Ms. A, a 40-year-old right-handed white female, was diagnosed with multiple sclerosis (MS) 12 years ago. She has been on glatiramer acetate for 8 years. Seven years ago, a 6-week episode of tonic spasms (repeatedly clenching of the left hand) was successfully treated with a limited course of phenytoin and the symptom has not recurred. Her brain magnetic resonance imaging (MRI) has been stable over the past 5 years, showing eight nonenhancing white matter lesions in the periventricular region, corpus callosum, and cerebellum. A cervical spine MRI done around the time of initial diagnosis showed a lesion in the posterior cord at level C3-4 and has been stable since.
Ms. A recently presented to her neurologist for an urgent visit because of numerous symptoms, including painful leg cramps, particularly severe at night, insomnia, urinary frequency, daytime sleepiness, and severe fatigue. An executive-level administrative assistant, she has noted increasing symptoms of cramping sensations and stiffness in both legs, and left arm and hand incoordination. She described her fatigue as "mental and physical" and "exhaustion," which is worse in late afternoons and improved by taking a nap. This fatigue has progressively worsened. She fell once in the past month without hurting herself. She tearfully stated that her job performance has been impaired. In fact, she was unable to work for 3 weeks due to these symptoms.
Regarding the insomnia, the patient stated that she has trouble falling asleep and awakens several times throughout the night. She attributed the difficulty falling asleep mostly to painful cramps and spasms in her legs that worsen at night, and the frequent awakenings with the need to urinate. She had one incident of urinary incontinence 6 months ago, without recurrence.
Medical history was significant for depression and anxiety, which preceded the diagnosis of MS, but were both worsened after this diagnosis. Prior to being diagnosed with MS, she was admitted to a psychiatric unit twice in the past, once with suicidal ideation. Past medical history is also significant for breast cancer 10 years ago, treated with lumpectomy and without recurrence. Family history is negative for MS. She is married to a verbally abusive husband and has no children. She reports drinking at least one mixed alcoholic drink per day and no present or past use of tobacco.
In addition to glatiramer acetate, current medications are bupropion sustained release 150 mg twice daily and paroxetine 20 mg once daily. She has been prescribed alprazolam 1 mg when needed by her primary doctor and reports taking up to 3 mg per day during the daytime, and an additional tablet at bedtime to help her sleep.
Physical examination was notable for: thin, anxious female; optic pallor OD with visual acuity of 20/50 OD and 20/20 OS; nystagmus with lateral gaze (of which the patient is unaware); moderately increased tone with spastic "catch" in both legs; increased deep tendon reflexes in the legs, more so than in the arms, with several beats of clonus at both ankles and bilaterally upgoing toes; mild dysmetria of left upper extremity on the finger-nose-finger test and of left lower extremity on the heel-knee-shin test, and symmetrical decreased vibration sense in both feet. She was unable to tandem walk, hop, or walk on toes and heels. Findings that were worse on examination compared with 6 months prior include: worse spasticity in legs, unsustained clonus at both ankles, and the inability to walk on toes and heels. All other neurologic abnormalities were old findings that had been noted on examination for several years.
The patient was tearful at several points during the examination. Her Beck Depression Inventory was 26/63, and she denied suicidal thoughts.
Clinical Decision Point 1: Managing Nocturia
Question 1: What is the first best step in managing the patient's nocturia?
- Urinalysis and culture to assess for urinary tract infection
- Schedule urodynamics to assess for neurogenic bladder
- Prescribe an anticholinergic medication to treat her urinary frequency and nocturia
(a) Insomnia is common in MS. In a self-reported questionnaire of 60 men and women with MS, approximately 50% of those surveyed reported trouble sleeping at least 2 nights per week, including falling asleep (initial insomnia), awakening in the middle of the night (middle insomnia), or awakening earlier than desired in the morning (terminal insomnia).1 Patients who had trouble falling asleep cited anxiety and pain/discomfort as the primary reasons, while patients who awakened in the middle of the night cited nocturia. Waking to urinate and external factors were the most common reasons for awakening early. A larger cross-sectional survey of 1063 patients with MS assessed sleep using the Medical Outcomes Study Sleep Scale (MOSSS) and the Women's Health Initiative Insomnia Rating Scale (WHIIRS).2 Mean scores on both scales showed significantly more sleep problems among patients with MS than the general population or other chronically ill patients.
