Treatment of dysautonomia in extrapyramidal disorders
- First Online:
- Cite this article as:
- Ziemssen, T., Fuchs, G., Greulich, W. et al. J Neurol (2011) 258: 339. doi:10.1007/s00415-011-5946-8
- 217 Views
Although extrapyramidal diseases are commonly thought to solely affect the (extrapyramidal) motor system, non-motor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed. Autonomic dysfunction is an important clinical component of extrapyramidal disease, but it is often not formally assessed, and thus frequently misdiagnosed. Symptoms of autonomic dysfunction can impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient. This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.
KeywordsExtrapyramidal diseaseParkinson’s diseaseAutonomic dysfunctionMultiple system atrophyTreatmentDysautonomia
Parkinson’s disease (PD) and other extrapyramidal disorders are clinically characterized by non-motor symptoms which include behavioural, sleep or perception dysfunctions as well as dysautonomia [48, 70, 71]. The prevalence of dysautonomia in PD varies between 14 and 80% depending on the population and methodology. The occurrence of dysautonomia increases as disease progresses, thereby impacting on the subjective picture of the symptoms, quality of life and the treatment of the disease [24, 53].
The almost ubiquitous loss of neurons and the appearance of Lewy bodies within completely different parts of the nervous system is thought to be a primary cause of this dysautonomia. Interestingly, Braak et al. observed the occurrence of lesions in the dorsal vagal nucleus and in other autonomic cerebral stem centres of PD patients before manifestation of clinical symptoms and of characteristic histopathological changes in the substantia nigra .
Beyond the atypical parkinsonian syndromes, multiple system atrophy (MSA) is an important differential diagnosis especially in the case of early dysautonomia in combination of extrapyramidal, cerebellar and pyramidal tract signs and histological neuron loss, gliosis and glial cytoplastic inclusion bodies . MSA subtypes (MSA-C vs. MSA-P) only differ little in their autonomic phenotype . Autonomic dysfunction in MSA generally involved more autonomic domains than in PD, and to a more severe degree, in particular with regard to inspiratory stridor . The role of autonomic dysfunction in progressive supranuclear palsy (PSP) patients is still quite unclear because of contradictory data on this issue [27, 55, 59].
For semiquantitative clinical interview, we suggest a structured detailed questionnaire with 26 items to evaluate the symptoms of autonomic nervous system in the past month (SCOPA-AUT) .
Cardiovascular system: Orthostatic hypotension
Orthostatic hypotension (OH) is the most frequent symptom of cardiovascular autonomic dysfunction [44, 50]. About 50% of PD patients with advanced disease and the majority of MSA patients complain about common symptoms of OH such as dizziness, lightheadedness, and nausea or pain during standing . OH results from a dysfunction of the sympathetic noradrenergic innervation of the cardiovascular target organs . Postprandial hypotension usually occurs 30 to 50 min after food intake while typical stress-induced OH is evoked by physical exercise in PD [10, 23].
Checklist for diagnostic work up of orthostatic hypotension in patients with extrapyramidal disorders
Treatment of orthostatic hypotension
There are alternative strategies for treatment of symptomatic OH when rehydration therapy and modification of antiparkinsonian medication fail to relieve symptoms. These therapies are used depending on their implementation levels and acceptance also in combination, irrespective of the severity of OH. For example, if the patient predominantly complains about postprandial hypotension it is suggested to increase the frequency of meals while decreasing the portion size and to administer carbohydrates evenly across the day. If orthostatic hypotension is caused by drug-induced hypovolemia (e.g. cardiovascular medication, psychiatric drugs, selegiline), it may be reversed by adjusting the dosage or by discontinuing the medication. If the condition is caused by prolonged bed rest, improvement may occur by sitting up with increasing frequency each day. Susceptible people should not sit down or stand up rapidly or remain standing still for long periods. Wearing fitted elastic stockings up to the waist may help reduce pooling of blood in the leg veins.
Antidiuretic hormones such as fludrocortisone may be administered to PD and MSA patients experiencing severe symptoms . However, the use of these hormones increases the risk of heart failure particularly in individuals with manifest heart disease. To limit the loss of potassium by fludrocortisone supplementation is indicated. Midodrine is considered a first line drug for treating orthostatic hypotension . It may be taken in combination with fludrocortisone to prevent the steep decline of blood pressure . Midodrine constricts arterioles, thereby increasing resistance to blood flow. In the 1950s it was found that an artificial amino acid, 3,4-threo-dihydroxyphenylserine (DOPS), was converted to norepinephrine (NE) in a single step by the enzyme L-aromatic amino acid decarboxylase (AADC). DOPS improved OH . Furthermore, we would recommend to use dopamine agonists in a 24-h prolonged-release formulation, e.g. ropinirole extended-release tablets.
