The Evolution in Diagnosis and Treatment of Multiple Sclerosis

The Evolution in Diagnosis and Treatment of Multiple Sclerosis

Tiffani Stroup, DO

University of Chicago Medicine, Chicago, Illinois

Management of multiple sclerosis (MS) has evolved significantly since the first disease-modifying therapy (DMT) was introduced. With increasing demand for magnetic resonance imaging (MRI), MS often is on the differential diagnosis of nonspecific white-matter lesions. Making an accurate diagnosis remains crucial to select appropriate therapies. Red flags in either the history or imaging should raise suspicion that an alternative diagnosis may be more likely. MRI is extremely useful to neurologists as they diagnose patients, monitor response to therapy, and, potentially, measure atrophy as a marker for disability. Treatment decisions should be individualized, but certain factors (eg, MRI evidence of clinically silent disease at diagnosis) can help physicians decide to use more aggressive therapies earlier. Transitioning to different DMTs can be guided by balancing the risks and benefits of such treatments. Treatment of symptoms due to MS can improve quality of life. Use of screening tools at follow-up visits can help in the identification of MS-specific symptoms. A multidisciplinary approach of incorporating ancillary services, addressing polypharmacy, and starting specific medications is most effective in combating common symptoms.

Tiffani Stroup, DOManagement of multiple sclerosis (MS) has changed significantly since magnetic resonance imaging (MRI) and the first disease-modifying therapies (DMTs) were introduced into clinical practice. Patients are being diagnosed earlier in the course of disease, and they may be maintained on DMT for decades. These developments have led to increased demand for making an accurate diagnosis and recognizing potential mimics of MS, because DMTs are expensive and may cause potentially serious side effects.

ESTABLISHING AN ACCURATE DIAGNOSIS
Based on a presentation by Heather Jean MacLean, MD, Department of Neurology, University of Ottawa, and Director, MS Clinic, The Ottawa Hospital, Ottawa, Ontario, Canada.

Since the 2010 McDonald criteria were introduced, there has been an urgency to diagnose MS early.1 These criteria allowed for diagnosis based upon just one MRI scan. Because multiple relapses early in the course of the disease lead to more disability, the focus of MS therapy remains prevention of attacks. Unfortunately, misdiagnosis occurs in approximately 5%–10% of cases and is largely due to misinterpretation of MRI findings and failure to recognize disorders that mimic MS.

Among the nearly 100 disorders that can mimic MS radiologically are microvascular disease, migraine headaches, and psychogenic phenomena.2 Treatment and prognosis vary for these disorders, making appropriate diagnosis crucial. Certain red flags in the history—such as progression of symptoms, childhood or elderly onset, a similar family history, or hearing loss—should prompt evaluation for another disease process. Similarly, red flags related to imaging include lesions that are tumefactive, longitudinally extensive, or do not involve the corpus callosum. When red flags are detected, the physician should create a differential diagnosis and proceed with the appropriate workup, which may include contrast-enhanced imaging of the neuroaxis, lumbar puncture, and evoked potentials.3 If appropriate, treatment can be started, but a working diagnosis should be maintained. The practitioner should keep a high index of suspicion that the case may evolve and that treatment eventually may need to be adjusted. Alternatively, it may be appropriate to delay treatment if the presentation is relatively benign and the diagnosis is still unclear. However, in typical cases, treatment should not be delayed, and ancillary tests can lead to false positives.2

Specific Diseases and Disorders That Mimic MS
Susac's syndrome
is a rare condition that typically occurs in people 20–40 years of age and more commonly in women than in men. This diagnosis is characterized by the classic triad of visual loss, hearing loss, and encephalopathy. Pathogenesis of Susac's syndrome is attributed to microangiopathic changes in the nervous system, with correlation of imaging findings in the corpus callosum and white matter. Notable findings along the corpus callosum include T2 hyperintensities or T1 black holes positioned around the midportion that project as radially oriented icicle- or snowball-shaped lesions. Characteristic white-matter lesions resemble a string of pearls in the internal capsule on diffusion-weighted imaging. Treatment is anecdotal and usually involves immunosuppression with corticosteroids, cyclophosphamide, mycophenolate mofetil, azathioprine, or intravenous (IV) immunoglobulin. Prognosis varies greatly from minimal disability to significant cognitive and hearing deficits, but most cases are self-limited and can last from 6 months to 5 years.3

