Constipation Treatment in Neurological Disorders

Constipation is common in both adults and children. Estimates would suggest a median prevalence of around 12-16% in the general population. While regarded as a minor nuisance in some cases, its consequences can be severe, with a substantial impact on quality of life. Secondary faecal soiling has a profound psychological effect at all ages. This book provides contributions from authors with a range of backgrounds which clarify the pathogenesis, diagnosis, and therapy of constipation for the general population and also for certain high risk groups.


Introduction
Bowel dysfunction is common in patients with neurological diseases. Its prevalence ranges from 30% to 60% in patients with cerebrovascular diseases and new-onset constipation occurs in 55% of patients after a stroke (Su et al., 2009;Harari et al., 2004;Robain et al., 2002;Bracci et al., 2007). In Multiple Sclerosis (MS) constipation is a frequent bowel symptom and it has been observed in up to 73% of patients (Crayton et al., 2004;Gulick et al., 2011;Wiesel et al., 2000). In Parkinson's disease (PD) constipation is one of the most frequent non-motor features, believed to occur in over 50% of patients (Wood et al., 2010;Pfeiffer et al., 2003;Wolters et al., 2009). Disorders of the anorectal sphincters consist of incontinence or difficulty in expelling faeces. Constipation is almost always associated with slowed bowel transit. It may be due to sphincter incoordination in relation to the detrusor mechanism or to detrusor weakness causing loss of propulsive force (Swash et al., 2001). Constipation may have a significant impact on quality of life and would restrict patient's social activities, increasing levels of anxiety and depression, so that symptoms' management is critically important (Ng et al., 2005). This review describes the possible pathogenesis of constipation in neurological disorders, pharmacological therapies available for constipation and management approaches that may increase the likelihood of satisfactory treatment outcomes.

Constipation in stroke
Constipation is defined as two or fewer bowel movements per week, the need to manipulate the rectum digitally to facilitate defecation all or most of the time, and/or use of laxatives, enemas or suppositories more than once a week (Hinds et al., 1990). Medical complications after acute stroke are common, ranging from 28% to 96% (Hong et al., 2008). Bowel dysfunction are the most frequent gastrointestinal complaints with a negative impact on patients' quality of life, restricting their social activities (Bracci et al., 2007;Su et al., 2009). The prevalence of constipation after stroke varies from 30% to 60% (Harari et al., 2004). New-onset constipation is seen in 55% of patients within a month after first stroke, strongly relating to disability. Its development may predict a poor outcome at 12 weeks in patients with moderately severe stroke (Su et al., 2009).
New onset constipation occurs in 30% of hemiplegic patients and has no relationship with the hemispheric side or with the severity of stroke even if a trend of reduced risk of constipation is described in patients with ischemic event and less widespread lesion (Bracci et al., 2007). Risk factors for constipation among stroke patients include use of a number of different drugs, dehydration, older age and immobility (Bracci et al., 2007;Su et al., 2009;Kumar et al., 2010). For the elderly, acute hospitalization is at higher risk to develop constipation than in other age groups (Cardin et al., 2010). The highest risk of new-onset constipation occurs on one week after stroke, so that early intervention may prevent the development of bowel dysfunction (Su et al., 2009). Treatment with nitrates and antithrombotics represents an independent risk factor for developing chronic constipation. Nitrates may cause constipation due to the inhibitory role in gut motility secondary to the release of nitric oxide. Antithrombotic drugs, such as acetyl salicylic acid (ASA), indobufen and ticlopidine, have been reported to be associated with bowel dysfunction. ASA and NSAID are more frequently associated with constipation probably via inhibition of the propulsive activity by preventing the release of prostaglandins. Indobufen and ticlopidine are usually associated with diarrhea. No significant association has been described between new onset constipation and ACE inhibitors or anticoagulants (Bracci et al., 2007). Anticholinergic drugs, such as antipsychotics, tricyclic antidepressants or oxybutynin, significantly increase the risk of faecal incontinence in patients with stroke, decreasing gut motility and causing constipation with overflow incontinence (Kumar et al., 2010). The use of diuretics such as mannitol or furosemide is associated with new-onset constipation (Su et al., 2009).
Bed rest and immobility contribute to constipation onset. Hypovolemia, as a result of dysphagia and/or impaired thirst mechanisms, is another risk factor. Between 37% and 78% of patients with stroke develop dysphagia, with a restriction of oral intake of dietary fibre and a high risk of undernutrition and dehydration (Ullman et al., 1996;Kumar et al., 2010;Su et al., 2009).
It is well known that the central nervous system (CNS) takes part in the control of visceral functions and its damage can lead to gastrointestinal impairment (Bracci et al., 2007). Lesions affecting the pontine defecatory centre may disrupt the sequencing of sympatical and parasympathical components of defecation, and impair the coordination of the peristaltic wave and the relaxation of the pelvic floor and external sphincter (Ullman et al., 1996). Constipation could be a clinical manifestation of spinal cord stroke as a consequence of pelvic autonomic dysfunction (Sakakibara et al., 2008).

