Multiple sclerosis: treatment of its symptoms

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By Jill Conway MD and Michael Kaufman MD

Fatigue. Fatigue has been defined as a reduction of effective output for the exerted input (Chaudhuri and Behan 2004), “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities” (Multiple Sclerosis Council for Clinical Practice Guidelines 1998a), and as reversible motor and cognitive impairment, with reduced motivation and strong desire to rest (Mills and Young 2008). Fatigue may occur spontaneously or after physical or mental activity, with rise in body temperature, or after food ingestion. It may be relieved by rest, with or without sleep, and is usually worse in the afternoon (Mills and Young 2008).

Fatigue is identified by patients as the most frequent and disabling symptom of multiple sclerosis, and two-thirds list fatigue as 1 of their 3 worst symptoms. Seventy-five percent to 90% of multiple sclerosis patients experience unusual fatigue as compared to about 30% of the general population. Fatigue impedes mobility for 50% to 60% of patients, and 40% describe it as their most disabling symptom (Greim et al 2007). Social Security Disability may be awarded on the basis of fatigue, and fatigue is 1 of the 2 major reasons for unemployment among people with multiple sclerosis. Two monographs that are useful references for the management of fatigue have been published (Multiple Sclerosis Council for Clinical Practice Guidelines 1998a; Krupp 2004).

It is important to differentiate fatigue related to multiple sclerosis from fatigue secondary to a sleep disorder (some of which, such as restless leg syndrome, may be of increased prevalence in multiple sclerosis patients) or lack of motivation (apathy), which may be a presentation of cognitive and behavioral impairments in multiple sclerosis. New or worsening fatigue may also be a sign of a multiple sclerosis relapse. Multiple sclerosis fatigue has numerous etiologies that may respond to different therapies. Unfortunately, no large, comprehensive study has been performed to define and differentiate the many theoretical causes of fatigue in this population. Still, it is important to distinguish fatigue as a consequence of modifiable conditions, such as sleep disorders.

In a small study, disrupted sleep has correlated with fatigue measured by the Fatigue Descriptive Scale (Attarian et al 2004). However, in another study of 6 relapsing-remitting multiple sclerosis patients with fatigue, there was no consistent polysomnographic evidence of disturbed sleep and normal body core temperature circadian rhythms (Vetrugno et al 2007). Nonetheless, almost half of all multiple sclerosis patients complain of sleep disturbances (Tachibana et al 1994) including periodic leg movements of sleep and restless legs, hypersomnia, insomnia or disrupted sleep, delayed sleep phase syndrome, and sleep apnea.

Insomnia, the most common complaint, has many potential causes. Conditions that are associated with fatigue may contribute to insomnia, such as depression/anxiety, medication side effects, pain, nocturia, restless legs, muscle spasms, sleep-related leg cramps, inactivity, and possibly alterations of the wake-sleep cycle caused by central nervous system pathology. In a group of 60 patients in London, insomnia in the middle of the night was most often caused by nocturia and was associated with daytime fatigue (Stanton et al 2006).

Treatment of insomnia should begin with an attempt at arriving at a specific diagnosis and treatment. If none is found, then non-pharmacological options should be used initially. Stimulants and insomnia-producing drugs should be avoided if possible, and regular sleep schedules should be established with sufficient “wind-down” time prior to sleep onset. Patients should be encouraged to avoid pre-sleep computer use or watching television in the bedroom, which can cause activation and difficulty in falling asleep. Daily exercise may improve sleep quality. Nocturia should be eliminated if possible. Polysomnography is reserved for patients with suspected sleep apnea, periodic leg movements, or other conditions that require quantification.

Long-term treatment of insomnia using sleep-inducing pharmacological agents is generally discouraged. The melatonin receptor agonist, ramelteon, appears to decrease sleep latency without rebound in some patients with chronic insomnia. Benzodiazepines may be effective, and a 12-month open-label study using eszopiclone showed continued efficacy of treatment in primary insomnia (Roth et al 2005).

Table 1. Treatment of Periodic Limb Movements in Sleep, Insomnia, and Cramps

Sleep disturbance

 

Therapy

 

Periodic leg movements

Diazepam (5 to 10 mg)

 
 

Clonazepam (0.25 to 2 mg)

 
 

Gabapentin (300 to 900 mg)

 
 

Carbidopa/L-DOPA (10/100 to 50/500)

 
 

Pramipexole (0.25 to 1.5 mg)

 
 

Ropinirole (0.25 to 1 mg)

 

Insomnia

Triazolam (0.125 to 0.25 mg)

 

 

 

 

Temazepam (7.5 to 30 mg)

 
 

Zolpidem (5 to 10 mg)

 
 

Trazodone (50 to 150 mg)

 
 

Zaleplon (10 mg)

 
 

Eszopiclone (1 to 3 mg)

 
 

Quazepam (7.5 to 15 mg)

 
 

Ramelteon (4 to 8 mg)

 

Secondly, fatigue may represent a side effect of certain medications. Antispasticity agents, anxiolytics, antiepileptic drugs, and analgesics may cause sedation, which may be perceived as fatigue. Disease-modifying therapies such as interferon-beta may also be associated with relatively persistent fatigue. If fatigue-inducing medications are essential and irreplaceable, stimulant use may be considered in order to counteract this side effect.

Affective disorders. Depression, anxiety, and perceived poor health are all associated with fatigue; at the same time, fatigue itself can induce social withdrawal and depression. Fatigue is worse for patients with tendencies for symptom somatization as well as for those who feel that they have little control over their environment (Vercoulen et al 1996).

Idiopathic lassitude. Lassitude is probably the most common and poorly understood form of multiple sclerosis fatigue. It may be the result of inefficient communication between areas of the brain that are supposed to interact whenever the patient is active. Diminished neuronal integrity, as demonstrated by diminished cerebral metabolism (Roelcke et al 1997), lowered N-acetylaspartate-creatinine ratio (Tartaglia et al 2004), and greater brain atrophy (Marrie et al 2005), has been associated with high levels of subjective fatigue. Inflammation may also cause lassitude. Interleukin (IL)-1, released by inflammatory cells, can induce lassitude when injected into the ventricles of animals. A relapse of multiple sclerosis is often associated with severe fatigue, possibly due to this mechanism. Some patients report improvement in fatigue after initiation of immunomodulators. This type of fatigue may occur without preceding activity and may be helped by a brief nap.

Chronic lassitude may be helped by caffeine, amantadine, and other stimulants (Table 2). The efficacy of amantadine is poorly supported at present (Taus et al 2003). Although a well-controlled trial of modafinil showed no greater effect on fatigue in multiple sclerosis patients than placebo (Shankoff et al 2005), in the authors’ experience and in the experience of others (Rammohan et al 2002), the vast majority of multiple sclerosis patients report dramatic response to it. In 1 self-report survey, 84% of 119 respondents with “primary MS-related fatigue” who had used modafinil found it to be helpful for fatigue (Stewart et al 2007). An ongoing clinical trial at the University of Missouri is studying the effects of armodafinil in cognitive fatigue in multiple sclerosis. Stimulants have also been used as adjuncts to treat depression and improve cognitive function after brain injury (Challman and Lipsky 2000). These drugs may exacerbate some preexisting psychiatric disorders, including anxiety, depression, paranoia, major thought disorders, and bipolar disorder. Mixed amphetamine salts and methylphenidate are generic drugs that some patients find helpful. Although controlled release products are generally preferred, in some patients they interrupt sleep to a greater extent than immediate release products. Cases of sudden death have been tied to the use of stimulants in both adults and children, primarily among those with preexisting structural heart defects. Extended release and transdermal delivery systems for methylphenidate, extended release dexmethylphenidate, and the pro-drug lisdexamfetamine dimesylate may offer advantages over the generics at a higher price.

Bupropion and some other antidepressants (Table 2) may be helpful in treating fatigue, although whether the effect is primary (Duffy and Campbell 1994) or secondary due to amelioration of depression (Schonfeldt-Lecuona et al 2006) is uncertain.

There are many studies supporting the effectiveness of regular exercise in lessening fatigue. A cross-sectional study found diminished fatigue in multiple sclerosis patients who exercise, compared to those who are sedentary (Stroud and Minahan 2009). Exercise 3 times weekly has been shown to improve fatigue and quality of life in patient-reported outcomes (McCullagh et al 2008). Yoga has been shown to be as helpful as regular exercise in combating fatigue (Oken et al 2004).

Patients are often interested in low-dose naltrexone, which is highly touted on multiple internet sites as an effective therapy for virtually any multiple sclerosis symptom (and a host of other diagnoses). Naltrexone, an opioid antagonist at higher doses, appears to have a mixed agonist-antagonist effect at lower doses. A patient-funded study conducted by Bruce Cree examined the effect of low-dose naltrexone on quality of life in a double-crossover trial design (Cree et al 2008). Multiple sclerosis patients taking low-dose naltrexone reported improved quality of life, diminished pain, and improved self-reported cognitive function. No improvement in physical quality of life was found, and comprehensive standardized disability ratings (expanded disability status scale score) were not conducted as part of the trial. Low-dose naltrexone appears to be well tolerated, and further research may clarify whether it offers symptomatic treatment to patients with multiple sclerosis. Some have observed that multiple sclerosis patients taking low-dose naltrexone tend to exhibit signs of euphoria, which may be perceived as improved energy level.

