Multiple Sclerosis Current Status and Strategies for the Future (2001) / Chapter Skim
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3 Characteristics and Management of Major Symptoms
3 Characteristics and Management of Major Symptoms
Pages 115-176
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From page 115... ...
The majority of fleeting cerebral abnormalities seen on magnetic resonance imaging (MRI) cannot be correlated with any symptoms; even chronically demyelinated areas of the optic nerve and spinal cord can be symptom free.~07 In general, MS patients report mental health as more important than physical impairment and bodily pain in determining their quality of life.
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From page 116... ...
noted that there was a negative reaction to his suggestions in the 1970s that cognitive dysfunction should be a focus of study by the National MS Society. At the time, it was estimated that only 5 percent of MS patients might incur cognitive change, and it was argued that cognitive change was relatively unimportant in MS.~43 By the 1990s, those views had changed, and in 1992, the MS Society and the International Federation of Multiple Sclerosis Societies jointly held a symposium on "Neurobehavioral Disorders in MS: Diagnosis, Underlying Pathology, Natural History and Therapeutics." Cognitive changes are now estimated to occur in about 43 percent of MS cases.54 The conviction that cognitive changes must be selectively analyzed and distinguished from other phenomena such as depression and fatigue has emerged only in the last few decades.
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From page 117... ...
Association with Other Symptoms Cognitive and neurological deficits do not appear to develop in parallel, at least not in patients whose disease is still in its early phased Disease duration is not a good predictor of cognitive function in MS, but disease course influences the likelihood of cognitive impairment. Chronic progressive patients tend to do more poorly on neuropsychological tests than relapsing-remitting patients (reviewed in 2001 by Fischer55~.
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From page 118... ...
However, only 4 percent had significant depression scores, and all of these had secondary progressive MS.53 A crosssectional study of 24 patients found significant association of cognitive impairment (using tests of abstract verbal and nonverbal memory) with depression, but not with the degree of neurological impairment, specific neurological symptoms, disability, or handicap.68 Neuropathological Correlates The traditional view that MS is characterized by discrete lesions does not explain the memory and cognitive changes, which would require a more widespread, bilateral change, especially since the complaints often arise early.
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From page 119... ...
relapsing MS patients had significantly better cognitive functions than placebo-treated controls.58 Although assessment of cognitive changes in MS clinical trials is challenging, further tests will be important to clarify this effect. Until ways of stopping or reducing cognitive change are developed, patients could benefit by any methods that at least help them and provide them with techniques to alleviate the problems.
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From page 120... ...
We need to know more about the impact of early cognitive changes on the quality of life.~40 Further research is needed into the MRI, functional MRI, and PET (positron emission tomography) scan correlates of the cognitive change.
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From page 121... ...
Research on depression in MS is complicated by the fact that validated depression rating scales rely, in part, on evaluations of fatigue and other bodily symptoms that are common in MS, and can occur independently of depression. The Beck Depression Inventory (BDI)
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From page 122... ...
Interestingly, the only study that compared depression and cognitive function in individual patients who were tested at times when they were not depressed and during bouts of major depression found no significant correlation between depression and cognitive performance.~54 While the causes of depression in MS are likely multifactorial, several pathophysiological correlates have been reported. Depression is far less common in patients with lesions that are restricted largely to the spinal cord as opposed to the brain.~36 Measures of brain atrophy, such as enlargement of subarachnoid spaces (sulci, fissures, cisterns)
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From page 123... ...
, there are few controlled clinical trials of antidepressant treatment in MS. A small double-blind study indicated that desipramine was effective in the treatment of depressive symptoms, although anticholinergic side effects limited the dose that could be given.~55 However, the study did not examine the effect of antidepressant treatment on the functional abilities or perception of disability in these patients.
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From page 124... ...
In MS it is used to treat bladder symptoms, including urinary frequency and incontinence, and also for the management of necrologic pain. Mechanism of the antidepressant effect of bupropion is not known.
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From page 125... ...