OH may be accompanied by supine hypertension . Supine hypertension is a common feature in chronic autonomic failure. Goldstein et al. observed that PD and MSA patients with orthostatic hypotension had higher mean arterial pressure during supine rest than those without. Supine hypertension is linked to low baroreflex-cardiovagal gain which is quite common in patients with extrapyramidal disease [17, 18]. Patients also exhibit lower plasma norepinephrine levels which suggest involvement of pressor mechanisms independent of the sympathetic nervous system. Recently, we observed a high prevalence of altered 24 h blood pressure profile including loss of the nocturnal blood pressure dip in PD and MSA patients . We found good correlations between orthostatic hypotension, supine hypertension and altered 24 h blood pressure profile.
Supine hypertension must be taken into consideration when treating OH. Antihypotensive medication should be taken later than 5 pm. At night, simple measures such as raising the head of the bed by 6–9 inches can be effective, but most patients require pharmacologic treatment. Transdermal nitroglycerin (0.1–0.2 mg/h) or nifedipine (30 mg, orally) has proved to be effective . Hydralazine and minoxidil are usually less effective but may be useful in a given patient. One key therapeutic concept is the hypersensitivity of these patients to depressor agents, requiring a careful titration of the doses on an individual basis. For those patients with proven residual sympathetic tone, as in MSA, central sympatholytics such as clonidine may provide an alternative . Repeated 24 h ambulatory blood pressure monitoring is recommended for evaluation of therapeutic efficiency .
James Parkinson unambiguously portrayed advanced dysphagia in the “shaking palsy” . Dysphagia refers to a dysfunction of the complex motor cascade beginning prior to the swallow and ending when a bolus passes the lower esophageal sphincter (ingestion). It is an often unrecognized complication that occurs in a majority of patients with extrapyramidal disorders, especially when radiological abnormalities are included . The consequences of dysphagia are usually both psychological (anxiety, reduction of food selection, social isolation) and physical (aspiration risk, anteroflexed posture, pneumonia is the most common cause of death) .
There are no satisfactory therapies of dysphagia. Dopamine agonists and levodopa ameliorate some symptomatic and radiological swallowing abnormalities . Anticholinergics can be used to reduce the production of saliva in dysphagia but may evoke potential side-effects such as constipation, urinary retention, memory problems and even hallucinations. In a select patient population, sublingual atropine drops are a simple and inexpensive treatment . Gastrozepin also can be used in the treatment of sialorrhea. The recommended dose is 50 mg two times daily. Positive effects of salivary gland botulinum toxin injections have been demonstrated as well , but these may be compromised by possible complications (i.e. dry mouth, possible injection errors, muscle weakness). By experience, speech therapy, physical aid (chewing gum to increase the swallowing frequency) and pharmacotherapy to optimize motor function play an important therapeutic role . Studies on non-pharmacological interventions of swallowing training such as dietary alternatives or modification of food consistency are extremely rare .
Impairment of gastric motility has been reported to be present in 70% of PD patients . Gastric motor dysfunction (delayed gastric emptying) is usually associated with early satiety, anorexia, abdominal fullness (possible bloated feeling), nausea and vomiting . A growing body of evidence indicates that gastrointestinal symptoms primarily reflect direct involvement of the gastrointestinal tract in the neurodegenerative process (Lewy bodies in autonomic plexus, loss of autonomic neurons) . Treatment of gastric dysfunction is important, not only because of its symptomatology, but also because it may affect drug absorption and consequently lead to manifestation of motor symptoms. Disturbed gastric motility may elicit at least partly the on–off phenomena . On the other side, dopamine-mimetic agents inhibit gastric emptying, thereby further exacerbating gastric dysfunction .
Nonpharmacological treatment includes a diet consisting of small but frequent low fat meals . Cessation of anticholinergic medication may also be beneficial in the management of gastroparesis. Erythromycin is the most potent prokinetic drug when given intravenously in the acute setting and is, therefore, indicated for the initial management of hospitalized patients with severe gastroparesis . Limitations of treatment with erythromycin include its potential to induce abdominal cramps and nausea, and to retard small-intestinal transit as well as its antibiotic effects. Gastroparesis can be efficiently treated by cisapride resulting in long-term symptomatic relief . Furthermore, it accelerates intestinal transit. Cisapride has been withdrawn from many markets owing to its potential to induce cardiac arrhythmias. Domperidone has antiemetic and prokinetic effects, although central nervous system reactions are uncommon owing to its inability to penetrate the blood–brain barrier . The prokinetic effects of domperidone seem to be comparable in magnitude to those of metoclopramide. Domperidone speeds up the emptying of the stomach, facilitates resorption of levopopa in the small intestine, and hence increases levopoda plasma levels. Domperidon can also be used as adjunct to levodopa therapy which reduces side-effects such as nausea . In a small percentage of patients the insertion of a gastrostomy or jejunostomy feeding tube may be indicated for administration of dopaminergic drugs and optimal nutritional care . Advances in understanding the normal gastric electromechanical function and its abnormalities has led to the development of gastric electrical stimulators, analogous to devices that stimulate other dysfunctional organs .
