Nonpharmacological treatments for Tourette syndrome and tic disorders: A protocol for systematic review and network meta-analysis.

BACKGROUND: A tic is a sudden, rapid, recurrent, nonrhythmic motor movement, or vocalization. Tic disorders are diagnosed based on the presence of motor or vocal tics, duration of tic symptoms, and age at onset. Current clinical practice guidelines strongly recommend behavioral therapies because they are more effective and safer than medications. To determine the most effective nonpharmacological intervention for tic disorders and Tourette syndrome, we will conduct a systematic review and network meta-analysis. METHODS: We will search the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycARTICLES, AMED, 3 Chinese databases (China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Data), 3 Korean databases (Korean Medical Database, Korean studies Information Service System, and ScienceON), and a Japanese database (CiNii). There will be no language or date restrictions. The primary outcome will be the tic severity scale, the Yale Global Tic Severity Scale. The secondary outcomes will include the effective rate defined by the trial authors, dropout rate, and adverse events. Methodological quality will be assessed using the Cochrane risk of bias tool. RESULTS: Results of this review and network meta-analysis will be published in a peer-reviewed journal. CONCLUSIONS: This systematic review will assess the effectiveness of nonpharmacological interventions for treating tic disorders. A systematic review or meta-analysis will provide an unbiased overview of the existing evidence.

Effect of diet, exercise and sleep on tic severity: a scoping review protocol.

INTRODUCTION: Tourette syndrome is a common childhood-onset neuropsychiatric disorder, with tics that wax and wane in frequency and severity over time. The purpose of the proposed scoping review is to map the types of evidence available pertaining to the effect of diet, sleep and exercise on tic severity and identify key concepts and gaps in research. METHODS: Our scoping review will use the six-step framework recommended by Arksey and O'Malley, with enhancements from Levac et al and Joanna Briggs Institute. We will attempt to identify all the relevant literature regardless of study design. We will search six electronic databases, the reference lists of all selected studies and the grey literature for studies examining an association between dietary factors, sleep or physical exercise and tics, or studies of interventions targeting diet, sleep or exercise to reduce tics. Our analysis plan includes description of the reported associations among dietary factors, sleep and physical exercise and tics, the effects of interventions, the research methodologies and how outcomes are measured. ETHICS AND DISSEMINATION: An approval from a recognised committee is not required to conduct the proposed review, as the study entails secondary analysis of the literature available publicly. For dissemination of the study, the results will be submitted for publication to peer-reviewed scientific journals and presented at relevant public forums and conferences.

Pallidal and thalamic neural oscillatory patterns in tourette's syndrome.

OBJECTIVE: Aberrant oscillatory activity has been hypothesized to play a role in the pathophysiology of Tourette's syndrome (TS). Deep brain stimulation (DBS) has recently been established as an effective treatment for severe TS. Modulation of symptom-specific oscillations may underlie the mechanism of action of DBS and could be used for adaptive neuromodulation to improve therapeutic efficacy. The objective of this study was to demonstrate a pathophysiological association of pallidal and thalamic local field potentials (LFPs) with TS. METHODS: Nine medication-refractory TS patients were included in the study. Intracerebral LFPs were recorded simultaneously from bilateral pallidal and thalamic DBS electrodes. Spectral and temporal dynamics of pallidal and thalamic oscillations were characterized and correlated with preoperative Yale Global Tic Severity Scale (YGTSS) scores. RESULTS: Peaks of activity in the theta (3-12Hz) and beta (13-35Hz) were present in pallidal and thalamic recordings from all patients (3 women/6 men; mean age, 29.8 years) and coupled through coherence across targets. Presence of prolonged theta bursts in both targets was associated with preoperative motor tic severity. Total preoperative YGTSS scores (mean, 38.1) were correlated with pallidal and thalamic LFP activity using multivariable linear regression (R² = 0.96; p = 0.02). INTERPRETATION: Our findings suggest that pallidothalamic oscillations may be implicated in the pathophysiology of TS. Furthermore, our results highlight the utility of multisite and -spectral oscillatory features in severely affected patients for future identification and clinical use of oscillatory physiomarkers for adaptive stimulation in TS. Ann Neurol 2018;84:505-514.

