Depression is a very common symptom in MS. Depression is characterized by feelings of hopelessness, the inability to enjoy things that once were pleasurable, feelings of worthlessness, disruption of sleep, crying, feelings of sadness or irritability, social isolation, decreased sexuality, and in some cases, suicidal thoughts. If these symptoms persist occur every day for two weeks or more, or include suicidal thoughts, medical attention is required immediately. Regardless of whether the depression is reactive (i.e., as a result of having a serious illness), genetic (endogenous depression), or a manifestation of the illness itself, medications can be helpful. Individual psychotherapy can also be helpful, either by itself or in combination with medication. However, studies suggest that in MS patients, depression usually requires some form of treatment - it is unlikely to spontaneously remit. In addition to an alteration of mood, depression may contribute to the fatigue experienced by patients with MS and this also may respond favorably to antidepressant medications. Useful agents in the treatment of depression include the selective serotonin reuptake inhibitors (e.g., fluoxitine [Prozac], 20-80 mg/day or sertraline [Zoloft], 50-200 mg/day), the tricyclic antidepressants (e.g., amitriptyline [Elavil], 25-150 mg/day; nortryptiline [Pamelor], 25-150 mg/day; or desipramine [Norpramin],100-300 mg/day), and the non-tricyclic antidepressants (e.g., venlafaxine [Effexor], 75-225 mg/day).
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Fatigue is characterized by diminished energy and endurance. Many patients with MS also experience an overwhelming sense of exhaustion that requires them to sit, recline, or fall asleep. This symptom is often aggravated by elevated temperature and can be reversed by cooling. Fatigue in MS can be severe and disabling. It affects almost 90% of patients to some degree and is characterized as moderate to severe in over half. It accounts (in part or in whole) for the disability in approximately 65% of patients unable to work. It is also multifactorial. Thus, depression can often contribute to a patients fatigue and may be managed successfully with anti-depressant medications. Patients who expend exceptional effort to accomplish basic ADLs may experience substantial fatigue and may benefit from assistive devices, from help in the home, or from successful management of their spasticity. Not infrequently, patients with MS have nighttime sleep disturbances that translate into day time fatigue. As one example, patients with frequent nocturia (and, thus, frequent nocturnal awakenings) may benefit from an anticholinergic medication at bedtime to prevent these night time arousals and improve the quality of their night time rest. In addition to these other sources of fatigue in MS, however, there is also an extreme lassitude that is more specifically related to the disease. This fatigue can be the sole manifestation of an attack and is often difficult to treat. Several effective medications are now available for the treatment of fatigue. These medications include amantadine (Symmetrel) 200 mg/day; methylphenidate (Ritalin) 5-25 mg q day, modafinil (Provigil) 200-400 mg/day, and armodafinil (Nuvigil) 50-250 mg/d. A cooling vest or cap may be helpful when symptoms are provoked by exposure to elevated temperatures.
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Spasticity (muscle stiffness) is usually accompanied by weakness, slowness of movement, poor coordination, and spontaneous spasms. Spasticity poses a considerable problem for the management of MS patients. Over 40% of patients describe their spasticity as moderate to severe. Typically it is most severe in the lower extremities and often interferes substantially with a patients ability to ambulate, to work, and to perform even the most basic activities of daily living. It is often painful and frequently associated with painful extensor (occasionally flexor) spasms. At times, however, the increased stiffness of the muscles may be helpful to patients by providing non-volitional support during ambulation. In such a circumstance, overly aggressive treatment may actually do more harm than good. Non-pharmacological approaches to the management of spasticity include physical therapy, regular exercise, and stretching, which can provide substantial relief. The avoidance of nociceptive inputs from a variety of sources (e.g., infections, fecal impactions, bed sores, etc.) is an extremely important first principal in patient management because such inputs are known to increase markedly the severity and extent of spasticity. Effective pharmacological agents for reducing both spasticity and spasms include lioresal (Baclofen) 20-120 mg/day; diazepam (Valium) 2-40 mg/day, and tizanidine (Zanaflex) 8-32 mg/day. Several other medications have also been reported to provide occasional benefit for patients with spasticity including clonazepam, carbamazepine, phenytoin, gabapentin, tetrahydrocanabinol, barbiturates, and alcohol. However, the efficacy of these agents is not well established.
When the spasticity is severe (or unresponsive to oral agents), and especially when the patient already has limited use of their lower extremities, a surgically implanted lioresal (Baclofen) pump (delivering the medication directly into the spinal fluid that bathes the spinal cord) can often provide substantial relief. This may also allow for improved hygiene and, thereby, reduce the frequency of urinary infections and bed sores. Botulinum toxin (Botox, Xeomin, Dysport), which causes muscle weakness, can also be injected directly into selected muscles in small amounts. This therapy often provides substantial relief of severe spasticity. Destructive procedures such as selective rhyzotomy, tenotomy, myotomy, and phenol injections should be reserved for only the most extreme cases that are unresponsive to other measures.
