Medical Pharmacology Topics   

Movement Disorders

The brain regions involved in movement disorders are often referred to as the extrapyramidal system. There are complex interaction between these regions and the pyramidal system that controls movement. The main regions of the extrapyramidal system are the cortex, basal ganglia, substantia nigra and thalamus. Diseases in these regions cause abnormal movements without paralysis. 

The cortex provides major input (glutaminergic) to the stratium. The basal ganglia, i.e. striatum and globus pallidus, are major sites regulating the flow of information from the cortex to motor neurons in the spinal cord. At the substantia nigra, the pars reticulata receives input from the striatum and the pars compacta contains cell bodies for dopamine projections to the striatum. The thalamus contains intermediate areas to process the information between the basal ganglia and cortex: subthalamic, ventrolateral and ventroanterior nuclei. Movement disorders are due to an imbalance among many neurotransmitters and pathways in the brain:

• Dopamine in nigrostriatal and mesolimbic pathways 
  • Deficiency: Parkinson's disease 
  • Excess: Tardive dyskinesia, Huntington's disease
    
    
• Acetylcholine in stratium interneurons
  • Deficiency: Huntington's disease
  • Excess: Parkinson's disease
    
    
• GABA in striatonigral pathway
  • Deficiency: Huntington's disease

Other neurotransmitters involved include glutamate, the major excitatory input from cortex, substance P, opioids, norepinephrine and seratonin. To date, there are no drugs available that alter GABA or glutamate function, despite the importance of these transmitters in the basal ganglia.

Parkinson's disease seem to be an imbalance between dopaminergic and cholinergic neurons in the striatum. Dopamine activity is significantly reduced, while cholinergic activity is significantly enhanced. This may be idiopathic or drug induced. Symptoms include akinesia, tremor, rigidity, and loss of postural reflexes. Treatment is of symptoms only, it does not alter the underlying disease process.

Huntington's disease is an autosomal dominant disease characterized by progressive development of choreiform movements, rigidity, akinesia and behavioral changes (aggression, depression, hallucinations, apathy, dementia). It is due to an imbalance between acetylcholine (decreased), GABA (decreased) and dopamine. Symptomatic treatment includes antidopaminergics like haloperidol.

Gilles de la Tourette's syndrome is characterized by chronic multiple motor and vocal tics, including sudden, brief repetitive movements usually involving the head, and sounds or words. The mechanism of this disease is unknown. Therapies include use of dopamine receptor antagonists and clonidine (imidazole-type alpha-2 agonist).

Several movement disorders are induced by antipsychotics (neuroleptics): acute dystonia, akathisia, parkinsonism, tremors (essential or perioral) and dyskinesias (tardive or withdrawal-emergent). Acute dystonia is characterized by slow twisting movements or spasms of the muscles of the tongue, face, neck or back. May generalize to involve many muscle groups and may look like seizures. It is treated with anticholinergic drugs and by reducing the antipsychotic dosage.

Akathisia is characterized by motor restlessness (unable to sit still, may include a subjective component, ?). It is treated by reducing the antipsychotic dosage, and anticholinergic drugs may help. Parkinsonism is characterized by bradykinesia, rigidity, tremor and lack of facial expression, and is treated with anticholinergic drugs. Essential tremor of the arms, upper body ad head is treated with alcohol (??) and propanolol. Perioral tremor ("rabbit syndrome") is a parkinsonian trremor of muscles around the mouth trated with anticholinergics.

The mechanism of dyskinesias seem to be development of supersensitivity to dopamine. Tardive dyskinesia is movement characterized by choreoathetosis, oral/facial involuntary movements and dystonic posture. It is a much delayed response to neuroleptic therapy, with an estimated 15% prevalence over spontaneous dyskinesias (?). Higher rates are probable with increasing age and/or sustained administration of higher doses. It may unmasked on withdrawal of neuroleptics. 

Tardive dyskinesia is not necessarily irreversible, as the patient may gradually stabilize and improve over several years, even with continued drug use. Prevention is crusial since there is no effective treatment. Symptoms can be blocked by increasing the dose of neuroleptic, but at the cost of more severe problems later. Withdrawal- emergent dyskinesia differ from tardive dyskinesias because they resolve over 1-2 weeks after withdrawing the antipsychotic. 

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