"otonin ~ and Dryness of mouth, constipation, increased appetite and weight gain, dizziness, drowsiness, decreased sexual ability, headache, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Dizziness, drowsiness, headache, decreased sexual ability, increased appetite, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Decrease in sexual drive or ability, headache, nausea, problems urinating, decreased or increased appetite, unusual tiredness or weakness, tremor, trouble sleeping, anxiety, agitation, nervousness or restlessness, changes in vision including blurred vision, fast or irregular heartbeat, tingling, burning, or prickly sensations, vomiting Anxiety, nervousness, insomnia, fatigue, tremor, sweating, gastrointestinal distress, anorexia, diarrhea, dizziness, decreased libido Dizziness, drowsiness, headache, decreased sexual ability, increased appetite, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Restlessness, agitation, anxiety, insomnia, delusions, hallucinations, psychotic episodes, confusion, paranoia, weight loss Nausea, diarrhea or loose stools, tremor, trouble sleeping, drowsiness, dry mouth, decreased appetite, weight loss, sweating, anxiety, or decreased sexual drive
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From page 126... ...
Hamilton Depression Rating coworkersl9 Scale 2. Beck Depression Inventory 3.
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From page 127... ...
Conclusions Despite the consensus that depression is a prevalent and troubling concern among MS patients, much remains unknown about the interaction of affective and neurological symptoms. In 1990, Minden and Schiffer recommended: "More research, using advanced imaging techniques and standardized psychiatric interviews and diagnostic criteria, is needed to clarify connections between depressive symptoms and the neurological disease.
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From page 128... ...
Spasticity in MS usually affects the legs more than the arms, and it can even offset muscle weakness and aid in standing, walking, and transferring.86 Spastic paresis, slight or incomplete paralysis due to spasticity, has been cited as the major cause of the loss of ability to work among persons with MS.60 The increase in resting muscle tone that characterizes spasticity is also associated with muscle spasms. In the progressive stages of MS, exaggeration of extensor tone can result in extensor spasms in which there is forceful activation of leg muscles inducing planter flexion of the ankle, together with hip and knee joint extension.
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From page 129... ...
This complementary muscle action depends on the transmission of signals along pathways connecting the brain, motor neurons in the spinal cord, and muscles (Figure 3.1~. The CNS damage caused by MS disrupts this FIGURE 3.1 Functions controlled by nerves at different levels of the spine.
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From page 130... ...
Mechanisms of Spasticity and Spasms The general features of spasticity in MS appear to resemble those observed in incomplete spinal cord injury, with the added complexities of concurrent hemispheric, visual, and cerebellar lesions. It appears that the effects of the distributed axonal loss and demyelination of the spinal cord are mediated primarily by spinal interneuronal systems that are normally held under tight descending control.
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From page 131... ...
fibers are known to exert potent reflex actions in spinal cord injury and are likely to be important in MS-induced cord damage as well. Animal models of incomplete spinal cord injury have shown that stretching the extensor muscles to the point where free nerve ending mechanoreceptors are activated produces a sharp inhibition of the same extensors, accompanied by excitation of flexors.~49 This sharp "clasp-knife" inhibition is manifest as a sudden drop in active force and is not causally dependent on the presence of a flexion withdrawal response.
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From page 132... ...
As with the other interneuronal systems discussed above, this excitatory Ib pathway may be under monoaminergic control, which is disrupted in spinal cord injury or MS. Treatment of Spasticity Although little can be done to counter the muscle weakness that occurs in MS, several forms of treatment can be applied to help limit the adverse effects of spasticity.
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From page 133... ...
Determine whether the extensor spasm is a product of the locomotion pattern generator and whether this interneuronal circuitry is under descending monoaminergic control. Determine the specific monoamine receptors that influence the stance phase of locomotion and, potentially, the extensor spasms of MS and spinal cord injury (see, for example, Kim et al.89~.
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From page 134... ...