Constipation in MS
Constipation may represent an early symptom of MS and large bowel impairment can precede the onset of MS by many years (Lawthom et al., 2003;Chellingsworth et al., 2003). Bowel dysfunctions are multifactorial and include neurological impairment, behavioural problems, inappropriate toilet facilities, side effects of drugs or coexistent disorders. A multidisciplinary approach is the best way to deal with this symptom. Bowel symptoms should be carefully treated because sometimes helping constipation can precipitate faecal incontinence. Certain patients would prefer to remain constipated if incontinence is thereby avoided (Wiesel et al., 2001). Gastrointestinal symptoms are common in patients with MS and are much more frequent than in the general population (Wiesel et al., 2001). The www.intechopen.com prevalence of constipation, alone or in association with faecal incontinence, ranges between 35% to 73%, depending on definitions and selection (Crayton et al., 2004;Gulick et al., 2011;Wiesel et al., 2000;Bakke et al., 1996). There is no difference between male and female patients regarding constipation frequency that presents a strong correlation with disability and disease duration (Hinds et al., 1990). Bladder and bowel dysfunctions have a significant role in psychosocial disability of MS patients, affecting quality of life (Wiesel et al., 2001).
Pathophysiology of constipation in MS is poorly understood. Central nervous system lesions, related to the disease process, may be responsible in some cases, affecting the extrinsic neurological control of gut and sphincter function. Autonomic nervous system impairment, specifically involving parasympathetic pathways, or some systemic mechanism not well known, similar to that which causes fatigue in MS, have been proposed (Fowler et al., 1997;De Seze et al., 2001;Guinet et al., 2011). Some authors have suggested a cerebral involvement or a motor spinal pathways failure as a cause of constipation in MS (Haldeman et al., 1982;Mathers et al., 1990). Abnormalities of colonic activity and prolonged colonic transit time have been demonstrated in some patients, and difficult defecation due to failure to relax the pelvic floor muscles has been found in others (Mark et al., 1999). Whether pelvic floor incoordination shown in some patients with MS should be regarded as a behavioural phenomenon, as in non-neurological constipation, or as related to the MS is yet unknown (Wiesel et al., 2000). Some authors associated large bowel dysfunction to demyelinating lesions of the conus medullaris, even if the role of more proximal lesions cannot be ruled out (Taylor et al., 1984). Other features connected to MS, compromising pelvic floor function and visceral motility, may contribute to constipation: muscle weakness, fatigue, spasticity and poor mobility. Also some medications, commonly used to manage different MS symptoms, such as anticholinergics, antidepressants, opiates and muscle relaxants, can affect bowel function (Wiesel et al., 2001;Fowler et al., 1997;Nordenbo et al., 1996;Gill et al., 1994). Finally, psychological factors or behavioural problems may also affect toileting (Wiesel et al., 2000).

