has been successful and so has guanfacine's use. Stimulating psychotropic drugs, like methylphenidate and amphetamines, have proved useful (28-29-30-36) in disorders caused by ADHD, while drugs that act selectively on serotonin reuptake (SSRI) seem in some way useful in obsessive-compulsive conditions. Table 4 reports drugs in use and their initial dosage for the various clinical aspects of Tourette's Syndrome. Dosages must however be adapted case by case. Interesting data has been recently published concerning the use of nicotine, also administered in the form of nicotine patches, often combined with neuroleptics, whose dosage can be reduced, as there are synergies between nicotine and dopaminergic receptors. Systemic drugs can be used along with avant-garde therapies like the Botulinum toxin used in the local treatment of muscle districts involved in the various pathological movements. The toxin relaxes muscles, which subsequently "move" less, but the relaxation also reduces proprioception with a subsequent reduced sensitive "feeling", which is often the first sign of fits of pathological movements (premonitory sensation). This method enables the infiltration of vocal cords, which are percutaneously injected and electromyographically monitored, with small doses of Botulinum toxin to modify the proprioception that detects muscle tension, thus reducing coprolalic "fits" or, generally speaking, reducing the vocalization or emission of pathological sounds. The Author has treated a series of patients by infiltrating their vocal cords, reached percutaneously with the method described by Scott et al., with Botulinum A toxin. Results obtained are to date highly satisfactory.

The only collateral effect is a transitory 85-90% loss of voice in the cases treated. Antibiotics are rarely required and only when a high antistreptolysin titre reveals a streptococcal infection. Plasmapheresis and immunoglobulins have been resorted to on the basis of the immunological premises described above. Stereotaxic neurosurgery, chiefly based on the stimulation of certain brain districts, hence non-invasive surgery, has been resorted to in some cases of Tourette's Syndrome and serious OCDs. Psychiatric and psychodynamic treatments are currently resorted to, though they present alternate results. They often back up psychotherapies, which make this disorder that greatly alters the individuals' and their families' quality of life, more bearable. It is a fact that the disease must also be studied outside the neurological sphere, if only to better understand the use of drugs that often do not consider Tourette's Syndrome among the indications recorded.

Conclusions
Tourette's Syndrome has recently been extensively "revisited", with subsequent changes in its psychopathological picture and management. The disease has been withdrawn from the list of extrapyramidal disorders and it has been moved from the sole psychiatric field to a neurological one and more besides. Epidemiology itself reveals the disorder's social relevance, considering its incidence; hence Tourette's Syndrome can no longer be considered an "orphan disease". Precise guide-lines are now being defined both from a diagnostic and therapeutic perspective. In the light of the brief considerations made herein too, the disorder's management and diagnostic approach have many facets that touch on neurology and psychology, psychiatry and sociology. Only close attention paid to the conditions presented by Tourette patients can change the quality of life of a relevant number of mostly young individuals, who are at times in serious conditions of discomfort. The above described drugs are therapeutically essential: their detailed knowledge is now necessary, though most have yet to be recognized by the Italian Ministry of Health as recommended for use in Tourette's Syndrome.