. Zanaflex64~73~92 Tizanidine Tizanidine is an oc2-adrenergic agonist that Sedation, reduces spasticity reducing the release of nervousn excitatory neurotransmitters and Substance P in urinary fr' the spinal cord.
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From page 135... ...
a dose.5 weeks ved to lectively inhibit holine at by rpling the e of Drowsiness or unusual tiredness, increased weakness, dizziness or lightheadedness, confusion, unusual constipation, new or unusual bladder symptoms, trouble sleeping, unusual unsteadiness or clumsiness, fainting, hallucinations, severe mood changes, skin rash or itching Sedation, dry mouth, dizziness, hypotension, vasodilation, constipation, diarrhea, flatulence, nervousness, anxiety, paraesthesia, tremor, seizures, vertigo, agitation, euphoria, stupor, urinary frequency and urgency, back pain, sinusitis, flu-like syndrome Confusion, depression, double vision or abnormal eye movements, hallucinations, lightheadedness or fainting spells, mood changes, excitability, movement difficulty, muscle cramps, tremors, weakness or tiredness, constipation or diarrhea, difficulty sleeping, headache, nausea, vomiting Somnolence, ataxia, dizziness, fatigue, nausea, vomiting rlransient weakness in injected or neighboring muscles, skin rash, and flu-like syndrome Diarrhea, dizziness, drowsiness, weakness, nausea, unusual tiredness, abdominal cramps, blurred or double vision, chills and fever, constipation, frequent urination, headache, loss of appetite, speech difficulties, sleep difficulties, nervousness
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From page 136... ...
Other peripheral changes that may contribute to muscle weakness include muscle wasting, fiber loss, muscle contracture, and joint contractures. Loss of Descencling Input to Spinal Premotor Interneurons Communication pathways between the interneurons of the spinal cord and the axons of sensory and motor neurons, which project outside the spinal cord, are essential for generating coordinated muscle commands.
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From page 137... ...
Changes in Muscle Tissue Observations in patients with spinal cord injuries suggest that patients with severe, long-standing MS may also develop weakness through overt changes in muscle tissue (although, note Tilbery et al.~77~. These changes consist of muscle wasting, shifts in the metabolic properties of muscle fibers (toward glycolytic systems)
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From page 138... ...
Do they shift in such a way as to indicate a reduction in efficiency of muscle activation? Determine the recruitment and firing rate properties of motoneurons in patients with muscle weakness associated with MS.
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From page 139... ...
Experience suggests that optimum results are obtained in patients with relatively stable disease, good mobility, and minimal overall disability status an extremely small group. Three recent papers have suggested that thalamic stimulation can also alleviate tremor
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From page 140... ...
The neurological basis for bowel dysfunction in MS is not as clearly defined as it is for the bladder, and treatment options are limited. Normal Blacicler Control Mechanisms Neural bladder function control occurs primarily in the sacral spinal cord, as well as the pons, diencephalon, and cerebral cortex in the brain.
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From page 141... ...
, inhibitory pathways provide for suppression of the micturition reflex, activation of sympathetic outflow, and voluntary contraction of the external sphincter. Voiding requires the coordination of a number of control systems such that detrusor muscle activation and relaxation of sphincter mechanisms results in bladder emptying with only a few milliliters of residual urine.
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From page 142... ...
A spastic or hyperreflexic detrusor muscle is usually secondary to lesions in the spinal cord, leading to increased contractility and decreased capacity of the bladder. Urinary urgency, the most common bladder symptom in MS, is caused primarily by detrusor hyperreflexia.
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From page 143... ...
Many of these studies will relate directly to spinal cord injury, and joint funding options may be available. Clinical research into bladder infections and keeping the urine sterile might be surprisingly fruitful, since infections restrict volume and compromise bladder function and pharmacological treatment.
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From page 144... ...
Detrol24 Tolterodine tartrate Urinary frequency, urgency, Acts as a urge incontinence antagonist ~ncreased Tofranill06 Imipramine Urinary frequency, Has mode: fecal incontinence effects an. effects; in, its active~ (desipram~ Zostrix38,39 Capsaicin Hyperreflexia A neuroto bladder lu partial dec permitting
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From page 145... ...
