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Ofatumumab Interruption Results in Disease Reactivation: A Case Report

Neurogenic bowel dysfunction ranks as one of the most frequent problems experienced by people with multiple sclerosis (MS); it is one of the first symptoms to appear at disease onset and continues throughout the course of the disease. This review, based on literature searches of Medline and PubMed, examines bowel dysfunction causes and cofactors (ie, impaired mobility, fatigue, depression and anxiety, childbirth) that occur over the course of the disease. Coverage includes management of bowel dysfunction with noninvasive methods, including diet and fluid intake, together with pharmacologic treatments for constipation and fecal incontinence as well as more advanced treatments (ie, biofeedback, abdominal massage, transanal irrigation, posterior tibial nerve stimulation), caregiver-provided treatments and extended care facilities. Bowel dysfunction problems and related cofactors impact quality of life throughout the MS disease course, requiring appropriate interventions to improve and/or maintain the quality of life of the individual with MS.

From the School of Nursing, Rutgers, The State University of New Jersey, Newark, NJ, USA (EEG). 

: Elise E. Gulick, PhD, FAAN, 28 Rocktown Hill Road, Ringoes, NJ 08551; 

 The author has disclosed no relevant financial relationships.

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease with neurodegeneration that causes neurologic disability.

 Although the disease course begins as relapsing-remitting MS (RRMS) and transitions to secondary progressive MS (SPMS), 15% of individuals with MS have a primary progressive (PPMS) course. The majority of MS patients who begin with PPMS progress to secondary progressive MS (SPMS) characterized by continuous and irreversible neurological decline unassociated with relapse after 8–20 years. Approximately 10 years after onset, disease progression results in 50% of individuals with MS being unable to perform household and employment responsibilities, and 50% are nonambulatory 25 years after disease onset.

 During the disease course, most patients with MS experience symptoms of bowel dysfunction, including constipation, fecal incontinence (FI), and both constipation and FI, which are associated with decreased quality of life (QOL).

 Patients with MS ranked bowel problems as the third most bothersome symptom after fatigue and issues with mobility.

 Among patients with MS, estimates of constipation and FI range from 39% to 73%

; estimates of constipation from 26% to 31%; and estimates of FI from 12% to 20%.

 The aim of this review is to trace neurogenic bowel dysfunction (NBD) in persons with MS over the course of the disease, looking at neurogenic causes, related cofactors, treatments/interventions, and effects on the QOL of the individual with MS.

Neurogenic abnormalities of the colonic and/or anorectal function are the likely cause of constipation and defecatory difficulty in MS.

 Impaired rectal sensation, increased rectal capacity, and rectal hypercompliance reflect a combined sensorimotor neuropathy that contributes to fecal retention by decreasing the frequency and intensity of the desire to defecate.

 Rectal hypercompliance is a secondary distention with feces causing overstretching of the rectal wall and resulting in constipation. Manometric measurements administered to 49 patients with MS with constipation or obstructed defecation showed that evacuation difficulties were associated with sphincter muscle weakness and impaired basal and voluntary contractions.

Causative factors of FI include reduced sensation of rectal filling, poor pelvic musculature contraction, reduced rectal compliance, and weakness of the anal sphincter.

 Many patients with MS have reduced voluntary and anal squeeze pressure associated with external sphincter dysfunction, resulting in the inability to delay defecation by contracting the sphincter muscle. Sphincter hypotonia in patients with MS is correlated with FI.

 Cerebral MS lesions in the right temporal region may compromise sympathetic modulation and may facilitate parasympathetic output, which contributes to rectal hyperreflexia, as well as internal anal sphincter relaxation, which results in bowel incontinence.

Bowel symptoms are known to predate a clinically isolated syndrome (CIS) due to a demyelination event in the central nervous system. Data from 385 patients with MS, obtained from 2 tertiary care centers, reported that 31.6% had bowel symptoms before CIS; constipation (43.9%) was the most common, followed by diarrhea (31.8%), irritable bowel syndrome (IBS) (21.7%), and FI (2.5%).

 Patients with MS from an Australian sample showed onset of bowel problems with a mean ± SD of 5.4 ± 7.0 years before the MS diagnosis for PPMS and 4.6 ± 6.8 years for SPMS relapse onset.

 Similarly, in another sample of 57 patients with MS, 28.1% reported constipation and FI before their diagnosis of MS.

 Bowel problems are reported to be worse in patients with progressive MS than in those with relapse onset. Overall, the mean ± SD time between a first bowel symptom and a CIS event was 3.7 ± 3.4 years.

The type and prevalence of bowel symptoms were assessed in a cohort of 53 patients with MS 2 to 5 years after diagnosis: 81.5% had RRMS, 9.3% had SPMS, and 9.3% had PPMS.

 Bowel problems included flatus (32%), constipation (31%), diarrhea (16%), and FI (12%). Forty-five percent of the patients had constipation and/or diarrhea and/or FI. Bowel problems were significantly worse in patients with progressive onset compared with relapse onset after accounting for confounding factors such as age and disease duration, with differences being worse early in the MS course.