Neurosarcoidosis. The pathogenesis of this rare disorder is related to inflammatory granulomas affecting multiple organ systems, such as the lungs, skin, eyes, joints, and nervous system. Neurologic involvement from sarcoidosis may include optic neuritis, cranial neuropathies, peripheral neuropathy, myopathy, chronic meningitis, or hypothalamic dysfunction. Most cases are monophasic, but one third of cases may be relapsing and remitting. In the United States, this disease predominantly affects African-Americans, whereas Caucasians are preferentially affected in Europe. Diagnosis includes MRI signs of parenchymal or leptomeningeal involvement, cerebrospinal fluid (CSF) findings of lymphocytic pleocytosis, imaging of other involved systems, and a gallium scan that may show a characteristic "panda sign" representing bilateral lacrimal and parotid gland uptake.3

Acute disseminated encephalomyelitis may be difficult to distinguish from MS. Patients present with fulminant neurologic dysfunction hours to days after vaccination or infection and typically are encephalopathic. Relapses can occur, although rarely, and new neurologic symptoms occurring within 3 months of the initial diagnosis are still considered monophasic. The workup includes MRI showing large white-matter lesions that are similar in age with variable enhancement. Lumbar puncture findings typically are negative for oligoclonal bands. Nearly one half of patients with this disease recover completely.3,4

Hereditary leukodystrophies. A history of family members dying young with significant neurologic disability should prompt investigation for hereditary leukodystrophies, which can also mimic MS. Most of these diseases present in childhood with progressive neurologic dysfunction and are due to an autosomal-recessive or X-linked recessive defect in myelin production or maintenance. An example of hereditary leukodystrophy that can present in adulthood is adult-onset autosomal-dominant leukodystrophy, which radiologically presents with confluent frontoparietal white-matter lesions that spare the periventricular area and involve the corticospinal tracts and cerebellar peduncles.3

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy should be considered in the differential diagnosis of MS. Clinical features include subcortical infarcts at a young age, migraine headaches with or without an aura, vascular dementia, and depression. Diagnosis can be made with genetic testing for the NOTCH3 mutation on chromosome 19 or by skin biopsy showing deposits in vessel walls that test positive with periodic acid-Schiff staining. Characteristic MRI findings include confluent white-matter T2 hyperintensities in the temporal poles and external capsules.3

Table 1Neuromyelitis optica (NMO) is a demyelinating disorder that may be mistaken for MS, but its distinct clinical features include preferential involvement of the optic nerves and longitudinally extensive transverse myelitis extending over three or more spinal cord segments (Table 1).5 Pathology of this disorder is necrotizing involvement of the parenchyma, and imaging can show swelling of the spinal cord. Other than MRI orbits and spinal imaging to demonstrate T2 lesions with variable enhancement, the diagnostic workup also includes MRI of the brain, which may demonstrate some T2 hyperintensities around the third and fourth ventricles but is otherwise unremarkable; CSF that typically shows elevated protein and neutrophilic pleocytosis and that tests negative for oligoclonal bands; and serum positivity to NMO immunoglobulin G (IgG). Treatment is empirical, consisting of immunosuppression with rituximab or azathioprine; however, prognosis is poor, as most patients are left with residual disability.5

Progressive multifocal leukoencephalopathy (PML) mimics MS and should be considered in immunosuppressed patients. Patients with PML present with subacute neurologic phenomena due to John Cunningham virus (JCV) infection of the brain. Classically, MRI shows large subcortical T2 hyperintensities with irregular borders, which can involve the gray matter, typically presenting in the temporal, parietal, and occipital regions and extending to the U fibers; these lesions do not enhance with contrast. Most affected patients undergo brain biopsy, which shows oligodendrocyte inclusions of JCV and enlarged astrocytes.3

THE USE AND MISUSE OF MRI IN DIAGNOSIS AND TREATMENT
Based on a presentation by Nicola De Stefano, MD, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.