Table 2. Treatment of Fatigue

Class of drug

 

Drug

Comment

 

Temperature modulator

 

Aspirin (650 mg at morning and noon)

Single study suggests efficacy.

 

Generalized stimulants

     

   • First line

Amantadine

(100 to 400 mg)

Has few side effects; works in less than half of patients (Murray 1985).

 

 

Activates tubero-

mammillary

nucleus

Modafinil

(100 to 200 mg, rarely 400 mg)

Does not produce much anxiety; 20% decrease in estradiol concentrations of contraceptive pills.

 

 

 

Inhibits dopamine

reuptake

Armodafinil

(50 to 250 mg)

Does not produce much anxiety; 20% decrease in estradiol concentrations of contraceptive pills.

 

 

   • Second line

Methylphenidate

(5 to 40 mg or extended release)

Formulations include extended release and transdermal patch; addictive, must rewrite prescriptions monthly.

 

 

 

Dexmethylphenidate

(10 to 20 mg)

 

 

 

Mixed amphetamine salts

(5 to 40 mg)

   
 

Lisdexamfetamine dimesylate

(30 to 70 mg)

In children, 39% decreased appetite, 19% insomnia.

 

 

 

Energizing

antidepressants

Bupropion

(100 to 300 mg)

 

May induce weight loss; contraindicated with history of seizures.

 

 

 

Fluoxetine

(10 to 40 mg)

   
 

Venlafaxine

(37.5 to 225 mg)

Extended release formulations are more expensive.

 
 

Desvenlafaxine

(50 to 100 mg)

 

Some multiple sclerosis–associated conditions may present with fatigue. Uhthoff phenomenon, for example, may affect motor, cognitive, and other functions. It is precipitated by emotional stress, a rise in body temperature, and activity. Presumably, increased recruitment of neurons or using the same neurons for multiple tasks makes them refractory to excitation, whereas high body temperature shortens the duration of action potentials, leading to electrochemical transmission failure along demyelinated axons. Thus, any activity or condition that raises body temperature may result in fatigue and weakness. Furthermore, patients with multiple sclerosis have difficulty regulating body temperature, and this may be linked to fatigue severity. This may also explain why a trial with 650 mg of aspirin taken at morning and noon improved fatigue in multiple sclerosis patients (Wingerchuk et al 2005). Turning the thermostat to a temperature of 65°F to 68°F may also help. The Multiple Sclerosis Association of America offers cooling vests free of charge to patients with heat sensitivity.

Fatigue similar to that seen with beta-adrenergic blockers has been linked to sympathetic vasomotor insufficiency (dysautonomia) in multiple sclerosis patients (Flachenecker et al 2003). Studies have also shown that the amount of change in cardiac stroke volume and ejection fraction measured at rest when compared to hyperventilation is inversely correlated with fatigue, suggesting that abnormalities of vagal function may be a factor, resulting in fatigue (Merico et al 2005).

Spasticity. Spasticity is a motor symptom associated with upper motor neuron dysfunction, and, as such, is commonly seen in multiple sclerosis. Spinal cord involvement in multiple sclerosis is more frequently accompanied by a higher degree of spasticity. Spasticity can be profoundly disabling and may lead to permanent contractures. Increased spasticity is frequently observed with urinary tract or other infections, and may also be one symptom of a multiple sclerosis relapse. Spasticity may be manifested as an increase in tone at rest (rigidity), tone that increases with the speed of movement (spasticity), slow contraction of antagonistic muscles (dystonia), heightened tendon reflexes, and myoclonic jerks. Clinically, these forms of spasticity may occur independently or together. Sub-primate systems have not proven useful in predicting the responses of humans to treatment of spasticity, so therapy largely has been empirically determined (Young 1994). The functional consequences of spasticity range from mild impairment of running to increases in adductor tone that compromise genitourinary hygiene. Despite the potentially disabling nature of spasticity, spasticity may be useful in severely weak and minimally ambulating multiple sclerosis patients in allowing them to stand, pivot, and transfer.

Spasticity may improve with an exercise program (Petajan et al 1996). Passive and active muscle stretching may reduce the amount of medication required to treat spasticity and can prevent contractures. Reduction of pain reduces spasms.

First-line agents for spasticity, baclofen, and tizanidine (Table 3), have different mechanisms of action and toxicities; therefore, they can be combined to improve outcomes (Paisley et al 2002). There are ongoing phase 3 clinical trials of 2 forms of arbaclofen, an extended-release active enantiomer of baclofen and arbaclofen placarbil, an R-baclofen prodrug, for the amelioration of multiple sclerosis–related spasticity.

In cases of severe sedation and other systemic side effects of baclofen or insufficient efficacy with oral administration, alternative modes of administration using intrathecal baclofen (ITB) pumps should be considered. ITB may especially benefit non-ambulatory patients when spasticity is painful, interferes with skin care or hygiene, or makes transfer and positioning difficult. It occasionally provides dramatic benefit for ambulatory patients with good strength but significant gait abnormalities due to spasticity; some patients who would otherwise be non-ambulatory have been able to ambulate due to ITB pump placement. The systemic side effects of baclofen are minimal with this form of administration due to the differences from metabolism of oral administration. Patients generally undergo a test dose of ITB (via lumbar puncture with or without temporary catheter placement) to determine responsiveness prior to undergoing surgical implantation of the ITB pump. A guide to the step-by-step implementation of this treatment has been published (Jarrett et al 2001).

Botulinum toxin injections can be used to relax single or small groups of spastic muscles (Snow et al 1990). They are especially useful for patients with a painful, dystonic posture of a hand, foot, and occasionally the neck, and in patients with compromised personal hygiene due to adductor spasm. OnabotulinumtoxinA is FDA approved for upper extremity spasticity; other forms of botulinum toxin have also been used in clinical practice and in clinical trials for spasticity.

Although controversial, cannabinoid compounds have been investigated for multiple symptoms, including pain and spasticity. A number of patients report that cannabinoids are beneficial in the management of their spasticity. In many studies, objective improvement has not been satisfactorily demonstrated to date (Killestein et al 2004), but there are a few studies showing some benefit. Trials to date are summarized in (Zajicek and Apostu 2011). Spasticity, as measured by the Ashworth scale (more recent trials of spasticity utilize the modified Ashworth scale), was not impacted by cannabinoids according to a large, randomized controlled trial (Zajicek et al 2003). However, the study tracked secondary outcomes with self-reported measures. Self-reported pain, spasms, spasticity, and sleep quality improved in patients taking cannabinoids. Subsequent trials have confirmed self-reported improvement in pain and spasticity. Legal issues surrounding use of cannabis and its derivatives complicate clinical trial design in many locations, whereas cannabinoid compounds have received regulatory approval for use in other locations. Dronabinol is used off-label in the United States. Nabiximols has been approved to treat multiple sclerosis symptoms in Canada and in the United Kingdom (Zajicek and Apostu 2011).

Table 3. Treatment of Spasticity

 

Class

Comment  

First line drugs

     

Baclofen (5 to 40

mg, every 3 to 6

hours)

 

Gamma-

aminobutyric acid

antagonist

May cause weakness, lethargy, confusion.

 

 

Tizanidine (2 to 12

mg, every 3 to 4

hours)

Noradrenergic

alpha-2 agonist

Sedation may help

insomnia and

painful nocturnal

spasticity.

 

Second line drugs

Gabapentin (200 to

900 mg, 3 to 4

times daily)

Anticonvulsant

Useful for dystonic

spasms. No effect

on hepatic

enzymes.

 


 

Carbamazepine

(100 to 400 mg, 3

times daily)

Anticonvulsant

Useful for dystonic

spasms. Can

induce severe

weakness.

 


 

Levetiracetam (250

to 1500 mg, twice

daily)

Anticonvulsant

May avoid some of

the cognitive

problems induced

by other AEDs.

 


 

Diazepam (2 to 10

mg, 2 to 3 times

daily)

Benzodiazepine

Some patients find

diazepam better

than first-line

agents.

 


 

Dantrolene (25 to

100 mg, 3 times

daily)

Prevents Ca++

release from

muscle stores

Causes weakness;

must monitor liver

enzymes.


 

Speculative

Clonidine

Alpha-adrenergic

agonist

 

   

Cyproheptadine

(max dose 16 mg)

Antihistamine and

serotonin

antagonist

 

Stimulates appetite. Ameliorates EAE

 

Some anticonvulsants and benzodiazepines have mild ameliorating effects on spasticity. Levetiracetam appears to modify phasic spasticity without inducing cognitive changes (Hawker et al 2003). It should be noted that ciprofloxacin use is inadvisable in patients taking tizanidine as it may increase tizanidine blood levels dramatically.

