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Neurodegenerative Disease Parkinson’s Disease

norepinephrine at the sinoatrial node, thereby increasing heart rate. Both of these sympathetically driven reflexes are blunted in PD patients with or without orthostatic hypotension.98

To complicate the issue

further, levodopa therapy can induce hypotension through its diuretic and naturetic properties. Low-dose dopamine stimulates vascular smooth-muscle cell receptors to cause vasodilatation. However, Goldstein and colleagues demonstrated that orthostatic hypotension in PD is independent of levodopa therapy.99

This is thought to be attributable to the underlying sympathetic deregulation in the overall disease process.

The combination of orthostatic hypotension and parkinsonism is often misdiagnosed as multiple system atrophy (MSA). However, MSA is distinguished from classic PD by intact sympathetic cardiovascular innervation. Studies with radioactive imaging agents, such as I-123metaiodobenzylguanidine and 6-fluorodopamine, show decreased uptake in the myocardium of PD patients regardless of the clinical presence of orthostatic hypotension.99

Work by Senard et al. revealed

that mean plasma norepinephrine is lower in PD patients, suggesting the possibility of a more generalized sympathetic denervation.100


conservative treatment includes increasing fluid intake, a high-salt diet, and high-compression stockings. If post-prandial hypotension is an issue, small and frequent meals can be helpful. Medications used include fludrocortisone and the selective alpha-1 agonist midodrine. Midodrine is currently on the market, but new studies may be needed for continued approval. Chronic sympathetic denervation can lead to supersensitivity to adrenoreceptor agonists, exacerbating supine hypertension. Pyridostigmine is a more favorable therapy owing to avoidance of this adverse effect, yet it is a less effective therapy.98

Genito-urinary System

Lower urinary tract symptoms (LUTS) affect 35–70 % of patients with PD, with most studies showing a correlation with the severity of the overall disease.101–103

These rates tend to be lower if MSA has been carefully eliminated from the study population, as LUTS are found in nearly all MSA patients.104

The most widely accepted theory explaining LUTS pathogenesis in PD is that the loss of basal ganglia neurons disrupts normal inhibition of the micturation reflex (located in the pontine micturation center), mediated by D1 receptors.105

This loss of reflex

inhibition leads to an unstable bladder, resulting in the urgency and frequency symptoms most often described by PD patients. This theory is supported by reports of improved LUTS after DBS of the subthalamic nucleus.106

with the severity of symptoms.107

The degree of cell degeneration has been shown to correlate Storage symptoms (urgency, frequency,

nocturia) are more common than voiding symptoms (straining, hesitancy) in PD patients with LUTS. The most common symptom is nocturia, with over 60 % of PD patients reporting having to urinate more than two times per night.108,109

However, the overlap of nocturia and primary sleep disturbances in PD patients makes it a difficult symptom to both follow and treat.107

Urinary urgency is reported in 33–54 % of PD patients.101 Voiding symptoms are found more often in older males, corresponding with the age-related growth of the prostate.101

Urodynamic studies (UDS)

can add significant value in the evaluation of LUTS in PD patients, giving information such as bladder volume, sensitivity, post-void residuals, presence/absence of incontinence, and storage pressures. Additionally, when trying to differentiate between PD and MSA, MSA patients are much more likely to have large post-void residuals, an open bladder

116 Respiratory System Most patients with PD report breathlessness.116 The etiology of this

symptom is likely multifactorial, including dysfunctions of the upper airway, respiratory muscles, and lung parenchyma. Diaphragm muscle function is likely preserved in PD. However, electromagnetic studies demonstrate clear abnormalities in the function of accessory muscles of respiration. Specifically, scalene and intercostal muscle tremor and tone serve to counteract the negative inspiratory pressure initiated by the diaphragm.117 These counteracting forces may result in net reduction of change in pleural pressure and the appearance of respiratory muscle weakness. Indeed, reduced inspiratory flow rates, and in some patients evidence of restrictive physiology, are identified upon pulmonary function testing. Upper airway dysfunction also occurs owing to tone and especially tremor of muscles controlling the glottis. This leads to airway obstruction of passive exhalation, the physiologic importance of which is variable. In general, the forced expiratory volume in one second is preserved in PD, although flow volume loops from spirometry may demonstrate the reduced flows consistent with variable (not fixed) upper airway obstruction.118


Neuromodulation of the sacral nervous input to the bladder offers a promising surgical intervention for refractory LUTS in PD patients. Surgical modulation is thought to override the altered central micturation reflex and coordinate voiding. Cystoscopic injection of botulinum toxin into the detrusor muscle of the bladder is another promising therapy that can improve bladder capacity and decrease urgency and incontinence episodes in PD patients.115

neck, and detrusor–sphincter dyssynergia on UDS than those with PD.104 Information from UDS can be especially useful when directing treatment in refractory disease.

All PD patients with LUTS should have a bladder infection ruled out before initiating treatment. Behavioral modification, including decreasing evening fluid intake to decrease nocturia and timed voiding to minimize daytime urgency and urge incontinence, should be initiated in all PD patients with LUTS. PD medications, such as levodopa, have been shown to affect bladder function, although there are conflicting reports as to whether they improve or worsen symptoms.102,110

In general, these

medications should not be considered as a primary treatment for de novo LUTS in PD patients.

Anticholinergic medications are considered first-line treatment for storage symptoms in PD patients. These medications act on the

parasympathetic nervous system in the bladder via the M3 receptors, and have been shown to decrease both the number of voids over 24 hours and the frequency of nocturia and urge incontinence through their inhibitory effect on the bladder wall smooth muscle.111


use of anticholinergic medication in PD patients, especially in elderly patients, has been linked to cognitive impairment, so the benefits of the medications must be weighed against these potential adverse effects. It is possible that more selective anticholinergics that do not cross the blood–brain barrier will improve their adverse effect profile.112,113


Desmopressin can decrease isolated nocturnal polyuria in PD patients with disrupted circadian vasopressin rhythms.108

medications such as diazepam, baclofen, duloxetine, and dantrolene may improve symptoms via effects on external sphincter and bladder sensation.114

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