 Significant increases in fatigue, depression and anxiety were shown in PPMS patients than PRMS patients.

 showed an increased frequency of bowel symptoms in a sample of 136 individuals with MS with a mean disease duration of 18.2 years: 48.9% experienced constipation and 31.9% experienced FI. Study results showed a positive and significant association between both constipation and FI and MS duration after adjustment for age. A significant positive correlation was shown between severity of fatigue and both constipation and FI after adjustment for level of disability and age. Symptoms of constipation become exacerbated from fatigue and reduced ability to exercise.

Constipation, FI, or both constipation and FI are known to be associated with many related conditions, including impaired mobility, fatigue, depression and anxiety, and childbirth.

Impaired mobility can contribute to problems with bowel incontinence by adversely affecting visceral and pelvic floor function.

 Poor mobility was reflected in slow/impaired walking and poor balance in 28% of a sample of 56 individuals with MS and bowel difficulties.

 Walking and balance difficulties and bowel problems were significantly worse in patients with progressive-onset MS than in those with relapse-onset MS.

 One intervention used by individuals with MS to help alleviate constipation was improving mobility through exercise.

 A survey of 111 women with MS asked questions about their physical activity (housework, yard work, exercise, recreation) and time devoted to it; sorted by disability level (mild, moderate, cane use, scooter/wheelchair use), responses indicated significantly more physical activity in patients with mild or moderate disability, and they reported significantly fewer elimination symptoms than patients who used canes.

 Managing bowel function was rated as having an impact equal to mobility difficulties on QOL by 78% of survey respondents, who had a median age of 50 years.

Fatigue is one of the most frequently reported MS symptoms and includes feeling a sense of exhaustion, a lack of energy or tiredness, and muscle weakness.

 The relationship between fatigue and cortical atrophy in patients with MS showed that fatigue, measured by the Modified Fatigue Impact Scale,

 was significantly correlated with reduced thickness of the cortical region of the frontal lobe.

 Pre-CIS fatigue and pre-CIS sensory disturbances were significantly associated with bowel symptoms before the CIS MS event.

 Significant positive relationships between fatigue and the severity of FI and constipation were shown when adjusted for level of disability and age.

 Patients with progressive-onset MS reported high fatigue early in the disease course, with relatively little increase over time.

 Fatigue severity for patients with relapse-onset MS was low early in the disease course and increased more strongly over time. Fatigue is reported to be significantly worse in patients with MS with low fluid intake compared with those with high fluid intake. This is related to bladder dysfunction, which drives fluid restriction.

 Thus, increased hydration may be helpful for people with MS who experience fatigue, particularly for those with bladder-related issues. In addition, Racosta et al

 recommend managing fatigue through physical conditioning, avoidance of cigarette smoking, and improvement of sleep hygiene. Improvement in these 3 areas may help improve the perception of fatigue, possibly by regulating autonomic function.

Depression and anxiety disorders are mental states that become a part of NBD in persons with MS.

 More than 50% of patients with MS experience depression. Suicide is 7 to 8 times more prevalent in individuals with MS compared with age-matched controls.

 In a sample of 218 individuals with MS in which 40% reported constipation, 7% reported FI, and 4% reported both constipation and FI, mood disorders were common: 36% reported depression, 28% reported anxiety, and 18% reported both depression and anxiety.

 In addition, intestinal bowel symptoms were more common in patients with MS who reported a comorbid mood disorder.

 In a sample of 6312 individuals with MS, depression and anxiety were closely related to an IBS diagnosis.

 Depression, anxiety, and bowel problems were significantly more prevalent in patients with progressive-onset MS than in those with relapse-onset MS.

 Individuals with MS and functional constipation and IBS showed a significant association between feelings of depression and a lower QOL.

 Interventions shown to significantly improve feelings of depression and/or anxiety among individuals with MS include bowel biofeedback

Constipation among individuals with MS can be due to a vaginal delivery.

 Vaginal delivery, particularly of one’s first child, may result in significant pelvic floor tissue stretching and pudendal nerve damage, resulting in incontinence of flatus among primipara and incontinence of both feces and flatus in multipara.

 In addition, childbirth is associated with FI in patients with MS due to the interaction of central lesions, conus medullaris lesions, and coincidental pelvic nerve lesions.

Bowel dysfunction management requires rigorous assessment of the objective and subjective bowel symptoms by a multidisciplinary team. As MS progresses over time, disability and impairment need to be reassessed. Thus, the patient, their caregiver(s), and their health care team must jointly determine the need for noninvasive treatment and/or more advanced treatment, up to and including surgical procedures.

Initial management of bowel problems must begin with a review of current medications, especially bladder anticholinergics, baclofen, oxybutynin, codeine analgesia, and nonsteroidal anti-inflammatories.

 Medications such as muscle relaxants and anticonvulsants are possible contributors to constipation;

 metformin, statins, and antibiotics may cause loose stools.