In neurologic practice, MRI is a useful tool to diagnose MS, monitor response to treatment, and evaluate possible side effects and tissue loss. Over the past 10 years, the number of MRI scans ordered has increased in both the United States and Europe.6 Thus, neurologists have become increasingly familiar with typical MS brain lesions, which are ovoid, irregularly shaped, and distributed asymmetrically. These lesions evolve in varying patterns and occur in typical locations: periventricular, juxtacortical, infratentorial, and along the corpus callosum.7

Clinically Isolated Syndrome (CIS)
Since the 2010 McDonald criteria were introduced (Table 2),1 patients with CIS have been diagnosed with clinically definitive MS if the initial MRI findings fulfill the criteria for both dissemination in space and time.

Table 2

Dissemination in space is defined as the presence of at least one lesion in two or more characteristic areas (periventricular, juxtacortical, infratentorial, or spinal cord). In contrast, dissemination in time requires either the presence of asymptomatic gadolinium-enhancing and non-enhancing lesions on one scan or a new T2 lesion or gadolinium-enhancing lesion on a repeat MRI scan.1 These criteria help to simplify the diagnostic process by requiring less imaging to diagnose MS.

Radiologically Isolated Syndrome (RIS)
Table 3RIS has been defined in recent years as incidental MRI findings that resemble MS lesions without any clinical correlate. Clinical criteria proposed to diagnose RIS (Table 3)7 require that patients have no history of neurologic dysfunction and that other MS mimics have been ruled out. At 5 years after initial diagnosis, two thirds of patients with RIS will show progression of MRI findings, and one third will have clinical manifestations. Certain risk factors that increase the odds of developing clinical progression include a cervical spinal cord or infratentorial location, numerous lesions, younger age, pregnancy, abnormal visual evoked potentials, the presence of oligoclonal bands in the CSF, or elevated IgG index plus the presence of at least 10 initial T2 lesions on MRI.6

Use of MRI for Treatment Decisions
For patients already on DMT, progression of MRI lesions over a prespecified period of time may help guide further treatment. Patients taking interferon β who experience more than one relapse or one relapse and at least four new T2 lesions within 1 year of initiating therapy are likely to be nonresponders.8,9

The Italian Neurological and Neuroradiological Societies have proposed that patients with CIS undergo MRI at baseline and at 3 months and 1 year after diagnosis; for patients with relapsing-remitting MS, MRI should be performed at 6, 12, 24, and 36 months after treatment begins and, if patients are clinically stable, every 2 years thereafter.10

MRIs may be useful for detecting PML, which can be a deleterious side effect of natalizumab therapy. In patients who are anti-JCV antibody positive, MRI should be repeated annually after natalizumab therapy begins, and discontinuation of natalizumab should be considered.11 Certain characteristics, such as lack of mass effect for large lesions and subcortical location, can help distinguish PML from a new MS lesion.3

Assessment of Brain Tissue Loss
Brain atrophy can be seen at any stage of MS, but it tends to be more severe in secondary progressive MS and correlates with clinical disability. Unfortunately, a lack of standardization limits the widespread use of brain atrophy measures in MS patients. To further complicate this issue, pseudoatrophy related to resolution of inflammation can be seen after initiation of DMT.12

MRI findings may be useful in guiding diagnosis, prognosis, and safety of MS treatment. For comparison purposes, patients should have repeat imaging done on the same MRI scanner with standardized MS protocols.12

TREATMENT OPTIMIZATION FOR RELAPSING MS
Based on a presentation by Mark S. Freedman, MD, MSc, Professor of Neurology and Director, Multiple Sclerosis Research Unit, University of Ottawa, Ottawa, Ontario, Canada.

