Parkinson’s disease (PD) is classified as a movement disorder caused by a loss of the dopaminergic neurons in the striatum’s substantia nigra. An 80% reduction in striatal dopamine levels results in the main symptoms of PD. These include rigidity, bradykinesia and resting tremor.¹ The autonomic nervous system (ANS) controls involuntary functions throughout the whole body. When the ANS is disrupted, in PD for example, the effects can be seen all over the body. This leads to a wide variety of clinical symptoms. PD is rapidly growing as a research topic worldwide due to the high prevalence; PD is the second most common neurodegenerative disorder in the UK.¹

Autonomic dysfunction occurs more frequently and more severely in patients with PD as opposed to controls of similar age.² The dysautonomias experienced by PD patients can have serious implications on their lives. Here, the focus will be on dysautonomias such as cardiovascular dysautonomias, gastrointestinal dysautonomias and genito-urinary dysautonomias. Other dysautonomias such as sialorrhoea, hyperhidrosis, seborrhoea, pulmonary dysfunction and sleep dysfunction will also be discussed.

Cardiovascular dysautonomia

The ANS is responsible for many aspects of cardiac function. The ANS controls heart rate, blood pressure and contractility. Cardiac function is controlled by the sympathetic (SNS) and parasympathetic (PNS) aspects of the ANS. The SNS acts by increasing heart rate and contractility within the heart. Following the departure of sympathetic nerves from the spinal cord, they change to prevertebral or paravertebral ganglia. This is located at the second sympathetic neuron. Dysfunction can be before or after the ganglia, namely, preganglionic and postganglionic. Acetylcholine and norepinephrine are essential neurotransmitters in the SNS.³

The parasympathetic nervous system (PNS) opposes the effects of the SNS in the heart. The main functions of the PNS include a reduction in heart rate and contractility. Acetylcholine is the main neurotransmitter for the PNS. It is also important to consider that secondary dysautonomias can be caused or potentiated by separate diseases such as diabetes and by certain medications.³

Cardiovascular dysautonomias that occur in PD are caused by vasomotor abnormalities and altered regulation of blood pressure. The exact cause of the symptoms is still under much research and it has proven difficult to distinguish between cardiac symptoms associated with PD and multiple system atrophy (MSA). Scintigraphy with [123]meta-iodobenzylguanidine (MIBG) is a diagnostic tool used to detect sympathetic dysfunction in the myocardium. This can be used to distinguish between MSA and PD as the cardiac sympathetic nerves are still intact in MSA.⁴ One study found that MIBG uptake is reduced in PD, even in the early stages of the disease.⁵

The most distinctive cardiovascular dysautonomia in PD is postural hypotension (PH). Some 50% of PD patients at a late stage in their disease suffer from PH.³ One study found that the severity of the PD was similar in patients with and without PH. It was also found to be present even in the early stages of the disease.⁶ PH is caused by reduced perfusion while upright. In severe cases, patients may experience syncope as a result of cerebral hypoperfusion. PH is classified by a systolic blood pressure < 20mmHg and a diastolic blood pressure < 10mmHg within three minutes of standing or tilting with the head up. 

Patients with PH are encouraged to avoid sudden changes in posture, ensure adequate hydration and avoid high concentrations of carbohydrates. They need to be closely monitored during any activities that involve the Valsalva manoeuvre. PH is treated by the administration of vasoconstrictors to reduce pooling and drugs to increase blood volume. Fludrocortisone and desmopressin are used to increase blood volume. Vasoconstriction is induced by sympathomimetic drugs such as ephedrine and etilefrine.⁷

Supine hypertension is another complication of cardiovascular dysautonomia. It is mainly associated with chronic autonomic dysfunction. Blood pressure in a patient with PH must be closely monitored as it is closely related to supine hypertension; 24-hour ambulatory blood pressure monitoring (ABPM) is useful for blood pressure monitoring. Clonidine is used to treat supine hypertension.³

There is much debate over the possibility of whether or not anti-Parkinsonian drugs actually cause PH. The use of dopamine agonists is closely related to low resting blood pressure and PH. However, there is still debate over this topic.³ One study found that the dopamine agonist bromocriptine causes venous and arteriolar dilation, resulting in hypotension.⁸ Another study suggested that fenoldopam (DA1 receptor agonist) could be used to treat hypertension.⁹

Gastrointestinal dysautonomia

The most common gastrointestinal (GIT) dysautonomia in PD is constipation. Patients have also been reported to experience dysphagia and delayed gastric emptying. The severity of constipation experienced in PD correlates with the severity of the disease and can lead to other complications such as megacolon, intestinal pseudo-obstruction, volvulus and bowel perforation. GIT dysautonomias are related to the presence of Lewy bodies in the enteric myenteric ganglia and the abdominopelvic autonomic plexus.⁷

One study compared PD patients to patients after receiving a vagotomy and found, using electrogastroenterography (EGEG), similar deficits in the autonomic nervous system between PD patients and vagotomised patients.¹⁰ GIT dysfunction can be measured by colonic transit time tests, anorectal manometry, defecography and electromyography.¹¹

The first line of treatment for constipation in PD is lifestyle changes. This includes physical exercise and diet. Symbiotic yoghurt containing bifidobacterium and fructo-oligosaccharide has been found to be effective in the treatment of constipation.⁷

One study found that Bifidobacterium lactis shortens whole gut transit time and reduces the frequency of gastrointestinal symptoms in adults.¹² Stool consistency can be improved by using dietary fibres, psyllium and polycarbophil. Stimulant laxatives are not recommended for chronic use as they can lead to alterations in the colonic mucosa. Osmotic laxatives such as polyethylene glycol and magnesium sulphate have been found to be very effective. 