Medical Cannabinoids in Children and Adolescents: A Systematic Review.

CONTEXT: Legalization of medical marijuana in many states has led to a widening gap between the accessibility and the evidence for cannabinoids as a medical treatment. OBJECTIVE: To systematically review published reports to identify the evidence base of cannabinoids as a medical treatment in children and adolescents. DATA SOURCES: Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of PubMed, Medline, and the Cumulative Index to Nursing and Allied Health Literature databases was conducted in May 2017. STUDY SELECTION: Searching identified 2743 citations, and 103 full texts were reviewed. DATA EXTRACTION: Searching identified 21 articles that met inclusion criteria, including 22 studies with a total sample of 795 participants. Five randomized controlled trials, 5 retrospective chart reviews, 5 case reports, 4 open-label trials, 2 parent surveys, and 1 case series were identified. RESULTS: Evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy. At this time, there is insufficient evidence to support use for spasticity, neuropathic pain, posttraumatic stress disorder, and Tourette syndrome. LIMITATIONS: The methodological quality of studies varied, with the majority of studies lacking control groups, limited by small sample size, and not designed to test for the statistical significance of outcome measures. Studies were heterogeneous in the cannabinoid composition and dosage and lacked long-term follow-up to identify potential adverse effects. CONCLUSIONS: Additional research is needed to evaluate the potential role of medical cannabinoids in children and adolescents, especially given increasing accessibility from state legalization and potential psychiatric and neurocognitive adverse effects identified from studies of recreational cannabis use.

Is cannabis treatment for anxiety, mood, and related disorders ready for prime time?

Anxiety and related disorders are the most common mental conditions affecting the North American population. Despite their established efficacy, first-line antidepressant treatments are associated with significant side effects, leading many afflicted individuals to seek alternative treatments. Cannabis is commonly viewed as a natural alternative for a variety of medical and mental health conditions. Currently, anxiety ranks among the top five medical symptoms for which North Americans report using medical marijuana. However, upon careful review of the extant treatment literature, the anxiolytic effects of cannabis in clinical populations are surprisingly not well-documented. The effects of cannabis on anxiety and mood symptoms have been examined in healthy populations and in several small studies of synthetic cannabinoid agents but there are currently no studies which have examined the effects of the cannabis plant on anxiety and related disorders. In light of the rapidly shifting landscape regarding the legalization of cannabis for medical and recreational purposes, it is important to highlight the significant disconnect between the scientific literature, public opinion, and related policies. The aim of this article is to provide a comprehensive review of the current cannabis treatment literature, and to identify the potential for cannabis to be used as a therapeutic intervention for anxiety, mood, and related disorders. Searches of five electronic databases were conducted (PubMed, MEDLINE, Web of Science, PsychINFO, and Google Scholar), with the most recent in February 2017. The effects of cannabis on healthy populations and clinical psychiatric samples will be discussed, focusing primarily on anxiety and mood disorders.

Putting the Pieces Together in Gilles de la Tourette Syndrome: Exploring the Link Between Clinical Observations and the Biological Basis of Dysfunction.

