Deep Brain Stimulation in Tourette Syndrome Joana Rodrigues* 62757 Joana Pinto* 63772 *Instituto Superior Técnico 2010/11 Biophysics
Abstract: Tourette Syndrome (TS) is a neuropsychiatric disorder with onset in early childhood. It is characterized by motor and vocal tics, often associated with behavioral disorders, such as obsessive-compulsive disorder (OCD). Even though symptoms often disappear before or during adulthood, there are several standard treatments, such as pharmacotherapy and psychotherapy. In a small percentage, however, symptoms are intractable to any of these conservative treatments and DBS may be a therapeutic option. In 1999, Deep Brain Stimulation (DBS) was introduced for intractable TS. The pathophysiology of TS is still a matter of considerable debate so multiple targets have been used in a small number of patients. In published reports, it is described that there is a tic reduction rate of at least 66%. Despite this advances, serious adverse effects have been reported, surgery related (e.g., hematomas) as well as stimulation related (e.g., altered mood, changes in sexual function). There is general agreement that, at present time, DBS should only be used in adult, treatment resistant, and severely affected patients, and there should be appropriate selection of target and follow-up evaluation. Keywords: Tourette’s syndrome, Deep Brain Stimulation, Tics, Behavior, Surgery.
2.1 Characteristics
1. Introduction
Tourette Syndrome, also called Tourette's syndrome or Tourette's disorder, was named after Georges Albert Edouard Brutus Gilles de la Tourette, a French neuropsychiatrist (1857-1904). In 1885, he described TS as ―a nervous affection characterized by lack of motor coordination accompanied by echolalia and 1,2 coprolalia‖. This chronic and neurobehavioral disorder is characterized by motor and phonic tics. Tics can be seen as fragments of normal motor action or vocal productions that are misplaced in context and that can be easily mimicked and at times confused with goal-directed behavior.3 Tics may be abrupt in onset, fast and brief (clonic tics), or may be slow and sustained (dystonic or tonic tics).4 There are simple and complex tics. Simple tics can be eye blinking, sniffing or throat clearing. Complex tics include head shaking, scratching, touching or uttering phrases. Coprolalia, or uttering obscene words is one
Tourette syndrome is a chronic neurobehavioral disorder that can demonstrate refractoriness to conservative treatments, invasive nonsurgical treatments or psychobehavioral treatments. In these cases, Deep Brain Stimulation can be an option. However, some relevant issues still persist in terms of appropriate indication to treatment, selection of target, and follow-up evaluation. In this essay, it will be introduced the concepts of Tourette Syndrome and Deep Brain Stimulation and, afterwards, discussed their relation. Furthermore, some issues of this technique and some other applications of DBS will be enumerated.
2. Tourette Syndrome
1
of the most distressing and recognizable symptoms. More than one third of clinical TS patients exhibit self-injurious behavior. After the tic onset at the age of about 6–8 years, tics have a waxing and waning course and reach a maximum at around 12 years. In the majority of patients tics tend to decrease during adolescence or early adulthood. One important feature of TS is its association with a wide range of psychiatric and behavioral abnormalities such as obsessive-compulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD). When present, these coexisting conditions can add greatly to the morbidity associated with TS and have a negative impact on the overall quality of life. Although once thought to be rare, TS is now recognized as a relatively common disorder with an estimated worldwide prevalence of 4 to 5 in 10000. It occurs here to four times more commonly in males. There is considerable variation among studies reporting on the prevalence of TS, which is most likely due to variations in sex, age, diagnostic criteria, and assessment methods.2 Regardless of symptom severity, individuals with Tourette have a normal life span. Although the symptoms may be lifelong and chronic for some, the condition is not degenerative or life-threatening. Intelligence is normal in those with Tourette, although there may be learning disabilities.