Bladder dysfunction. Bladder dysfunction includes difficulties in storage and emptying of urine and the effects of inappropriately high pressures within the bladder. Urgency, caused by detrusor hyperreflexia, is often associated with frequency due to reduced bladder capacity. Difficulty initiating flow is usually the result of inability to relax the external sphincter. A low flow rate may result from increased external sphincter tone or loss of tone in the detrusor. The latter, often referred to as areflexic bladder, is usually associated with marked leg spasticity or weakness. Detrusor-sphincter dyssynergia is used to describe the combination of a hyperreflexic bladder with inability to relax the external sphincter. Many multiple sclerosis patients have this combination of symptoms resulting in urgency, hesitancy, and incomplete bladder emptying. Urosepsis, once a major cause of mortality among patients with multiple sclerosis, usually can be avoided (Andrews and Husmann 1997).

Three major risk factors for serious urinary tract complications are: an indwelling catheter, detrusor-sphincter dyssynergia in men, and detrusor pressures less than 40 cm of water. Aims of therapy should be to avoid these and to protect upper urinary tracts.

Initiation of therapy is aided by the ability to measure urine volume and by knowing the following facts:

  1. The normal bladder can accommodate 450 to 500 cc of urine before the urge to void.
  2. Normal volume of voided urine is 300 to 500 cc, 3 to 8 times daily.
  3. Post-void residual urine volume is normally only a few milliliters.
  4. The detrusor muscle is muscarinic (parasympathetic) and contracts in response to acetylcholine to empty the bladder.
  5. Adrenergic stimulation increases the tone of the external sphincter and inhibits the parasympathetic innervation of the detrusor, increasing the capacity of the bladder to store urine.
  6. The usual progression of bladder symptoms in multiple sclerosis is hyperreflexia of the detrusor muscle, then detrusor-sphincter dyssynergia, and then areflexia.
  7. Most multiple sclerosis patients with good leg strength will have a hyperreflexic bladder. Detrusor-sphincter dyssynergia and areflexia are usually not found in patients until leg weakness is present, but exceptions occur.

Evaluation of bladder function includes gathering information about the number of times the patient voids, the degree of urgency and hesitancy, severity of nocturia, the amount of fluid intake, the force and constancy of stream, the amount of urine voided, and the amount of and circumstances leading to incontinence. With only a clinical history, however, nearly 50% of patients are misdiagnosed (Katz and Blaivas 1983). A carefully recorded micturition diary describes urinary function more precisely than the history alone. Ultrasound urine volumes, ideally done at the time of first urge to void and after voiding (post-void residual), can be obtained noninvasively. Post-void residual urine volumes as measured by ultrasound do not correlate well with reported symptoms (Kragt et al 2004). Some patients may be managed initially with relative confidence based on history, micturition diary, and pre- and post-void residual urine. The goals of therapy are to maintain a residual urine volume of less than 100 cc, produce a ratio of residual volume to voided volume that is less than one third, and to prevent recurrent urinary tract infection.

A guide for the treatment of bladder dysfunction containing a number of algorithms is available (Multiple Sclerosis Council for Clinical Practice Guidelines 1998b). In the case of hyperreflexic bladder, behavioral management includes reduced intake of substances that may irritate or stimulate the bladder such as caffeine or acids, reduced fluid intake when a lavatory will be unavailable or before sleep, and timed voiding. Timed voiding requires the patient to anticipate when the next need to empty the bladder will occur and void before the urge to urinate is felt. Patients should not reduce fluid intake during the day when a bathroom is available because concentrated urine is more irritating to the bladder. Over-the-counter calcium glycerophosphate, 333 mg, 1 to 2 doses with meals can be useful in reducing urinary acidity and decreasing urgency. Pelvic muscle training and relaxation techniques may be of some benefit (Wallace et al 2004).

Anticholinergics with strong anti-muscarinic activity are the treatment of choice for a hyperreflexic bladder and for increasing bladder capacity. Oxybutynin, a commonly used and inexpensive agent, has potentially helpful weak muscle-relaxant and local anesthetic actions.

Anticholinergic therapies are often associated with the unpleasant side effect of dry mouth. This may cause patients to drink more fluids, aggravating their frequency. Glycerin swabs or candies can occasionally be helpful in combating this problem. Blurred vision in bright light and acute angle closure glaucoma can be precipitated by anticholinergics because they cause papillary dilation. Another concerning side effect of anticholinergic medication is impaired cognition (Mulsant et al 2003). In addition to traditional anticholinergics, many other drugs (antihistamines, cimetidine, prednisolone, theophylline, and digoxin) can have detectable anti-muscarinic effects, potentiating the problem in older and cognitively impaired patients. In such patients, physicians may wish to use darifenacin for its M3 selectivity or trospium chloride, tolterodine, or solifenacin, which have low lipid solubility limiting their entry into the brain. M3 receptors are found in gastrointestinal smooth muscle, salivary glands, iris sphincter, and bladder but not in CNS tissue. It also may be advisable to combine these medications with newer, and unfortunately more expensive, therapies to substitute for drugs with anticholinergic effects in order to reduce the “total cholinergic burden” in patients susceptible to confusion.

Table 4. Medications for Bladder Dysfunction

 

Class

Comment

 

Hyperreflexia

     

Anti-muscarinic

agents

Imipramine (10 to 50

mg, up to twice daily)

Anticholinergic, alpha-adrenergic agonist, and cortical effects.

 

 

 

Oxybutynin (2.5 to 10

mg, up to 3 times daily

or extended release

daily)

 

Formulations include extended release and transdermal patch.

 

 

Tolterodine (2 to 8 mg,

up to twice daily or

extended release daily)

 

Extended release compounds useful in minimizing side effects.

 

 

Trospium Cl (20 mg,

once or twice daily)

Give on empty stomach; renally excreted.  
 

Solifenacin (5 to 10 mg,

once daily)

 

   
 

Darifenacin (7.5 to 15

mg, once daily)

 

Relatively selective for M3 receptor.

 

 

Hyoscyamine (0.125 to

0.25 mg, 3 or 4 times

daily or extended

release 0.375 mg)

 

   
 

Propantheline (15 to 30

mg, up to 4 times daily)

   

Detrusor dyssynergia

     

Alpha-

adrenergic

agonists

Clonidine (0.05 to 0.1

mg, twice daily)

May induce hypotension. Doxazosin should be gradually titrated in dose. Tamsulosin and alfuzosin should be given within half hour after a meal.  
 

Terazosin (1 to 5 mg, daily)

 

   
 

Doxazosin (1 to 8 mg, daily)

 

   
 

Tamsulosin (0.4 to 0.8 mg, daily)

 

   
 

Alfuzosin HCl (10 mg, daily)

 

   

Areflexia

Bethanechol (25 to 100 mg, 3 times daily)

Must rule out obstruction first. Do not use in asthma, CAD, PUD.  

Nocturia

Desmopressin (0.1 to 0.4 mg at bedtime) (Hilton et al 1983)

Independent of bladder function, follow for hyponatremia.

 

In 2011, the FDA approved onabotulinumtoxinA, at a total dose of 300 units, for injection at multiple sites into the detrusor muscle (Schurch et al 2000) for the treatment of urinary incontinence due to detrusor overactivity associated with neurologic conditions, such as multiple sclerosis.

Alpha-blockers are used to treat difficulty initiating a urinary stream (hesitancy) initially. Care must be exercised to avoid induction of hypotension when these agents are used. Saw palmetto, an herbal preparation available without prescription, has been used to alleviate symptoms of hesitancy in association with benign prostatic hypertrophy, but in a well-controlled and adequately powered study, one preparation performed no better than placebo (Bent et al 2006).

An areflexic bladder may respond to muscarinic agonists. Double-voiding, a Credé maneuver that applies pressure on the bladder, or a vibrator placed over the lower abdominal wall may improve emptying of an areflexic bladder. A permanent intraurethral catheter is rarely appropriate and usually only used for patients with immobility and limited surgical options. Common problems associated with chronic catheter use include recurrent stones, urethral erosion, urinary leakage, and urinary tract infections. Suprapubic catheterization reduces the risk of infection and avoids the difficulties involved with intraurethral catheters (Branagan and Moran 2002). Urological surgery including suprapubic catheters, augmentation cystoplasty, continent urinary diversion, ileovesicostomy, external sphincter stent prosthesis and external sphincterotomy in men, and implantation of InterStim devices can be helpful, although the latter precludes future MRI examinations.

Referral to a urologist should be considered if a post-void residual volume is greater than 200 cc. Volumes in this range can be associated with chronically elevated pressures (greater than 30 cm of water) in the bladder that lead to reflux of urine into the ureters and, in the setting of bacteriuria, infection of the urinary tract. If urinary pressures are high, intermittent catheterization is needed to prevent recurrent urinary tract infections, albeit improper catheterization can also lead to recurrent infection. Women, as compared to men, have a short urethra that provides less resistance to the contraction of the detrusor muscle. Changes in the pelvic floor induced by surgery and childbirth and the thinning of the vaginal mucosa with menopause make women more likely to be incontinent, although these changes also lead to low bladder pressures.