This patient's insomniaâinitial and middleâis likely to be multifactorial in origin. As the patient already stated, nocturia is interrupting her sleep and urinary frequency is a presenting complaint. The first step in assessing bladder symptoms is to rule out urinary tract infection by urinalysis and urine culture.3 If infection is present, appropriate antibiotic therapy can be started. If infection is ruled out, the focus of investigation can turn to neurogenic bladder dysfunction.
Neurogenic bladder dysfunction affects approximately 50% to 90% of patients with MS, particularly those who have difficulty walking.4 While more common in women, the specific symptoms of neurogenic bladder often vary between men and women.5 For men, typical symptoms include hesitation, interrupted or weak flow, and incomplete emptying. For women, incontinence is more frequent. Urgency, frequency, pain, and nocturia are equally common in both men and women. Neurogenic bladder dysfunction can be broadly categorized as a failure of the bladder to either empty or store urine.3 These categories may be differentiated by measuring postvoid residual (PVR) urinary volume with ultrasound bladder scan or catheterization immediately after voiding. Failure to store urine, and the resulting frequency, urgency, and nocturia, may be treated with anticholinergic agents such as oxybutynin, or the newer bladder-selective anticholinergic agents, such as tolterodine.3 It should be noted, however, that the increased PVR that can be a side effect of these agents is associated with increased incidence of bladder infection.6 In the patient with a borderline elevated PVR, the PVR should be rechecked after initiating the anticholinergic agent.
Unfortunately, in many cases MS bladder dysfunction is more complicated than simple failure to store or failure to empty. Lesions between the pontine micturition center and above the sacral spinal cord can lead to incoordinated contraction of the bladder detrusor muscle and the urinary sphincter.5 This condition is known as detrusor sphincter dyssynergia. Patients with this type of dysfunction can have involuntary interruption of the urinary stream, hesitancy, or inability to void. This situation may require urodynamic studies for diagnosis, and intermittent catheterization for treatment. Urologic consultation and urodynamics should be considered in patients with frequent urinary tract infections, and in males older than age 40 years where prostate hypertrophy might be contributing to the bladder symptoms.
Nocturia can also be specifically managed by decreasing nighttime urine production with intranasal desmopressin acetate (1-desamino-8-d-arginine vasopressin, or DDAVP) taken prior to bedtime.7 DDAVP is a synthetic analog of arginine vasopressin, a hormone produced by the posterior pituitary gland that controls urinary concentration. In a 6-week double-blind cross-over trial of DDAVP in 17 ambulatory patients with MS, DDAVP reduced the percentage of nights with nocturia from 97% to 66% and the average number of episodes per night from 2.35 to 1.09 compared with baseline. Importantly, uninterrupted sleep increased from a maximum of 3.74 to 5.77 hours. The major potential adverse effect was hyponatremia, affecting 4 of 17 patients, asymptomatic in all but 1 patient who reported headache and vague malaise. Serum sodium, therefore, should be monitored if this agent is used.
This patient's insomnia may be at least partly iatrogenic. Bupropion, taken by this patient for depression, has the side effect of insomnia in about 11% to 16% of patients.8 Considering the range of antidepressant options, however, this particular agent is less likely to exacerbate the patient's complaint of fatigue than some other antidepressant agents (eg, tricyclic antidepressants).
The importance of helping patients achieve adequate and uninterrupted sleep cannot be overstated. A study of 120 patients with MS found that 47% could be identified as "poor sleepers."9 Correlation of sleep patterns with quality of life measures, including the Short Form (SF)-36, mental component summary (MCS), and physical component summary (PCS), showed poor sleep to be an independent predictor of quality of life. Furthermore, bladder dysfunction among these patients was found to be an independent predictor of mental status on the MCS.
Audio Commentary by Dr. Miller
Clinical Decision Point 2: Evaluating Nocturnal Cramping
Question 2: What is the most likely explanation for the patient's nocturnal cramping sensation?