challenges the autosomal dominant hypothesis, and suggests an additive model involving multiple genes. In some cases, tics may not be inherited; these cases are identified as sporadic Tourette syndrome (also known as tourettism) because a genetic link is missing. A person with Tourette syndrome has about a 50% probability of passing the gene(s) to one of his/her children. Gender appears to have a role in the expression of the genetic vulnerability, with males more likely to express tics than females. Tourette syndrome is a condition of incomplete penetrance, meaning not everyone who inherits the genetic vulnerability will show symptoms. Tourette's also shows variable expression, even family members with the same genetic makeup may show different levels of symptom severity. The gene(s) may express as Tourette syndrome, as a milder tic disorder (transient or chronic tics), or as obsessive compulsive symptoms with no tics at all. Only a minority of the children who inherit the gene(s) will have symptoms severe enough to require medical attention. There is currently no way to predict the symptoms a child may display, even if the gene(s) are inherited. Recent research suggests that a small number of Tourette syndrome cases may be caused by a defect on chromosome 13 of gene SLITRK1. Some cases of tourettism (tics due to reasons other than inherited Tourette's syndrome) can be caused by mutation. The finding of a chromosomal abnormality appears to apply to a very small minority of cases (1–2%). Studies to locate all of the genes implicated in Tourette's syndrome are ongoing. Relatively to the non-genetic, environmental, infectious, or psychosocial factors, these can influence the severity of the disorder. Twin studies have shown that the twin with lower birth weight is more likely to have more noticeable symptoms. Other perinatal events, such as maternal
2.2 Causes The exact cause of Tourette Syndrome is still unknown, but it is well established that both genetic and environmental factors are involved. Genetic studies, including twin studies, have proven that the overwhelming majority of cases of Tourette syndrome are inherited, although the exact mode of inheritance is not yet known. Tic disorders have long been thought to be inherited as an autosomal dominant gene, but recent research 2
stress, maternal smoking, and obstetric complications, while not causing tics, may be risk factors for increased severity of tics.4
According to the Diagnostic and Statistical Manual of Mental Disorders (DSM), Tourette’s may be diagnosed when a person exhibits both multiple motor and one or more vocal tics (although these do not need to be concurrent) over the period of a year, with no more than three consecutive tic-free months. The previous DSM included a requirement for "marked distress or significant impairment in social, occupational or other important areas of functioning", but this requirement was removed in the most recent update of the manual, in recognition that clinicians see patients who meet all the other criteria for Tourette's, but do not have distress or impairment. The onset must have occurred before the age of 18, and cannot be attributed to the direct physiological effects of a substance or a general medical condition. Hence, other medical conditions that include tics or tic-like movements (e.g. autism or other causes of tourettism) must be ruled out before conferring a Tourette's diagnosis. There are no specific medical or screening tests that can be used in diagnosing Tourette's; it is frequently misdiagnosed or underdiagnosed, partly because of the wide expression of severity, ranging from mild (the majority of cases) or moderate, to severe (the rare, but more widely-recognized and publicized cases). Coughing, eye blinking and tics that mimic asthma are commonly misdiagnosed. The diagnosis is made based on observation of the individual's symptoms and family history, and after ruling out secondary causes of tic disorders. In patients with a typical onset and a family history of tics or obsessive–compulsive disorder, a basic physical and neurological examination may be sufficient. There is no requirement that other comorbid conditions (such as ADHD or OCD) be present, but if a physician believes that there may be another condition present that could explain tics, tests may be ordered
2.3 Relation with OCD and ADHD As it was mention above, one important feature of TS is its association with a wide range of psychiatric and behavioral abnormalities such as obsessivecompulsive disorder (OCD) and attention deficit-hyperactivity disorder (ADHD). Some forms of obsessive-compulsive disorder (OCD) may be genetically linked to Tourette, or an alternate expression of the condition; genetic studies show an increased rate of tics and obsessivecompulsive behaviors or OCD in relatives of patients with Tourette, and reinforce the idea that at least some forms of OCD are etiologically related to TS, and may, therefore, be a variant expression of the same etiologic factors that are important for the expression of tics. Further evidence supporting that OCD and Tourette are alternative expressions of a common genetic vulnerability is that males inheriting the genetic vulnerability are more likely to display tics, while females are more likely to display obsessive-compulsive traits. The genetic relationship of attention-deficit hyperactivity disorder (ADHD) to Tourette syndrome is less clear, with some evidence to suggest no genetic linkage, and some evidence to suggest that some forms of Tourette syndrome may be genetically related to ADHD. Not all persons with Tourette's syndrome will have ADHD or OCD, although in specialty clinics where the most impaired patients are treated, a high percentage of patients seeking treatment do have ADHD. The high cooccurrence of ADHD observed in specialty clinics may be due to clinical ascertainment bias. 12
2.4 Diagnosis 3
as necessary to rule out that condition. An example of this is when diagnostic confusion between tics and seizure activity exists, which would call for an EEG, or if there are symptoms that indicate an MRI to rule out brain abnormalities. TSH levels can be measured to rule out hypothyroidism, which can be a cause of tics. Brain imaging studies are not usually warranted. In teenagers and adults presenting with a sudden onset of tics and other behavioral symptoms, a urine drug screen for cocaine and stimulants might be necessary. If a family history of liver disease is present, serum copper and ceruloplasmin levels can rule out Wilson's disease. Most cases are diagnosed by merely observing a history of tics.