Gilles de la Tourette syndrome is a complex, idiopathic neuropsychiatric disorder whose pathophysiological mechanisms have yet to be elucidated. It is phenotypically heterogeneous and manifests more often than not with both motor and behavioral impairment, although tics are its clinical hallmark. Tics themselves present with a complex profile as they characteristically wax and wane and are often preceded by premonitory somatosensory sensations to which it is said a tic is the response. Highly comorbid with obsessive-compulsive disorder and attention deficit-hyperactivity disorder, it is purported to be an epigenetic, neurodevelopmental spectrum disorder with a complex genetic profile. It has a childhood onset, occurs disproportionately in males, and shows spontaneous symptomatic attenuation by adulthood in the majority of those afflicted. Although not fully understood, its neurobiological basis is linked to dysfunction in the cortico-basal ganglia-thalamo-cortical network. Treatment modalities for Tourette syndrome include behavioral, pharmacological and surgical interventions, but there is presently no cure for the disorder. For those severely affected, deep brain stimulation (DBS) has recently become a viable therapeutic option. A key factor to attaining optimal results from this surgery is target selection, a topic still under debate due to the complex clinical profile presented by GTS patients. Depending on its phenotypic expression and the most problematic aspect of the disorder for the individual, one of three brain regions is most commonly chosen for stimulation: the thalamus, globus pallidus, or nucleus accumbens. Neurophysiological analyses of intra- and post-operative human electrophysiological recordings from clinical DBS studies suggest a link between tic behavior and activity in both the thalamus and globus pallidus. In particular, chronic recordings from the thalamus have shown a correlation between symptomatology and (1) spectral activity in gamma band power and (2) theta/gamma cross frequency coherence. These results suggest gamma oscillations and theta/gamma cross correlation dynamics may serve as biomarkers for dysfunction. While acute and chronic recordings from human subjects undergoing DBS have provided better insight into tic genesis and the neuropathophysiological mechanisms underlying Tourette syndrome, these studies are still sparse and the field would greatly benefit from further investigations. This review reports data and discoveries of scientific and clinical relevance from a wide variety of methods and provides up-to-date information about our current understanding of the pathomechanisms underlying Tourette syndrome. It gives a comprehensive overview of the current state of knowledge and addresses open questions in the field.

Centromedian-Parafascicular Complex Deep Brain Stimulation for Tourette Syndrome: A Retrospective Study.

Deep brain stimulation (DBS) of the thalamic centromedian/parafascicular (CM-Pf) complex has been reported as a promising treatment for patients with severe, treatment-resistant Tourette syndrome (TS). In this study, safety and clinical outcomes of bilateral thalamic CM-Pf DBS were reviewed in a series of 12 consecutive patients with medically refractory TS, 11 of whom met the criteria of postsurgical follow-up at our institution for at least 2 months. Five patients were followed for a year or longer. Consistent with many patients with TS, all patients had psychiatric comorbidities. Tic severity and frequency were measured by using the Yale Global Tic Severity Scale (YGTSS) over time (average, 26 months) in 10 subjects. One patient was tested at 2-week follow-up only and thus was excluded from group YGTSS analysis. Final YGTSS scores differed significantly from the preoperative baseline score. The average (n=10) improvement relative to baseline in the total score was 54% (95% CI, 37-70); average improvement relative to baseline in the YGTSS Motor tic, Phonic tic, and Impairment subtests was 46% (95% CI, 34-64), 52% (95% CI, 34-72), and 59% (95% CI, 39-78), respectively. There were no intraoperative complications. After surgery, 1 subject underwent wound revision because of a scalp erosion and wound infection; the implanted DBS system was successfully salvaged with surgical revision and combined antibiotic therapy. Stimulation-induced adverse effects did not prevent the use of the DBS system, although 1 subject is undergoing a trial period with the stimulator off. This surgical series adds to the literature on CM-Pf DBS and supports its use as an effective and safe therapeutic option for severe refractory TS.

Sixteen years of deep brain stimulation in Tourette's Syndrome: a critical review.

INTRODUCTION: The aim of this paper was to perform a critical and systematic review of the published papers on deep brain stimulation (DBS) for Tourette's Syndrome (TS). EVIDENCE ACQUISITION: A PubMed search on DBS in TS was conducted selecting papers that reported on the clinical outcome of DBS. EVIDENCE SYNTHESIS: The majority of papers were case reports or small series. The thalamus and the globus pallidus internus appear to be the most promising targets. However, in light of the great methodological diversity a balanced comparison of clinical outcome and understanding of the role of DBS in TS remains difficult. CONCLUSIONS: Despite 16 years of experience with DBS in TS a consensus on many issues, foremost on target selection and the age of inclusion continue to be missing. Class I evidence and international collaborations, to increase the number of included patients, are urgently needed, in order to evaluate further the role of DBS in TS.