Next, noninvasive procedures should be considered, including a toileting plan that considers timing to take advantage of the gastrocolic reflex and sitting position to exploit gravity; dietary interventions; and pharmaceutical approaches to increase the bulk of bowel motions, including the use of stimulants and/or local rectal preparations. Clinical experience dictates that a laxative regimen needs to be patient-specific because many variables affect efficacy. More than 1 laxative might need to be attempted before satisfactory effects are obtained.

 Active management of the neurogenic bowel is required to avoid constipation and FI to maintain QOL.

When the cause of bowel problems is unknown, treatment is largely empirical. Initial treatment for constipation often includes increasing fluid intake and following a high-fiber diet.

 Decreased dietary intake of grains has been shown to significantly increase elimination symptoms in severely disabled individuals with MS.

 Excessive intake of caffeine, alcohol, and foods containing sorbitol can cause stools to become loose and lead to FI.

 Dietary practices in studies with 123 to 335 individuals with MS showed inadequate nutrition and overweight/obesity in more than 50%, and most did not meet the United States Department of Agriculture’s recommended daily dietary intake.

 In contrast, a high-quality diet was associated with significantly lower depression and fatigue symptoms in a sample of 2015 individuals with MS.

 Dietary intake of fruit and vegetables and dietary fat predicted a better QOL and less likelihood of a higher level of disability compared with respondents with a poor diet.

 Results of a pilot clinical trial with 60 patients with RRMS who were randomized to follow a ketogenic diet for 6 months or a very-low-calorie diet for 3 of every 7 days demonstrated higher QOL than those in the control group.

Pharmacologic Treatments for Constipation  

 studied the efficacy of pharmacologic treatments for chronic idiopathic constipation using randomized placebo-controlled trials. Treatment time varied between 4 weeks

 Outcome measures included 3 or more complete spontaneous bowel movements per week and an increase over baseline by 1 or more complete spontaneous bowel movement per week.

 Data analysis used network meta-analysis.

 Treatments with prucalopride, bisacodyl, sodium picosulfate, and velusetrag were significantly more effective than placebo at 4 weeks or more. Treatments with prucalopride, linaclotide, and tegaserod were significantly more effective than placebo at 8 to 12 weeks.

 Of these, only bisacodyl was associated with adverse effects, including abdominal pain.

A systematic review of randomized controlled trials of laxatives for chronic constipation in long-term care patients conducted by Alsalimy et al

 found that senna in combination with bulk laxatives, ie, psyllium, were more effective than lactulose. Caution should be exercised when using lactulose because it is likely to cause or aggravate symptoms of bloating as well as having the potential of being ineffective.

 compared the effectiveness of polyethylene glycol–based bisacodyl (PGB) and hydrogenated vegetable oil–based bisacodyl (HVB) suppositories in improving bowel care for patients with spinal cord injuries. Comparison of a bisacodyl suppository based in polyethylene glycol (PGB) for a 2-week period 2–3 times per week was shown to reduce bowel care time by about 50% compared to similar patients given bisacodyl suppository based in hydrogenated vegetable oil (HGV).

 Similarly, 14 patients with upper motor neuron spinal cord injury given PGB bisacodyl suppositories for 6 sequential bowel care sessions was shown to stimulate reflex defecation sooner and shorter than the HVB suppository. 

 Fifteen patients with upper motor neuron spinal cord lesions given 3 PGB suppositories for each of 6 scheduled bowel care sessions also demonstrated a significant reduction in bowel care time than 10 similar patients given HVB suppositories.

 Suppository effectiveness was determined by the time, to the nearest minute, between insertion of the suppository and completion of bowel evacuation and cleanup. These 3 studies demonstrated that PGB suppositories significantly reduced bowel care time by approximately 50% compared with HVB suppositories.

 Bowel care with HVB suppositories included more digital stimulations during the defecation period than did PGB suppositories.

In addition to comparing the effectiveness of HVB and PGB suppositories, House and Stiens

 also compared the effectiveness of HVB and PGB suppositories with that of polyethylene glycol–based/glycerine/docusate sodium mini-enemas. The PGB suppository and the mini-enema produced significantly better and consistently similar results in total time for the treatment session, stool production, number of incontinence episodes, and number and total time of digital stimulations compared with the HVB suppository.

Pharmacologic Treatments for FI/Diarrhea 

In a double-blind crossover trial, 15 patients with chronic diarrhea were randomized to 4-week treatment periods to compare the efficacy of loperamide and codeine in alleviating incontinence.

 Both drugs significantly alleviated the symptom of urgency, improved stool consistency, and decreased the incidence of adverse effects, which included nausea and vomiting, drowsiness, dizziness, depression, and blurred vision obtained from daily diary recordings. Although not statistically significant, patients given codeine reported more adverse effects than patients receiving loperamide. The importance of diary recordings was also shown by Vaizey et al.

 who developed a new scale to measure fecal incontinence based on the patient’s daily record of fecal leakage, urgency, use of a pad, and medication taken for fecal incontinence.