the scoring for the Rush Video-Based Tic Rating Scale. This 10-minute film protocol includes near and far body views obtained under two conditions, patient relaxed with and without the examiner in the room. The new scoring system provides a 0-4 comparison in five domains (number of body areas, frequency of motor and phonic tics, and severity of motor and phonic tics) plus a total score of overall tic disability. A video-based rating scale is advantageous for several reasons, including the collection of data with the patient in a relaxed setting without direct scrutiny, and the ability for the video to be replayed and validated. To date, a long-awaited standardized Unified Tic Rating Scale is still being field-tested. In addition to challenges in the measurement of tic severity, until recently there has been no existing instrument to measure the lifetime likelihood of a person having or ever having had TS, which is important information for accurate pedigree linkage analysis. To correct this deficiency, a collaborative group of experts developed the Diagnostic Confidence Index: a questionnaire independent of current severity that provides a graded score of 0 to 100. Several of the more highly weighted diagnostic confidence factors include a history of coprolalia, complex motor or vocal tics, a waxing and waning course, echophenomena, premonitory sensations, an orchestrated sequence, and age of onset.6
Figure 1. Tourette's syndrome 17
2.5 Tic Rating Scales Because of their wide variability, spontaneous waxing and waning, and ability to be partially volitionally suppressed, tics are difficult to rate with reliability. This problem is not new, but has been emphasized in several recent studies focusing on tic status during stimulant treatment. In particular, investigators questioned a clinician’s ability to rank changes in tic severity by counting the number of tics observed during a 2-minute interval. One recent effort to improve an existing protocol includes modification of
2.6 Neuroanatomical basis It is widely believed that abnormalities in dopamine neurotransmission play a fundamental role in the Tourette Syndrome. This is because several clinical observations showed that dopamine-blocking agents provoke the decreasing of tics, while potentiation of dopamine transmission with stimulant medications may increase them. Besides that, a number of functional neuroimaging studies have shown abnormalities in 4
dopamine transporter and dopamine receptor binding in the striatum of TS patients. Dopamine has a strong regulatory function on striatal activity. The striatum, consisting of the caudate nucleus, the putamen, and the nucleus accumbens (ventral striatum), is the input structure of the basal ganglia, receiving information from the cortex. The striatum projects to the globus pallidus, and further via the thalamus, back to the (pre)frontal cortex, thus forming a circuit. Within the brain, there are anatomically segregated, parallel circuits representing different functions. They all traverse the cortex, striatum, globus pallidus and thalamus. Each circuit has a direct and an indirect pathway. In the direct pathway, information is sent from the striatum to the internal part of the globus pallidus (GPi), while in the indirect pathway, the striatum projects towards the external part of the globus pallidus (GPe). GPe neurons project to the subthalamic nucleus (STN), which sends its projections to the GPi. The modulatory effect of dopamine is different at the level of the direct and the indirect pathway, and in normal circumstances, there is a balance between the direct and the indirect pathway. This means, for motor function, that the execution of the intended movement is
enabled through the direct pathway, while, through the indirect pathway, competing movements are prevented from interfering with the desired one. Dopaminergic hyperactivity might facilitate the direct pathway and inhibit the indirect pathway. Both lead to an over-activity of the thalamocortical drive. Through these feedback loops, the thalamic hyperactivity would lead to a hyperactivity of the striatum. In the direct pathway, this hyperactivity would be reinforced by dopamine, thus leading to a hypoactivity of GPi. In the indirect pathway, this striatal hyperactivity would be inhibited by the excess of dopamine, even so resulting in a hypo-activity of GPi. Several studies have suggested that both the sensorimotor and the limbicinnervated parts of the basal ganglia including the dorsal and ventral striatum are involved in the pathophysiology of TS. To sum up, dopaminergic hyperactivity might dysregulate at least the sensorimotor and limbic circuits within the basal ganglia, leading to a thalamic hyperactivity. This thalamic hyperactivity would lead to an excessive stimulation of the cortex, and maintain itself through a feedback loop towards the striatum which is inappropriately modulated by an excess of dopamine. 7
5
Figure 2. Schematic representation of the activity of the striatal-basal ganglia thalamocortical circuits with normal (left) and excessive (right) dopamine activity. 7
blocking (haloperidol) agents. Other drugs such as clonidine, clonazepam, and risperidone, and injections with botulinum toxin, or nowadays also widely used. Selective serotonin reuptake inhibitors are recommended for the treatment of obsessive-compulsive behavior.