The effectiveness and safety of plum-blossom needle therapy for Tourette syndrome: study protocol for a randomized controlled trial.

BACKGROUND: Previous studies have indicated that acupuncture can alleviate the symptoms of Tourette syndrome (TS), but the evidence is insufficient. So far, there have been no reports on plum-blossom needle therapy for TS. Here we present a protocol for a randomized controlled trial using plum-blossom needle therapy to treat TS. METHODS/DESIGN: Sixty patients will be randomly allocated into either the plum-blossom needle therapy group or the habit reversal training (HRT) group. All patients in each group will be given 12 weeks of treatment, with follow-up at the 24th week. The primary outcome measure will be the mean change from baseline in the total tic score on the Yale Global Tic Severity Scale (YGTSS) at the 12th week. Secondary outcome measures will include the scores on the TS Clinical Global Impression Scale (CGI) and the mean changes from baseline in the YGTSS score and the Children and Adolescents' Quality of Life Scale (CAQOL) at other time points. Safety will also be evaluated. DISCUSSION: This trial will evaluate the effectiveness and safety of plum-blossom needle therapy for TS compared with HRT. A limitation of this trial is that patients and acupuncturists cannot be blinded. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02403258 (Date of registration: March 31, 2015).

[ESSENCE gathers the diagnoses into a whole]. / ESSENCE samlar diagnoserna till en helhet.

Co-existence of attention-deficit/hyperactivity disorder, oppositional defiant disorder, tic disorders, developmental coordination disorder, language disorder, learning problems, and autism spectrum disorder and sharing of symptoms across disorders, contribute to the typical clinical presentation in child psychiatry as well as in developmental medicine. The acronym ESSENCE refers to Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations. Affected children are brought for clinical assessment because of impairing symptoms that raise concern before the age of about 5 years in general development, communication and language, social inter-relatedness, motor coordination, attention, activity, behaviour, mood, and/or sleep. Such children are usually in need of a range of expert assessments, but a holistic approach is rarely taken from the start. Major problems in at least one ESSENCE domain before 5 years of age predict poor mental health later in life. Expert ESSENCE centres for assessment, habilitation and treatment of these children are needed.

Aripiprazole for the treatment of adolescent Tourette's syndrome: a case report.

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric, lifelong disorder with onset in childhood. The essential features of this disorder are multiple motor tics and one or more vocalizations. The neurochemical pathophysiology of GTS involves an unknown abnormality in the central dopaminergic system. Atypical antipsychotics, such as aripiprazole, serve as a new therapeutic option for GTS. The authors describe a unique case of Tourette's syndrome (TS) in an adolescent in which aripiprazole resolved the patient's symptoms. A 17-year-old, 5'11'' tall, African American male weighing 220 lbs was diagnosed with TS at 9 years old. By age 16, the patient developed prominent symptoms of intermitted eye blinking, forehead raising, finger snapping, heavy breathing, and head bobbing. Clonidine, in addition to homeopathic remedies (N-acetylcholine and alpha lipoic acid), was administered to the patient without significant diminution of symptoms. Later, aripiprazole was initiated at 5 mg/d. As a result, noticeable symptomatic improvement occurred within 48 hours. Aripiprazole was titrated over the next 4 weeks to 6.5 mg/d, with significant results. Over the next 6 months, aripiprazole was titrated again to 10 mg/d with additional symptom reduction. This case illustrates a patient who responded to aripiprazole with no reported adverse effects, when standard therapy failed to improve symptoms.

Neuroimaging of tic disorders with co-existing attention-deficit/hyperactivity disorder.