In a double-blind randomized trial of FI, in which 24 patients received zinc-aluminum ointment and 20 patients were given placebo, both groups demonstrated significantly decreased Wexner Incontinence scores with a greater decrease in the treatment group after treatment.

 Although no adverse effects were reported, the authors indicate concern over the toxic effect that aluminum may produce in the central nervous system, but no evidence of topical absorption was shown with this treatment.

 Patients treated with zinc-aluminum ointment also had significant improvement in their Fecal Incontinence Quality of Life Scale scores (FIQLS).

 The FIQLS has been validated in the Spanish language based on 118 patients who suffered from FI that can be used as a measure of health in patients with FI.

Biofeedback is the next treatment for NBD when maximal laxative therapy within a bowel regimen has failed.

 Biofeedback has been used for the management of idiopathic constipation and pelvic floor incoordination. It teaches patients to be more conscious of a stimulus distending the rectum, to relax the anal sphincter, and to improve anorectal coordination and sensory perception, in addition to habit training pertaining to defecatory behavior and laxative use.

 Biofeedback can be administered in a physician’s office or a patient’s home, with similar positive outcomes and decreased cost when administered at home.

The few studies that have investigated the effect of biofeedback on patients with MS had prospective observational designs and small samples ranging from 13 to 52 patients.

 The effectiveness of biofeedback in managing bowel dysfunction was assessed by administering pretreatment and posttreatment

 anorectal physiological tests to determine anal resting pressure, squeeze, and endurance squeeze pressure

; rectal sensibility to balloon distention

 Biofeedback outcomes were also determined by administering the Wexner Constipation and Wexner Incontinence scales,

 pretreatment and posttreatment standardized bowel questionnaires,

After biofeedback, results of the anorectal physiology tests indicated significant improvement in endurance squeeze pressure.

 In terms of posttreatment bowel symptoms, Wexner Constipation and Wexner Incontinence scores improved significantly, indicating a reduction in bowel symptoms.

 After biofeedback, maximal sphincter pressure, paradoxical contraction of the anorectal musculature, and anal inhibitory reflex

 improved significantly, together with anorectal improvement.

 Decreased bowel movement straining, FI, and laxative use was reported.

 Patients with MS who benefited from biofeedback had mild to moderate disability with a quiescent or non-relapsing pattern.

 Biofeedback is unlikely to work in patients who are wheelchair bound and have lost complete anorectal function.

 In addition, biofeedback was ineffective in a sample of patients from the general population who had slow transit constipation.

Results of a systematic review of the effectiveness of physiotherapy techniques for women to prevent and treat FI showed that biofeedback and sphincter muscle exercises, pelvic floor muscle training, and electrostimulation are effective in relieving symptoms of FI.

 In addition, electromyographic biofeedback treatment for constipation due to pelvic floor dyssynergia was significantly more effective compared with non-electromyographic biofeedback treatment (eg, laxatives, placebo, sham training).

Biofeedback studies have not proved to be superior to a well-established bowel regimen or any other treatment, but biofeedback is considered as the next step when laxative therapy within a bowel regimen has failed.

 recommend improving research by standardizing a bowel treatment training program and evaluating patient learning and behavioral changes.

 conducted a study of 30 patients with MS who had constipation to determine the feasibility of administering abdominal massage. Participants were recruited through a website and from MS groups and day centers located in Ireland. Participants were randomly allocated to a massage group or a control group. The mean age of the 30 patients was 55 years, and mobility varied from walking unaided (10%) to wheelchair bound (40%). Massage participants and their caregivers were taught how to perform abdominal massage and were given a teaching DVD that demonstrated the massage techniques. The abdominal massage protocol lasted approximately 15 minutes and was to be performed daily. The intervention period was 4 weeks, with participants in both groups receiving weekly visits from the physiotherapist in which discussions were included regarding bowel patterns and symptoms, together with advice regarding good defecation posture, adequate fluid intake, and the importance of diet and exercise. Study results at week 8 showed improvement in constipation symptoms for both the massage and control participants; however, the massage group improved significantly more than the control group. Symptoms associated with bowel dysfunction, as measured by the Neurogenic Bowel Dysfunction Score (NBDS),

 including frequency of bowel movements, headache, discomfort before or during defecation, medication, time spent defecating, FI, and flatus, were significantly less in massage patients than in control patients.