Avoidance and prompt treatment of bladder infections is paramount to the care of multiple sclerosis patients. A urine analysis should be obtained in the setting of new urgency to look for infection. Patients with altered bladder sensation, however, often do not have typical symptoms in the setting of a urinary tract infection. A urine analysis can screen patients using 2 of the most sensitive indicators of infection, (1) leukocyte esterase and (2) moderate bacteriuria by microscopy. Patients can be given a urine dipstick to test their urine at home if they have malaise or worsening symptoms in conjunction with low-grade fever. However, conventional urine analysis can overlook about 14% of infections (Van Nostrand et al 2000). Therefore, multiple sclerosis patients with a decline in neurologic status or a change in bladder function should obtain a urine culture, even if the dipstick test or urine analysis is normal. A 3-day course of trimethoprim-sulfamethoxazole as initial therapy is sufficient for uncomplicated urinary tract infections in patients with early multiple sclerosis and minimal bladder symptoms. If resistance to these drugs is high, antibiotic choice is based on susceptibility testing. Patients with high residual urine volumes and high bladder pressures or who are taking immunosuppressive therapy require longer periods of treatment (7 to 10 days) to eradicate infection (Fihn 2003). Patients taking immunosuppressive therapy should undergo a repeat urine analysis at 5 days after initiation of therapy to ensure an appropriate response and a culture 10 days after the completion of therapy to verify complete resolution of the infection.

Elevated white blood cell counts are not a definite indicator of infection when patients have urinary catheters. Patients with Foley catheters and more than 100,000 CFUs by urine culture should be treated only if symptomatic.

More than 3 urinary tract infections per year is another reason for referral to a urologist. Patients who self-catheterize may be more susceptible to infection and may benefit from suppression of bacteria with uroquid acid (methenamine/sodium biphosphate) or methenamine and vitamin C, 4 times daily. Suppression with antibiotics can be done by alternating treatments using 1 month of nitrofurantoin, 50 mg per day, followed by 1 month of trimethoprim-sulfamethoxazole or trimethoprim alone, 400 mg per day. More aggressive suppression can be accomplished by irrigation of the bladder with gentamicin 240 mg in 500 ml of normal saline with 1 ampoule of sodium bicarbonate daily for 7 to 10 days. Irrigation is performed after changing the bladder catheter. Initially, 60 ml of normal saline is used to irrigate the bladder via catheter. Then 30 ml of gentamicin solution is placed into the bladder, and the catheter is cross-clamped for 30 minutes. The gentamicin mixture is drained through the catheter.

Bowel dysfunction. Constipation historically has been defined as 12 weeks or more of symptoms per year, hard stools, straining, incomplete evacuation, use of manual maneuvers to pass stool, or a sense of difficulty passing at least 1 in 4 stools and/or fewer than 3 bowel movements per week. Because patients tend to underestimate their stool frequency (Manning et al 1976), a bowel diary may clarify the history. Any patient with blood in the stool, weight loss, or whose onset of symptoms occurs at an advanced age should be referred to a gastroenterologist. Multiple sclerosis patients are vulnerable to constipation resulting from medications (anticholinergics, nonsteroidal anti-inflammatory agents, calcium supplements, opiates, and amantadine), decreased mobility, and dehydration (Romero et al 1996).

The treatment of constipation begins with behavioral therapies. Bowel entrainment can be fostered by timing elimination 30 to 60 minutes after the same daily meal. Regular exercise, dietary fiber and fruits, and good hydration all contribute to good bowel function. One half cup of a mixture of one-third prune juice, one-third apple sauce, and one-third bran cereal ingested once or twice daily is well tolerated and beneficial when symptoms are mild. Pineapple also seems to be particularly useful as a food that promotes regularity. Some patients have reported that the use of bifidobacteria-containing yogurt has been helpful for them.

Concentrated fiber preparations increase the bulk and water content of stool. Colonic bacteria metabolize natural fiber sources such as psyllium, oat bran, and fruits, which results in the release of gas. This phenomenon does not occur with synthetic or insoluble fibers such as methylcellulose and polycarbophil or wheat bran/dextrin. Stool softeners can be added to fiber. Softeners include docusate sodium and docusate calcium.

Hyperosmolar agents, such as sorbitol, lactulose, and polyethylene glycol can be effective but may also cause bloating. The American College of Gastroenterology Chronic Constipation Task Force has made a grade A recommendation for both lactulose and polyethylene glycol for improving stool consistency and frequency (American College of Gastroenterology Chronic Constipation Task Force 2005). Pyridostigmine 30 to 60 mg or erythromycin 333 to 400 mg taken before meals may increase peristalsis.

A number of relatively inexpensive stimulants (bisacodyl, senna, cascara, and phenolphthalein) and saline laxatives are available for intermittent use. Some "natural remedies" contain significant amounts of senna and cascara. Decreased absorption of fats and fat-soluble products and induction of refractory constipation limit the use of all stimulants. Glycerin suppositories used every other day or bisacodyl suppositories every third day may also help.

Gastrointestinal propulsives include cisapride, domperidone, and metoclopramide. Cisapride and domperidone both have cardiac toxicity whereas metoclopramide can induce parkinsonism.

Lubiprostone is a chloride channel activator that increases intestinal fluid secretion. It has low systemic absorption but can cause nausea. Trials using 24 mcg twice per day appear to show benefit in chronic constipation.

Any individual with fecal incontinence should be assessed for constipation with overflow (National Guideline Clearinghouse 2004).

Sexual dysfunction. Sexual dysfunction generally affects patients with spinal cord symptoms of multiple sclerosis. During intercourse, multiple and easily perturbed neural networks on both conscious and unconscious levels coordinate to reach a successful culmination. Decreased libido, numbness and dysesthesias, vaginal dryness, autonomic dysfunction, vascular insufficiency, emotional and cognitive impairment, spasticity, bladder dysfunction, and side effects of medications all can contribute to unsatisfactory intercourse. Furthermore, most antidepressants affect sexual function, although bupropion and mirtazapine generally spare the ability to achieve orgasm. Alpha-adrenoceptor antagonists, frequently used to treat urinary hesitancy, can lead to disorders of ejaculation. Oral baclofen can occasionally induce sexual dysfunction. Beta-blockers, antipsychotics, thiazide diuretics, and spironolactone may also induce sexual dysfunction. Marital discord can cause sexual dysfunction, but nearly 25% of patients believe that the lack of sexual fulfillment has contributed to marital problems. Surprisingly, corticosteroid treatment has been observed to sometimes improve sexual function (Mattson et al 1995).

Fifty percent to 75% of men with multiple sclerosis report erectile dysfunction. This has become much easier to treat with the development of oral phosphodiesterase inhibitors, sildenafil, vardenafil, and tadalafil. These medications should be used with caution or not at all when patients are taking other vasodilators. Medications that inhibit the P-450 system such as statins, protease inhibitors, and systemic triazole antifungals increase the plasma levels of the oral phosphodiesterase inhibitors and increase side effects. Vacuum devices and alprostadil urethral suppositories can be used alone or added to phosphodiesterase inhibitors. Intracavernous injections of prostaglandins E1, papaverine, and phentolamine in different concentrations can be effective as well. The cost of these preparations varies depending on the composition from approximately $75 to $350. As many as 25% of men with multiple sclerosis have premature ejaculation. This generally responds well to selective serotonin reuptake inhibitors taken an hour before intercourse.

Testosterone maintains sexual desire, and levels have been found to be slightly lower in men with multiple sclerosis. Other endocrine causes of erectile dysfunction are hyperthyroidism and prolactinomas. The vascular risk factors of inactivity, diabetes, hypertension, and dyslipidemia are associated with restricted pudendal artery flow and erectile dysfunction. Patients with Peyronie disease develop pain and penile curvature with erections that results in dysfunction. A more detailed review of erectile dysfunction is available (Beckman et al 2006).

The most common complaints of women are inadequate lubrication, anorgasmia or hypo-orgasmia, reduced libido, and diminished perineal sensation. An association of cerebellar disturbances and orgasmic dysfunction has been found (Gruenwald et al 2007). Vaginal creams and water-soluble lubricating jellies can be used to treat vaginal dryness. Petroleum-based jellies should be avoided because they can leave residues that promote bacterial vaginitis. Patients experiencing diminished sensitivity often respond to vibrators. Oral sildenafil may be an adjunct to sexual arousal, but small studies have shown only a limited effect on lubrication. This agent has also been compounded as a cream, sometimes combined with L-arginine, and applied to the clitoris with anecdotal success. Ten percent of women with multiple sclerosis have painful perineal dysesthesias that may be manageable with carbamazepine or gabapentin or the local application of 2% Xylocaine gel. Women with incontinence should empty the bladder prior to intercourse, and those with high residual volumes should empty afterwards. Intercourse for patients with urinary catheters and spasticity may be possible with proper positioning and treatment of spasticity. For diminished libido, treatment with bupropion may provide some benefit (Segraves et al 2004).

