Tourette Syndrome

Tourette Syndrome: it is a genetic neurological disorder characterized by chronic motor and vocal tics, beginning before adulthood. The affected individuals present with repetitive Involuntary movements and vocalizations such as blinking, sniffing, facial movements or tensing of abdominal musculature. 

Pathophysiology: underlying this disorder remains unknown. But genetic, biochemical, imaging studies reveal that it is an inherited developmental disorder of neurotransmission. Atypical autoimmune response to a streptococcal infection may also contribute to the severity of tourette syndrome. 

CDC reports say that 3 out of every 1,000 children between the ages of 6 & 17 years suffer from this condition and males are 3 times more likely to suffer from the disorder than females.

Abnormal functioning in motor control areas of brain, like frontal cortex and basal ganglia have been seen to be associated with Tourette Syndrome. Hypertrophy of thalamus is also believed to play a role in this case. Increased expression of dopamine receptors and presence of excessive amount of dopamine in brain is believed to be another contributing reason. Low serotonin and tryptophan levels have been identified in such patients. 

More recent studies support the role of abnormal GABA receptors in developing tics.

Classification of tics: it is divided into two types.

a.Simple: which has a short duration and involvement of only few muscles is present.  Example, shoulder shrugging, tongue clicking, throat clearing, making animal noises, head jerking. 

b.Complex: is of longer duration and involves multiple muscle groups. Example, repetition of words, sounds, atypical speech, bizarre gait, kicking etc.

Factors involved in increasing the risk: 

a. Mother who had severe episodes of nausea and vomiting during the first trimester of pregnancy. 

b. Mother who was under severe stress during her pregnancy. 

c. Drinking a lot of coffee, smoking cigarette, drinking alcohol during pregnancy. 

d. No enough oxygen or blood supply during birth.

e. Lower birth weight.

Treatment: medications affect different people differently. Medicines may affect and show desired effects in one person, but may not work in the same manner on another person. Similarly, dosage might have a similar effect. One patient at a specific dose may show reduction or improvement but another patient on the same dose may not. So the physician needs to find out the medicine and its dose that will have best results and fewest side effects on the patient. The better option is to start at low doses and increase it slowly according to the clinical presentation and outcomes of a patient. 

Pharmacological treatments: treatment options are only directed towards correcting the abnormalities and imbalances. Initiation of pharmacological treatment is recommended when this disorder starts to interfere the person’s life, sociological life, school or job performance. 

Alpha adrenergic agonists: these are used as first line treatment in people with mild to moderate tics due to their better tolerability and proven efficacy. Mostly used drugs out of this class are clonidine and guanfacine. Guanfacine is often preferred over clonidine as guanfacine causes less somnolence.  The starting dose of guanfacine which is recommended is 0.25 to 0.5mg daily. The dose can be increased by 0.5mg every week to achieve a maintenance dose of 0.5 to 3mg per day. These agents bind to alpha 2a adenoreceptors and decreases sympathetic nerve impulses. Reduced adrenergic impulses are believed to inhibit the overctivity of dopaminergic pathways responsible for tics. Postsynaptic alpha 2 agonist stimulation may regulate subcortical activity in the prefrontral cortex, which may be responsible for regulating areas of the brain responsible for attentions and behaviors. 

Most common side effects of thes medications include somnolence, headache, fatigue, dizziness, constipation, hypotension, irritability. 

Typical antipsychotics: these drugs block postsynaptic dopamine D2 receptors and helps in decreasing the dopamine levels. Amoxapine, haloperidol, fluphenazine, pimozide gives the most effective response due to their strong D2 receptor blockade. Doses of these antipsychotics lower than those used for psychiatric disorders often responds to TS. In US, FDA has only approved haloperidol and pimozide for treating TS. Initial doses of haloperidol is 0.2 to 0.5mg and is titrated to the maintenance dose of 0.05 to 0.075mg/kg/day in 2 to 3 divided doses.