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Pain is an under appreciated symptom of MS. Over half of MS patients complain of pain and, in a substantial fraction, the pain is described as severe, at least at times. MS-related pain can be experienced as jolts of electricity, continuous dull burning, disagreeable tingling, or raw sensations. An improved understanding of the mechanisms that produce pain of central origin has produced several successful approaches to its management, including the anticonvulsant drugs (e.g., carbamazepine [Tegretol], 100-1000 mg/day or phenytoin [Dilantin], 300-600 mg/day or gabapentin [Neurontin], 300-3600 mg/day), or the antidepressant drugs (e.g., amitriptyline [Elavil], 25-150 mg/day or nortryptiline [Pamelor], 25-150 mg/day or desipramine [Norpramin],100-300 mg/day or venlafaxine [Effexor], 75-225 mg/day), or the anti-arrhythmic drugs (e.g., Mexiletine [Mexitil], 300-900 mg/day). If these treatments are unsuccessful, some patients may respond to a comprehensive pain management program. Such persons may be referred to the UCSF Clinical Pain Research Center.
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Ataxia/Tremor is a common and often intractable symptom in MS that is difficult to treat effectively. Tremor may involve the hand, arm, leg, head, or voice. These movements may be barely noticeable or they can be severely incapacitating. Some medications are occasionally helpful including clonazepam (Klonopin), 1.5-20 mg /day, mysoline (Primadone) 50-250 mg/day, propranalol (Inderal) 40-200 mg/day, or ondansetron (Zofran) 8-16 mg/day. The use of weights on the wrists may occasionally reduce tremor in the arm or hand. Unfortunately, however, the success of most attempts at therapy is limited. Recently, there has been interest in the use thalamotomy and/or the placement of deep brain stimulators to control tremor. However, even in the best of hands the response to this intervention is often partial, the response rate is limited (~50%), the duration of any therapeutic benefit is unknown. Moreover, the surgical procedure itself carries risk.
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Several different types of bladder dysfunction occur in MS. Not infrequently, different types of dysfunction co-exist in the same patient and, as a result, urodynamic testing can often provide useful clinical information. During normal reflex voiding there is a coordinated relaxation of the bladder sphincter that is precisely timed to the detrusor muscle (bladder wall) contraction. The urinary stream is stopped by a reversal of the above mechanisms with bladder wall relaxation coordinated with sphincter contraction. The bladder reflex is activated by stretch of the bladder wall during filling and it can be voluntarily inhibited. Symptoms of bladder dysfunction are present in over 90% of patients with MS. Many of these symptoms occur only occasionally and are quite mild. In this circumstance, they do not require specific intervention. Nevertheless, over 30% of MS patients experience bladder symptoms of sufficient severity to result in episodes of incontinence weekly or more often. Fortunately, bladder symptoms can often be treat successfully. These symptoms include (1) urinary frequency the need to go to the bathroom frequently; (2) urgency the need to go to the bathroom immediately; (3) hesitancy difficulty initiating the urine stream; and (4) retention the inability to completely empty the bladder. Most patients can regain continence or experience significant improvement in these symptoms.
The first type of bladder dysfunction, results from decreased inhibition of the bladder reflex. Symptomatically, this decrease causes urinary frequency (having to urinate more often than usual), urinary urgency (having to get to the bathroom right away when you feel the urge), and uncontrolled bladder emptying (incontinence). When these symptoms are mild they can sometimes be treated with fluid management techniques such as evening fluid restriction to prevent night time incontinence or the use of frequent voluntary voiding to prevent day time incontinence. If these simple approaches fail to control the problem, however, there are several medications available that can inhibit bladder wall contraction and thereby lessen the bladder reflex. These medications include propantheline bromide (ProBanthine) 10-15 mg/day; oxybutinin (Ditropan) 5-15 mg/day, hycosamine sulfate (Levsin) 0.5-0.75 mg/day, tolteridine tartrate (Detrol) 2-4 mg/day; and solifenacin (Vesicare) 5-10 mg/d. Often the co-administration of an over-the-counter medication such as pseudoephedrine (Sudafed, 30-60 mg) which cause contraction of the bladder sphincter can help maintain continence.
The second type of bladder dysfunction, results from the loss of coordination and synchronization between the bladder wall and sphincter muscles (dyssynergia). This results in a difficulty initiating or stopping the urinary stream (hesitancy) and leads to the retention of residual urine in the bladder following voiding. Occasionally, this condition will respond to medications such as phenoxybenzamine (Dibenzyline, 10-20 mg/day) but more often this condition requires the use of intermittent or continuous catheterization. A third type of dysfunction, loss of reflex bladder wall contraction, generally results from a chronically over-filled bladder, which, itself, is often due to long-standing dyssynergia. This condition can occasionally respond to medications such as bethanecol (Urecholine), 30-150 mg/day, but often this condition also often requires intermittent or continuous catheterization.