Pain. Pain is common in multiple sclerosis. Over half of the subjects in a cross-sectional study described acute or chronic pain syndromes during the course of the disease (Moulin et al 1988). Nearly a quarter of patients take analgesics daily as compared to less than 10% of a control population; 19.3% of multiple sclerosis patients reported that pain interfered with daily life “all the time” versus 7.4% of controls (Svendsen et al 2003). It is frequently challenging to differentiate between pain caused by tissue damage in multiple sclerosis and pain that is behaviorally associated. Although both can be difficult to treat, the latter may be characterized by confrontation between patient and caregivers. Other causes of pain should always be considered when a patient develops a new pain syndrome. Chronic neurogenic dysesthesias are commonly experienced in patients with secondary progressive multiple sclerosis (Salaro et al 2004).

Pain can be classified into categories that aid in the selection of treatments:

Paroxysmal neuralgic pain. Paroxysmal neuralgic pain is variably described as sharp, stinging, burning, shocking, or by an equivalent phrase. In a study, this was the most common type of pain experienced (Griswold et al 2003). These paroxysmal pains may be atypical in patients with multiple sclerosis when compared to "idiopathic" cases. Paroxysmal neuralgic pain includes trigeminal neuralgia, glossopharyngeal neuralgia, occipital neuralgia, pseudoradicular pain, and Lhermitte phenomenon.

Table 5. Treatment of Paroxysmal Pain

 

Medication

 

Comment

 

First line

Carbamazepine (200 to 400 mg, 3 times daily)

 

May induce severe weakness. Asians with HLA-B*1502 are subject to serious skin reactions.  
 

Gabapentin (300 to 900 mg, 3 to 4 times daily)

Largely unmetabolized, has few drug interactions.

 

 

 

Phenytoin (200 to 600 mg, daily)

 

   
 

Valproic acid, valproic acid ER (15 to 60 mg/Kg, daily in divided doses)

   
 

Pregabalin (100 to 300 mg, twice daily)

Calcium channel modulator similar to gabapentin.

 

 

Second line

Oxcarbazepine (300 to 1200 mg, twice daily)

 

Fewer drug interactions than carbamazepine.

 

 

 

Zonisamide (200 to 400 mg, daily)

May cause diminished sweating with increased body temperature. Is a sulfonamide.

 

 

 

Levetiracetam (500 to 2500 mg, daily)

 

Few drug interactions.

 

Of special use in trigeminal neuralgia

Topiramate (50 to 200 mg, twice daily)

May induce weight loss and a hyperchloremic metabolic acidosis.

 

 

 

Misoprostol (200 µg, 4 times daily)

Prostaglandin E agonist.

 

 

 

Lamotrigine (100 to 400 mg, daily)

Dose must be carefully titrated, Stevens-Johnson syndrome.

 

 

 

Baclofen 40 to 120 mg daily in 3 to 4 divided doses

May cause weakness, lethargy, and confusion.

 

Side effects, such as sedation and induction of weakness, limit the doses of these agents.

*AAN Summary of Evidence-based Guidelines advise that strong evidence exists only for the use of carbamazepine in the treatment of classical trigeminal neuralgia and that good evidence exists for only oxcarbazepine and topical ophthalmic anesthesia (AAN 2008).

Chronic neurogenic pain. Chronic neurogenic pain involves the feet and legs more commonly than the hands. Although chronic neurogenic pain is not associated with quantitative sensory threshold changes, mechanical or thermal hyperalgesia is common (Svendsen et al 2005). If the pain is well localized, application of a 5% lidocaine patch is sometimes helpful. Up to 3 patches may be applied for up to 12 hours within a 24-hour period. Patches may be cut to fit the area involved. The long-lasting effects of short-term intravenous lidocaine treat chronic neurogenic pain as well as musculoskeletal pain (McCleane 2007). Tricyclic antidepressants and anticonvulsants are the mainstay of treatment, but many therapies have been used when the pain is intense. To minimize side effects, one may start with gabapentin, and, if a partial response is obtained, consider adding an additional anticonvulsant and/or a muscle relaxant to assist at night, when pain may be most noticeable.

Table 6. Treatment of Chronic Neurogenic Pain

   First line


Medication
Comment
 

Antidepressants

Amitriptyline (50 to 150 mg)

   
 

Desipramine

   

Anticonvulsants

Carbamazepine (200 to 400 mg, 3 times daily)

 

   
 

Gabapentin (300 to 900 mg, 4 times daily)

Largely unmetabolized, has few drug interactions.  
 

Pregabalin (100 to 300 mg, twice daily)

   

Second line

Anticonvulsants

Zonisamide (200 to 400 mg, daily)

 

   
 

Lamotrigine (100 mg, twice daily)

 

   
 

Levetiracetam (500 to 2500 mg, daily)

 

   
 

Pregabalin (up to 600 mg daily, in 2 or 3 divided doses)

 

   
 

Oxcarbazepine (600 to 1200 mg, twice daily)

 

   

Antispasticity

Baclofen (up to 200 mg, 4 times daily)

 

   
 

Tizanidine (up to 8 mg, 4 times daily)

 

   

Opiates

See Table 7

Doses are extremely variable; higher doses require contract and possible referral.

 

 

Alpha-adrenergic

agonist

Clonidine

   

Antidepressant

Duloxetine HCl (20 to 60 mg, twice daily)

 

Duloxetine HCl and venlafaxine, selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors, are useful in diabetic neuropathy and in some forms of myofascial pain. A double-blinded randomized clinical trial demonstrated superiority of duloxetine over placebo in the treatment of the central neuropathic pain of multiple sclerosis. There is an ongoing trial of various doses of dextromethorphan plus quinidine in the treatment of the central neuropathic pain of multiple sclerosis.

If pain is severe only at night, a hypnotic may be helpful. Capsaicin cream, 0.075% applied 3 to 5 times daily, may be an adjunct to other therapies. The cream should be initiated at the 0.025% dose and advanced slowly to the 0.075% concentration. Transdermal lidocaine patches (5% lidocaine) have been used effectively by some patients with chronic pain problems. Compounded topical creams are widely available to help ameliorate pain, and they may be useful in the treatment of pain related to multiple sclerosis.

Treatment of nonmalignant pain with opiates should be done cautiously, and the help of a pain center is recommended. Opiate abuse may vary demographically. A 2002 study reported that 21.5% of 242 inner-city drug users had taken sustained-release oxycodone, methadone, or hydrocodone within the prior 30 days (Vivian et al 2005).

The FDA Anesthetic and Life Support Drug Advisory Committee has concluded that physicians need to meet 7 documentation requirements when making opiates part of pain management for nonmalignant pain. These requirements are: (1) appropriate history and examination, (2) a “recognized medical indication,” (3) a written treatment plan, (4) a pain management treatment plan signed by the patient, (5) reasonable follow-up where progress is reviewed, (6) maintenance of accurate records, and (7) close monitoring of patients with a history of substance abuse. Doses of opiates necessary to control pain vary greatly, although keeping the dose of these addictive medications low is desirable. Combinations of deterrent agents, such as naltrexone or niacin, and opiates are being developed to reduce the addictive potential of opiates when used to treat pain.

Table 7. Oral Opiates for Chronic Pain

Drug

Dose

 

Morphine

 

15 or more mg, every 4 hours

 

Extended release

Morphine

 

15 to 60 mg, every 12 hours

 

Oxycodone

 

5 to 10 mg, every 4 hours

 

Extended release

Oxycodone (increasingly abused)

 

30 mg, every 12 hours

 

Fentanyl transdermal patches 25 to 100 mcg/hr can be used in patients who are tolerant to oral opioids. The 25 mcg/hr dose of fentanyl is equivalent to approximately 100 mg/day oral morphine, 50 mg/day oral oxycodone, 12 mg/day oral hydromorphone, or 30 mg/day oral methadone.

Clonidine or tizanidine can be used as an adjunct to opiate use. Intrathecal morphine (800 to 10,000 µg per day) and clonidine (400 to 750 µg per day) can be used if a continuous infusion pump is implanted (Klein et al 2002).

Cannabis-based medications are being tested in chronic pain states with modest effects on pain and few side effects (Rog et al 2005).

Headache or back pain. Headache or back pain can be a sign of a relapse. In some situations, such as retrobulbar optic neuritis, pain may be well localized. Treatment of chronic headaches in multiple sclerosis patients is not different than for idiopathic headaches. The relatively recent additions of topiramate and botulinum toxin have made treatment easier, but one must be careful not to add to cognitive disturbances of multiple sclerosis patients with topiramate. There is conflicting epidemiological data on whether migraine headaches are more common in multiple sclerosis patients than in the general population (Kantor 2010), and headaches in multiple sclerosis patients may be caused by the multiple sclerosis itself or as a side effect of the disease-modifying agents or symptomatic therapies.

Musculoskeletal pain. Musculoskeletal pain can be caused by ligamentous and bursal inflammation from inactivity, overuse of muscle groups, improper mechanics of joint movement, muscle spasms, pressure sores, and syndromes of undefined etiology. Most neurologists will utilize orthopedic and rheumatologic consultants to manage these diverse problems. Due to the association of avascular necrosis of the femoral head and other bones with corticosteroid administration, neurologists should be familiar with its symptoms and differential diagnoses. The absence of pain with flexion and extension of the hip and external rotation (Patrick-Fabere test) is useful in differentiating trochanteric bursitis from intra-articular hip disease (Shbeeb and Matteson 1996).