A randomized controlled trial for abdominal massage in patients with MS by McClug et al

 included 99 control patients and 90 intervention patients, all of whom had bothersome NBD. The participants’ mean age was 52 years, 154 were female, and 21 were wheelchair dependent. The intervention began with individualized training for the intervention group, followed by daily abdominal massage for 6 weeks. Advice on good bowel management as per an MS society advice booklet was given to both the intervention and control groups. The research nurse made weekly telephone calls to all participants. Based on the NBDS, the study assessed presence of headache, perspiration, or discomfort before or during evacuation; medication used for constipation and/or FI; time used for evacuation; frequency of digital stimulation or evacuation; frequency of FI, and skin problems. Study results at week 24 demonstrated no significant difference in the NBDSs of the intervention and control groups. The intervention group did, however, perform significantly better in weekly stool evacuation frequency and in the number of times per week that participants felt they had emptied their bowels completely. Seventy-five percent of the participants reported benefits pertaining to less difficulty passing stool, more complete evacuations, less bloating, and improved appetite, and 85% continued with the massage therapy.

Additional Treatment Options for Managing NBD

When conservative treatment options such as diet/fluid intake adjustments, lifestyle alterations, oral medications (eg, stool softeners, laxatives), digital stimulation, suppositories, biofeedback, and abdominal massage) are unsuccessful in managing NBD, transanal irrigation (TAI) is a treatment option. It assists the evacuation of feces from the bowel. In addition, posterior TNS is the least invasive form of neuromodulation and may be a treatment option when conservative treatment options fail to successfully manage FI.

 conducted a study of the long-term efficacy of TAI to measure health-related QOL and identify factors predictive of TAI outcome in 49 patients with MS whose bowel symptoms had not responded adequately to lifestyle changes or optimal laxative therapy. Before starting TAI therapy, patients underwent anorectal physiology tests and completed the EQ-5D

 detailing anal incontinence, constipation, obstructed defecation, and the impact of bowel dysfunction on QOL. The patients used the Peristeen TAI system (Coloplast Corp), which is usually self-administered except for patients with limited dexterity who may need assistance from a caregiver. At the follow-up at 40 months, 55% of patients had successfully used the TAI treatment (63% with constipation and 37% with FI). The frequency of FI episodes fell significantly from 4.8 at baseline to 0.9 at follow-up. Sensory threshold was a significant predictor of long-term continuation of therapy. In addition, urinary tract infections were reduced by 54%, and the annual number of hospitalizations was reduced by 41% in patients using TAI. Patients’ visits to general practitioners, specialists, and dietitians and caregiver dependency were reduced by 27%, 19%, 55%, and 44%, respectively. These reductions suggest that TAI use leads to a decrease in the cost of health care for patients with MS who have NBD. This finding is consistent with another study of the long-term cost-effectiveness of initiating TAI in patients with NBD (116 spinal cord injured, 62 MS, 27 cauda equina syndrome, 15 spina bifida) who failed standard bowel care.

 Treatment with TAI over one’s lifetime is predicted to decrease FI episodes by 36%, urinary tract infections by 29%, and stoma surgery by 36%. A decline in health-related QOL occurred in this study, which could be related to the progressive and disabling nature of MS. Study results indicate that TAI is an effective treatment option for patients with MS and NBD, particularly when conservative treatment options are unsuccessful.

 conducted a pilot study to evaluate the efficacy of TNS in treating FI in 33 patients with MS with urge (n = 23) and passive (n = 4) and mixed (n = 9) FI. After failing conservative therapies for FI and anorectal physiology investigations, the patients were given TNS over a 3-year period. At baseline and immediately after completion of TNS therapy, patients completed the Wexner Incontinence Questionnaire, the Rockwood score, and the Bristol Stool Form Scale.

 Some study participant statistics: 25 were female, median age was 48 years, mean time since MS diagnosis was 14 years, mean duration of FI was 10 years, and 22 had RRMS, 3 had PPMS, and 8 had SPMS. At the end of the treatment, 26 patients (79%) were classified as responders and 7 (21%) were non-responders according to their Wexner scores. Responders also demonstrated an improvement in Rockwood depression score and stool consistency after treatment. Patients with RRMS had a significantly greater likelihood of treatment response than those with PPMS and SPMS. Overall, 81% of patients exhibited a high rate of TNS treatment success.

A postal survey of methods and strategies used to manage FI in 47 patients with MS indicated a wide array of treatments.

 Survey results indicated that 14 respondents avoided high fiber or high-fiber foods, which they found to be moderately helpful. Twelve respondents used medication, including b-blockers, bowel irrigation, laxatives, and antidiarrhea agents. Three respondents reported using complementary therapy (acupuncture, colonic irrigation, reflexology). The reported variety of treatments may be due to differences in the type of MS (RRMS, SPMS, PPMS) and/or trying a different treatment after the initial treatment was unsuccessful in alleviating the symptom(s). Most of the patients reported only limited effectiveness of most interventions.

As MS progresses, individuals with MS have increased symptoms that interfere with their daily independence and increase their need for care from a spouse, family members, or assisted living facilities. The Caregiving Tasks in Multiple Sclerosis Scale was developed based on responses from 232 caregivers and their care recipients recruited through the MS Society of Queensland, Australia.

 The scale represents 4 caregiving task domains: Instrumental Care, Activities of Daily Living (ADL) Care, Psycho-Emotional Care, and Social-Practical Care shown by principal factor analysis. The ADL Care domain includes items pertaining to toileting and continence/diapers. Thus, the Caregiving Tasks in Multiple Sclerosis Scale delineates key dimensions of MS caregiving tasks that include bowel care.