- Restless legs syndrome
- Periodic limb movements of sleep
(b) Pain, acute or chronic, is reported by approximately 30% to 65% of patients with MS, and painful spasms and sensations in the legs are quite common.10-13 Pain may be related to limb dysesthesias, joint pain, spasticity (described as cramping, stiffness, or spasm), and deconditioning associated with MS.12,13 Among the 20,969 patients with MS who are registered in the North American Research Committee on MS (NARCOMS) Patient Registry, 16% report no spasticity, 31% minimal, 19% mild, 17% moderate, 13% severe, and 4% total.13 Due to the prevalence of spasticity in general, and leg pain specifically, among patients with MS, the cause of this patient's nocturnal leg cramping sensation may be assumed to be due to spasticity. If additional diagnostic differentiation is needed, a sleep study may be ordered to assess periodic limb movement. Serum electrolytes should be obtained to rule out hypokalemia, especially in patients taking diuretics.
Another possible cause of nighttime leg discomfort is restless legs syndrome (RLS). Both spasticity and RLS can cause uncontrollable leg movements that are worse at night. RLS has been reported to be at least three times more common in MS patients than the general population, and is seen more frequently in MS patients having more disability.14 According to The International Restless Legs Syndrome Study Group, RLS is identified by four criteria: 1) an urge to move the legs, usually accompanied by uncomfortable sensations in the legs; 2) the urge to move and unpleasant sensations begin or worsen during inactivity; 3) the urge to move and unpleasant sensations are partially or totally relieved by movements; and 4) the urge to move and unpleasant sensations are worse in the evening or at night.15 Pain and spasms due to spasticity are differentiated from RLS based on the cramping quality of the leg pain and the physical examination showing spasticity in the involved limbs.
Spasticity does not always require medical treatment, but when it causes pain or interferes with normal daily living or sleep, as it does in this patient, treatment is in order.11 Cramps due to spasticity are relieved by the same categories of medications that improve general spasticity, such as baclofen, tizanidine, and the benzodiazepines (diazepam and clonazepam).11,13 These medications might be useful at bedtime in this particular patient, due to their sedating properties, which might also help with her insomnia. Of note, clonazepam is also used for RLS, and might be prescribed if it is not clear which is the cause of the leg discomfort. However, the same agents used during the daytime could worsen her fatigue. For daytime spasticity, another option would be to use gabapentin, which has been reported in a cross-over trial to lessen painful spasms and cramps due to spasticity and without the sedating effects of baclofen and tizanidine.16
Audio Commentary by Dr. Miller
Clinical Decision Point 3: Identifying the Cause of Fatigue
Question 3: Which of the following is the most likely cause of the patient's fatigue?
- A combination of the above
(d) Fatigue is extremely common in MS subjects, reported in over 75% of people with MS.17,18 It can arise due to secondary factors such as sleep deprivation, inactivity, comorbid depression, and the sedating side effects of medications commonly used in MS, as well as due to the primary MS disease process itself. "Lassitude" is a term used to describe the unique MS-related fatigue and can be differentiated from other types of fatigue by certain characteristics, such as time of occurrence (see Table).19 Chronic MS-related fatigue may be further identified by its presence to any degree on at least half of the days in a 6-week period.20
Table. Characteristics of MS-Related Fatigue
|Usually occurs daily
|Occurs independent of restful sleep on preceding night
|Worsens in the afternoon
|Aggravated by heat and humidity
|Generally more severe than normal fatigue
|Interferes with activities of daily living
This patient's description of fatigue is compatible with MS-related fatigue described by MS patients in that it occurs nearly daily, is worse in the afternoon, is described as "severe," and interferes with her daily activities. Furthermore, other relevant secondary factors are likely contributors to her fatigue, including sleep disruption, due to the nocturia and leg cramps, and her use of medications with sedating side effects.
For anxiety, this patient is taking alprazolam, a benzodiazepine derivative, during the day and at bedtime, and at a dose greater than prescribed. This drug commonly causes drowsiness and sedation.21,22 Slow weaning with ultimate discontinuation of alprazolam should benefit the daytime fatigue. Abrupt stopping should be avoided due to common withdrawal and rebound symptoms, as well as the risk of seizure.22,23
Paroxetine is a serotonin specific reuptake inhibitor (SSRI) that has anxiolytic properties, and may be used for anxiety in place of alprazolam without the sedation side effect.24 As an SSRI, it will have the additional benefit of treating depression. (The patient's Beck Depression Inventory was 26/63, indicating moderate to severe depression.25) Thus, the dose of paroxetine might be increased as needed, and consultation with the patient's psychiatrist should be sought.