Pimozide can be started at 0.05mg/kg and can be increased every 3 days upto 0.2mg/kg/day. It is not to exceed 10mg/day. Patients who are slow metabolizers should not exceed doses >0.05mg/kg/day because this drug is metabolized by CYP2D6 and exceeding the recommended dose could lead to accumulation and toxicity. 

The adverse effects reported by this class of antipsychotics include akathesia         (state of restlessness and inability to sit or lie down quietly), sedation, dry mouth, akinesia(impairment of power of voluntary movement), constipation,  muscle rigidity, ECG changes.

Atypical antipsychotics: Risperidone is being used off-label for the treatment of TS. Atypical antipsychotics show lesser side effects as compared to the typical antipsychotics ones, so they are a good alternative treatment option. Risperidone is a serotonin and dopamine receptor antagonist and regulates dopamine pathway function in the brain. 

A newer atypical antipsychotic, Aripiprazole has also proven to be effective in treating TS. 

Atypical antipsychotics may have lesser extrapyrimidal effects but they do show some significant metabolic effects, such as hyperglycemia, hyperprolactinemia, weight gain, hyperlipidemia.

Benzodiazepines: e.g. Clonazepm are thought to reduce tics by modulating GABA but these drugs are highly associated with tolerance and risks of addiction are very high so these drugs should be used with caution.

Tetrabenazine: reduces the uptake of monoamines (dopamine, serotonin) into synaptic vesicles and causes depletion of monoamine stores from nerve terminals by inhibiting the human vesicular monoamine transporter type 2. This drug has proved itself effective in treating patients who suffer from severe TS. Its adverse effects usually include sedation, fatigue, depression, anxiety, irritability, nausea.

Nicotine patch: blocks nicotine receptors in brain. Some investigators compared its usage and found out that a single patch was effective in reducing complex tics and improving attention in children and teenagers receiving neuroleptic medications. Nicotine patch is used more as a supplement to tic medications.

Baclofen: It is a GABA receptor agonist and is used as a muscle relaxant. It is being studied and being considered as an alternative therapy  option.

Antiepileptics: topiramate has recently been started to treat tics. It produces reduction in tics by enhancing the activity of GABA. Some tests have shown promising results but some other studies have not given desired results or benefits when compared to placebo.

Tricyclic antidepressants: desipramine inhibits the Norepinephrine reuptake and so has proven helpful in this area of treatment. 

Botulinum toxin: is being considered in patients with dystonic tics.

Antiemetic: ondansetron acts as a selective 5 HT3 receptor antagonist and binds to 5 HT3 receptors in CNS and as well as in the periphery. Studies showed reduction in tics in patients taking ondansetron versus placebo.

Omega 3 fatty acids: are seen to have anti inflammatory properties and can be helpful in reducing this disorder, especially that which is related to autoimmune etiology.

Marijuana: DHHS rejected petitions to use marijuana for the treatment of Tourette syndrome. 

Behavioral therapy: a randomized trial of behavioral therapy for adults with TS was done to test whether a comprehensive behavioral therapy for tics in adults is effective or not. Results showed that it is rather safe and an effective intervention for such adults.

Behavior therapy for children with TS: studies done on Behavior therapy for children with TS showed positive results, which were reduction in the severity of this disorder in children and adolescents. 

A comprehensive behavioral therapy with supportive therapy and education shows great improvements in this problem.

Thalamic deep brain stimulation: may show results in some patients and might not work in others. Further studies need to be done to evaluate its efficacy. 

Role of Pharmacist: pharmacist is in the best position to educate patients and their families about the disorder and the various treatment options that are available. Pharmacist can properly educate the patient about their medications and how to adhere to their treatment regime and how to cope with side effects (if possible) to bring about the best therapeutic results.

Reference:

1. JAMA.

2. CDC guidelines.

3. ncbi.

4. American psychiatric association. Manual of Mental disorders

5. US Pharmacist.

 

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