On average, 81% of total time spent caring for individuals with MS is provided by family members living with the patients. When the patient with MS’s partner is available, they perform most of the home care therapy. The disability level of an individual with MS influences the amount of care family and friends must provide and is shown to be 4.6 and 12 hours per day for moderately and severely disabled individuals with MS, respectively.

 Aronson et al studied 530 informal caregivers who assisted individuals with MS.

 The individuals with MS were 64% female and averaged 58.4 years of age; 95% had experienced at least moderate interference in their daily lives. The caregivers were 54% male, and their average age was 59.2 years. Caregivers were interviewed via telephone to ascertain their caregiving experiences. Worse overall health in the individual with MS increased financial strain, threatening relationships with family members; however, a greater interference in the independence of the individual with MS significantly improved or strengthened the caregiver/care recipient relationship, and the longer the caregiver/care recipient relationship lasted, the more significant the link to positive relationship perceptions. If the caregiver perceived that assisting the person with MS was burdensome, this had a significant negative impact on the caregiver/care recipient relationship.

 and the 29-item Multiple Sclerosis Impact Scale

 were used to assess the impact of caregiver mood on the caregiver’s perception of the functional impact on the day-to-day life of the individual for whom they were caring.

 Negative caregiver moods (eg, fatigue, anger, depression) were reported as most distressing to caregivers. Forty-two percent of the caregivers expressed that their most elevated mood disturbance was related to fatigue inertia. Thirty percent of caregivers with elevated or very elevated mood scores on Anger-Hostility, Depression-Dejection, Tension-Anxiety, and Confusion-Bewilderment were associated with greater functional impact of MS on the person receiving care. Caregivers’ anxiety and depression has also been linked to caregivers’ negative perceptions of the physical impact of MS on affected individuals.

Relational satisfaction of spousal/partner caregivers, important for continued care and support, was investigated by Tzitzika et al.

 The study of 909 caregivers (62% men, mean age of 48.9 years, 85% married) showed that caregiver commitment to the relationship with the person with MS had a significant positive effect on the caregiver/care recipient relationship. However, caregiver burden had a direct negative effect on the relationship. Male caregivers tended to be more satisfied with their relationship than female caregivers. Spousal/partner caregivers in longer relationships tended to be more satisfied with their spouse/partner who had MS.

Extended Care Facility of Nursing Home Possibility 

Due to increased disability and functional incapacity, a significant increase in the percentage of patients with MS requiring bowel care are transferred to institutions.

 Increasing age, bowel dysfunction, and functional decline, as well as caregiver burden, are associated with caregiver perceptions of increased possibility of future admission to extended care facilities or nursing homes.

 Female caregivers are much less likely to perceive the need for future placement in extended care facilities than male caregivers. However, improving access to MS-focused care brought into the home lowers the risk of admission to extended care facilities or nursing homes.

Multiple sclerosis is a chronic, complex, neurodegenerative disease with an onset usually occurring in early adulthood. Bowel dysfunction in people with MS may result from the disease process that affects the cerebral vascular system along with common causes unrelated to MS neuropathy. One of the first symptoms of MS is NBD. In fact, bowel symptoms, including constipation and FI, are known to predate a CIS by 3 to 7 years. Over the course of the disease, several cofactors are associated with neurogenic bowel symptoms, including impaired mobility, fatigue, depression and anxiety, and childbirth. Problems with mobility include decreased exercise resulting in constipation. Increased fatigue is associated with fluid dehydration and insufficient physical activity. Depression and anxiety, comorbid mood disorders, occur early in the MS disease course along with constipation and FI and are associated with lower QOL. Interventions shown to improve depression and anxiety include bowel biofeedback and TNS. Laxative regimens need to be specific to the patient because many variables affect their efficiency. Difficult vaginal deliveries during childbirth can cause pudendal nerve damage to the pelvic flow musculature, resulting in possible constipation and/or FI.

Noninvasive treatments for NBD given to patients with MS increased their QOL. When noninvasive bowel management procedures (ie, toileting plans, dietary interventions, pharmaceutical approaches) no longer alleviate constipation and/or FI, more advanced techniques (ie, biofeedback, abdominal massage, TAI, TNS) may be considered. Studies have shown that biofeedback treatment is successful in improving bowel dysfunction in patients with mild to moderate MS disability. Abdominal massage was associated with decreased frequency of bowel movements, headache, discomfort before and/or during defecation, medication treatments, time spent defecating, FI, and frequency of stool evacuation per week. Transanal irrigation reduced the frequency of FI, urinary tract infections, and visits to health care professionals. Tibial nerve stimulation improved QOL and stool consistency, with treatment response being more effective in patients with RRMS than in those with PPMS and SPMS. The treatment/s must be individualized according to the patient’s specific bowel symptoms. The success of various treatments depends on a variety of factors: changes in the functioning of neural and muscular integrity of the bowel that may occur due to MS disease progression, presence of cofactors (ie, impaired mobility, fatigue, depression and anxiety), medications, and diet. These changes require regular assessment of bowel function and appropriate treatment changes.