Constipation in spinal cord injury
Bowel dysfunction is one of the major sequelae of spinal cord injury (SCI), with a severe impact on long-term quality of life, also increasing anxiety and depression. The prevalence of constipation in subjects with SCI is 20-58% (Ng et al., 2005). It is well known that constipation in SCI is due to prolonged colonic transit time. In SCI the extrinsic neural control is lost with an altered sympathic function (Winge et al., 2003). There is a clear association between constipation and the presence of a higher level of injury, as demonstrated by a mouth-to-cecum transit time prolonged in quadriplegics rather than paraplegics (Rajendran et al., 1992). Patients with cauda equina lesions may have an atonic bowel and develop severe and chronic constipation (Winge et al., 2003).
The variation in constipation prevalence in patients with different levels of neurologic deficit are related to different factors, such as attenuated gastrocolonic reflex, weakness of abdominal and perineal musculature, anorectal dysfunction and body immobilization (Stark et al., 1999;Ng et al., 2005).
Treating constipation in SCI subjects can be demanding. The usual management is a combination of bulking agents and scheduled enemas. Bowel training is used to evacuate www.intechopen.com the colon at regular intervals and an adequate fiber and fluid intake maintains bowel movements in a soft and bulky form. Shortly after breakfast, a rectal suppository and digital stimulation of the anorectum are used to induce reflex evacuation. These treatments usually leads to a daily planned evacuation. When they fail, prokinetic agents, parasympathetic nerve stimulators or colostomy can be used (Stark et al., 1999). In selected patients, transanal irrigation improves bowel function, compared with conservative management (Christensen et al., 2006).

Constipation in Parkinson Diseases (PD)
Bowel dysfunction is the most commonly observed non-motor feature of PD and it is a major factor in determining quality of life, progression of disability and nursing care (Hely et al., 2005). Some authors found constipation in 29% of patients (Edwards et al., 1991). However this symptom is under-recognised and under-treated but it has the potential to be more debilitating than motor features. The reason of this could be the patients' unawareness that these symptoms are linked to PD. Constipation is frequently reported as a prominent complaint before the onset of motor symptoms in about 50% of patients (Wood et al., 2010). Recently, an epidemiological study revealed an association between frequency of bowel movements and the risk of developing PD. Those patients with an initial finding of constipation were at a 3-fold increased risk of developing PD after 10 years from the initial report of constipation (Abbott et al., 2001). Bowel dysfunction can occur across all stages of PD but often occurs earlier during disease course and it might precede motor symptoms onset by more than a decade, correlating closely with the progression of Lewy pathology (Korczyn et al., 1990;Chaudhuri et al., 2009).
Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency and difficulty with the act of defecation itself with excessive straining and incomplete emptying (anorectal dysfunction). Anorectal dysfunction is the more prevalent form of bowel impairment in PD Recognition can lead to earlier and potentially more effective therapeutic intervention (Pfeiffer et al., 2003).
An efficient and successful defecation requires the coordinated contraction and relaxation of several muscles. Defecography, anorectal manometry and analsphincter electromyography have been used to study defecation in PD, showing different abnormalities (Stocchi 2000). In a group of patients, anorectal dysfunction caused a paradoxical contraction of voluntary sphincters during defecation, which is believed to be a type of focal dystonia (Mathers et al., 1989).
Control of gastrointestinal function is complex and involves components of the central, autonomic, and enteric nervous systems (Pfeiffer et al., 2003). Changes in parasympathetic autonomic supply to the gut could certainly account for the impairment of gastrointestinal function in PD but abnormalities in the enteric nervous system within the gut itself have also been identified, including both Lewy-body formation and loss of dopaminergic neurons (Pfeiffer et al., 2003).