It is also important to monitor patients for urinary tract infections and treat them promptly when they are identified. Patients who have large volumes of post-void residual urine in their bladders are predisposed to bladder infections and patients at risk for such complications may be identified by measuring a post-void residual volume. It is also often helpful to take steps to prevent infections. Acidification of the urine with cranberry juice or Vitamin C inhibits some bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to bladder colonization by resistant organisms and can result in infections that are more difficult to treat. Intermittent catheterization may be necessary to allow complete bladder emptying and to prevent recurrent infections.
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Constipation is a common symptom in MS, occurring in over 30% of patients. High fiber diets (often with supplemental fiber) in addition to plenty of fluids is usually the best approach. Natural or other laxatives can also help. Fecal incontinence is much less common than constipation although 17% of patients (more so in men) report at least some episodes. If it is severe enough to warrant treatment, fecal incontinence may respond to a reduction in total dietary fiber.
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Several different paroxysmal syndromes occur in MS. These syndromes are distinguished by their brief duration (10 seconds to 2 minutes); high frequency of occurrence (5-40 paroxysms/day); lack of any alteration of consciousness or change in background EEG during the events; a self-limited nature (generally lasting only months and then subsiding). They may be precipitated by hyperventilation or movement. These syndromes include the familiar Lhermittes sign (electric shock like sensations induced by neck flexion), tonic seizures, paroxysmal dysarthria/ataxia, paroxysmal sensory disturbances, and several other less well characterized syndromes. These syndromes are also distinguished by their marked responsiveness to very low dosages of anticonvulsant medications such as carbamazepine (Tegretol), 50-400 mg/day, phenytoin (Dilantin), 50-300 mg/day, or acetazolamide (Diamox) 200-600 mg/day. Patients with MS may also suffer from trigeminal neuralgia (tic douloureux) which often responds to similar medications.
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Many MS symptoms are aggravated by exposure to heat or with fever. Keeping away from the direct heat of the sun and the use of air conditioning are often necessary to prevent these symptoms. Cooling vests or caps may be useful in select patients.
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The potassium channel blockers (e.g., 4-amino pyridine, 10-40 mg/day; and 3,4-di-amino pyridine, 40-80 mg/day) may help some MS symptoms (especially heat sensitive symptoms) and some patients experience improvements in walking or other neurologic functions. An extended release formulation of 4-amino pyridine (Ampyra), 20 mg/day; has been approved by the FDA to assist with walking in selected ambulatory MS patients. These drugs presumably work by prolonging the duration of the nerve action potential (the physiological apparatus that permits electrical conduction in nerves) and, thereby, facilitating the conduction of electricity through demyelinated nerve fibers. At high enough doses they may also cause seizures for similar reasons. These agents are currently available either by prescription (Ampyra) or from one of several compounding pharmacies around the US.
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Sexual dysfunction was reported by over 60% of the women and over 75% of the men in a survey of MS patients in northern California. The greater dysfunction in men resulted not only from impotence (61%) but also from less sexual desire and less demonstrated interest by their partners. Nevertheless, sexual dysfunction can be a considerable problem for either gender. Women experiencing sexual dysfunction often experience numbness in the genital area, diminished orgasmic response, unpleasant sensations, and diminished vaginal lubrication. Men commonly report impaired genital sensation, delayed ejaculation, decreased force of ejaculation, and/or inability to achieve and maintain an erection. Approaches such as couples or psychological therapy may help in selected cases. Communication between partners is essential. Teaching your partner how you need to be touched or positioned can result in a return of pleasure and excitement instead of discomfort or pain. The use of water soluble lubricants may be an essential aid in genital stimulation and sexual arousal. The use of vibrators may provide pleasurable and sexually stimulating sensations. Spasms, pain, spasticity, fatigue, and bladder/bowel dysfunction may contribute to sexual dysfunction, and medications to alleviate these symptoms may help. Thus, the effective management of adductor spasticity, the use of devices (e.g., vibrators) to make up for loss of deep sensation, penile injections of papaverine or prostaglandin, or prosthetic devices to assist with maintaining erection may also be helpful in some circumstances. The biggest advance in treatment of impotence (erectile dysfunction), however, has been the introduction of phosphodiesterase inhibitor medications such as sildenafil (Viagra) 50-100 mg; tadalafil (Cialis) 5-20 mg; and vardenafil (Levitra) 5-10 mg ; taken orally 1-2 hours prior to sex.
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Cognitive problems, including problems with memory, are common in MS. Between 45% and 65% of people with MS will have some problems with cognitive functioning. Cholinesterase inhibitor medications such as donepezil (Aricept) 5-10 mg/d; galantamine (Razadyne) 8-24 mg/d; and rivastigmine (Exelon) 6-12 mg/d, are used to treat memory difficulties and the lack of mental focus in patients with early Alzheimer’s disease. Two small, non-randomized, uncontrolled studies have shown some benefit for MS patients with memory problems. Larger, placebo-controlled studies are needed to prove that this therapeutic approach is of value in the MS population. While this medication is not currently approved by the FDA for the treatment of memory problems in patients with MS, it may be of some help to selected patients.
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