Dr. K is a 54-year-old physician with secondary-progressive multiple sclerosis (SPMS). He is currently receiving treatment with subcutaneous interferon beta-1a. He is married and has two teenaged daughters.
Dr. K has requested an urgent visit because in the last few days he has had eight episodes in which his speech abruptly became garbled, "like marbles in my mouth." Each episode lasted approximately 30 seconds, after which his speech just as suddenly returned to normal.
During the office visit, Dr. K also states that he recently purchased a new walk-aid device, which he had hoped would improve his gait. However, his perception is that the device has not helped, and he continues to drag his left leg. He says that since a prior visit 3 months ago, his gait has continued to deteriorate and he has had increasing impairment in his left-hand function.
Examination shows normal speech pattern, spasticity in the left upper extremity, mild spasticity in the left lower extremity, and weakness in the left hand. Strength in the iliopsoas and hamstrings is nearly 5 and in the tibialis anterior muscle is a little less than 3 on the Medical Research Council Scale for Muscle Strength. The Timed 25-Foot Walk (T25FW) test is repeated twice and results are 7.6 and 7.8 seconds with the patient using an ankle-foot orthosis and cane. While walking, he is spastic, circumducting his left leg. He has mild proximal weakness and a substantial foot drop. Dr. K asks if more can be done to improve his gait.
Decision Point 1. Paroxysmal Dysarthria
How would you manage his speech impairment?
- Perform electroencephalography (EEG)
- Regard it as an MS attack and treat with steroids
- Initiate low-dose carbamazepine
- Regard it as a new MS attack and order another magnetic resonance imaging (MRI)
Answer: c. The episodes of altered speech represent paroxysmal dysarthria. Paroxysmal dysarthria, like all paroxysmal symptoms, is likely to respond to low-dose carbamazepine.1
Paroxysmal symptoms are transient repetitive symptoms with sudden onset and abrupt resolution.2 They are caused by spontaneous discharge of partially demyelinated neurons or ephaptic (electrical) transmission of adjacent nerve fibers.3 The typical presentation is an arm or leg spasm that lasts for a few seconds and stops.4 It may repeat a few seconds or minutes later.4 However, as seen in this case study, these spasms can also affect the mouth muscles, resulting in slurred speech or impaired swallowing.4,5 Hyperventilation may reproduce the symptoms.5 Paroxysmal dysarthria may occur early in the course of disease, potentially as the initial MS attack.5,6
Audio commentary from Dr. Miller
Carbamazepine, which increases membrane stability,3 has long been used as an effective treatment for paroxysmal symptoms. Case series dating back to the 1960s and 1970s have reported response of paroxysmal symptoms, including paroxysmal dysarthria, to carbamazepine.1,2,6 Benefit is often seen within 48 hours of initiation, and complete remission of symptoms is not uncommon, even with small doses (100â200 mg/day).1 Carbamazepine can be started at 100 or 200 mg orally two or three times per day and then increased weekly if needed, to the maximally tolerated dose.3 The extended-release tablets can be given at an initial dose of 200 mg daily and then increased by 200 mg/day in two doses if necessary.3 Carbamazepine is contraindicated in patients with active hepatic disease, previous blood dyscrasia, and those taking monoamine oxidase inhibitors.3 Caution is required in elderly patients, those with glaucoma, renal or hepatic dysfunction, and patients who are pregnant or breastfeeding.3 Adverse events may include dizziness, nausea, confusion, blurred vision, nystagmus, ataxia, increased or decreased blood pressure, allergic skin rash, syndrome of inappropriate antidiuretic hormone hypersecretion, blood dyscrasia, arrhythmias, heart failure, hepatitis, and hypocalcemia.3 Clinicians should monitor renal and hepatic function at baseline and periodically.3
Audio commentary from Dr. Miller
Paroxysmal symptoms are easily confused with seizures,4 but are not epileptic and are not associated with altered brain waves on EEG.1 Dr. K's symptoms are strongly suggestive of MS-related paroxysmal symptoms. Since the symptoms are unlikely to be seizures, an EEG is unnecessary.
Although this is, technically, a new MS attack, MRI and steroids are both probably unnecessary. MRI does not have to be performed with every MS attack. It should be ordered only if there is a concern that something other than MS may be contributing to the symptoms, or if a change in therapy is planned and the MRI is being used as a baseline for the new treatment.
High-dose corticosteroids are the standard of care for managing major relapses that require short-term therapy.7 Although steroids might help resolve the acute attack more quickly, they commonly have side effects and are not always necessary in minor relapses.7 Steroids are probably unnecessary in this case given that carbamazepine is likely to be effective and have a sufficiently rapid onset.
Decision Point 2. Addressing Gait Dysfunction
What would you recommend to help him improve his gait?