The basis of treatment for most musculoskeletal pain is the application of heat, stretching and strengthening exercises, body mechanics, bracing, and nonsteroidal anti-inflammatory drugs. Therapies that are useful in chronic pain syndromes may be of use in this setting (see above). Patients with multiple sclerosis are commonly affected by common painful conditions such as migraine and fibromyalgia (chronic, widespread, axial pain). All 3 conditions are more common in women. Pregabalin, duloxetine, and milnacipran are now approved for the pain of fibromyalgia.

A high incidence of hypovitaminosis D has been found in American patients with nonspecific musculoskeletal pain. However, treatment with vitamin D did not improve chronic pain in randomized, controlled clinical trials (Warner and Arnspiger 2008; Straube et al 2009).

Pruritus. Intense itching can be problematic. Anecdotally, anticonvulsants, antidepressants (particularly mirtazapine), and antihistamines may benefit this condition.

Paroxysmal (nonpainful) disorders. Recurrent, brief, painless neurologic symptoms occur infrequently yet are treatable symptoms of multiple sclerosis. If the physician is unaware of these manifestations of multiple sclerosis, they can be misconstrued as functional. Symptoms often begin suddenly or subacutely and continue for weeks to months. Paroxysms usually last seconds but may occur several times a week to several times an hour. These disorders include tonic (dystonic) muscle spasms, diplopia, and convergence spasm; dysarthria, ataxia, and paresthesias; akinesia and motor impersistence; itching and paresthesias; and nausea and diarrhea (Ostermann and Westerberg 1975; Miller 2000). Anticonvulsants are the mainstay for the treatment of entrenched paroxysmal symptoms (Table 5).

Cognitive disorders. Between 40% and 65% of patients with multiple sclerosis have measurable cognitive disorders by neuropsychological testing. Cognitive impairment appears early in the course of multiple sclerosis, affecting over half (57%) of patients with clinically isolated syndromes (Feuillet et al 2007). Interestingly, cognitive abnormalities were found in patients with spinal cord and optic nerve, as well as with cerebral, localizations for their symptoms. Finally, a small series of patients with “subclinical” multiple sclerosis shows cognitive impairments either at discovery or after a brief follow-up (Hakiki et al 2008). Although cognitive impairment is common, it appears to change slowly, at least in treated patients (Schwid et al 2007). Only 5% to 7% of multiple sclerosis patients will display severe dementia (Boissy and Cohen 2007).

Formal neuropsychological testing suggests that measures of information-processing speed (Hoffmann et al 2007), word list generation, and verbal memory (Achiron et al 2005) are the earliest markers of impairment. Correlation with gait impairment is poor, and cognitively impaired patients may appear otherwise relatively well. Although cognitive dysfunction is not usually severe, even mild impairments can greatly disturb people with high baseline ability.

Underemployment, social isolation, and greater need for assistance at home and in the community are experienced by cognitively impaired people. Few studies have characterized the types of cognitive deficits that multiple sclerosis patients experience. Although it is commonly believed that most of the intellectual decline is subcortical, cortical demyelination can be severe, and subpial lesions found in the infoldings and sulci of the brain may be the cause of cognitive defects, particularly in patients with progressive multiple sclerosis (Kutzelnigg and Lassmann 2006). Numerous studies have now shown that cognitive impairment correlates with atrophy of deep and cortical gray matter and with axonal loss.

A number of batteries are available to diagnose cognitive decline. A practical 15-question survey, the MS Neuropsychological Screening Questionnaire, provides reasonable sensitivity for the detection of cognitive impairment when completed by a non-patient informant (Benedict et al 2003; 2004).

A multicenter, randomized, double-blind clinical trial has not shown any benefit on memory for multiple sclerosis patients treated with donepezil compared to placebo (Krupp et al 2011). Unfortunately, a study investigating whether memantine could benefit those with cognitive impairment was stopped early due to worsening of neurologic symptoms in those taking memantine at higher-than-recommended doses (Villoslada et al 2009). Methylphenidate improves tests of attention in multiple sclerosis patients with impaired attention (Harel et al 2008), as it does in people with these deficits who do not have multiple sclerosis. A small double-blind, placebo-controlled, crossover study testing the efficacy of armodafinil in reducing cognitive problems in patients with multiple sclerosis revealed an improvement in delayed memory (Bruce et al 2012). The care partner/caregiver may be the most reliable observer when measuring response to therapy.

Depression and anxiety. Emotional distress occurs commonly in multiple sclerosis. A Canadian population-based study found major depression to be about 2.3 times more prevalent in persons with than without multiple sclerosis, affecting approximately 26% of patients between 18 and 45 years of age (Patten et al 2003). The lifetime prevalence of major depression in multiple sclerosis appears to be about 50%, with higher rates for presence of some depressive symptoms. Those with left anterior temporal or parietal lesions by MRI scan may be at a slightly increased risk (Siegert and Abernethy 2005). Among male veterans with multiple sclerosis, risk factors for depression included high risk of falling, bowel impairment, absence of a marital partner, unemployment, and poverty (Williams et al 2005). Depressed veterans were likely to utilize health care providers more frequently than non-depressed individuals. Although it has been difficult to establish, many experienced clinicians feel that interferon-beta therapy may bring out depressive symptoms in multiple sclerosis patients. Patients with multiple sclerosis have a higher incidence of bipolar disorder than the general population (Schiffer et al 1986). It is commonly accepted, though not proven, that emotional stress to a poor prognosis for multiple sclerosis (as it does for other chronic conditions). In support of this observation is evidence that interferon-gamma production by peripheral blood mononuclear cells falls with the treatment of depression (Mohr et al 2001).

A quick, simple screen developed for use in primary care has been validated in multiple sclerosis (Mohr et al 2007). It identified 99% of patients meeting the criteria for a major depressive disorder. The test is not specific for major depression because 27.3% of those identified had a less severe form of depression. The screen consisted of 2 questions: (1) “During the past 2 weeks, have you often been bothered by feeling down, depressed, or hopeless?” (2) “During the past 2 weeks, have you often been bothered by little interest or pleasure in doing things?”

Antidepressants may even be used to address multiple symptomatic complaints by taking advantage of their side effects. Discontinuation of antidepressants depends on the severity of the depression and the residual symptoms. In general, planned treatment discontinuation may begin as early as 6 months, but longer periods of therapy are associated with a lower recurrence rate (Mann 2005).

Table 8. Commonly Used Antidepressants

  Comment  

Energizing antidepressants

   

Fluoxetine (10 to 40 mg)

May benefit the course of multiple sclerosis.

 

Venlafaxine (37.5 to 225 mg)

May aggravate hypertension.

 

Desvenlafaxine (50 to 100 mg)

R-enantiomer of venlafaxine.

 

 

Bupropion (100 to 400 mg)

May aggravate seizures; spares sexual function. Sometimes combined with SSRI.

 

 

Analgesic antidepressants

   

Amitriptyline (50 to 150 mg for pain; up to 300 mg for depression)

Moderate anticholinergic effects. Weight gain problematic.

 

 

Desipramine (100 to 200 mg)

Tricyclic with mild anticholinergic properties.

 

Duloxetine (20 to 60 mg, once or twice daily)

 

   

Sedating antidepressants

   

Trazodone (50 to 300 mg)

   

Antidepressants used in special circumstances

   

Mirtazapine (7.5 to 30 mg)

Possibly useful in tremor and nausea; spares libido. Has mixed, unique MOA.

 

 

 

Imipramine (25 to 75 mg, at bedtime)

Useful for headache and nocturia.

 

Anxiolytic antidepressants

   

Sertraline (25 to 100 mg, daily)

   

Paroxetine (20 to 60 mg, daily)

   

Citalopram (20 to 60 mg, daily)

Does not induce liver enzymes.

 

Escitalopram (10 to 20 mg, daily)

S-enantiomer of citalopram.

 

Antidepressant treatment may prevent loss of hippocampal cells in patients with recurrent depression (Sheline et al 2003), and their stimulation of neurogenesis may be crucial to the treatment of depression (Santarelli et al 2003). These observations suggest that the use of antidepressants may be warranted for extended periods in patients with recurrent depression.

Drugs blocking the reuptake of both 5-HT and NE (SNRIs) produce a high rate of treatment response for depression and anxiety, generally showing a slight superiority to drugs that block only 5-HT (SSRIs) uptake for patients with moderate to severe depression. However, they also have more side effects including nausea, constipation, fatigue, insomnia, sexual dysfunction, night sweats, dry mouth, erectile dysfunction, and activation of hepatic metabolism systems. Unlike SSRIs, SNRIs are helpful in relieving pain (Table 8). 5-HT and NE reuptake inhibitors do so with the following relative potencies – the higher the number, the higher affinity for the transporter (5-HT:NE): milnacipran (2:1), duloxetine (9:1), venlafaxine (30:1) (Stahl et al 2005). Of these, only venlafaxine, due to its affinity for the dopamine transporter, can cause hypertension. Patients using antidepressants that inhibit the reuptake of serotonin concomitantly with nonsteroidal anti-inflammatory drugs can increase upper gastrointestinal bleeding by 12-fold (Loke et al 2008).