Treatment of MS should be individualized for each patient. However, certain factors, such as estimated risk of disease progression and medication safety profile, may help guide such decisions. Relapses early in the course of MS decrease the functional reserve of the brain and contribute to axonal loss. With the diagnostic criteria for CIS, physicians may intervene at the first neurologic presentation of MS. The type of treatment initially provided may vary if the patient is presenting early, with a relatively mild disease burden on MRI, or later, with a high radiologic burden of previously silent disease.13

What Factors Should Be Considered Before Initiating Treatment?
During the first 5 years after diagnosis, factors related to a poor prognosis with risk for faster disease progression include non-Caucasian descent; initial presentation with multiple neurologic deficits; increased numbers of attacks; shortened time between attacks; evidence of disability; high lesion load on MRI; and early involvement of disease affecting motor, cerebellar, or bowel and bladder function. High disease burden on MRI is defined by two or more gadolinium-enhancing lesions with at least nine T2 hyperintensities.13 Individualization of MS treatment should account for the current severity of the disease, the patient's experience with other therapies, medical comorbidities, and desired onset of therapeutic effect.

Determination of estimated disease progression soon after diagnosis can be challenging, but this can be a key factor in deciding whether first-line or more aggressive therapies should be started. Patients with a low risk of imminent disease progression should be placed on first-line agents with proven long-term safety. Alternatively, patients with the previously mentioned risk factors for poor prognosis at disease onset can be considered at high risk for imminent disease progression and may be candidates for more aggressive immunosuppressant medications that have a narrow safety profile.13

Clinical trials of DMT have shown variable relapse rates for MS. However, a clear definition of treatment tiers is complicated by a lack of comparison trials. Moreover, the use of older agents in newer studies has been associated with lower relapse rates than previously noted, perhaps as a result of trial patients entering trials early in the course of disease or after they have received DMT.13 Lastly, treatment should be individualized, as trial data are not necessarily applicable to all patients.

Table 4In the low-risk patient, initiation of first-line therapy with interferons, glatiramer acetate, or any of the oral agents is reasonable (Table 4).13 Key factors to further individualize therapy include safety based on medical comorbidities and tolerability, since this medication is intended to be used for a long period. In the high-risk patient, escalation of therapy to second-tier agents and above may be considered with the trade-off of more serious safety concerns. Escalation of therapy can be temporary; for example, in induction, a second-line or above agent is used to achieve a desired response goal, and then therapy is switched to a safer first-line agent when the disease is relatively quiescent. An alternative approach involves the use of permanent escalation, during which a second-line agent is initiated and maintained for the best efficacy.13

Defining Response to Treatment
Nonresponse to treatment can be defined as continued disease activity despite the use of DMT. Within the first year of diagnosis, patients should be followed every 3 or 4 months, encouraged to contact the office with medication side effects or relapses, have neuroimaging at baseline and surveillance at 1 year, and have laboratory parameters monitored based on the therapy used.13 Baseline neuroimaging should be accomplished when the drug is effective, which means at least 3 months after starting a drug that affects lymphocytes; these cells must undergo one life cycle before the full effect of the drug is seen. Markers for disease progression include the number of clinical relapses, disability progression, and MRI findings.