2.7 Treatment There are several types of treatment for this disease. For patients with mild symptomatology, supportive reassurance and psycho-behavioral methods might be sufficient. However, for patients with more severe symptoms, which begin to interfere with peer relationships, social interactions, academic or job performance, or with activities of daily living, pharmacological treatment may be considered. The therapy must be individualized and the most troublesome symptoms should be targeted ďŹ rst. For patients refractory to any medical treatment, surgery may be the treatment of last resort.7 Therapies such as psychotherapy or cognitive behavioral therapy may also help to avoid or ameliorate depression and social isolation, and to improve family support. Educating a patient, family, and surrounding community (such as friends, school, and church) is a key treatment strategy, and may be all that is required in mild cases. Pharmacological intervention is reserved for more severe symptoms. The most commonly prescribed medications for the motor and vocal tics are dopamine depleting (tetrabenazine) and dopamine
Figure 3. Clonidine is one of the medications typically tried first when medication is needed for Tourette's. 20
Psychostimulants, such as methylphenidate, are the treatment of choice for attention deďŹ cit hyperactivity disorder. Because children with tics often present to physicians when their tics are most severe, and because of the waxing and waning nature of tics, it is recommended that medication not be started immediately or changed often. Frequently, the tics subside with explanation, reassurance, understanding of the condition and a supportive environment. When medication is used, the goal is not to eliminate symptoms: it should be used at the lowest possible dose that manages symptoms without adverse effects, given that these 6
may be more disturbing than the symptoms for which they were prescribed. For patients who are refractory to any medical treatment, surgery may be the treatment of last resort. In the past, various attempts have been made to treat these patients through neurosurgical ablative procedures. Although reports of neurosurgical procedures for derangements in behavior and thinking date back to the late 1800s, the earliest formal series of procedures specifically aimed at the treatment of psychiatric disorders were performed in the mid 1930s. Egas Moniz, a Portuguese neurologist, and Almeida Lima, a neurosurgeon, performed a series of frontal leucotomies starting in November of 1935 after hearing a lecture on frontal lobe function and anxiety states in primates. With the development of human stereotactic techniques by Spiegel and Wycis in the 1940s and later the introduction of computed tomography and magnetic resonance imaging, the ability to accurately and discretely place lesions in the brain significantly improved. 19 However, for TS, the target sites have been diverse for this type of neurosurgical procedures and the results have often been unsatisfactory or major side-effects have occurred such as hemiplegia or dystonia. In 1999, deep brain stimulation (DBS) was introduced as a revolutionary new surgical technique in the treatment of intractable TS.
changes brain activity in a controlled manner and is perceived as having an advantage over prior surgical procedures that carry the stigma of lesioning targets in the brain permanently. DBS is adjustable, with multiple stimulation parameters that can be manipulated by the practitioner including amplitude, frequency, and Figure 4. DBS-probes shown in X-ray of the skull. 8 width of the stimulating pulse, and to a lesser extent the location and shape of the stimulating field. In addition, it is nondestructive and reversible, meaning that the presence of the electrode itself in the brain does not disrupt the normal brain circuitry, and when the stimulator is off, it is in essence ―not there‖. The latter provides the potential for more rigorous clinical trials with subjects and evaluators blinded to the stimulation condition, something that is impossible to accomplish with lesioning procedures unless a placebo-controlled sham trial is used. This procedure is considered highly invasive, expensive, and requires long-term expert care. Besides that, hardware complications such as lead fracture, infection, patient compliance issues, and in some cases the need for very frequent battery changes, are all potential disadvantages of DBS over lesioning procedures. However, despite its various benefits, DBS underlying principles and mechanisms are still not completely clear. The Food and Drug Administration (FDA) approved DBS as a treatment for essential tremor in 1997, for Parkinson's disease in 2002, and dystonia in 2003. DBS is also routinely used to treat chronic pain and has been used to treat various affective disorders, including major depression. In 1999, deep brain stimulation (DBS) was
3. Deep Brain Stimulation 3.1 Characteristics Deep Brain Stimulation is surgical treatment involving the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. This technique has provided remarkable therapeutic benefits for otherwise treatment-resistant movement and affective disorders such as Parkinson's disease, tremor and dystonia. It directly 7
introduced as a revolutionary new surgical technique in the treatment of intractable TS.
