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CME: Neurology

A current understanding of multiple sclerosis

Shull, Catherine MPAS, PA-C; Hoyle, Brittany MMS, PA-C; Iannotta, Caylin MMS, PA-C; Fletcher, Eden MMS, PA-C; Curan, Megan MMS, PA-C; Cipollone, Victoria MMS, PA-C

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Journal of the American Academy of Physician Assistants: February 2020 - Volume 33 - Issue 2 - p 19-23
doi: 10.1097/01.JAA.0000651716.72042.21
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Box 1
Box 1

A 59-year-old man with a history of hypertension and vision changes presents to an outpatient family practice clinic with a 2-day history of intermittent dizziness, lightheadedness, and fatigue.

The patient's symptoms are present at rest and worsen with movement. He has difficulty walking in a straight line and his wife has noticed that he walks with a wider, broader-based gait and has problems with balance. Seven months ago, the patient was seen in clinic and by his optometrist; he had experienced 4 weeks of blurred vision while reading. Both physical examination and a formal eye evaluation noted no pathology. A brain MRI was performed and showed multiple lesions in the periventricular white matter. At that time the patient was referred to a neuro-ophthalmologist who believed the vision changes were due to scotoma and unrelated to the MRI findings of possible sarcoidosis or multiple sclerosis (MS). The patient's visual symptoms subsequently resolved without recurrence. However, he and his wife are worried about his new-onset dizziness, gait problems, and unsteadiness. He was referred to a neurologist who felt that a diagnosis of MS could be made based on this second acute neurologic event.


MS is an autoimmune inflammatory disorder characterized by selective demyelination of central nervous system (CNS) axons. Although its exact cause remains unknown, MS likely is due to a combination of environmental, immunologic, and genetic influences. Patients present with various neurologic symptoms based on the location of demyelinated lesions. Therefore, providers must be able to recognize potential MS presentations and provide timely referral to a neurologist specializing in this disorder. Current management strategies focus on treating acute flares and reducing disease progression. Several medications are approved for treatment, though various adverse reaction profiles and patient comorbidities determine their use. A specialist team manages disease-modifying therapies (DMTs) for MS, but providers play a vital role in recognizing initial symptoms or relapses and assisting in management strategies.

Box 2
Box 2


The predicted prevalence of MS in the United States in 2017 was 913,925, which is more than twice the previous estimate of 400,000 patients.1,2 Women are two to three times more likely than men to develop MS, though some less common subtypes of the disease have a male predominance.3 Disease prevalence is highest in patients ages 55 to 64 years.1 Vitamin D deficiency has been identified as a risk factor for MS development, and patients who live farther from the equator are more susceptible.2 Current interpretation of this trend is attributed to limited atmospheric absorption of UVB radiation at latitudes of 42° and greater during the winter months. Adequate levels of the active form of vitamin D (75 mmol/L or greater) reduce the likelihood of developing MS by 61%.4,5 Other important environmental risk factors include cigarette smoking, early-onset obesity, and previous Epstein-Barr viral infections.6

A positive family history also is a predisposing factor for the disease, as siblings of affected patients have about a 30% higher risk of developing MS compared with the general population.7 Genetics influence patient susceptibility, as more than 100 genes have been identified in association with MS.6 Although multiple aspects contribute to the development of MS, modifiable factors such as tobacco use and vitamin D deficiencies can be targeted to reduce risk.