Assessment of constipation
A carefully taken history, including ongoing drugs and physical examination may be adequate in most cases. To perform more specific tests depend on single cases. It is possible to evaluate different aspects of bowel dysfunction. Measurement of whole gut transit time, swallowing a radio-opaque contrast medium, is the most widely used, non-invasive and inexpensive method to quantify large bowel function (Gill et al., 1994;Prokesch et al., 1999;Nicoletti et al., 1992;Evans et al., 1992). Anorectal function and pelvic floor incoordination can be assessed by anorectal testing, anorectal manometry and a balloon expulsion test. For instance, in this way it has been possible to demonstrate pelvic floor incoordination in MS patients (Diamant et al., 1999;et al., Weber 1987;Jameson et al., 1994;Chia et al., 1996). To evaluate distal colon innervation, electrical rectal sensory testing is a useful tool. It can distinguish between constipation connected to impaired central innervation of the gut or idiopathic form (Kamm et al., 1990).

Pharmacological therapies
Several drugs are available for patients with chronic constipation, ranging from older overthe-counter laxatives to more recently developed prescription drugs (Lembo 2003

Fibers
Fibers intake such as eating high-fiber foods (fruits, vegetables) or taking fiber/bulk supplements (bran, psyllium, methylcellulose or polycarbophil) is recommended during the initial treatment of constipation (Lembo et al., 2003;Locke et al., 2000). Unfortunately a long treatment (about 2-3 months) is required to obtain symptom relief. Despite the widespread use of fiber supplementation, this approach is effective in only a subset of patients and clinical trial supporting the use of increased fiber intake is limited.

Osmotic laxatives
Osmotic laxatives (poorly absorbed/non-absorbed sugars, saline laxatives and polyethylene glycol [PEG]) cause intestinal water secretion and may be recommended when fiber therapy www.intechopen.com is ineffective (Lembo et al., 2003). Many osmotic laxatives require few days to be effective and can result in electrolyte and volume overload in patients with renal or cardiac failure (Lembo et al., 2003). Osmotic laxatives can induce abdominal cramping, bloating and flatulence.
Osmotic agents are ions or molecules that are poorly absorbed by intestine and therefore they cause water retention in the intestinal lumen. Small intestine and colon are not able to keep an osmotic gradient between luminal contents and plasma, in contrast to stomach. Osmotic agents include: incompletely absorbed salts such as magnesium, sulphate and phosphate salts; sugar alcohols such as sorbitol or mannitol; poorly absorbed disaccharides such as lactulose and polyethylene glycol (PEG).
These agents keep water in intestinal lumen, increasing stool frequency, softening their consistency and decreasing straining. Non-absorbable sugars induce little improvement in stool frequency and consistency, but they cause colonic fermentation and consequently bloating and abdominal distention. Sodium sulphate reduces water absorption, stimulating peristalsis.
Bisodic phosphate is partially absorbed into the small bowel and it is well tolerated even if hyperphosphatemia can be observed as a consequence of overdose.
Magnesium hydroxide and magnesium salts improve stool frequency and consistency. Their systemic absorption is limited and the most common side effects are electrolyte abnormalities (i.e. hypokalemia and sodium overload) and diarrhea. In this light, magnesium should be used with great care in patients with hearth or/and renal failure and in the elderly (Golzarian et al., 1994;Schiller et al., 2001;Spinzi et al., 2007).
Lactulose is a complex sugar that is not digested and metabolized by bowel bacteria to form lactic, acetic and formic acids. In this way, it causes acidification of intestinal lumen, water secretion, production of H 2 and CO 2 , and colon distension. Lactulose is very effective but induces flatulence and borborygmuses; moreover, its use should be avoided in patients with lactose intolerance.
In a systematic review of controlled trials, PEG was more effective than lactulose (Lee-Robichaud et al., 2010). PEG preparations are available with or without electrolyte supplements, and at different doses.
Macrogol 3350 is a mixture of non-absorbable polymers with high molecular weight. It is not metabolized by bowel bacteria and it works as a pure osmotic agent by keeping water into colon, causing rehydration and softer stool. The amount of water and electrolytes carried by macromolecular structure of macrogol is related to dose. The presence of electrolytes reduces risk of electrolyte imbalance, increasing safety in patients with kidney diseases Glycerine is a well tolerated laxative, available just for rectal use. It works mainly by osmotic mechanism and stimulates evacuation lubricating stool.

