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Research Areas

Therapeutic Trials
Pharmacogenetics
Genetics
Autoimmunity
Neurobiology

Therapeutic Trials

Medications used for tic suppression are generally reserved for patients whose tics are psychosocially disabling. None of the available tic-suppressing agents are curative and all are associated with potential side effects. Classic neuroleptic drugs, antagonists at dopamine D2 receptors, are generally the mainstay of tic treatment, but side effects often limit their usefulness. Hence, there is an ongoing need to search for alternative, non-neuroleptic therapy therapies for tics in TS.

Levetiracetam is a broad spectrum anti-epileptic agent with potential advantages including a high therapeutic index, a desirable pharmacokinetic profile, minor adverse effects and a lack of effect on serum levels of other agents. Levetiracetam has been shown to be beneficial for myoclonic epilepsy and possibly tics. A double-blind, placebo-controlled, crossover, pilot project with 20 patients between the ages of 8 to 16 years with TS has recently been completed and results are being analyzed. Follow up studies are planned.

A multicenter therapeutic trial is in the planning phase. This study is designed to compare the efficacy of two atypical neuroleptics, risperidone and aripiprazole. Risperidone is a benzisoxazol derivative that at low doses acts on 5-HT2 receptors, while at higher doses it is a potent D2 antagonist. Several studies have suggested that risperidone may be effective for some patients and that it compares favorably with pimozide. Aripiprazole is the most recently approved atypical antipsychotic medication in the US. Unlike other antipsychotics it demonstrates a mix of agonist and antagonistic effects at dopamine receptors, depending on testing conditions. It is considered a D2 receptor partial antagonist, exerting relatively weak agonism as compared to natural endogenous dopamine. Furthermore, consistent with other partial agonists it shows agonistic effects most clearly when there is little dopamine with which to compete or when receptors are maximally responsive. Aripiprazole has similar partial agonist effects at serotonin 5HT1a receptors and antagonistic effects at 5HT2a receptors.

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Pharmacogenetics

When individuals with TS are treated with medications to suppress tics, some improve, others have little or no response, and several may develop significant side-effects. In order to explain this variability, pharmacogenetic research has focused on two major areas, drug metabolism and drug site of action.

Fifteen established genetic variations (polymorphisms), including those from of metabolizing enzymes (CYP2D6), dopamine and serotonin transporters (DAT,5-HTT), dopamine receptors (D2, D3, D4) and serotonin receptors (5HT2A and 5HT2C), are being investigated in children with TS using DNA obtained from buccal swabs. Major objectives include determining whether the presence of specific patterns of neurotransmitter polymorphisms can predict the tic-suppressing pharmacologic effect of typical and atypical neuroleptics. The patient’s response to pharmacotherapy is based on a prospective evaluation of response to therapy.

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Genetics

Strong support that TS is a heritable disorder is provided by family studies, evaluation of monozygotic and dizygotic twins, and by follow-up investigations of at-risk children. Nevertheless, despite extensive evaluations including genetic linkage, cytogenetic, candidate gene, and molecular genetic studies, the precise pattern of transmission and the identification of the gene(s) remain elusive. The failure of family and candidate gene studies to identify a precise linkage to TS has led investigators to examine polymorphism associations.

The goal of an ongoing study is to determine whether there is an association between TS and polymorphisms located on several dopaminergic markers. Several dopaminergic polymorphisms (the dopamine transporter (DAT1 DdeI and DAT1 VNTR), dopamine receptor (D4 Upstream Repeat and D4 VNTR), dopamine converting enzyme (dopamine-?-hydroxylase), and the acid phosphatase locus 1 (ACP1) gene) are examined for associations with TS and attention-deficit hyperactivity disorder (ADHD). DNA samples are obtained from buccal swabs. In preliminary results a significant association has been identified for the TS-total and TS-only vs. control groups for the DAT DdeI polymorphism. Data show that the TS-total group has an increased heterozygote frequency with GA alleles as compared to controls (46% v. 33%, respectively). Further investigations are in progress.

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Autoimmunity

An autoimmune etiology has been hypothesized as the underlying pathophysiologic mechanism in some children with tic disorders. In these individuals, it is postulated that antibodies (possibly formed against infectious agents) cross react against specific central nervous system neurons, through a process of molecular mimicry, and cause tics. PANDAS, an acronym for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infection, has received wide spread notoriety in both scientific and lay publications. Nevertheless, the existence of PANDAS is controversial.