The insomnia from which the patient suffers is likely to exacerbate her daytime sleepiness and overall fatigue.1 A vicious cycle is being created. There are other possible treatable causes of fatigue, such as anemia and hypothyroidism, which should be considered as well and can be evaluated by routine bloodwork (eg, complete blood cell count, thyroid stimulating hormone).
Randomized controlled treatment trials of agents for MS-related fatigue are few and have been limited by large placebo effects, small sample sizes, short study durations, and the subjectivity of self-reporting questionnaires.26 Several small double-blind, placebo-controlled studies have suggested that the drug amantadine may have some benefit in MS-related fatigue.27-29 Although its specific mechanism of action in MS-related fatigue is unknown, it has effects on cholinergic, dopaminergic, adrenergic, and glutamatergic neurotransmission.26 If amantadine is ineffective or suboptimally effective, modafinil at a dose of 200 mg taken daily in the morning might also be tried based on a small trial.30 However, another controlled trial of modafinil for MS-related fatigue failed to support its effectiveness.31
Fatigue has a direct impact on quality of life for patients with MS, due to its interference with activities of daily living and the loss of control patients feel as a result.20 Fatigue alters outlook, mood, and coping ability; reduces energy and endurance; and slows motor and cognitive function.32 Up to 60% of patients with MS consider fatigue to be the worst disease symptom.20 It is one of two major reasons for unemployment in this population. Among 9205 respondents to a survey of patients in the NARCOMS Patient Registry, only 29% of those with severe fatigue reported being employed compared with 55% of those with mild/moderate fatigue.33
Audio Commentary by Dr. Miller
A urinalysis and urine culture showed no evidence of urinary tract infection. Postvoid residual urinary volume of 25 mL was measured using ultrasound performed soon after the well-hydrated patient voided 350 mL. Based on these findings, the patient was started on oxybutynin 5 mg taken at bedtime. Furthermore, she was advised to take her second dose of bupropion no later than 2 PM.
For cramping, the patient was begun on nightly baclofen 10 mg at bedtime, and 5 mg as needed in the morning and at midday. Baclofen is sedating, so lower doses were used during the day. The patient was also advised to begin an exercise program combining stretching exercises and walking 1 mile daily to improve the spasticity. For fatigue, the patient was given a prescription for amantadine.
The patient was advised to begin taking these medications in a staggered fashion at least 7 days apart and to phone the office to provide updates after initiating each one. Baclofen at bedtime was begun first because painful cramping at night was her worst complaint. She reported back after 1 week that her nighttime leg cramps had improved and falling asleep was easier, but she continued to be awakened during the night by nocturia, and to feel fatigued the following day. At that point, oxybutynin 5 mg was added at bedtime. After 1 week of both baclofen and oxybutynin at bedtime, the patient called to report improved sleep quality. However, she continued to report some painful daytime leg cramps, and her fatigue, although improved, was still a problem. At that point, amantadine twice daily (100 mg in the morning and 100 mg at around 2 pm) was added.
After 4 weeks, the patient returned to the clinic, reporting that her sleep quality was improved and her daytime fatigue was improved. She felt the daily exercise program had not only improved her pain, but also her mood. She was advised to use one-half tablet (5 mg) baclofen up to three times per day for cramps on an as-needed basis. A urinalysis was performed with normal results.
Audio Commentary by Dr. Miller
Quality of life is easily eroded in patients with MS and must be guarded in every way possible. Sleep deprivation is a common problem in this population and is directly linked to reduced quality of life. Physicians should evaluate any complaint of insomnia so as to identify the cause or causes. As this case demonstrates, nocturia due to bladder dysfunction and nocturnal pain contribute to insomnia, but can be addressed with pharmacologic, and often nonpharmacologic, measures. The problem of MS-related fatigue is complicated by numerous contributing secondary factors, requiring the clinician to carefully assess multiple health parameters and coordinate treatment among the presenting symptoms.
- Stanton BR, Barnes F, Silber E. Sleep and fatigue in multiple sclerosis. Mult Scler. 2006;12:481-486.
