Porth's Essentials of Pathophysiology, 4e

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Disorders of Neuromuscular Function

C h a p t e r 3 6

Treatment. The approach to treatment of Parkinson disease must be highly individualized. It includes non- pharmacologic, pharmacologic, and, when indicated, surgical methods. 33,34,40 Nonpharmacologic interventions offer group support, education, daily exercise, and ade- quate nutrition. Botulinum toxin injections may be used in the treatment of dystonias such as eyelid spasm and limb dystonias that frequently are associated with Parkinson disease. Persons with parkinsonism other than idiopathic Parkinson disease usually do not respond significantly to medications developed for Parkinson disease. Pharmacologic treatment usually is determined by the severity of symptoms. Antiparkinson drugs act by increasing the functional ability of the underactive dopa- minergic system, or by reducing the excessive influence of excitatory cholinergic neurons. Drugs that improve the function of the dopaminergic system include those that increase dopamine levels (levodopa), stimulate dopamine receptors (dopamine receptor agonists), or retard the breakdown of dopamine (monoamine oxi- dase-B inhibitors). 40 Levodopa, a dopamine agonist, is administered with carbidopa, which inhibits its peripheral metabo- lism, allowing therapeutic concentrations of the drug to enter the brain without disabling adverse effects. A later adverse effect of levodopa treatment is the so-called on–off phenomenon, in which frequent, abrupt, and unpredictable fluctuations in motor performance occur during the day. These fluctuations include “on” peri- ods without dyskinesia, “on” periods with dyskinesia, and periods of bradykinesia (the “off” response). Some fluctuations reflect the timing of drug administration, in which case the “on” response coincides with peak drug levels and the “off” response with low drug levels. Dopamine agonists such as pramipexole (Minaprex) and ropinirole (Requip) directly stimulate dopamine receptors. Rotigotine is a dopamine agonist that is sup- plied in a transdermal system. The dopamine agonists can be used as initial or adjunctive therapy in Parkinson disease and can be given in combination with carbidopa/ levodopa. Rotigotine is only approved by the U.S. Food and Drug Administration (FDA) for initial treatment of Parkinson disease. Amantidine, an antiviral agent, was found by chance to have antiparkinson properities. It is thought to aug- ment release of dopamine from the remaining intact dopaminergic terminals in the nigrostriatal pathway of persons with Parkinson disease. It is used to treat per- sons with mild symptoms but no disability. Several medications are used for adjuvant therapy as the initial therapy becomes less effective in control- ling motor complications. As the therapy less effec- tively controls the symptoms, there is less “on time” (when the symptoms are controlled) and more “off time”. Apomorphine is a dopamine agonist that can be given intravenously. It is often used as a rescue medica- tion in patients experiencing sudden “off” periods or delayed “on” periods. Monamine oxidase-B inhibitors, such as selegiline and rasagiline, hinder the metabolic breakdown of dopamine. Selegiline and rasagiline may be used as adjunctive treatment to reduce mild on–off

fluctuations in the responsiveness of persons who are receiving levodopa. Because dopamine transmission is disrupted in Parkinson disease, there is a preponderance of cholin- ergic activity. Anticholinergic drugs (e.g., trihexyphe- nidyl, benztropine) are thought to restore a “balance” between reduced dopamine and uninhibited cholinergic neurons in the striatum. They are more useful in alleviat- ing tremor and rigidity than bradykinesia. The anticho- linergic drugs lessen the tremors and rigidity and afford some improvement of function. However, their potency seems to decrease over time, and increasing the dosage merely increases side effects such as blurred vision, dry mouth, bowel and bladder problems, cognitive dysfunc- tion, and hallucinations. Deep brain stimulation, which involves the surgical implantation of electrodes into the subthalamic nuclei or the pars interna of the globus pallidus, is an option for many persons who develop symptoms despite opti- mal medical therapy. 40,41 The electrodes are connected to a surgically implanted impulse generator that delivers electrical simulation to block the abnormal nerve activ- ity that causes tremor and abnormal motor activity in Parkinson disease. The system allows the stimulation to be programmed to control the individual person’s symp- toms, and the stimulation parameters can be changed over time as the disease progresses. Deep brain stimu- lation is used for persons with Parkinson disease who respond to levodopa but experience side effects associ- ated with it (e.g., motor fluctuation or dyskinesia). It is not a cure but serves to increase the duration of the “on” periods, allows for a reduction in medication dos- ages (in subthalamic nuclei stimulation), and improves function. Of note, other movement disorders can be treated by placing electrodes in different target sites (e.g., thalamus for tremor and globus pallidus internus for dystonia). ■■ Both uncoordinated and abnormal muscle movements can result from disorders of the cerebellum and basal ganglia. ■■ The functions of the cerebellum, which are especially vital during rapid muscular movements, use afferent input from various sources, including stretch receptors, proprioceptors, tactile receptors in the skin, visual input, and the vestibular system. Signs of cerebellar disorders include dystaxia, ataxia, tremor, and dysarthria. ■■ The basal ganglia organize basic movement patterns into more complex patterns and release them when commanded by the motor cortex, contributing gracefulness to cortically initiated SUMMARY CONCEPTS

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