The Canadian Treatment Optimization Model has been proposed as a guide to switching therapy based on low, medium, or high risk of disease progression (Table 5).13 Patients at low risk of disease progression have up to one attack by 2 years of treatment, less than a 20% change noted in the Timed 25-Foot Walk Test (T25FWT) at 6 months, and fewer than two new T2 lesions on MRI. Conversely, high-risk patients have more than one attack in the first year of treatment, a greater than 100% change in the T25FWT at 6 months, and three or more new T2 lesions on MRI.13

Table 5

Approaching Disease Breakthrough
A suboptimal response to treatment may result from poor tolerance to the DMT prescribed, financial issues, or disease breakthrough. A change to a new agent may be accomplished by a lateral switch to a similarly effective DMT, induction therapy, or escalation maintenance. Patients considered at low risk of imminent disease progression can be switched via a lateral move, and high-risk patients typically require either temporary or permanent escalation. The lateral approach can be used with first-line medications—patients are monitored in a manner similar to that used during the first year of treatment, with therapy escalated if further disease activity is noted. For patients with more aggressive disease, an induction strategy using a second-line agent (eg, natalizumab) may be given for 1–2 years; use of the first-line agent then may be resumed with a more acceptable safety profile. In even more aggressive cases, escalation maintenance may be used, such that a second-line or higher-tier medication is used indefinitely, since first-line agents may no longer be effective in this population.

The long-term safety profile of these agents is not well defined. Treatment with natalizumab for more than 2 years in patients who are positive for anti-JCV antibody increases the risk of PML, and use of mitoxantrone is limited by lifetime maximum exposure. As with any treatment decision, switching should be based on a risk-benefit profile, although newer agents do not have a clearly defined long-term safety profile outside of clinical trials.

Individualization of a treatment plan should be based on the perceived risk of disease progression, with use of more aggressive treatments reserved for patients with a large burden of silent lesions at initial presentation or early disease progression.13 Early on, a plan should be in place for switching medication if the patient has early disease progression or cannot tolerate therapy with a particular agent.

SYMPTOMATIC MANAGEMENT
Based on a presentation by Stephen Krieger, MD, Assistant Professor of Neurology, Mount Sinai Medical Center, New York, New York.

Managing MS patients entails a comprehensive evaluation of symptoms that may affect them as a result of the disease. At each visit, addressing these components can help improve patient functioning and quality of life. Often, addressing the symptoms of disease involves a multidisciplinary approach and, in some cases, is achieved by reducing polypharmacy. Common symptoms affecting MS patients include fatigue, spasticity, weakness, balance, mobility, tremor, paroxysmal symptoms, bladder issues, pain, and depression.

Fatigue
Fatigue may be the most common MS symptom. Assessment of fatigue involves screening for depression, common medical problems (eg, hypothyroidism), polypharmacy, and sleeping difficulty. The pathophysiology of fatigue in MS is multifactorial and likely includes a combination of cytokines and neurochemicals secreted throughout the nervous system. Underlying disability may require extra energy expenditure, and fatigue may be most prominent in excessively warm weather or at the end of the day.14

Factors that can contribute to poor sleep in patients with MS include poorly treated pain or spasticity, restless legs syndrome, and anxiety. The Epworth Sleepiness Scale is a simple questionnaire that can be completed by patients to clarify whether poor sleeping habits are contributing to fatigue. Affected patients may be referred to a sleep disorders clinic, since management of sleeping problems can significantly improve fatigue.15 After sleeping problems and polypharmacy have been addressed, patients with continued fatigue can try pharmacologic therapies. Various medications such as amantadine, modafinil, and methylphenidate have been used to combat fatigue in patients with MS with limited success and should be selected on a case-by-case basis.14

Spasticity
On physical exam, signs suggesting that a patient is starting to develop spasticity may include weakness, pain, and hyperreflexia. Identifying the type of spasticity as phasic or tonic may help guide further treatment decisions. Phasic spasticity is defined as painful muscle spasms that occur intermittently. Conversely, tonic spasticity is long-lasting and is associated with stiffness and restricted mobility.16 The Modified Ashworth Spasticity Scale can help quantify tonic spasticity and may allow comparison across visits.17

Effective management of spasticity can aid in pain control, hygiene, prevention of contractures, mobility, and functional independence.

The most critical portion of spasticity treatment is to remove any contributing noxious stimuli. Spasticity initially should be addressed by physical therapists.