BACKGROUND: Tourette syndrome (TS) and Attention-Deficit/Hyperactivity Disorder (ADHD) are common and debilitating neuropsychiatric illnesses that typically onset in the preschool years. Recently, both conditions have been subject to neuroimaging studies, with the aim of understanding their underlying neurobiological correlates. OBJECTIVE: The relation of TS and ADHD is discussed against the background of findings from previous Magnetic Resonance Imaging (MRI) studies. METHODS: We review the designs and major findings of previous studies that have examined TS with comorbid ADHD, and we briefly contrast these findings with those in ADHD without comorbid tic disorders. RESULTS: The frequent comorbidity of TS and ADHD may reflect a common underlying neurobiological substrate, and studies confirm the hypothesized involvement of fronto-striatal circuits in both TS and ADHD. However, poor inhibitory control and volumetric reductions in fronto-striatal circuits appear to be core features of ADHD, whereas reduced volumes of the caudate nucleus, together with activation and hypertrophy of prefrontal regions that likely help to suppress tics, seem to be core features of TS. CONCLUSION: The etiological relationship between TS and ADHD must be clarified further with cross-sectional and, if possible, longitudinal imaging studies that examine samples of substantial size, including subgroups with pure TS and ADHD, as well as with comorbid conditions.

Increased number of subcortical hyperintensities on MRI in children and adolescents with Tourette's syndrome, obsessive-compulsive disorder, and attention deficit hyperactivity disorder.

OBJECTIVE: To investigate whether cerebral hyperintensities on T2-weighted magnetic resonance images (MRI) are associated with childhood neuropsychiatric disorders. METHOD: The authors compared the frequency of cortical and subcortical cerebral hyperintensities in 100 children and adolescents with Tourette's syndrome, obsessive-compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD) and 32 healthy comparison subjects. RESULTS: The frequency of cerebral hyperintensities was significantly higher in subjects with Tourette's syndrome, OCD, or ADHD than in healthy comparison subjects; each diagnostic group seemed to contribute to this effect. Among the patient groups, the likelihood of detecting cerebral hyperintensities in the subcortex (primarily the basal ganglia and thalamus) was significantly greater than in the cortex. CONCLUSIONS: A childhood diagnosis of Tourette's syndrome, OCD, or ADHD significantly increased the likelihood of detecting cerebral hyperintensities, particularly in the subcortex, supporting the notion that subcortical injury may play a role in the pathophysiology of these conditions.

Abnormal thalamic volume in treatment-naïve boys with Tourette syndrome.

OBJECTIVE: Thalamic abnormality has been implicated in the pathophysiology of Tourette's syndrome (TS). We examined the presence of aberrant thalamic volume from the treatment-naïve boys with TS using magnetic resonance imaging (MRI). METHOD: Volumetric MRI was performed on 18 treatment-naïve boys with TS, aged 7-14 years, and 16 healthy comparison subjects. The anatomical boundaries were then manually parcellated to measure the thalamic volume. RESULTS: Tourette's syndrome subjects had a significantly larger left thalamus in comparison with those of healthy subjects. On the contrary, no group difference was observed from the right thalamic volume. TS subjects also showed a significant reduction in rightward asymmetry in thalamic volume compared with the healthy subjects. CONCLUSION: Our findings provide new evidence of abnormal thalamic volume in pediatric TS.

Brain magnetic resonance spectroscopy in Tourette's disorder.