Brief euphoria, slight dizziness, feeling of abdominal distention Dry mouth, blurred vision, increased heart rate, dry eyes, headache, nervousness, urinary retention or hesitation, weakness Runny or stuffy nose, abdominal or stomach cramps, flushing of the skin, headache, nausea, pain in the vulva Dryness, drowsiness, blurred vision, dizziness, abdominal pain, back pain, flu syndrome, hypertension, palpitation, vasodilatation, constipation, diarrhea, flatulence, gastroesophageal reflux, arthritis, insomnia, nervousness, confusion, impaired urination Nausea, vomiting, skin rash Constipation, decreased sweating, dryness of mouth, nose, and throat, bloated feeling, blurred vision, difficulty swallowing Dry mouth, headache, dizziness, somnolence, fatigue Dizziness, drowsiness, headache, decreased sexual ability, increased appetite, nausea, unusual tiredness or weakness, unpleasant taste, diarrhea, heartburn, increased sweating, vomiting Transient burning following application, stinging, erythema, cough, respiratory irritation
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From page 146... ...
People with bladder dysfunction are less likely to keep adequately hydrated, and the anticholinergic drugs often used to treat detrusor hyperreflexia can cause constipation since sphincter mechanisms are primarily cholinergic. Fecal Incontinence Fecal incontinence is usually associated with constipation and occurs due to rectal overloading and overflow or when sphincter control and coordination are diminished due to sphincter muscle weakness.
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From page 147... ...
Also, studies of pelvic floor musculature in spinal MS might reveal new data on how to improve the mechanical aspects of sphincter function. As stated above, studies of spinal cord injury would complement studies on patients with spinal MS.
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From page 148... ...
Estimates of the risk for developing MS within 15 years of an acute bout of optic neuritis range from 45 percent to 80 percent.~35 MRI is the most powerful predictor of whether MS will develop following optic neuritis, as evidenced by the presence and number of lesions in the brain.~35 The Optic Neuritis Treatment Trial is the most extensive study of optic neuritis. This study of 457 subjects with acute optic neuritis found that patients with no initial brain lesions had a 16 percent chance of developing clinically definite MS within the 5-year study period, whereas those with three or more lesions had a 51 percent chance; clinically definite MS developed in 27 percent of all subjects, and probable MS developed in 9 percent.~75 The Optic Neuritis Study Group found no benefit of oral or intravenous steroid treatment over nontreatment in ultimate visual outcome or in the development of MS.
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From page 149... ...
These patients, together with those who fail to recover from an acute episode, might benefit from visual aids. Abnormal Eye Movements Abnormal eye movements result from demyelination of afferent nerve pathways to the eye muscles and occur frequently in MS patients.
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From page 150... ...
150 Cat ad an o an 5 o ¢ Cut · ~ .= C)
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From page 151... ...
Fatigue that is more chronic and pervasive is frequently associated with illness, stress, and sleep disturbances. Fatigue as a distinct clinical symptom in MS must, however, be distinguished from true muscle weakness, sleepiness or drowsiness, and depression.
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From page 152... ...
i3 Neuroimaging of chronic fatigue syndrome, which has been much more widely studied in this regard than MS, has likewise yielded conflicting results.99 i05 At this stage, reports of fatigue-associated neuropathology in MS should be interpreted cautiously. Measurement of Fatigue Because fatigue is multidimensional, with distinct physical and mental elements, measurement tools must be carefully constructed and carefully used to produce valid, reliable, and meaningful distinctions among the separate elements and differing levels of fatigue.
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From page 153... ...
Nonetheless, if carefully selected, some of the currently available measurement tools are adequate for clinical trials. These are primarily self-report instruments, such as the SF-36.
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From page 155... ...
