Treatment of autonomic dysfunction in Parkinson disease and other synucleinopathies

Abstract

Dysfunction of the autonomic nervous system afflicts most patients with Parkinson disease and other synucleinopathies such as dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure, reducing quality of life and increasing mortality. For example, gastrointestinal dysfunction can lead to impaired drug pharmacodynamics causing a worsening in motor symptoms, and neurogenic orthostatic hypotension can cause syncope, falls, and fractures. When recognized, autonomic problems can be treated, sometimes successfully. Discontinuation of potentially causative/aggravating drugs, patient education, and nonpharmacological approaches are useful and should be tried first. Pathophysiology-based pharmacological treatments that have shown efficacy in controlled trials of patients with synucleinopathies have been approved in many countries and are key to an effective management. Here, we review the treatment of autonomic dysfunction in patients with Parkinson disease and other synucleinopathies, summarize the nonpharmacological and current pharmacological therapeutic strategies including recently approved drugs, and provide practical advice and management algorithms for clinicians, with focus on neurogenic orthostatic hypotension, supine hypertension, dysphagia, sialorrhea, gastroparesis, constipation, neurogenic overactive bladder, underactive bladder, and sexual dysfunction. © 2018 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; autonomic failure; dysautonomia; multiple system atrophy; nonmotor symptoms; treatment.

Figure 1. Algorithm for the management of neurogenic orthostatic hypotension in patients with synucleinopathies

A stepwise management of neurogenic orthostatic hypotension (nOH) includes: a) correcting aggravating factors, b) implementing non-pharmacological measures and c) drug therapies. When OH is asymptomatic, treatment may not be required or may be limited to non-pharmacological measures. When nOH is symptomatic (i.e., causing symptoms of organ hypoperfusion such as dizziness, lightheadedness, blurry vision or feeling about to faint) pharmacological treatment is usually required. *Droxidopa appears to be particularly effective in patients with low baseline plasma norepinephrine levels (usually patients with Lewy body disorders). **Atomoxetine appears to be particularly effective in patients with high baseline plasma norepinephrine levels (usually patients with multiple system atrophy).^{63 #}Caution is advised when combining droxidopa, with norepinephrine transporter (NET) inhibitors (e.g., atomoxetine) as this combination has not been systematically studied and there is a possibility of increasing the risk of arrhythmias and other adverse events. BP: blood pressure. OH: orthostatic hypotension.

Figure 2. Sites of action and mechanism of therapeutic agents used for the treatment of neurogenic orthostatic hypotension

Pyridostigmine inhibits acetylcholine esterase (AChoE) in the sympathetic ganglion thereby increasing the levels of acetylcholine (ACh) and enhancing sympathetic neurotransmission. Droxidopa is converted to norepinephrine (NE) through the action of the enzyme aromatic amino acid decarboxylase (AAAD) both in neuronal and extra-neuronal tissues. Atomoxetine and similar medications block the NE transporter (NET) thereby increasing NE levels in the sympathetic terminal. Midodrine is a direct alpha-adrenergic agonist that activates the same receptor as NE. Finally, fludrocortisone is a synthetic mineralocorticoid that increases intravascular volume.

Figure 3. Sites of action and mechanisms of therapeutic agents used for the treatment of gastroparesis

Several receptors (dopaminergic, cholinergic muscarinic, cholinergic nicotinic, serotoninergic) are involved in the regulation of gastric motility. Eventually, all modulate acetylcholine release in the enterocyte, which induces gastric motility. Agents used to increase motility include dopamine D₂ receptor blockers (e.g., domperidone and others), serotonin 5-HT₄ receptor agonists (e.g., cisapride and others), acetcylcholinesterase inhibitors (e.g., pyridostigmine) and muscarinic agonists (e.g., betanechol). Conversely, 5-HT₃ antagonists (e.g., alosetron, ondansetron) reduce gastric motility and are used for diarrhea or vomiting.

Figure 4. Algorithm for the management of constipation in patients with synucleinopathies

Management includes non-pharmacological approaches, removal of aggravating factors (e.g., opioids), fiber supplements, stool softeners, and pharmacotherapy with laxatives. The asterisk (*) denotes non-pharmacological and pharmacological agents tested in clinical trials of patients with Parkinson disease. Enemas and manual disimpactions may be required in severely affected patients (not shown in algorithm).

Figure 5. Luminal chloride channel activators for the treatment of chronic constipation in patients with synucleinopathies

Lubiprostone is a locally acting chloride type 2 channel activator. Linaclotide is an agonist of the guanylate cyclase 2C receptor. Activation of guanylate receptors leads to a metabolic cascade that increases the secretion of chloride and HCO₃ via the CFTR receptor. Linaclotide also increases smooth muscle contraction, promoting bowel movements, and reduces activation of colonic afferent sensory neurons, theoretically reducing gastrointestinal pain. Plecanatide, another oral guanylate cyclase-C receptor agonist, also showed efficacy in placebo-controlled randomized trials to increase spontaneous bowel movements.

Figure 6. Sites of action and mechanisms of therapeutic agents used for the treatment of neurogenic overactive bladder

Cholinergic pelvic nerves release acetylcholine (ACh), which, via activation of muscarinic M3 receptors, induce contraction of the detrusor muscle and emptying of the bladder. Anti-muscarinic agents (e.g., solifenacin) block the muscarinic receptor and reduce detrusor muscle contractions. Hypogastric adrenergic nerves release norepinephrine (NE), which causes urinary retention by activating β₃-adrenergic receptors in the detrusor muscle and alpha-adrenergic receptors in the internal sphincter of the urethra. Mirabegron, a β₃-adrenergic receptor agonist, reduces bladder contractions in patients with neurogenic detrusor overactivity. Of note, the classical nomenclature of the sacral autonomic outflow has been recently challenged.

Figure 7. Algorithm for the management of underactive bladder in patients with synucleinopathies

Incomplete bladder emptying as a consequence of detrusor underactivity is common in multiple system atrophy (MSA) but seldom reported in patients with other synucleinopathies. Estimation of the post-void residual (PVR) bladder volume is a simple and useful test in patients with MSA; even though their urinary complaints may be limited to urinary urgency or frequency, patients are usually unaware that their bladders do not empty completely. PVR can be measured by ultrasound echography or transurethral catheterization. If the patient has a PVR > 100 ml, clean intermittent self-catheterization must be recommended. Either the patient or the caregiver can usually perform this after education is provided. In patients with advanced disease and severe neurological disability, a permanent indwelling catheter, usually suprapubic, may be required. Antimuscarinic or β₃-adrenergic treatment to reduce bladder overactivity should be added regardless of the PVR. (*) Replaceable remote-controlled intra-urethral prosthesis for women with underactive bladder have been recently approved by the Food and Drug Administration. Our experience in women with MSA, although limited, is very positive.