Class
Active These agents include: surface active agents, such as docusate and bile acids; diphenylmethane derivatives, such as phenolphthalein and bisacodyl; ricinoleic acid; anthraquinones, such as senna and cascara. Senna and bisacodyl cause rhythmic contractions of intestinal muscles, increasing bowel motility; moreover they increase water secretion into bowel. Bisacodyl is hydrolyzed in both small intestine and colon into a freeform that inhibits water absorption, but it also has an effect on enteric nervous system, inducing peristaltic response. Therefore, it should be avoided in patients with suspected intestinal obstruction. It is not clear whether these laxatives can induce damage to myenteric www.intechopen.com plexus, whereas it is known that their chronic use is associated with colonic melanosis that is reversible with drug withdrawal (about 5-6 months).
The cathartic activity of bisacodyl and sodium picosulphate may depend on their conversion to compounds with free diphenolic groups (Sund et al., 1981).
Phenolphthalein inhibits water absorption in small intestine and colon by effecting prostaglandins, kinins and the Na + K + -ATPase pump. Phenolphthalein is absorbed and can be undergone to an enterohepatic circulation which may prolong its effect. It has been withdrawn from sale in the United States because some studies in rodents suggested it may be carcinogenic (Garner et al., 2000;Josefson et al., 1997). Adverse reactions of derivatives of diphenylmethane are cramping and abdominal pain; high doses induce severe diarrhea, electrolyte depletion, damage to enterocytes, skin allergies and Stevens-Johnson syndrome (phenolphthalein).
Docusates are ionic detergents which were designed to allow water to interact more effectively with stool solids, thereby softening stools. Bile acids are natural detergents that have been used as components of proprietary laxative preparations. If exogenous bile acid is taken orally, normal ileal absorptive capacity may be enormous and sufficient bile acid may get to the colon to reduce water and electrolyte absorption or to stimulate water secretion.
Anthraquinones are a group of chemicals based on tricyclic anthracene nucleus. They are produced by different plants. Monoanthrones can form dianthrones and can be conjugated with sugars to yield glycosides. They are pro-drugs, not absorbed in small intestine and hydrolyzed by colon bacteria to active forms. The effects on water secretion with increased fecal water may appear about 6-8 hours after administration. These compounds are indicated to treat chronic constipation. Adverse drug reactions include allergies, loss of body fluid and electrolytes, reversible melanosis.
The laxative action of Castor oil is due to an irritant action on tenuous intestine by rinoleic acid released by hydrolysis of triglycerides by pancreatic lipase. It has several action mechanisms: -Na + -K + -ATPase inhibition -cAMP levels increasing mucose permeability increasing -NO synthesis Castor oil is used to preparation bowel for diagnostic or surgical procedures. Adverse reactions include abdominal-cramps and intestinal wall damage (e.g. erosion of the mucosa and epithelial desquamation).

Stool softeners
Laxatives which mostly soften or lubricate stools (e.g. sodium dioctyl sulfosuccinate and liquid paraffin) seem to be more effective than placebo to increase bowel movement frequency. Liquid paraffin, since it may interfere with absorption of fat-soluble vitamins, should be avoided in patients with oropharyngeal dysphagia (Gondouin et al., 1996).

Bulk lassatives
Undigestible fibres attract water, causing larger and softer fecal mass, increasing bowel movements by 1.4 per week (Ramkumar et al., 2005;Tramonte et al., 1997). Fibres are usually well tolerated, although some symptoms, such as bloating, may get worse.