Beyond physical therapy and stretching, medications can be useful. First-line oral medications (eg, baclofen, tizanidine, and benzodiazepines) can be helpful, but their use often is limited by sedation. Certain antiepileptics (eg, gabapentin, carbamazepine, and levetiracetam) are useful for managing phasic spasticity, particularly to break the cycle of pain and spasticity. Injection with botulinum toxin may improve focal spasticity, particularly in distal muscles, but it causes weakness of the injected muscle. For patients with generalized spasticity that requires high doses of oral medications, an intrathecal baclofen pump is another treatment option.18

Limited Mobility
Mobility can be limited due to weakness, dorsal column sensory loss, visual impairment, edema, or ataxia in MS.19,20 External factors such as social attitudes, accessibility of businesses, and climate also contribute to limited mobility. Incorporation of physical therapy for gait assessment and evaluation for assistive devices can be important in improving mobility in these patients. Specific interventions such as ankle-foot orthosis, electrical stimulation, and compression stockings also may be beneficial.

The T25FWT is a useful screening tool for walking impairment and may be used as a comparison tool across visits to assess changes. Treatment with dalfampridine can improve performance on the T25FWT but may cause dizziness, gastrointestinal upset, and insomnia. At higher doses, there is a risk of seizures.

Balance and coordination often is affected in MS patients. Once again, physical therapy has a significant role in teaching balance-training exercises to patients.20

Bladder Difficulties
Bladder difficulties can occur in MS patients due to either a spastic (storage) or hypotonic (emptying) dysfunction. Differentiating between the types of dysfunction is crucial to guide treatment.

Patients with spastic bladder typically complain of urinary frequency and urge incontinence, which are best treated with medications such as oxybutynin. However, patients with hypotonic bladders typically complain of urinary hesitancy, which is treated with α-adrenergic 1 antagonists or intermittent catheterization. Initial evaluation of bladder disorders should include screening for urinary tract infection, post-void residuals, and occasional referral to a urologist for urodynamic testing or cystometry.21

Episodic Symptoms
Episodic symptoms in MS can also be disturbing. Paroxysmal symptoms include pain, tonic spasms causing intermittent dysarthria, myokymia, sensory phenomena (eg, trigeminal neuralgia, Lhermitte's phenomenon, and numbness), or Uhthoff's phenomenon, which causes transient visual impairment. Treatment should be directed at the type of complaint, but pain and sensory symptoms have improved with use of either antidepressants or anticonvulsants (eg, carbamazepine or gabapentin). Patients with trigeminal neuralgia who do not respond to pharmacologic intervention may be referred to a neurosurgeon for surgical intervention. A course of IV corticosteroids is a reasonable option if the sensory or visual complaints are new and signify a relapse.18,22

Mood Impairment
Mood impairment can be a disabling symptom of MS. Depression is common; its exact cause is not known, but it may be a reaction to the diagnosis, a sign of the unpredictability of the disease, or a side effect of interferon therapy. Unfortunately, patients with untreated depression can experience worsening of other MS symptoms. Screening for depression includes administering a simple two-question test recommended by the US Preventive Services Task Force, which screens for depressed feelings or anhedonia over the previous 2 weeks.

Common side effects of antidepressant therapy include anticholinergic effects, sexual dysfunction, and weight gain.23,24 Pseudobulbar affect characterized by outbursts of inappropriate laughing or crying also may occur in MS patients. A US Food and Drug Administration–approved medication that combines dextromethorphan and quinidine may significantly reduce the frequency and severity of outbursts due to pseudobulbar affect.24

Summary
Incorporating ancillary services, referrals to other specialists, and appropriate pharmacologic interventions may improve the quality of life of MS patients significantly. Too often, patients may express hopelessness due to the diagnosis of a chronic, potentially disabling disease. Management of secondary symptoms is as valuable as prevention of further relapses.

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Dr. Stroup is a Multiple Sclerosis Fellow in the Department of Neurology, University of Chicago Medicine, Chicago, Illinois.

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