It has been shown in thalamic slices from mice that DBS causes nearby astrocytes to release adenosine triphosphate (ATP), a precursor to adenosine A1 (through a catabolic process). In turn, adenosine A1 receptor activation depresses excitatory transmission in the thalamus, thus causing an inhibitory effect that mimics ablation or lesioning.8
3.2 Components and Biochemistry The deep brain stimulation system consists of three components: the implanted pulse generator (IPG), the lead, and the extension. The IPG is a battery-powered neurostimulator encased in a titanium housing, which sends electrical pulses to the brain to interfere with
3.3 DBS in Tourette Syndrome The first reported DBS for treatmentrefractory TS was performed by Vandewalle et al, on a 42-year-old patient. After a 12 month post-DBS follow upevaluation, tics decease from 38 to 0 a minute.5 Since then 24 studies including a total of 63 patients have been published describing the results of DBS in TS and chronic tic disorder. Most of these reports describe DBS in single patients. In 59 of 63 TS patients, DBS resulted in a significant tic improvement. In TS patients the most often used targets of stimulation are the thalamus and the globus pallidus internus but there have been described 7 others like the subthalamicus nucleus or the nucleus accumbis. Although no serious persistent adverse effects (AE) have been reported so far, surgical as well as stimulation –related AEs may occur, such as haematomas, apathy, blurring of vision, changes in sexual function. So, despite widely publicized early successes, DBS remains a highly experimental procedure for the treatment of Tourette's, and more study is needed to determine whether long-term benefits outweigh the risk. Because diagnosis of Tourette's is made based on a history of symptoms rather than analysis of neurological activity, it may not always be clear how to apply DBS for a particular patient. Due to concern over the use of DBS in the treatment of Tourette syndrome, the Tourette Syndrome Association convened a group of experts to develop
neural activity at the target site. The lead is a coiled wire insulated in polyurethane with four platinum iridium electrodes and is placed in one of three areas of the brain. The lead is connected to the IPG by the extension, an insulated wire that runs from the head, down the side of the neck, behind the ear to the IPG, which is placed subcutaneously below the clavicle or in some cases, the abdomen. The IPG can be calibrated by a neurologist, nurse or trained technician to optimize symptom suppression and control side effects. All three components are surgically implanted inside the body. Under local anesthesia, a hole about 14 mm in diameter is drilled in the skull and the electrode is inserted, with feedback from the patient for optimal placement. The right side of the brain is stimulated to address symptoms on the left side of the body and vice versa. DBS leads are placed in the brain according to the type of symptoms to be addressed. For Tourette Syndrome, because the unknown exact location of the target, in several studies, the lead has been placed in different sites, such as the thalamus or the globus pallidus internus.
Figure 5. The three components of DBS: IPG, lead and extension 21
8
recommendations guiding the use and potential clinical trials of DBS for TS.
stimulation (improvements documented in three out of five patients, with an average reduction of tics of 50%) rather than unilateral stimulation. The internal globus pallidus, GPi, is one of the output nuclei of the basal ganglia, that act as a relay for the output patways of the basal ganglia. A continuous high frequency stimulation of this region has been shown to ameliorate dystonia. In
3.3.1 Targets There are a few sites in the brain that can be targeted to achieve differing results in DBS. However the most appropriate one, with the optimal simulation parameters and long-term effects and efficacy, remain
Figure 6. Brain areas that have been targeted in surgery for TS, and some other relevant neuroanatomical structures. 1
unknown. The three most common and different nuclei for DBS treatment of refractory Tourette correspond to: the intralaminar thalamic nuclei, the Globus pallidus internus (GPi), and the nucleus accumbens.
other words, stimulation of the GPi is able to modify the neuronal activity of the Vo nucleus, which is in turn involved in initiating planned movement and suppressing unwanted movement. The nucleus accumbens, corresponds to a collection of neurons within the striatum. It plays a crucial role in several feelings types of feelings as reward, pleasure, addiction, aggression, fear , among others. Each half of the brain has one nucleus accumbens, and it is located where the head of the caudate and the anterior portion of the putamen meet just lateral to the septum pellucidum. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum, which is part of the basal ganglia. The ventral striatum is presumed to have a modulatory activity on amygdaloid basal ganglia-prefrontal cortex circuitry and, as the activity of its neurons is modulated by
The intralaminar nucleus corresponds to a nucleus of the thalamus which contains several nuclei, such as central lateral, centromedian, paracentral and parafascicular. This nuclei complex is involved in sensorimotor and motor circuitry of the basal ganglia.The anterior CM-Pf influences cells involved in tremor generation located in a wide area including the nucleus ventralisoralisanterior (VoA) and nucleus ventralis oralis posterior (Vop). Stimulation of both the CM-Pf and VoA complex has proved to be effective in the treatment of behavioral aspects of TS as well as alleviation of tics. Superior results are obtained with simultaneous bilateral 9
dopamine and a high proportion of cells have a high concentration of dopamine D1 and D3 receptors, the nucleus accumbens is believed to also be involved in addiction and OCB . Early results have demonstrated the effectiveness of DBS of the nucleus accumbens in patients with severe OCD and anxiety disorder, being some of these disturbances in various degrees associated with TS. 7
and CT-MR are obtained. After data acquisition, all images are transferred to a workstation and projected in three dimensions (axial, coronal, and sagital). Initial values for target localization are calculated. Final target coordinates are determined by combining the initial target coordinates and target observed in MR and CT-MR images. The anatomical virtual electrode length along the trajectory line in the target is measured after the final planning stage. In the operating room, patients are placed in the supine position for the procedure with the neck flexed at 20—30° in order to minimize cerebrospinal fluid (CSF) leakage. Under local anesthesia, a hole is drilled at or just anterior to the coronal suture, and the dura is minimally opened only enough to insert electrodes. After incision of the dura and arachnoid-pia layer, the arachnoid membrane and pia layer are coagulated to minimize CSF leakage. The microelectrode is inserted through the burr hole followed by completely sealing the hole with fibrin glue to prevent CSF leakage during microelectrode recording. The microelectrode is positioned above the theoretical target using the