Presenting signs and symptoms vary based on lesion location and MS type. Typical presentations can include acute unilateral optic neuritis, diplopia, trigeminal neuralgia, facial sensory loss or motor disturbances, cerebellar ataxia, nystagmus, urinary urge incontinence, constipation, or erectile dysfunction.8,9 Fatigue, which affects up to 80% of patients, is one of the most common and overwhelming symptoms.9 Other common manifestations involve visual disturbances such as diplopia, unilateral vision loss or reduced vision, and painful eye movements.9 Many patients experience ascending sensory disturbances and asymmetric limb weakness, which contribute to problems with mobility and balance and cause frequent falls.9 Some may develop Lhermitte syndrome, which presents as a shooting, electric-like sensation down the spine with occasional radiation into the limbs following cervical flexion.9 Patients also may experience Uhthoff phenomenon, in which exposure to high temperatures such as hot showers or baths can reduce visual acuity and cause other optic abnormalities.10 Have a high suspicion for MS in any patient younger than age 50 years who presents with a history of neurologic symptoms occurring for several days to weeks with subsequent improvement.9


Classic MS can be categorized into four types:

  • Relapsing-remitting, the most common type, accounts for about 85% of patients with MS.8 This type of MS is characterized by periods of stable neurologic disability with intermittent acute exacerbations.11
  • Primary progressive is characterized by subsequently worsening neurologic function without relapse.11
  • Secondary progressive is associated with an initial relapsing-remitting course that becomes a steady neurologic decline.11
  • Clinically isolated syndrome (CIS) is a more recent classification, and represents a first clinical presentation that may demonstrate focal or multifocal inflammatory demyelination, but does not meet diagnostic criteria for MS.11 Patients who have a single neurologic episode that meets criteria for CIS are at increased risk for a subsequent flare leading to an MS diagnosis.11

Myelocortical MS was identified in 2018.3 In this new subtype, demyelinated lesions are isolated to the spinal cord and cerebral cortex; typically, they are not present in the white matter of the brain.3 This variance in distribution results in a symptomatic presentation and diagnostic workup that is different from the more classically occurring subtypes.3 One study found that 12% of patients previously diagnosed with other MS variants could be posthumously reclassified as having the myelocortical subtype.3 Because researchers are still attempting to elucidate the differences between myelocortical MS and other classifications, this subtype will not be the focus of this article.


Diagnoses that present similarly to MS include varying types of vasculitis, HIV infection, Lyme disease, thyroid dysfunction, and several nutritional deficiencies.12 Many of these require less invasive testing for diagnosis and should be performed before imaging for MS. Eliminating these disorders from the differential diagnosis can be accomplished by evaluating thyroid, liver, and renal function; HIV serology; vitamin B12 levels; inflammatory markers; comprehensive metabolic panel (CMP); and complete blood cell (CBC) count.9

If preliminary test results lead the clinician to suspect a MS diagnosis, a neurology consult is warranted in case a more thorough workup or long-term management is required. Gadolinium-enhancing T2 MRI of the brain and spinal cord remains the most sensitive diagnostic test for relapsing-remitting MS. New advances in MRI technology are leading to higher-resolution imaging that may be tailored to the assessment of individual patients. Depending on the location of a suspected demyelination, variations in the type and orientation of MRI can enhance visualization of lesions. These improvements are being successfully implemented in clinical practice.13 When following an initial CIS presentation, an MRI can be used to achieve the most rapid MS diagnosis and treatment initiation.12 The 2017 McDonald diagnostic criteria enable clinicians to identify relapsing-remitting MS more rapidly than previous protocols allowed (Table 1). Similar to the 2010 McDonald criteria, the 2017 update requires the presence of lesions identified via MRI that are separated in both space and time for a diagnosis of relapsing-remitting MS. However, inclusion of cerebrospinal fluid (CSF) findings and more broadly localized lesions now satisfy new diagnostic parameters.14 In one study, diagnosis was achieved more quickly in 63.5% of patients using the 2017 McDonald criteria, with a reduction time of 7.2 months compared with the 2010 criteria.12

2017 diagnostic criteria for relapsing-remitting MS13

Demyelinating lesions found on MRI must satisfy several basic diagnostic parameters, the most fundamental of which is the presence of lesions disseminated in space and time.