Lubiprostone is a fatty acid compound used in the treatment of constipation in PD. It increases fluid secretion by stimulating chloride channels.⁷ Lubiprostone is limited, however, by side-effects; mainly nausea.¹³ Serotonergic and cholinergic drugs are also commonly used in the treatment of constipation. Some dopaminergic drugs have been found to be useful in the treatment of constipation in PD. Some treatments are in the early stages of investigation; for example, botulinum toxin for dystonia of the puborectalis muscle and sacral nerve stimulation for stimulating muscles of the pelvic floor and hindgut.⁷

Genitourinary dysautonomia

Genitourinary dysautonomia includes urinary dysfunction and sexual dysfunction. Urinary dysfunction occurs in 27-39% of PD patients, according to the most recent studies.¹ The main symptoms are nocturia, urgency and frequency.¹⁴ The mechanism of bladder control is complex and it co-ordinates input from the somatic, autonomic and dopaminergic systems.¹ PD leads to urinary dysfunction by detrusor overactivity. It has also been suggested that bradykinesia can affect the external urethral sphincter. There is considered to be a loss in D1 receptor inhibition which leads to detrusor overactivity. This would then lead to the urinary symptoms.¹

Urinary symptoms in PD have also been attributed to the pharmacological effects of PD. More research is needed in this area as there are many contraindications.¹ The main treatment for urinary dysfunction in PD is anticholinergic drugs. Anticholinergic drugs reduce urine outflow, counteracting the increased detrusor activity. Because of this, these drugs can lead to urine retention in some patients. The traditional anticholinergic drug used was oxybutynin. The disadvantage of this drug was that it is not specific for the muscarinic receptors on the bladder.¹ In one study, oxybutynin is compared to tolterodine, another non-selective anticholinergic drug. Tolterodine is as potent as oxybutynin at the detrusor muscle but it is eight times less potent at the parotid gland. This allows for the comparison of side-effects caused by the action of the drugs at the parotid gland. 

The study found a statistically significant difference between the side-effects of the two drugs but no statistically significant difference between their clinical efficacies. Side-effects included dry mouth, hypohidrosis, hyperpyrexia, constipation, flushing, dizziness, headache and dyspepsia.¹⁵ Newer agents have been established that are specific for the M3 receptors in the bladder. Solifenacin and darifenacin are examples of such drugs.¹

Another dysautonomia relating to the genitourinary system is sexual dysfunction in PD. This dysautonomia is experienced by both men and women. Symptoms most frequently experienced among women include reduced arousal and difficulty reaching orgasm. Men with PD more commonly complain of erectile dysfunction.⁷ Dopamine is a vital neurotransmitter for sexual intercourse and it is released throughout. Dopamine is also vital for sexual motivation and sexual reward.¹⁶ There are, however, a considerable amount of other factors to consider such as age, depression and medication. The most common treatment of erectile dysfunction in PD is sildenafil citrate. This is a phosphodiesterase-5 selective inhibitor.⁷

Other autonomic dysfunctions in PD

Sialorrhoea is a condition that involves excessive salivation. Sialorrhoea in PD patients is thought to be caused by impaired swallowing. Non-pharmacological approaches can be effective. An example of this is when the patient is encouraged to consciously swallow at a given time interval. Pharmacological approaches include anticholinergic drugs such as glycopyrrolate and botulinum toxin injection.⁷

Hyperhidrosis is manifested throughout PD patients. PD patients can suffer from thermoregulatory dysfunction and hyperhidrosis can occur in conjunction with this. Hyperhidrosis can occur at any time but it has been seen to occur when blood levodopa levels are low.¹⁷

Seborrhoea is a condition that involves the rate of sebum excretion. Sebum is important in skin and hair maintenance but the rate of excretion of sebum has been found to increase in PD patients. One study compared 70 PD patients to 60 controls and found that the PD patients had increased sebum excretion rates.¹⁸

Pulmonary dysfunction is a significant dysautonomia in PD. This can be severe in patients who suddenly withdraw from taking dopamine agonists. A large contribution to pulmonary dysfunction in PD is from rigidity and bradykinesia of respiratory muscles. A high incidence of restrictive and obstructive pulmonary abnormalities has also been found in PD patients.¹⁹ One study found that levodopa improved forced vital capacity and peak expiratory flow in patients with PD, demonstrating the link between pulmonary symptoms and PD.²⁰

Another symptom experienced by PD patients is sleep dysfunction. This is experienced by 60-90% of PD patients. Autonomic dysfunction disrupts sleep and causes the patient to wake up frequently throughout the night. One sleep dysfunction seen in PD patients is REM sleep behaviour disorder (RBD). This is caused by muscle activity during sleep and leads to violent dreams through which the patient and their partner can get injured. PD has also been linked to obstructive sleep apnoea leading to further sleep dysfunction. 

Nocturia is common in PD patients and this can disrupt their sleep greatly. Excessive daytime somnolence, secondary narcolepsy and restless leg syndrome are problems also faced.²¹ The variety of symptoms experienced by PD patients is diverse. Within the ANS symptoms alone, there is a huge variety of symptoms that affect a number of different parts of the body. The ANS can essentially affect any part of the body and this is what makes this aspect of PD so detrimental for patients. 

Some dysautonomias related to PD can put patients in a lot of danger, such as postural hypotension and pulmonary dysfunction. Other dysautonomias can have negative effects on patients’ quality of life, such as sleep dysfunction and hyperhidrosis. There are a huge number of dysautonomias related to PD. The most clinically significant dysautonomias are those that put patients’ lives in danger and those that have strong negative impacts on the patients’ quality of life.  

References

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