- Evaluation by a physical therapist
- Botulinum toxin injections
- Trial of dalfampridine ER
Answer: (a and/or c) It is reasonable to have the patient evaluated by a physical therapist and/or to try dalfampridine ER to see if it is beneficial.
Diminished motor function is a common physically and socially debilitating symptom of MS.8 Signs of gait impairment may be apparent even in recently diagnosed patients,9 and about half of persons diagnosed with relapsing-remitting MS (RRMS) need some assistance with walking within 15 years.10 There are numerous reasons why patients with MS may have difficulty walking (see Table).3,4,8,11 It is important to address issues of mobility to help patients maintain function, facilitate performance of activities of daily living, and reduce the risk of secondary complications.11 Patients who remain ambulatory are less likely to develop contractures, decubitus ulcers, venous thromboembolism, osteoporosis/fracture, and bowel and bladder complications.8 Mobility may change over time, so it is important to periodically repeat assessments of gait and evaluation of the patient's needs.3
Table. Causes of Reduced Mobility in MS3,4,8,11
- Impaired balance and/or proprioception
- Foot drop
- Diminished sensory feedback in the feet
- Impaired coordination
Audio commentary from Dr. Miller
Evaluation by a physical therapist is reasonable for patients with gait impairment. Such experts can provide gait training and any necessary walking aids.3 Physical and occupational therapy may be able to address specific problems with balance and weakness.11 Stretching and range-of-motion exercises can reduce spasticity, and conditioning and adaptive exercises can improve strength and balance.11 Physical therapy can also help the patient focus on gait mechanics to improve posture and reduce lower back and joint pain that can result from improperly shifting body weight to the back and joints.11 Lower-extremity resistance training has been shown to improve leg extensor power, but not balance and mobility.12 In a series of five cases, lower-extremity endurance training with repeated maximum knee flexions reduced peripheral muscle fatigue and resulted in improvements on visual analog scale ratings of general fatigue, general health, physical fitness, somatic health, and mood.13 A recent meta-analysis concluded that exercise training could produce small improvements in walking mobility in MS patients, with the largest effect sizes associated with supervised exercise training and short-term (<3 months) exercise programs.14
Orthotics and mobility devicesâsuch as the ankle-foot orthosis and cane used by the case patientâcan be helpful in countering weakness and foot drop and can help prevent falls,11 but orthotics have also been found to increase sway and to shift center of pressure medially and posteriorly.15 A proper orthosis should be light and not too cumbersome and should be fitted to increase the stability of the patient's stance and allow for adequate clearance during leg swing.8
Patients with foot drop may also be candidates for functional electrical stimulation devices that stimulate the common peroneal nerve to induce ankle dorsiflexion.8 Two such devices are now available, but are generally not covered by insurance and cost about $5000 to $6000.7 While some patients find them more convenient than traditional orthoses, they are also not universally beneficial, especially when patients have significant proximal weakness.7 These devices must be fitted by a physical therapist or orthotist.16 They are worn around the leg just below the knee and use sensors to detect gait and appropriately time the stimulation.16
Scooters and wheelchairs may be necessary for patients with more severe impairments in order to maintain mobility and functionality, especially in patients who also have fatigue.11
The FDA recently approved dalfampridine extended release tablets to improve walking in patients with MS.17 Dalfampridine-induced potassium channel blockade is thought to improve the duration and amplitude of action potentials, thereby improving conduction in demyelinated axons17,18 and upregulating the release of neurotransmitters in neurologic synapses.18 Increased walking speed in patients taking dalfampridine was demonstrated in two randomized, double-blind, placebo-controlled multicenter trials.17,19
In the first clinical trial, 301 patients with any type of MS were randomized 3:1 to dalfampridine 10 mg twice daily or placebo for 14 weeks.19 To be eligible for the study, patients had to complete two trials of the T25FW test in an average time of 8 to 45 seconds at screening.19 There was a 2-week placebo run-in period at the start of the study and a 4-week posttreatment follow-up period at the end.19 The primary outcome measure was response on the T25FW test, defined as faster walking speed on at least three out of four follow-up visits during the treatment period compared with the fastest speed during any of the four visits in the run-in and follow-up periods.19 The response rate was 35% with dalfampridine versus 8% with placebo (P <.0001).19 Walking speed improved an average of 25.2% in the dalfampridine responders compared with 4.7% in the placebo group.19 Results on the 12-Item MS Walking Scale, which captures patient's perceptions of their ambulatory disability, indicated that the responders to dalfampridine noticed a reduction in their ambulation-related disability.19 Similar results were seen in the second trial, in which response was reported in 42.9% of dalfampridine-treated patients versus 9.3% of controls.17
The approved dose of dalfampridine is one 10-mg tablet (swallowed whole) twice daily.17 This dose should not be exceeded, as higher doses have been associated with an increased risk of seizure.17 (The frequency of seizure at the approved dose has been too low in clinical trials to determine the magnitude of risk.19) Dalfampridine is contraindicated in patients with moderate or severe renal impairment and patients with a history of seizure.17 Side effects occurring in â¥5% of treated patients include urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, and balance impairment.17
Botulinum toxin injections should be considered only for cases of intractable spasticity that involve a limited number of small muscle groups.3 Spasticity is typically first treated with oral agents (eg, baclofen, dantrolene sodium, tizanidine).3 Because this patient has only mild spasticity in his leg, even these therapies may not be necessary. The decision whether to treat spasticity, particularly mild spasticity, is based on clinical judgment and patient preference.