Four different approaches are being used in our laboratory at Johns Hopkins in an attempt to confirm an autoimmune mechanism; 1) quantification of serum antineuronal antibodies using ELISA, 2) analysis using Western immunoblotting, 3) immunofluorescent histochemistry, and 4) determining the behavioral effect of serum infusions into rodent striatum. Antineuronal antibodies have been assessed in patients with PANDAS with variable results. Results from the Singer laboratory, using several different epitopes, including supernatant (S1), pellet (P2), and synaptosomal fractions from homogenized fresh human postmortem caudate, putamen, and globus pallidus were unable to distinguish 15 PANDAS subjects from controls (Singer 2004). In addition, a recent study comparing serum ANAb against supernatant fractions from fresh adult postmortem caudate, putamen, and prefrontal cortex (Brodmann’s area 10) in 48 children with PANDAS to similar fractions in 46 children with TS and 43 controls, failed to identify differences in ELISA optical density values or bands identified on immunoblotting (Singer et al 2005). Lastly, the microinfusion of sera from children with PANDAS into rodent striatum did not change the number of observed motor stereotypy behaviors (Singer et al 2005). Our neuroimmunological studies raise concerns about PANDAS being an autoimmune-mediate process. The entity of PANDAS remains an intriguing but controversial clinical syndrome.

Current research studies are designed to assess in a longitudinal fashion the association between streptococcal infection and tics. Johns Hopkins is an active participant in two separate NIH multi-center protocols designed to evaluate autoimmunity in TS.

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Neurobiology

Convincing evidence, both direct and indirect, indicates that cortico-striatal-thalamo-cortical (CSTC) pathways are involved in the expression of TS and its accompanying neuropsychiatric problems (Singer and Minzer 2003; Minzer et al 2004). Although there is general consensus of a CSTC circuit abnormality, the precise pathophysiologic location(s) remain speculative. Many investigators have focused primarily on the striatal component perhaps influenced by knowledge of associations between basal ganglia dysfunction and movements in other disorders. In contrast, we would suggest that evidence is accumulating to support a cortical dysfunction in TS.

At the cellular level, the presence of dopaminergic (DA), glutamatergic, GABAergic, serotoninergic, cholinergic, noradrenergic, and opioid systems within CSTC circuits raises the possibility that a variety of transmitters may be involved in the pathobiology of TS. Even though the author’s bias is that the DA system has a significant role, because many transmitters systems are interrelated in the production of complex actions, it is indeed possible, if not probable, that imbalances exist within several transmitter systems.

Post Mortem Brain Studies -- Early analyses on TS brain tissue have been limited to several small studies including four brain samples evaluated in our laboratory at Johns Hopkins [Singer et al, 1990, 1991, and 1995]. Recent post mortem neurochemical studies, designed to further pursue proposed dopaminergic abnormalities, suggest the presence of a prefrontal-dopaminergic abnormality in TS. More specifically, we have shown that the prefrontal area BA9 has increased levels of D2 dopamine receptors, dopamine transporter, vesicular monoamine transporter type 2, and alpha adrenergic receptors (Minzer et al 2004). Since dopaminergic fibers arise from the ventral tegmental area and form synapses on both pyramidal neurons (stimulate) and interneurons (inhibit) within the prefrontal cortex, we have postulated a prefrontal dopaminergic abnormality. These results emphasize the requirement for a greater focus on the frontal lobe. Biochemical studies in additional postmortem samples are currently in progress.

Microarray analysis in postmortem basal ganglia tissue has also been used to investigate the presence of abnormally expressed genes in TS. For example, in a recent study we have identified several genes that were up- or down-regulated in the putamen of three subjects with TS (Hong et al, 2004)

Positron Emission Tomography -- The possibility of a dopaminergic abnormality in TS is also being investigated by use of nuclear imaging protocols. With some variability, available striatal data suggest that there are 1) inconsistent changes increases in the number of dopamine receptors, 2) elevated levels of dopamine transporters (not associated with dopamine hyperinnervation except possibly in the ventral striatum), and 3) increased intrasynaptic dopamine release (for review see Singer and Minzer 2003; Singer 2005). Based on available information, we have hypothesized that a tonic-phasic model of dopamine release could provide a unifying hypothesis for TS (Singer et al 2002). More specifically, an overactive dopamine transporter system or abnormalities of cortical excitation could result in a system with an increased phasic release of dopamine.

In current studies, we are obtaining PET scans in larger numbers of TS subjects using techniques in which measurements of dopamine receptors, dopamine transporter, and dopamine release are available for each individual subject. This new information should provide further clarification of the dopaminergic system in adults with Tourette syndrome. Confirmation of a release abnormality in larger numbers of patients with TS could, in turn, lead to the development of new tic-suppression pharmacotherapy.

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