Since Parkinson’s first description, constipation or decreased bowel movement frequency due to colonic dysmotility is one of the most common problems among PD patients even before diagnosis of the illness . Constipation is closely linked to slow colonic transit time, which continues to lengthen during the disease. Constipation can cause megacolon, pseudo-obstruction, volvulus, ileus or perforation. The pathophysiology of reduced colon transit time may include dysfunction of central autonomic centres (e.g. Barrington’s nucleus) and peripheral changes in the myenteric and submucosal autonomic plexus itself [5, 45]. The treatment of slow-transit constipation can be difficult and frustrating. First, an increased fiber and fluid intake is recommended. If dietary measures do not relieve constipation sufficiently, an osmotic laxative such as lactulose or sorbitol may be additionally administered. More recently, the effectiveness of polyethylene glycol electrolyte-balanced solutions has been demonstrated in PD patients . This colon-cleansing agent is routinely used in large amounts in preparation to colonoscopy. Regular administration of small doses are considered safe for treating constipation in PD. Patients often make use of effective but irritant laxatives, such as senna-containing compounds. These laxatives are not recommended for daily use since they may damage the myenteric plexus. The value of prokinetic agents in the treatment of constipation is uncertain . A recent placebo-controlled study showed the efficacy of an isosmotic macrogol electrolyte solution in the treatment of constipation in PD. It was well tolerated and, especially, did not affect the course of PD . Discontinuing anticholinergic agents may increase bowel motility. Increasing physical activity can also be helpful.
The defecation process can also be disturbed. Anorectal dysfunction, characterized by excessive straining with concomitant sensation of incomplete evacuation and sometimes of pain, is the most prevalent form of bowel dysfunction [12, 61]. The treatment of defecation dysfunction is complicated because common laxatives do not improve the coordination of the anorectal muscles but commonly worsen symptoms. Laxatives lead to preterm arrival of stool in rectum which may increase rectal retention time, and thus water reabsorption. Dopaminergic medication or apomorphine injections may individually improve anorectal function . Injection of botulinum toxin into the puborectalis muscle is effectively in treating outlet obstruction-type dysfunction . Behavioral techniques such as defecation training and biofeedback measures have been successfully employed in the treatment of outlet obstruction constipation .
Urogenital dysfunction is present in up to 93% of PD patients with frequency, urgency and urge incontinence being predominant symptoms [30, 39]. Voiding dysfunctions play an important social role among PD patients. Frequent voiding considerably impairs nocturnal sleep and quality of life. Urogenital dysfunction can occur in consequence of medications or primary neurodegenerative disease, independently of extrapyramidal disease. Like PD patients MSA patients develop early symptoms of urinary and erectile dysfunction [28, 42]. Lower urinary tract infections are a major cause of morbidity and mortality in MSA . More than 50% of MSA patients suffer from recurrent infections and a significant number (approximately 25%) die of subsequent complications.
Urogenital symptoms are usually based on a multitude of central and peripheral nervous abnormalities which are sometimes superimposed on previous local pathological conditions such as benign prostatic hyperplasia and perineal laxity. Missclassification of urogenital autonomic dysfunction as benign prostatic hyperplasia has been reported which may increase the risk of unnecessary urological surgery . A therapy should be implemented in close cooperation with a neuro-urologist. The primary goal of the therapy is to control voiding and to avoid incontinence. Patients with parkinsonism who report urogenital symptoms should be offered medical management rather than urological surgery . As yet there are no biomarkers which may predict successful surgical outcome. Urologists should be aware of the necessity to rule out MSA prior to surgery.
Checklist for diagnostic work up of neurourological symptoms in patients with extrapyramidal disorders
Medical history, including SCOPA-AUT 
Urinalysis ± culture
Medical (empiric) treatments
Measurement of post-void residual urine
(Neuro-)Urologist (e.g. urodynamics)
Sweating (i.e. sudomotor) abnormalities have long been described in PD. More recently, it has been reported that sweating abnormalities may antedate their initial diagnosis. Research findings indicate that the severity of sweating abnormalities increases as motor function declines . Both hypohidrosis as well as hyperhidrosis have been described. Hypohidrosis is most common at lower extremities whilst the upper trunk, neck and face are rather affected by hyperhidrosis . Head and neck hyperhidrosis could be a compensatory response to impaired sweating in other body regions. Because this type of hyperhidrosis may be an appropriate thermoregulatory compensatory response to appendicular sudomotor dysfunction, it should not be specifically treated. Hyperhidrosis may occur on a paroxysmal basis with the paroxysms being triggered by OFF periods . This episodic hyperhidrosis may improve with optimised dopaminergic therapy which may be achieved by adjunct therapy with either a second dopamine agonist, a COMT inhibitor or beta blocker (e.g. propanolol) or by a closer spacing of levodopa dose. Administration of anticholinergics such as 50 mg pirenzepin twice daily or 100 mg sage extract three to four times daily may efficiently treat hyperhidrosis . Topical externa of aluminium basis or botolinum toxin injections can be applied in the rare cases of focal hyperhidrosis .
It should be reiterated that extrapyramidal disorders frequently affect the autonomic nervous system. As early as 1913 Lewy described that “The dynamic character of the clinical picture of an extrapyramidal disease must result from other participating (non-motor) systems we do not know enough about” . Therefore, diagnosis and therapy of these often neglected autonomic symptoms should become routine in clinical practice.
Conflict of interest
All authors have nothing to disclose.