Figure 7. During DBS, stereotactic coordinates have to be chosen to place the electrodes in target area.1
3.3.2 Surgical Procedure The technique of DBS applied to TS is similar to that used for more classic indications, such as Parkinson’s disease. The preference and experience of the surgeon play a key role in choosing the imaging technique for the target localization. Magnetic Resonance (MR) or fused Computerized Tomography/Magnetic Resonance (CT-MR) images are often used. However the target for TS, such as the nuclei of the medial part of the thalamus, are invisible in current imaging techniques. The procedure becomes more complicated and difficult making the intra-operative findings like the effects of stimulation more important. Several steps of DBS procedure are enumerate next. A stereotactic frame is applied to the patient before being taken to a MR unit, where usually images of MR
Microdrive System Figura 8. Insertion of electrode during surgery under C-arm 8 guidance. Along using a stereotactic frame. this trajectory, passage into the target can result in a marked increase in signal amplitude above the background activity. The microelectrode is then advanced further until the background activity subsides and the activity of the substantia nigra is evident. 8
10
Macrostimulation is performed as the electrode is withdrawn, and the patient’s neurological response is carefully monitored. Electrode length in target is measured and compared with the expected length. Repositioning of the electrode is considered if the difference between the expected length of the target and the length obtained by microelectrode recording is too great; if the electrode length in the target as measured using microelectrode recording is less than 4 mm; or if side effects (e.g., dysarthria, gaze disturbance, or other neurological abnormalities) are observed. After determining the electrode position, a definitive electrode for long-term stimulation is inserted, and stimulation is performed to confirm the beneficial effects of electrical stimulation and voltageinduced side effects. After closing the wound, the patient returns to the MR unit in the stereotactic frame to obtain a postoperative MRI. Postoperative MR images are transferred to the workstation and are independently registered with the preoperative MRI. Then, postoperative MR images are merged with the preoperatively planned target and trajectory. The accuracy of electrode placement is assessed using two parameters: the anterior-posterior (AP) difference and the lateral difference. The lateral difference is defined as the shortest distance between the planned target and the center of the actual electrode trajectory in the arch parallel view with full magnification. The AP difference is defined as the shortest distance between the planned target and the center of the actual electrode trajectory in the sagital view. If the actual electrode position is acceptable, an implantable pulse generator is inserted into subcutaneous area in the subclavicular region.6 Note that TS patients may pull themselves out of the stereotactic frame because of the frequent motor tics that occur. One solution would be to operate
with the patient under general anesthesia. But, because of the uncertainty of the ideal target and the importance of the intraoperative findings, it is preferable to have the patient awake and cooperative during surgery. To avoid general anesthesia, patients may be sedated with a combination of Iormetazepam and clonidine, or with a Profopol target controlled infusion, which reduces tics sufficiently to im prove the safety and efficacy of a stereotactic procedure.2 Relatively to programming, the best effect in the majority of patients is obtained with a frequency between 75 Hz and 100 Hz and a pulse width of 210 Âľs. From postoperative day 1, bipolar stimulation is started (to obtain the most selective effect), with each pole made active during four consecutive days (e.g., day 1: pole 0 negative, pole 1 positive; day 2: pole 1 negative, pole 2 positive, and so on). During programming, the voltage is progressively increased until unwanted side effects occur. Thereafter, the combination of electrodes may be altered (for example, two electrodes negative), or monopolar stimulation may be chosen, as suggested by clinical effects. As for other DBS indications, programming is a matter of trial and error, as directed by the best clinical effects and fewest adverse effects.7
3.3.3 Considerations 3.3.3.1 Patient selection As it was said before Tourette syndrome is more common in pediatric populations, tending to remit in adulthood. Not all patients require therapy, and those who do, only a minority seem to respond to a conservative treatment. In another words, only a small percentage of TS patients are potential candidates for surgery. Candidates for DBS in TS should be evaluated by a multidisciplinary team 11
including, at minimum, a neurologist, a psychiatrist, and a doctoral-level psychologist or neuropsychologist with expertise in TS and comorbid conditions. The Dutch-Flemish Tourette Surgery Study Group has established guidelines that decide which patients are considered for DBS. The TS patients considered for this surgery should comprise only severe cases that have already fruitlessly implications for patient selection. The following four recommendations have emerged as selection criteria for inclusion: 2,7 1. The patient has a definite Tourette’s syndrome, established by two independent clinicians and the diagnosis is established according to DSM- IV criteria; 2. The patient has severe and incapacitating tics as his primary problem and the treatment of these tics, not of other co-morbid behaviors such as OCD, SIB or ADHD is the main aim of the therapy; 3. The patient is treatment refractory, which means that he has not or very partially responded to 3 different types of medications each during at least 12 weeks in adequate doses, or has proven not to tolerate medication due to side-effects after serious attempts at taking medication have been made; 4. The patient has to be over 25 years of age. In terms of exclusion criteria, patients should be excluded from neurosurgical treatment if they have a tic disorder other than TS, severe psychiatric comorbid conditions (psychotic, dissociative, depressive disorders, substance use disorders), or mental deficiency. Besides that, there are several contraindications for surgical treatment for DBS in TS, such as severe cardiovascular, pulmonary, or hematological disorders, structural abnormalities revealed on MRI and active suicidal ideation.