As MS progresses, the individual needs caregiver assistance. The longer the caregiving relationship lasts, the more positive and committed the caregiver becomes. However, caregiver burden, particularly due to fatigue, has a negative effect on the relationship. Increasing age, bowel dysfunction, and functional decline in individuals with MS as well as caregiver burden are associated with caregiver perceptions of increased possibility of future admission to extended care facilities or nursing homes. The next research step is to study the health status, care needs, and QOL of patients with MS who reside in extended care facilities.

Neurogenic Bowel Dysfunction Over the Course of Multiple Sclerosis: A Review

Up to 50% of individuals with multiple sclerosis (MS) who are prescribed disease-modifying treatments (DMTs) do not take them as advised. Although many studies report on DMT adherence rate, few studies report on interventions involving individuals with MS. The current paper describes the development of an intervention aimed at improving adherence to DMTs among identified nonadherent individuals with MS.

An intervention was developed using an Intervention Mapping approach, recommendations from reviews on medication adherence, and input from individuals with MS. Its content was determined by theories of health behavior (specifically, a perceptions and practicalities approach), empirical evidence collected among the specific target population (an observational “needs assessment” stage [n = 186]), and other studies.

A personalized intervention was tailored to the reasons for nonadherence, uncovered during the observational needs assessment stage, to be delivered sequentially by a neurologist and a psychologist. After the intervention objectives were identified, components of the intervention were set: psychoeducation and ways of coping with adverse effects; modification of unhelpful treatment beliefs (such modifications were found predictive of adherence in the observational phase of the study); improving confidence and self-efficacy; and developing strategies for remembering to take DMTs. These components were embedded within motivational interviewing.

Intervention Mapping was useful in developing an intervention grounded both in the theoretical approach of perceptions and practicalities and in empirical evidence from the literature and the target sample; concurrently, identifying determinants that the intervention did not address. The effectiveness of the intervention—which could potentially improve adherence among individuals with MS—needs to be examined.

From the Behavioral Sciences Department, Ruppin Academic Center, Emeq Hefer, Israel (EN); Multiple Sclerosis Center and Neuroimmunology Unit, Carmel Medical Center, Haifa, Israel (AM); and Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel (EN). 

: Efrat Neter, PhD, 3 Bait, Ruppin Academic Center, Emeq Hefer, Israel 4025000; 

 Ariel Miller, MD, PhD, has served on a scientific advisory board and received personal compensation/honoraria/grant support for consulting/speaking activities and research from Avanir Pharmaceuticals, Bayer-Schering Pharma, Biogen Idec, Mapi Pharma, Medison Pharma Ltd, Merck Serono, Novartis, Sanofi-Genzyme, and Teva Pharmaceutical Industries Ltd. Efrat Neter, PhD, has no disclosures.

 This work was supported in part by Novartis, Biogen Idec, Sanofi-Genzyme, and Merck Serono.

Multiple sclerosis (MS) is the most prevalent chronic inflammatory demyelinating disease of the central nervous system and is currently incurable.

 Although no treatment fully prevents or reverses the progressive neurologic deterioration, disease-modifying treatments (DMTs) have been shown to limit the number of relapses and prevent new lesion formation, as well as reduce the accumulation of disability

 among individuals with relapsing remitting MS (RRMS). For individuals with RRMS, these outcomes translate into lower risk of relapse, better quality of life, and higher treatment satisfaction. More than a dozen DMTs are now available.

Many of the DMTs require consistent self-administration across time; however, a meta-analysis on adherence to oral DMTs found that by the end of the first year of treatment, 20% of individuals with RRMS were not taking their DMTs as prescribed,

 and 25% discontinued treatment, known as nonpersistence.

 Studies with a 2-year follow-up period reported that only 60% of individuals with RRMS persisted in their treatment.

 Both nonadherence and nonpersistence are associated with lower quality of life as well as with increases in relapse risk, hospitalizations, emergency department visits, neuropsychological issues, work loss, and MS-specific medical costs.

 Notably, adherence rates among individuals with MS are higher than among those with other conditions such as epilepsy, Parkinson disease, and rheumatoid arthritis.

Adherence to DMT poses special challenges. Despite the chronic nature of RRMS and the necessity of long-term treatment, the need for DMTs may be less obvious during periods of disease inactivity. Disease progression can occur with no noticeable symptoms, potentially making individuals with RRMS less concerned about appropriate adherence. Benefits of treatment accrue only in the long term, yet adverse effects (AEs) of medication that reduce quality of life are immediate.

