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Non-motor Symptoms in Parkinson’s Disease are associated with the development of psychosis in PD.66 Psychosis can


occur with all of the antiparkinsonian medications. The pathophysiology of psychosis in PD is poorly understood and may be attributable to hypersensitization of dopamine receptors in the mesolimbic/mesocortical pathways. Serotonin may also be involved since the atypical antipsychotic drugs are purported to work through their high affinity for serotonin receptors. The first step in managing PD psychosis is to treat any reversible causes, such as infection, metabolic derangements, social stress, and drug toxicity. After that, antiparkinsonian medications should be reduced and discontinued if possible. If psychosis persists, the use of an atypical antipsychotic agent is warranted. A recent American Academy of Neurology guideline looked at the evidence behind atypical antipsychotics for the treatment of psychosis in PD and recommended clozapine (level B) and quetiapine (level C).67


Although there are stronger data for the efficacy


of clozapine for PD psychosis, it is used rarely in practice because of the concern for agranulocytosis and mandated blood monitoring. As a result, quetiapine is typically used first and, if it is not helpful, clozapine is then substituted. Olanzapine may worsen motor function in PD.


Impulse Control Disorders


These behaviors are associated with dopaminergic replacement therapies, especially dopamine agonists, and may result in devastating consequences for patients and their families. Younger patients, patients with a history of smoking or substance abuse problems, and patients with a family history of gambling problems are at greater risk for developing ICDs.68,69


Impulse control disorders (ICDs), such as pathologic gambling, excessive shopping, overeating, hypersexuality, and excessive dopaminergic medication use, are estimated to occur in up to 14 % of treated PD patients.68


ICDs in patients with PD are


also associated with more depressive and anxiety symptoms, increased obsessionality, more novelty seeking behavior, and higher levels of impulsivity.69


Ideally, when an ICD is present, the dopamine agonists should be reduced and discontinued; however, patients often do not tolerate this because of motor worsening. Subthalamic nucleus DBS has been proposed as a way of treating ICDs71


The ‘overdose’ theory has been proposed to explain the presence of ICDs in PD. Because the ventral striatum (associated with cognitive and limbic pathways) is relatively preserved in PD compared with the dorsal striatum (associated with motor dysfunction), there may be a relative ‘overdosing’ of dopamine in the ventral striatum that results in these ICDs when dopaminergic treatment is initiated for motor symptoms.70


because it allows a reduction


in medication doses while helping motor symptoms, but ICDs have been reported to occur after DBS surgery.72


A recent double-blind cross-over


study reported that amantadine could improve pathologic gambling in PD,73


but it is unclear if all ICDs are helped by this medication. Apathy


Apathy is defined as a loss of motivation, interest, and effortful behavior.74 Although apathy frequently occurs in conjunction with depression, it can occur independently in PD.74 develop apathy.74,75 risk factors,75


Dementia and axial motor decline appear to be


and increased apathy has been reported post-DBS surgery.76 The neurologic basis of apathy is most commonly ascribed to frontal lobe dysfunction. Apathy is difficult to treat and often bothers caregivers more than the patient. Unfortunately, there are no effective treatments for apathy in PD.


US NEUROLOGY Approximately 50 % of PD patients may Cardiovascular System


Orthostatic hypotension is frequent in PD and can increase susceptibility to disabling falls and life-threatening injuries. The mechanism of sympathetic neurocirculatory failure in PD is not clear. However, Lewy bodies are observed in both central and peripheral autonomic pathways.97 Norepinephrine is decreased in the post-ganglionic region in the sympathetic nervous system, especially in the heart. Abnormal physiologic reflexes also contribute to orthostatic hypotension. In normal individuals, the cardiovagal baroreceptor reflex refers to the change in R-R interval (interval between successive R waves on electrocardiogram) per unit change in systolic blood pressure. This reflex is known to contribute to the beat-to-beat control of arterial blood pressure. Also, with Valsalva maneuver, the increased intrathoracic pressure leads to reduced venous return, stroke volume, and cardiac output. These physiologic changes stimulate a sympathetic response that releases


115


Lesions similar to the ones observed in the brain have been identified in the submucosal plexus of the enteric nervous system on routine colonic biopsies of PD patients.84


In addition to the fact that constipation


is associated with future risk of PD and with incidental Lewy bodies in the locus ceruleus or substantia nigra, constipation is associated with low substantia nigra neuron density even in people without PD independent of the presence of incidental Lewy bodies (suggesting a pre-diagnostic stage of PD).85


Gastroenterology


Constipation occurring as early as 20 or more years before the onset of motor symptoms is associated with an increased risk of PD.77


Constipation


is common in PD; many patients need oral laxatives and 7 % of PD patients meet criteria for severe constipation, which is associated with disease duration and severity.78


predictors of nutritional impairment in PD.78 symptoms predict future cognitive impairment in PD.79


emptying with solids is seen in 60–90 % of PD patients and is associated with the severity of parkinsonism,80,81 early stages of the disease.82


even though it is also seen often in Abnormal gastric emptying can affect motor


symptom control adversely by leading to unpredictable fluctuations in the levels of dopaminergic drugs.83


Constipation is one of the most important Early gastrointestinal Delayed gastric


The most likely causes of constipation


and gastric emptying problems in PD are degenerations of the dorsal vagal nucleus and the intramural plexus of the whole intestine, which probably develop prior to the degeneration of dopaminergic neurons of the substantia nigra.83 mice,86,87


Animal models of PD (transgenic monkeys,88 dopaminergic neurons,89


1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]-treated rats with unilateral 6-hydroxydopamine lesion of nigrostriatal rotenone-infused rats90


) show abnormalities in


gastrointestinal motility, clinical, and electrophysiologic features, and pathologic findings in the enteric nervous system, which are similar to human disease.91


Treatment of constipation is usually unsatisfactory despite multiple interventions (dietary modification, bulk-forming agents, stool softeners, and laxatives).92


using tegaserod,92,93 subthalamic nucleus DBS.95


Preliminary studies suggested benefits for constipation isosmotic macrogol electrolyte solution,94 A preliminary study showed potential benefit


or


from mosapride on shortening gastric emptying half-time with a concomitant decrease in motor response fluctuations.96


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