For the assessment of clinical effects, a careful and detailed description of the effect of DBS on tics and associated behavioral disorders and stimulationinduced side effects is mandatory. The most commonly used scale for tic rating is the Yale Global Tic Severity Scale (YGTSS). The Rush Videotape scale is also commonly used. For a more objective evaluation, the patient should also be recorded on video with and without stimulation. The tics should be rated on video by two independent investigators. Ideally, the patient and investigator should be blinded to the status of the stimulation. A careful psychiatric and neuropsychological evaluation should be performed at regular intervals (e.g., at 3, 6, and 12 months). It is essential that any investigation of the clinical effects of DBS for TS include accurate postoperative imaging to identify the exact electrode placement. In a region such as the medial thalamus that encompasses many small vessels, the localization is especially important. The most prudent approach may be to perform a postoperative computed tomography scan and fuse these images with preoperative MRI images—although many centers successfully apply other imaging approaches. Only if these prerequisites are fulfilled and a maximum amount of data is exchanged between centers the optimal target can be established. 7
3.3.4 Side-effects and Complications Although DBS is really helpful for some patients, there is also the potential for neuropsychiatric side effects. Reports in the literature describe the possibility of apathy, hallucinations, compulsive gambling, hypersexuality, cognitive dysfun ction, and depression. However, these symptoms may be temporary and related to the correct placement and calibration of the
3.3.3.2 Pos-Operative Evaluation 12
stimulator, so they are potentially reversible. Another problem that might occur is related to the fact that the brain can shift slightly during surgery. There is also the possibility that the electrodes can become displaced or dislodged. This may cause more severe complications such as personality changes, but electrode misplacement is relatively easy to identify using CT, for example. There may also be complications of surgery, such as bleeding within the brain (intracranial hemorrhage), and this is one of the most serious complications of DBS, because it can cause a stroke. 8 DBS risks may also include infection, seizures and allergic response to implanted materials. Any of these problems may require removal of part or all of the deep brain stimulation system.
3.3.5 Another DBS’s Applications 3.3.5.1 Parkinson’s disease Parkinson's disease (PD) is a neurodegenerative disease whose primary symptoms are tremor, rigidity and postural instability. Deep Brain Stimulation does not provide a cure for Parkinson's disease, but it can help manage some of its symptoms and consequently improve the patient’s quality of life. Nowadays, the procedure is used only for patients whose symptoms cannot be adequately controlled with medications, or whose medications have severe side effects. 8 Its direct effect on the physiology of brain cells and neurotransmitters is currently debated, but by sending high frequency electrical impulses into specific areas of the brain it can mitigate symptoms and/or directly diminish the side effects of this disorder, allowing a decrease in medications, or making a medication regimen more tolerable. Different sites of stimulation provide different clinical effects in PD.9
Figure 9. Axial CT scan showing bilateral subcortical intracerebral haematomas along. 9
Table 1. Reports on deep brain stimulation in patients with Tourette Syndrome. 7
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Figure 10. A person with Parkinson’s disease.