Dissemination in space refers to evidence of demyelination in multiple distinct CNS regions, such as the spinal cord and cortical, juxtacortical, supratentorial, or periventricular brain regions.14

Dissemination in time correlates with the development of new demyelinating lesions in the CNS at different points in time.14 With the 2010 criteria, these parameters were only satisfied by lesions found on MRI that were not directly related to symptomatic presentation.14

With the exception of lesions in the optic nerve and associated optic neuritis, both symptomatic and nonsymptomatic lesions now meet diagnostic criteria.14

Dispersal of brain lesions also has been expanded with the 2017 criteria, and allows inclusion of juxtacortical and cortical lesions, as well as those in the spinal cord, to satisfy the requirement for dissemination in space (Table 1).14 Cortical and juxtacortical lesions are considered equivalent, however, and the presence of both in the absence of an additional lesion outside this domain is insufficient to satisfy dissemination in space.12 The 2017 criteria still require the presence of at least one periventricular lesion, and the identification of more is recommended in patients who have other potentially causative factors such as vascular disease, migraines, or advanced age.14 In addition to brain MRI, the Consortium of MS Centers strongly recommends cervical cord imaging if MS is suspected. Symptomatically silent lesions most commonly are found in this region, and may be used to expedite diagnosis if discovered on MRI. These lesions also have a high specificity for progression to true MS when identified in patients presenting with CIS.13,15

The most drastic change to the diagnostic criteria for relapsing-remitting MS is that the presence of oligoclonal banding in CSF may now be used to satisfy dissemination in time.14 The banding manifests as a result of intrathecal antibody development due to demyelinating lesions and now fulfills this criterion, even in the absence of new lesions on MRI.12 Furthermore, the presence of banding is a proven indicator of increased patient risk for subsequent symptomatic flares.12 Under the 2010 criteria, dissemination in time was only confirmed with new lesions developing over weeks to months.14 The use of oligoclonal banding in the diagnosis now enables earlier administration of DMTs and improved outcomes.12


Although MS has no definitive cure, treatment can manage relapses and delay long-term disease progression. A relapse is defined as acute or subacute symptoms and neurologic findings that last at least 24 hours in the absence of fever or infectious signs.14 Patients presenting with these exacerbations should be treated with a short course of high-dose corticosteroids such as oral methylprednisolone 0.5 g daily for 5 days.9 Patients who cannot tolerate oral corticosteroids or whose symptoms are unresponsive can be given 1 g IV methylprednisolone daily.9 Oral and IV methylprednisolone have similar efficacy and safety profiles.16

Early and accurate diagnosis is essential, and newly diagnosed patients should be referred to a specialist for initiation of DMT, which can reduce relapse frequency and disease progression. Several DMTs are approved for treatment of relapsing-remitting MS, but only one has been shown to reduce disease progression in patients with primary progressive MS.17 In 2018, the American Academy of Neurology (AAN) released guidelines advising clinicians on initiation, continuation, and cessation of various DMTs.17 AAN recommends that the specialist team discuss switching medications if the patient continues to experience exacerbations after 1 year of using a given DMT, or if two or more new lesions have been found on MRI.17 The guidelines also recommend offering DMTs to patients with CIS. For patients with neurologic symptoms that do not meet diagnostic criteria, treatment with certain DMTs can reduce the risk of conversion to MS.17,18 With numerous new DMTs added to the market over the past several years, clinicians can choose from many options that have varying efficacies, safety profiles, routes of administration, and monitoring requirements.


Much like the multifactorial decision for DMT therapy, an individualized approach toward nonpharmacologic treatments can reduce relapse rates and improve patient quality of life. Both pharmacologic and nonpharmacologic treatment regimens must be quickly optimized to prevent cognitive and neurologic decline.19 Therapy optimization includes addressing specific deficits such as energy, cognitive function, physical ability, motor strength, and mental resilience.20 Individualization of nonpharmacologic therapy requires a comprehensive team of neuropsychologists, clinical psychologists, occupational and physical therapists, nutritionists, nurses, speech and language therapists, social workers, and continence specialists.9,20 Due to symptom variability and the progressive nature of MS, all care aspects should be thoroughly reviewed annually.9