OBJECTIVE: Although abnormalities of neural circuits involving the cortex, striatum, and thalamus are hypothesized to underlie Tourette's disorder, the neuronal abnormalities within components of these circuits are unknown. The purpose of this study was to examine the cellular neurochemistry within these circuits in Tourette's disorder using proton magnetic resonance spectroscopy, a method that has not previously been used in neurobiological investigations of the disorder. METHOD: Proton magnetic resonance spectroscopic imaging examinations were conducted in 25 males with Tourette's disorder (age 10.9 +/- 2.0 years) and 32 male comparison subjects (age 11.5 +/- 2.7 years). Spectra from frontal cortex, caudate nucleus, putamen, and thalamus were analyzed, and N-acetylaspartate, creatine, choline, myoinositol, and glutamate + glutamine were quantified and compared between the groups. RESULTS: Patients with Tourette's disorder demonstrated a reduction in N-acetylaspartate and choline in the left putamen, along with reduced levels of creatine bilaterally in the putamen. In the frontal cortex, patients had significantly lower concentrations of N-acetylaspartate bilaterally, lower levels of creatine on the right side, and reduced myoinositol on the left side. CONCLUSIONS: The results of this study suggest compromised neuronal integrity and deficits in density of neuronal and nonneuronal cells in components of the neural circuits implicated in Tourette's disorder.

[Multidisciplinary therapy of Tourette syndrome]. / Tourette-szindróma multidiszciplináris kezelése.

The marked fluctuation in symptoms with a spectrum of behavioral problems contribute to misdiagnosis of Tourette syndrome. The authors review the recent progress in diagnosis and management with an emphasis on multidisciplinary approach. Possible associations with various genes have been found in etiology of Tourette syndrome. Development of the disease comes of dopaminerg neurotransmission disorder resulting in cortico-striato-thalamic system dysfunction. Tics are brief movements or sounds that occur intermittently and unpredictably mimicking fragments of normal behavior. Diagnostic criteria are based on the motor and vocal phenomena and their dynamics. The key concept in management are the tic severity scaling correlating with quality of life measurements. Therapeutic interventions indicated at severe alteration in patient's quality of life. Treatment plan combines various drug protocols, psychotherapy and behavioral therapy which should be optimalized for most disabling symptom. Social isolation and self injurious behavior complicates the treatment resistant, severe cases. In these subgroup of patient, an adequate selection of stereotactic intervention could provide an effective control of tic severity or behavioral disorder. Tourette syndrome, as a typical neuropsychiatric disorder, is a striking example for improved efficacy of multidisciplinary approach.

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.

Tactile prepuff inhibition of startle in children with Tourette's syndrome: in search of an "fMRI-friendly" startle paradigm.

BACKGROUND: Functional magnetic resonance imaging (fMRI) studies in neuropsychiatric populations will be enhanced by "on-line" tasks that assess brain activation linked to neurocognitive and psychophysiological functions. In some cases, task modifications may be required for use in an fMRI environment. Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in specific neuropsychiatric disorders, including schizophrenia, Huntington's disease, and Tourette's syndrome (TS). This study examined whether a modified "fMRI-friendly" PPI paradigm is suitable for use in children and adequately sensitive to detect PPI deficits in TS. METHODS: Bilateral eyeblink PPI was measured in children using chin air puffs to elicit startle and prepuffs to the dorsal hand surface as inhibiting stimuli. This paradigm involved no metallic objects or acoustic stimuli, making it suitable for an fMRI environment that is magnetically sensitive and acoustically complex. Children were also assessed in a "standard" acoustic PPI paradigm. RESULTS: Robust startle was elicited via either puffs or noise bursts, and these responses were inhibited by prepuffs and prepulses, respectively. Compared to control subjects, children with TS exhibited comparable startle magnitude and habituation but significantly reduced prepuff inhibition and acoustic PPI. CONCLUSIONS: Sensorimotor gating can be assessed in an "fMRI-friendly" paradigm that detects inhibitory deficits in TS.

[Gilles de la Tourette syndrome]. / Enfermedad de Gilles de la Tourette.

OBJECTIVE: To make a specific review of the definition and symptomatology of Gilles de la Tourette syndrome. DEVELOPMENT AND CONCLUSION: We made an basic syndrome evaluation and at the same time established a relationship with/between the most significant co-morbid features. We also refer briefly to current drug treatment and dosage and mention some of the most relevant side-effects of these drugs. The exact etiology of this disorder is still not fully understood but it is thought to be due to autosomal dominant inheritance, with marked penetration in males.