 These are the challenges described in the therapy-related factor in the World Health Organization (WHO) adherence model

; the other factors are social and economic (eg, age, ethnicity, education), health care system (eg, type of insurance), condition related (eg, duration, comorbidity), and patient related. The patient factor in particular is often studied because its components—such as perceptions of illness, medication beliefs, habits in medication, and affective states—are considered potentially modifiable in interventions. In MS, most studies on adherence and persistence have focused on the socioeconomic factor, data on which are easily retrieved from administrative records, and only a few studies have investigated patient-related

Implementing interventions to increase adherence is essential to improve the care of individuals with RRMS. However, despite avid interest in assessing adherence and unravelling its predictors/correlates, few studies have used previous findings to develop interventions. This paper focuses on the development of an evidence-based and theory-driven motivational interviewing intervention—a technique focused on exploring and resolving ambivalent feelings and perceptions—to support individuals with RRMS who are taking DMTs and to improve their adherence rates.

We designed the intervention described here based on theory and prior empirical evidence to ensure the possibility of replication and adoption, if successful. We used the Intervention Mapping (IM) approach

 to structure the process of design and implementation. The study follows recent guidelines requesting more comprehensive and transparent reporting

; this affords a better understanding of the considerations that led to choosing specific intervention components, as well as potential pitfalls in the process. One model for such reporting is a self-management intervention for medication adherence among survivors of breast cancer.

The IM framework is anchored in 2 principles: First, include stakeholders to ensure relevance, acceptability, implementability, and contextual and cultural appropriateness; second, use theories and evidence. The framework includes 6 stages: (1) assessing needs, (2) identifying intervention objectives and behavioral determinants, (3) designing and/or selecting theory-based methods for behavior change, (4) organizing and producing the intervention; (5) implementing the intervention, and (6) evaluating the intervention (see 

, at the bottom of this article). The first 4 stages are described in detail in the rest of this paper.

The first stage, which included data collection, was approved by the Institutional Review Board of Carmel Medical Center (#0061-14-CMC). All participants signed written informed consent forms confirming that they were free to leave the study at any time.

The first stage of IM involves carrying out a needs assessment to establish the extent of the health problem and to identify the determinants associated with the problem behavior. This needs assessment was informed by a review of the literature, using search terms around “DMT,” “MS,” “adherence,” and “persistence,” as well as a search for systematic reviews on medication adherence in general and in MS.

 In addition, we carried out a longitudinal observational study pertaining to the patient factors in medication adherence in the target population of individuals with RRMS. This study assessed medication adherence and persistence among individuals with RRMS taking oral and injectable DMTs in multiple modalities (eg, self-reported; administrative records) and examined the prospective associations among demographic, clinical, and perceptual predictors to adherence and persistence.

 As results from the longitudinal study began accumulating, we adopted the Necessity-Concerns Framework, which evolved into the Perceptions and Practicalities Approach (PAPA).

 This approach to the analysis of patients’ actions in regard to their medication use focuses both on perceptions that shape an individual’s motivation (ie, intentional non-adherence) and on practical issues sometimes beyond a patient’s control, regardless of intention (ie, unintentional nonadherence).

Stage 2: Identify Intervention Objectives

The intervention’s desired results were determined in this stage. Specific goals for enhancing adherence were developed via theory-based PAPA constructs and guided by the specific needs of individuals with RRMS. These goals were dissected to determine particular activities or techniques that could improve adherence. At this point in the process, practitioners can be explicit about the intervention goals and the targeted determinants.

Stage 3: Identify Theory-Based Methods and Practical Strategies

In stage 3, we identified theory-based behavior change techniques and methods that relate to the determinants found in the needs assessment (ie, stage 1) by scanning the literature for studies that offered insights into the determinants specified in the intervention objectives.

In this stage, the identified behavioral strategies are combined to develop the intervention. The development was an iterative process and was informed by feedback from the research team, individuals with RRMS, and clinicians. Two psychologists in the clinic reviewed the content of the intervention. In addition, 5 female individuals with RRMS taking a DMT gave their opinions at 2 decision points. Their primary language was Hebrew (n = 3) or Arabic (n = 2). They were recruited either via their physician’s recommendation or after filling out a survey.

Nonadherence to oral DMT among individuals with RRMS was found to be prevalent. A recent systematic review and meta-analysis evaluated adherence using either the medication possession ratio or the proportion of days covered, which are based on administrative records of persons being supplied with prescribed medication within a given time period. The mean medication possession ratio of >80%— which is considered adherent—was present in 63.5% to 88.5% of individuals with RRMS, and it decreased over time.

 Moreover, discontinuing 1 medication or switching medication in the first year of treatment was common (25%).

We conducted a prospective cohort study to examine adherence and persistence, and their predictors, among individuals with RRMS (n = 186). The study included demographic and clinical characteristics as well as patient-reported medication beliefs, illness perceptions, medication habits, perceived health, and affect (ie, depression and anxiety). The patients were prospectively assessed at 3 time points: baseline, 6 months later, and 12 months later. Using multiple measures (multiple self-reports, military personnel records, and others

Jeffrey Hernandez, DNP, APRN

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