Patients with resistant depression should be followed by a psychiatrist. People with bipolar disorders often require a mood stabilizer such as lithium, lamotrigine, or divalproex in addition to an antidepressant. Some people with refractory depression will respond to antipsychotics, mood stabilizers, thyroid hormone, or vagal nerve stimulation, which was approved by the FDA in 2005.

In patients willing and motivated to change behaviors, insight-oriented psychological counseling can treat depression. Psychotherapy and pharmacotherapy appear to be synergistic, producing more rapid and long-term results. Exercise is beneficial in improving depression in multiple sclerosis (Petajan et al 1996), while also helping patients become stronger and slimmer, improving cardiovascular fitness, reducing fatigue, increasing positive social interactions, and contributing to better bowel function.

Pseudobulbar affect. A recent large-scale, cross-sectional, point prevalence epidemiological study (PRISM or Pseudobulbar Affect Registry Series) revealed that pseudobulbar affect (as measured by the Center for Neurologic Studies Lability Scale or CNS-LS) occurs in approximately 40% of patients with multiple sclerosis (Crumpacker et al 2012; Fellus et al 2012; 2013; Kantor and Kaye 2012; Kantor et al 2012a; 2012b; 2012c). Inappropriate and/or involuntary emotional responses such as laughing or crying can cause significant emotional distress, social isolation, and embarrassment. A fixed-dose combination of dextromethorphan and quinidine (20 mg/10 mg) reduced episodes of pseudobulbar affect by 49% over 12 weeks in a randomized, controlled, clinical trial (Pioro et al 2010) and was approved by the FDA in November 2010. Another medication that may provide benefit is fluvoxamine. In a small trial, emotional outbursts dropped considerably when patients took 100 mg fluvoxamine each evening (Iannaccone and Ferini-Strambi 1996). Pseudobulbar affect is underrecognized and underreported, so patients should be screened during office visits as it appears to be undertreated (Pioro et al 2010), especially considering the availability of an FDA-approved treatment.

Movement disorders and ataxia. There are numerous etiologies for movement disorders in multiple sclerosis. Some are iatrogenic, such as carbamazepine-induced dystonia and athetosis in patients with advanced multiple sclerosis, whereas others, such as restless legs syndrome, may be more prevalent in multiple sclerosis patients than in the rest of the population. Even when they resemble treatable idiopathic conditions, movement disorders associated with multiple sclerosis generally respond poorly to treatment. There are case reports of success with deep brain stimulation in treating tremor in multiple sclerosis, and the FDA is currently considering the results of a National Institutes of Health (NIH)-funded trial of dual lead deep brain stimulation for Holmes tremor in multiple sclerosis. It is important to distinguish between a resting tremor, which may be amenable to deep brain stimulation, and a rubral or cerebellar tremor, which is typically less responsive. Treatment of essential tremor has more success, with gratifying outcomes using propranolol and other beta-adrenergic blockers, primidone, benzodiazepines, gabapentin, high-dose topiramate, and levetiracetam. Initial treatment may consist of either propranolol 40 mg twice daily or primidone 50 to 250 mg at night. Deep brain stimulation is effective in the treatment of essential tremors but is reserved for medical failures. Some drugs, including caffeine, beta-adrenergic agonists, selective serotonin reuptake inhibitors, excess thyroxin, clozapine, and lithium may induce an essential tremor that disappears when the drug is withdrawn or the dose is lowered.

Other forms of tremor and dysmetria respond suboptimally to medications that are generally selected empirically. Acetazolamide, isoniazid, buspirone, carbamazepine, glutethimide, ondansetron, and levetiracetam have been reported to be useful in some, but not all, studies. Providers should be aware of the potential for a placebo effect with any medication and should not continue them without intermittent reassessment.

Transient ataxia may result from sudden discontinuation of selective serotonin uptake inhibitors and can be mistaken for an exacerbation. A systematic review of therapy for ataxia has failed to find any pharmacotherapy to be of benefit (Mills et al 2007). Cerebellar tremor (particularly of the head) due to multiple sclerosis may respond to vagal nerve stimulation (Marrosu et al 2007). Tremors that are particularly prominent in a single plane can be ameliorated by botulinum toxin injections. Antihistamines and benzodiazepines are commonly used to treat unsteadiness but are rarely beneficial. Occupational and physical therapists can evaluate the need for adaptive equipment to help deal with ataxia and tremor.

Gait (walking) impairment. Gait dysfunction occurs in multiple sclerosis for a variety of reasons, including weakness, spasticity, and balance difficulties due to ataxia and sensory loss. Management of difficulty walking includes appropriate exercise to improve strength and assistance with mechanical devices as needed. Ankle-foot orthoses allow greater mobility, with decreased risk of falling and injury. For patients with significant imbalance, walkers may help with safety. Reducing fatigue and spasticity may also improve gait, although reduction of spasticity with pharmacotherapy may increase weakness. A few anecdotes and common sense suggestions may be helpful to patients and providers:

  1. A supervised exercise regimen, especially if pushed to the individual’s limit, may improve exercise capacity, fatigue, and measurements of quality of life (McCullagh et al 2008). Regular exercise may affect inflammation, appearing to raise resting concentrations of both TNF-alpha and IFN-gamma in multiple sclerosis patients (Castellano et al 2008).
  2. Weight loss to ideal body weight is desirable.
  3. Stretching prior to activity and maximizing treatment of spasticity in appropriate patients may prevent falls.
  4. Balance therapy and gait training can improve coordination in some individuals.
  5. If the patient walks more comfortably behind a grocery cart, he or she is often a good candidate for a rolling walker.
  6. If hyperextension of the knee with walking cannot otherwise be treated, a long-leg brace should be considered.
  7. An ankle-foot orthosis is helpful in stabilizing patients with foot drop. Electrical devices that stimulate the peroneal nerve distal to the knee have been well-received by patients, but are generally not reimbursed by third-party payers (some nonprofit organizations assist patients with funding).
  8. One-story housing, appropriate seating, and placing safety bars in bathrooms will conserve energy and improve safety.

In addition, gait-specific symptomatic therapy is now available commercially and can also be obtained from a compounding pharmacy. It should be noted that compounded 4-aminopyridine (4-AP) has been used in multiple sclerosis practice for decades; however, compounding is not FDA-regulated and may be associated with risk of dosing errors. Furthermore, compounded 4-AP has a relatively short therapeutic duration of effect. Based on this experience, extended-release dalfampridine (dalfampridine ER), a twice-a-day, sustained-release form of 4-aminopyridine, was studied in multiple sclerosis patients with walking impairments.

A phase 3, placebo-controlled randomized clinical trial demonstrated improvement in walking speed and subjective walking assessments in 35% of multiple sclerosis patients treated with dalfampridine ER, compared with 8% in placebo-treated patients (Goodman et al 2009). There was some increased risk of seizures, and subjects with abnormal EEG were excluded from the study. A second phase 3 trial demonstrated similar results, with 43% responders in those treated with dalfampridine ER versus 9% in those treated with placebo (Goodman et al 2010). In 2010, dalfampridine ER 10 mg every 12 hours was approved by the FDA as a treatment to improve walking in patients with multiple sclerosis. In 2012, a post-marketing trial failed to demonstrate the efficacy of lower dose dalfampridine ER (5 mg every 12 hours). In a subset of study participants, the distance walked in 6 minutes was measured, and there was a statistically significant improvement in the distance walked for those on standard dalfampridine ER 10 mg every 12 hours versus placebo (increase of 129 feet versus increase in 42 feet, p = 0.014).

Combative or psychotic behavior. Occasionally, patients with chronic organic brain syndrome can exhibit psychotic behavior. Similar to patients with Alzheimer disease, these patients’ behavior can be modified with low doses of antipsychotic medication (De Deyn et al 1999). The typical and atypical neuroleptics relieve symptoms to a similar degree, with the exception of clozapine, which appears uniquely efficacious. Atypical neuroleptics have significantly fewer side effects, especially in regard to movement disorders (Jibson and Tandon 1998); however, they may induce obesity and arrhythmias. These drugs may be especially useful when patients develop steroid psychosis and occasionally in refractory anxiety and pain syndromes.

Table 9. Atypical Neuroleptics

Aripiprazole

 

Extrapyramidal: 0

 

Hypotension: ±

 

Sedation: +

 

Weight gain: +

 

 

Clozapine

 

Extrapyramidal: 0

 

Hypotension: +++

 

Sedation: +++

 

Weight gain: +++

 

 

Olanzapine

 

Extrapyramidal: ± to +

 

Hypotension: +

 

Sedation: ++

 

Weight gain: +++

 

 

Quetiapine

 

Extrapyramidal: ±

 

Hypotension: ++

 

Sedation: ++

 

Weight gain: +

 

 

Risperidone

 

Extrapyramidal: ± to +

 

Hypotension: ++

 

Sedation: +

 

Weight gain: ++

 

 

Ziprasidone

 

Extrapyramidal: ± to +

 

Hypotension: +

 

Sedation: +

 

Weight gain: ±

From (Tandon and Jibson 2003).