This is not surprising considering the variable nature of the necrologic disorder. Up to 91 percent of men with MS and 72 percent of women have adverse effects on their sexual function, and up to 80 percent of men with MS report erectile dysfunction.~7 67 i00 i8i Desire and Satisfaction Sexuality has both psychological and physiological components, and both aspects contribute to the level of a person's sexual functioning.
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From page 156... ...
and conus medullaris (lowermost portion of the spinal cord) lesions are thought to occur in up to 63 percent of patients.~°i Thus, some patients will have necrologic lesions affecting the pathways for sexual function whereas others will not.
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From page 157... ...
Another difficulty in the study of sexual function stems from the inaccuracies associated with self-report data.l59 Most importantly, the issues noted in the previous paragraphs should be addressed through the performance of controlled, laboratory-based research to systematically document the physiologic effects of specific neurological dysfunctions associated with MS on sexual function. This should also provide information regarding the incidence of psychological sexual dysfunction affecting persons with MS.
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From page 158... ...
Sildenafil, a drug previously shown to be safe and effective in the treatment of erectile dysfunction, was recently tested in a small study of 19 women with spinal cord injuries. The results showed that sildenafil can significantly increase the level of subjective sexual arousal in women with neurogenic sexual dysfunction.
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From page 159... ...
159 o .= Cal an .= A at o an Cq o EM a ·_ ·= 8 o a ·~ C)
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From page 160... ...
In contrast, painful tonic spasms and tic doloreux in young people are so rarely seen, except in patients with MS, that they probably result directly from the demyelinating process. Optic neuritis is often painful during the acute attack; presumably this is a direct result of the inflammatory process and activation of primary afferent nociceptors.*
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From page 161... ...
Painful Tonic Spasms In contrast to trigeminal neuralgia, painful tonic spasms are rarely observed except in MS.~°8 In MS they seem to be relatively common, occurring in between 10 and 20 percent of patients.~83 Their clinical presentation has unique and highly
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From page 162... ...
i83 The association of spinothalamic tract-type deficits and continuous dysesthetic pain is characteristic of central pain syndromes such as poststroke and spinal cord injury pain. These syndromes are notoriously resistant to analgesic treatments.
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From page 163... ...
, which demonstrated significant improvement in tremor and spasticity with a synthetic CB1 receptor agonist.* This evidence warrants controlled clinical trials.
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From page 164... ...
Pain Due to Increased Muscle Tone In any neurological condition characterized by spasticity (i.e., upper motor neuron disease) , patients are at risk for muscle pain due to spasm.
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From page 165... ...
Paroxysmal phenomena (trigeminal neuralgia and painful tonic spasms) are recurrent and appear to respond well to anticonvulsant medications.
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From page 166... ...
The extensive literature on spinal cord injury and pain offers a number of models that could be extended to this type of study so that it can address demyelinating lesions (for example, Brewer and Yezierski, 199821~. In addition, although it is difficult to assess continuous pain in animals, the mouse models for inflammatory demyelination offer an area where parallel human and animal work could progress.
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From page 167... ...
1988. Sexual dysfunction and electroejaculation in men with spinal cord injury: review.
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From page 168... ...
1998. Capsaicin and neurogenic detrusor hyperreflexia: a double-blind placebo-controlled study in 20 patients with spinal cord lesions.
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From page 169... ...
in men with erectile dysfunction caused by spinal cord injury. Neurology.;51:1629-33.
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From page 170... ...
1994. Depression, cognitive impairment and social stress in multiple sclerosis.
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From page 171... ...
2000. Axonal changes in chronic demyelinated cervical spinal cord plaques.
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From page 172... ...
Sexual dysfunction and its response to medications. Arch Neurol.;52:862-8.
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From page 173... ...
1998. Optic neuritis.
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From page 174... ...
2000. The necrologic basis for sexual arousal and orgasm: effects of spinal cord injury.
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From page 175... ...
1997. Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial.
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From page 176... ...
2000. Axonal changes in chronic demyelinated cervical spinal cord plaques.
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