- Bamer A, Amtmann D, Cook K, Johnson K. Comparing sleep problems in MS using the WHI insomnia rating scale and MOS sleep scale. Abstract P19. Presented at: 22nd Annual Meeting of the Consortium of Multiple Sclerosis Centers: The Challenges of MS Care and Research; May 28-31, 2008; Denver, Colo.
- Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004;70:1935-1944.
- Del Popolo G, Panariello G, Del Corso F, De Scisciolo G, Lombardi G. Diagnosis and therapy for neurogenic bladder dysfunctions in multiple sclerosis patients. Neurol Sci. 2008;29(suppl 4):352-355.
- Kalsi V, Fowler CJ. Therapy insight: bladder dysfunction associated with multiple sclerosis. Nat Clin Pract Urol. 2005;2:492-501.
- Hesch K. Agents for treatment of overactive bladder: a therapeutic class review. Proc (Bayl Univ Med Cent). 2007;20:307-314.
- Valiquette G, Herbert J, Maede-D'Alisera P. Desmopressin in the management of nocturia in patients with multiple sclerosis. A double-blind, crossover trial. Arch Neurol. 1996;53:1270-1275.
- Wellbutrin SR [package insert]. Research Triangle, NC: GlaxoSmithKline; 2007.
- Merlino G, Fratticci L, Lenchig C, et al. Prevalence of 'poor sleep' among patients with multiple sclerosis: an independent predictor of mental and physical status. Sleep Med. 2009;10:26-34.
- Clifford DB, Trotter JL. Pain in multiple sclerosis. Arch Neurol. 1984;41:1270-1272.
- Schapiro RT. Management of spasticity, pain, and paroxysmal phenomena in multiple sclerosis. Curr Neurol Neurosci Rep. 2001;1:299-302.
- Kerns RD, Kassirer M, Otis J. Pain in multiple sclerosis: a biopsychosocial perspective. J Rehabil Res Dev. 2002;39:225-232.
- Rizzo MA, Hadjimichael OC, Preiningerova J, Vollmer TL. Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler. 2004;10:589-595.
- Manconi M, Fabbrini M, Bonanni E, et al. High prevalence of restless legs syndrome in multiple sclerosis. Eur J Neurol. 2007;14:534-539.
- Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-119.
- Cutter NC, Scott DD, Johnson JC, Whiteneck G. Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil. 2000;81:164-169.
- Freal JE, Kraft GH, Coryell JK. Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1984;65:135-138.
- Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45:435-437.
- National Multiple Sclerosis Society. Fatigue. Available at: http://www.nationalmssociety.org/about-multiple-sclerosis/symptoms/fatigue/index.aspx. Accessed on: February 23, 2009.
- Multiple Sclerosis Clinical Practice Guidelines Council. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC: Paralyzed Veterans Association; 1998.
- Verster JC, Volkerts ER, Verbaten MN. Effects of alprazolam on driving ability, memory functioning and psychomotor performance: a randomized, placebo-controlled study. Neuropsychopharmacology. 2002;27:260-269.
- Verster JC, Volkerts ER. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drug Rev. 2004;10:45-76.
- Breier A, Charney DS, Nelson JC. Seizures induced by abrupt discontinuation of alprazolam. Am J Psychiatry. 1984;141:1606-1607.
- Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19:567-596.
- Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988:8;77-100.
- Schwid SR, Murray TJ. Treating fatigue in patients with MS: one step forward, one step back. Neurology. 2005;64:1111-1112.
- Murray TJ. Amantadine therapy for fatigue in multiple sclerosis. Can J Neurol Sci. 1985;12:251-254.
- Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46:676-680.
- Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45:1956-1961.
- Rammohan KW, Rosenberg JH, Lynn DJ, Blumenfeld AM, Pollak CP, Nagaraja HN. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72:179-183.
- Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005;64:1139-1143.
- Bakshi R. Fatigue and multiple sclerosis: a review. Medscape Neurol Neurosurg. 2003:2. Available at: http://www.medscape.com/viewarticle/462361. Accessed on: February 23, 2009.
- Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American Research Committee on Multiple Sclerosis (NARCOMS) survey. Health Qual Life Outcomes. 2008;6:100.