Neuromuscular agents
Some patients with colonic inertia seem to have a reduction in cholinergic nerve activity. This could be due to a damage to the enteric nervous system or to agents with anticholinergic effects. In such instances it would be useful to increase cholinergic stimulation of colonic smooth muscle by supplying a cholinergic agonist agent. Bethanechol can be used for this purpose with good results in some patients. Neostigmine has recently been suggested as effective therapy for acute colonic pseudo-obstruction.

Opiate antagonists
Opiate antagonists have also been suggested to treat constipation. These agents block opiate receptors in intestine avoiding mucosal absorption and inhibition of intestinal transit, caused by opiate. Thus mucosal absorption should be reduced and intestinal transit should be increase by the administration of drugs like naloxone and naltrexone. An early report suggested a role for this type of agent in idiopathic constipation, but a successive report denied it (Ragavan et al., 1983;Fotherby et al., 1987).

Management of constipation in neurological disorders
Managing bowel function is a main concern in neurological patients, having an impact equal to mobility impairment on quality of life (Norton et al., 2010). It is important to get information on current bowel status in order to provide an effective treatment (Gulick et al., 2011). The frequent coexistence of faecal incontinence represents a challenge in the management of constipation (Hinds et al., 1990). On the other hand, treatment of constipation is essential, because constipation itself may worsen bladder symptoms (Hinds et al., 1989). Treatment of bowel dysfunction in MS patients is often empirical and there are a few studies comparing the efficacy of different measures such as high fibre diet, adequate intake of fluids, bowel habits, physical exercise and the use of medication (Winge et al., 2003).
Increasing dietary fibre may be useful in MS patients to soften faeces, but it is not helpful in patients with severe constipation, as observed in spinal cord injury (Cameron et al., 1996). Furthermore the need for adequate fluid intake when taking bulking agents should be strongly encouraged.  Kumar et al., 2010). A systematic assessment of bowel habits by nursing staff with a simple practice-based approach towards bowel management and patient/caregiver education has been shown to be helpful in patients with stroke (Harari et al., 2004).
A step by step approach, from simple to more complex treatment measures, is strongly recommended also in PD patients. Increasing daily fibre and fluid intake is the first step, since it is deficient in many patients with PD. Fibre supplements with psyllium or methylcellulose is useful and it significantly increases stool frequency and weight. The second step is to add a stool softener, such as docusate. Then patient can use an osmotic laxative, such as lactulose or sorbitol. Also the regular use of polyethylene glycol electrolyte balanced solutions is effective. It would be better to avoid irritant laxatives and enemas, even if they could be useful in selected cases (Pfeiffer et al., 2003).
Intrajejunal infusion of duodopa in patients with advanced-stage PD determine an improvement in constipation and other bowel symptoms in addition to other non-motor symptoms (Chaudhuri et al., 2009). Treatment of defecatory dysfunction in PD is more demanding. Laxatives do not improve the impaired anorectal muscular coordination and may increase the problem. Dopaminergic drugs may be useful, being observed an improvement in anorectal manometric during "on" periods, with deterioration when "off"' (Pfeiffer et al., 2003). Also apomorphine therapy can improve anorectal dysfunction in PD (Chaudhuri et al., 2009). Botulinum-toxin injections into the puborectalis muscle have been used successfully in the treatment of parkinsonian defecatory dysfunction. Faecal incontinence is a potential complication. Behavioural treatment approaches such as biofeedback training have not been specifically investigated in PD (Pfeiffer et al., 2003).

Conclusions
Bowel dysfunction is a frequent complication in neurological disorders and it can be due to neurological lesions or non-neurological causes. Owing to a complex physiopathology and to the involvement of autonomic system, a specific treatment is limited. A multimodal approach is needed to manage symptoms successfully and to provide individualized care for a particular patient. It is essential to determine realistic aims. Training bowel habits associated with physical activity, proper use of medication and biofeedback, just for selected patients, is an effective strategy to improve constipation in neurologic patients for some time, depending largely on disability level. Bowel management is still often empirical in neurological disorders and well-designed controlled trials are needed. www.intechopen.com