Vitamin D. Recent research into the role of vitamin D in heart disease, chronic pain, multiple sclerosis progression, cognitive function, and depression highlights scientific interest in this vitamin. Although adequate vitamin D and calcium have long been thought necessary to bone health (see Osteoporosis section), they appear to be important in many aspects of health. Epidemiological studies suggest that a low intake of vitamin D may be a risk factor for multiple sclerosis (Munger et al 2004). Two small studies suggest that 25-OH vitamin D3 at approximately 5000 IU daily reduces the number of new MRI lesions in patients with multiple sclerosis. Vitamin D3 supplementation at multiple escalating doses up to 40,000 IU daily reduced clinical attacks compared to typical supplementation levels of 1000 IU daily (Burton et al 2008). A serum 25-hydroxyvitamin D level below 20 ng/ml is considered a deficiency by many experts, but levels below 30 ng/ml may be inadequate for optimal health (Holick 2007). There is no medical consensus on optimal levels for patients with multiple sclerosis. The Institute of Medicine suggested an upper limit of 4000 IU daily for most individuals (Ross et al 2011).

Osteoporosis. Osteoporosis may be defined clinically by a fracture from a low-impact trauma (due to a fall from a standing height or less) or fragility (no obvious trauma), or by a low bone mineral density. Clinicians should expect patients with multiple sclerosis to have osteoporosis, which seems to be linked to inflammation found in a number of chronic disease states. Dual-energy x-ray absorptiometry (DXA) is the current standard for assessing bone density. T scores are used in people over 50 and compare density to normal gender-matched young adults. Z scores are used for those under 50 (especially in premenopausal women) and are age- and sex-matched. A score less than or equal to -2.0 is of concern, although some experts would be concerned at a Z score below 1.0 (Mauck and Clarke 2006). DXA scans can be useful in following the efficacy of therapy for patients with bone loss. Because of the variability in measurements, the recommended interval is generally between 2 and 5 years, although this can be done more frequently in patients at high risk for fracture while on aggressive therapy. Multiple sclerosis patients lose bone mass more rapidly and experience more fractures than age- and gender-matched controls. They also may have low levels of vitamin D, possibly due to low dietary intake and avoidance of the sun (Cosman et al 1998). Immobility causes loss of bone, and bed rest for 1 year results in loss of more than 10% of bone density. The use of glucocorticosteroids demineralizes bone. Continuous use of the older antiepileptic drugs phenytoin, phenobarbital, carbamazepine, or primidone has also been associated with diminished bone mineral density and is estimated to increase the risk of hip fracture by 29% over 5 years in women over the age of 65 years (Ensrud et al 2004). Thyroid hormone excess is another cause of osteoporosis and is frequently iatrogenically induced and a thyroid-stimulating hormone test should be measured in all patients taking thyroid replacement.

Bone loss can be minimized by weight bearing, cessation of smoking, avoidance of high alcohol intake, ingestion of 1500 mg of calcium (in 3 divided doses) and 600 to 800 IU of vitamin D daily for both men and women. Calcium carbonate is less expensive than calcium citrate but requires stomach acid for absorption. Patients taking gastric acid-inhibiting drugs should take calcium citrate. The absorption of some medications, such as levothyroxine, fluoroquinolones, or angiotensin-converting enzyme inhibitors, is inhibited by calcium and should be taken only when a 90 minute interval occurs between their combined use. Vitamin D supplementation may also improve muscle strength, and a meta-analysis has suggested it reduces falls in those at risk (Bischoff-Ferrari et al 2004).

Patients with T or Z scores below -2.0 or with scores below 1.5 and additional risk factors or previous vertebral or hip fracture should be treated with pharmacological intervention. When any of these conditions are encountered, bisphosphonate therapy can be undertaken using alendronate, risedronate, or ibandronate. Bisphosphonates inhibit bone resorption by reducing osteoclast activity. The first 2 come in sustained release formulations that can be given once weekly. Ibandronate can be taken once monthly. Patients must take these medications 30 to 60 minutes before the first morning meal with a full glass of water and remain erect for 30 minutes after taking them. They should not lie down until they have eaten breakfast. Bisphosphonates should not be used, or should be used cautiously, in patients with hypocalcemia, renal insufficiency, esophageal irritation, or trouble swallowing. Other treatments include raloxifene, nasal calcitonin, and teriparatide. The selective estrogen modulator raloxifene avoids some of the cardiac and breast cancer risks of estrogen. It is contraindicated in patients with a history of venous thromboembolic events. Nasal calcitonin is administered as 1 dose in alternating nostrils daily. It does not appear to be as potent as the other therapies and is generally considered second-line therapy. Teriparatide is a recombinant human parathyroid hormone analogue. It is the first anabolic drug approved for the treatment of severe osteoporosis. Although it is a potent drug, it must be given subcutaneously at a dose of 20 micrograms once daily and has significantly more side effects than the other compounds. It also is currently 5 to 8 times more expensive than the other drugs.

The monoclonal antibody, denosumab, an inhibitor of the receptor activator of nuclear factor-κB ligand, improves low bone mass in postmenopausal women, offering another approach to treat osteoporosis (McClung et al 2006).

Common correctable causes of osteoporosis may be sought through relatively simple testing such as serum calcium and phosphorous; 24-hour urine calcium and, if elevated, parathyroid hormone level; liver function panel; creatinine; serum protein electrophoresis to exclude multiple myeloma; thyroid panel; and hormone levels (Herndon and Mohandas 2000).

Sialorrhea and dry mouth (xerostomia). Sialorrhea is rather rare in multiple sclerosis. It can be treated with a mouth rinse made of 4 drops of atropine ophthalmic solution in 30 ccs of water. The patient should rinse with but not swallow this solution. Botulinum, 80 units of toxin A or 1000 units of toxin B, can be injected into the submandibular and parotid glands on each side.

Dry mouth induced by medications is a more common problem and more difficult to treat. For mild symptoms, glycerin candies may be helpful. For more severe cases, artificial saliva such as Biotene or BioXtra may be helpful.

Visual problems. Many states have services for people with low vision, including large print books and tape recording of important materials at no cost. Several computer programs improve the contrast and size of print displays on monitor screens. All patients with chronic visual complaints should be referred to an ophthalmologist and possibly a low vision specialist.

Acquired primary gaze pendular nystagmus can be severely disabling due to the illusion of constant motion of the environment. Gabapentin will occasionally reduce nystagmus and improve visual acuity (Averbuch-Heller et al 1997). Anecdotally, nystagmus responds to cannabinoids, baclofen, and memantine. Severe disabling nystagmus can be treated with retrobulbar injections of botulinum toxin, but induction of ptosis is a risk.

We just discussed the most frequent symptoms of multiple sclerosis and adequate symptomatic treatment, which may improve multiple sclerosis patients’ quality of life. Some severe and fortunately less common symptoms also deserve to be mentioned. The symptoms we discuss below usually occur in gravely disabled multiple sclerosis patients and may lead to their death. By knowing the causes of death of multiple sclerosis, clinicians can take measures to prevent and treat them. In a series spanning 1972 to 1988, it was observed that despite normal longevity in the majority, 47% of multiple sclerosis patients died of the direct complications of their disease, not counting suicide (Sadovnick et al 1991).

  1. Patients who are no longer ambulatory almost always have respiratory compromise (Smeltzer et al 1988). These patients may die as a result of restrictive lung disease resulting in hypercarbia and suppressed respiratory drive. They often become slowly more confused and somnolent as they retain carbon dioxide, which sometimes can be treated with nocturnal assisted breathing devices (BiPAP).
  2. The urinary tract, lungs, and decubitus ulcers all can be the source of infections that lead to death. Infection must always be considered as the cause of a sudden change in neurologic status in a patient with multiple sclerosis.
  3. Some patients die of pulmonary emboli secondary to deep vein thrombosis. Although the use of warfarin is problematic in this population, compression stockings, aspirin, and elevation of the legs may be helpful in preventing this complication of the disease.
  4. Falls resulting in hip fractures and subsequent surgery are especially pernicious for patients with advanced multiple sclerosis. Osteoporosis is a common, treatable problem in multiple sclerosis. To prevent falls, strength and balance training and the use of vitamin D (greater than 800 IU) and calcium (greater than 500 mg) supplements appear helpful (Kannus et al 2005).
  5. Suicide may account for 15% of all deaths of multiple sclerosis patients (Sadovnick et al 1991).
  6. Hypothermia (temperature less than 35 degrees Celsius) appears to be an ominous development in people with advanced multiple sclerosis. Such patients may have other signs of dysautonomia, particularly postural hypotension that precedes temperature regulation problems.

In This Article

Introduction
Historical note and nomenclature
Scientific basis
Indications
Contraindications
Goals and endpoint
Description
Outcome
Adverse effects
Prognosis
Clinical vignette
Pregnancy
References cited
Contributors