Modafinil is sometimes used to treat MS-related fatigue, although recent trials are not particularly supportive.3 This patient, who has weakness and slowed movement, is not complaining of fatigue. Modafinil is unlikely to be effective in treating this patient's symptoms.
Dr. K is prescribed carbamazepine and dalfampridine. He is instructed to start taking the carbamazepine first and the dalfampridine 1 week later.
He returns for a follow-up visit 6 weeks after starting the dalfampridine. He states that his paroxysmal dysarthria stopped immediately after initiation of carbamazepine, but his walking has not improved on dalfampridine. His wife, who has accompanied him to the visit, says she thinks he is walking faster. His physical exam, including neurologic exam, is unchanged compared with the last visit. His walking speed has improved. Results of a pair of T25FW tests are 6.8 and 6.7 seconds.
Decision Point 3. Assessing Response and Need for Continued Therapy
What would your next step(s) be?
- Discontinue carbamazepine
- Discontinue dalfampridine ER
- Tell him his trial period on dalfampridine has not been long enough to determine response yet and he should continue it another 6 weeks
- Seek additional information about the patient's condition from his two teenaged children
Answer: (a and probably b).
Paroxysmal symptoms are usually self-limited, lasting a matter of weeks to months before resolution. Thus, it is best to stop treatment periodically to determine if the symptoms have resolved. Clinical experience suggests that the natural course of a minor MS relapse is about 4 to 6 weeks; however, some physicians prefer to wait 2 to 3 months before discontinuing carbamazepine.3 When discontinuing carbamazepine, patients should probably gradually reduce the dose before stopping,3 especially if they have been taking high doses or using carbamazepine for a long duration. If symptoms return upon discontinuation, carbamazepine can be restarted.
Dalfampridine is a symptomatic therapy, analogous to using acetaminophen for a headache; therefore, if a patient's symptoms are not noticeably improved in a way that makes a meaningful difference to the patient, there is no need to continue it. Although the T25FW test was used as an objective and quantitative measurement to study the effects of dalfampridine in a group of MS patients in a clinical trial setting, determination of response in clinical practice should be based on the individual patient's perception of dalfampridine's benefit. If the patient does not notice any improvement in his gait while taking dalfampridine, then the perceptions of his wife and children, and even the results of the T25FW test, are not clinically meaningful and should not be factored into a decision as to whether to continue use of this therapy.
In the clinical study of dalfampridine, those who responded were significantly improved after 2 weeks.19 However, it has been observed that some individual patients may take as long as 8 weeks to show improvement, so if the patient wants to wait a little longer, he could potentially continue dalfampridine for a few more weeks before assessing response. At that time, if there is still no improvement, he should discontinue it.
If stopping both drugs, it is best not to do so at the same time. The patient should be advised to stop carbamazepine and then later the dalfampridine.
Audio commentary from Dr. Miller
The patient discontinued carbamazepine and has had no more paroxysmal episodes. A week later, he stopped dalfampridine and did not notice any difference in his gait. His wife says she is not sure whether he walks any differently now that he has stopped taking the dalfampridine. He is continuing with physical therapy.
Patients with SPMS and patients with RRMS who have more than mild deficits commonly have persistent symptoms that warrant attention in clinical practice. Such symptoms should be managed to allow for better function and quality of life.
Paroxysmal symptoms are common and can represent an initial MS attack or a subsequent relapse. Most paroxysmal symptoms respond dramatically to carbamazepine, but are time-limited and may not require long-term treatment.
Many MS patients experience chronic and sometimes progressive difficulty walking. Assessment of gait should be performed periodically, as patient needs may change over time. Referral for physical therapy, rehabilitation, and walk aids (if needed) is warranted for patients with gait impairment. The goal of dalfampridine is functional improvement in the patient's ability to walk. Patients who show good response with noticeable improvements in mobility can continue on dalfampridine. However, if the patient does not perceive improvement, there is no reason to continue dalfampridine because it does not have disease-modifying activity.
For more information about symptom management in MS, please visit Chapter 6 in the Living Medical Textbook: Multiple Sclerosis 2010 Edition.
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