to pharmaceutical drug. Since there is still no cure available for this disorder, treatment only allows minimizing the symptoms and it’s very difficult. 13 So, after trying DBS for the treatment of PD and tremor, there was a natural temptation to try also for this disease. Stereotaxic ablations of the globus pallidus or thalamus had been used for many years in the treatment of medically refractory generalized dystonia, but their performance was not widespread. The globus pallidus became, because of that, the primary target for dystonia. In spite of the fact that DBS for treating dystonia requires further investigation, early results of this surgical procedure in dystonia patients were very promising (in patients with primary generalized dystonia, there was a – improvement in symptoms gradually over a period of weeks to months), and that’s why this technique is currently the most effective treatment for medically refractive dystonia.9
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3.3.5.2 Tremor A tremor corresponds to an involuntary, rhythmic, muscle contraction and relaxation involving to-andfro movements of one or more body parts. 15 The main cause of tremor remains unknown, although it does run in some families. The first widespread use of DBS in the United States and in Europe was for the treatment of Essential Tremor (ES) or the tremor of PD. Single and multicenter studies have consistently reported substantial benefit of Ventral Intermediate Nucleus of the Thalamus stimulation with an average tremor reduction of over 80% in the majority of patients. 9
3.3.5.4 Pain DBS has been used for more than 50 years to treat a variety of intractable pain syndromes, such as neuropathic pain, phantom-limb pain, failed low back pain, and cluster headache pain. Several experiences have been made and they suggest that DBS provides short- or longterm benefit in a variety of these syndromes. This benefit varies depending upon length of follow-up, the condition treated, the definition of adequate pain relief, and the site of stimulation, which have varied from the sensory thalamus to the periaqueductal gray, periventricular gray, the motor cortex, among others.9
3.3.5.3 Dystonia Dystonia is a neurological movement disorder, characterized by sustained muscle contractions that cause twisting and repetitive movements and abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning, as lead poisoning or even by a reaction
Figure 11. A person with induced dystonia. 13
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4. Conclusion
5. References
In recent years, remarkable advances have been made in order to understand the etiology and the pathophysiology of Tourette syndrome. In this disorder, neurologists play an important role in the accurate diagnosis, as well as in explaining its implications to patients and their relatives. This disease is still not well understood nowadays. An interest in DBS as a potential therapy for patients with intractable TS, is increasing. This technique is known for its beneficial effects in TS, with several targets. The most optimal target has not yet been defined, and therefore continuous exchange and ongoing assessment of clinical experience will be important. This procedure has also the potential to provide substantial benefit for a variety of other neuropsychiatric conditions. Despite the marked clinical benefit, we still have much to learn about the mechanism of action of DBS. There are some negative effects associated with this procedure, such as, changes in sexual behavior, which may become prominent later in the course of the postoperative follow up. Patients should be very carefully informed about this risk prior to surgery. On the other hand, the use of the current advanced techniques available to perform DBS might reduce major complications such as intracerebral hematomas to a minimum. In conclusion DBS in TS, although experimental, can be considered a safe procedure. If it remains in the hands of experienced neurosurgeons working with a team of scientists who have expertise in diagnosing and treating TS and there is continuous assessment and timely exchange of clinical experience, DBS can become a standard treatment procedure for selected intractable patients with TS.
1.Temel Y, Visser-Vanderwalle V. Surgery in Tourette Syndrome. Movement Disorders 2004;91:3-14. 2. Ackermans L, Temel Y, VisserVandewalle V. Deep Brain Stimulation in Tourette’s Syndrome. The American Society for Experimental Neurotherapeutics 2008;5:339-344. 3. Leckman JF, Bloch MH, ScahillL, Kig RA. Tourette Syndrome: the self under siege. J Child Neurol 200621:642-649. 4. Robertson MM. Tourette Syndrome, associated conditions and the complexities of treatment. Brain 2000;123:425-462. 5.http://en.wikipedia.org/wiki/Causes_and_ origins_of_Tourette_syndrome 6. Chang WS, Kim HY, Kim JP. Bilateral Subthalamic Deep Brain Stimulation using single track microelectrode recording Acta Neurochir 2011;153:1087-1095. 7. Visser-Vandewalle V. DBS in Tourette syndrome: rationale, current status and future prospects. Acta Neurochir Suppl 2007; 97(2):215-222. 8. http://en.wikipedia.org/wiki/Deep_brain_sti mulation 9. Idris, Z., Rahman, A. et al. (2010). Intracerebral haematomas after deep brain stimulation surgery in a patient withTourette syndrome and low factor XIIIA activity. Journal of Clinical Neuroscience ,17, 1343–1344. 10. Larson P. Deep Brain Stimulation for Psychiatric Disorders. The American Society for Experimental Neurotherapeutics 2008;5:50-58 11. Perlmutter, J.S.&Mink, J.W.(2006).Deep Brain Stimulation. The Annual Review of Neuroscience, 29, pp. 229–257.Doi: 10.1146/annurev.neuro.29.051605.112824 12. http://en.wikipedia.org/wiki/Causes_and_or igins_of_Tourette_syndrome 15
13. http://en.wikipedia.org/wiki/Dystonia 14. http://www.pharmas.co.uk/blog/zappingparkinson%E2%80%99s-disease 15. http://www.clevelandclinic.org/health/healt h-info/docs/0900/0953.asp 16. http://www.medtronic.com/healthconsumers/dystonia/therapy/benefits-andrisks/index.htm 17. http://www.kellykite.com/352/tourettessyndrome.html 18. http://www.tsausa.org/Medical/definitio.ht ml 19.Sassi M, Porta M, Servello D. Deep Brain Stimulation therapy for treatmentrefractory Tourette’s Syndrome. Acta Neurochir 2011;153:639-645. 20.http://en.wikipedia.org/wiki/Clonidine 21.http://www.webmd.com/parkinsonsdisease/deep-brain-stimulation
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