Exercise and mindfulness training have emerged as effective nonpharmacologic treatments. Moderate progressive resistance training, aerobic exercise, balance, and stretching such as yoga can improve mobility and reduce fatigue.9 Exercise is a safe intervention and patients are at no greater risk for adverse reactions than patients without MS.21 Physical activity shows no detrimental effects during wellness intervention studies and may be associated with fewer relapses.21

Cognitive behavioral therapy, fatigue management, and mindfulness training address psychologic stressors and improve MS-related fatigue.9 Mindfulness training encourages the practice of nonjudgmentally acknowledging one's thoughts and focusing awareness on the present moment. This can help to improve patient quality of life by minimizing symptoms of worsening anxiety, depression, and other manifestations of psychologic distress that often develop after an MS diagnosis.22 Tailor interventions to patient interest, symptom profiles, and pharmacologic DMTs for true optimization of MS management and quality of life.


Newly diagnosed MS patients may find it helpful to understand disease progression and prognosis. Clinicians benefit from recognizing diagnostic factors that put patients at increased risk for more debilitating disease or, in those presenting with a CIS, progression to true MS. The Expanded Disability Status Scale (EDSS) is routinely used to assess disability related to disease progression.23 Although the EDSS has been criticized for its reliance on walking as the primary means of determining debility, it remains the most widely used screening tool. The disability severity scale ranges from 1 (no disability) to 10 (death related to disease progression), with a score of 3 or greater corresponding with significant disability.23

The number of presenting lesions on initial MRI and the presence of oligoclonal bands are the most critical factors for determining recurrence and debility of diagnosable MS. The best predictive factor for MS development and related disability with a CIS is the initial number of demyelinating lesions identified on T2 MRI; the presence of oligoclonal banding correlates with increased recurrence of symptomatic flares.12,23 One study found that for patients with a larger number of presenting lesions (10 or more found on MRI), the likelihood of developing significant disability within 5 years of diagnosis was about 11%, and up to 30% within 10 years.23

Gender does not appear to play a statistically significant role in MS recurrence or progression, despite an overall greater risk of initial CIS presentation in females.23 Younger patients with CIS onset have an increased risk of progression to diagnosable MS, but a lower risk of developing significant disability, though the statistical significance is marginal.23 Interestingly, CIS presentation associated with optic neuritis appears to be a protective factor, reducing the likelihood of significant future disability and an eventual diagnosis of MS.23

Mortality associated with disease progression has been difficult to quantify, as the most common causes of death are complications related to longstanding MS and resulting immobility, including cardiac and respiratory failure, malnutrition, aspiration, uremia, and septic shock.24 Survivability therefore is not typically used as an outcome measurement for determining treatment efficacy.16 Patient mortality is influenced by MS classification, age at diagnosis, presence and severity of systemic complications, and delays in initiation of DMTs.23 Regardless of the underlying cause of death, patients with MS have a predicted 7- to 14-year reduction in their total life expectancy.24


Although clinical research is rapidly expanding our understanding of MS, it remains a complex disorder with variable presentations. Clinicians must be able to recognize risk factors, signs, and symptoms suggestive of MS in order to make appropriate and timely neurologic referrals. These referrals can now be made to MS centers across the United States that have multidisciplinary teams providing a comprehensive approach to care. The 2017 updates to the McDonald criteria can bring about expedited diagnosis and treatment, with a focus on managing acute flares, preventing relapse, and slowing long-term progression using corticosteroids and DMTs. Nonpharmacologic treatments aim to maintain motor function, manage psychologic stress, and improve quality of life. Further research into disease processes, risk factors, and comparative efficacy of DMTs and their long-term effects will continue to increase our knowledge of MS and improve patient care. In order to be integral members of the comprehensive care team as research evolves, clinicians should remain current in their understanding of MS presentation, diagnosis, and treatment.


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multiple sclerosis; epidemiology; risk factors; 2017 McDonald criteria; clinical manifestations; treatment strategies

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