Diagnosing MS: Recognizing Common Symptoms and Interpreting MRI Results
Michael C. Levin, MD
W. Clay Jackson, MD, DipTh
Multiple sclerosis (MS) is a common cause of neurological disability, with a lifetime risk of 1 in 400 and more than 400,000 US adults affected.1,2 Typically diagnosed in people between 20 and 40 years of age, MS affects 2 times more women than men.2 While demyelination in the CNS causes the inflammation and sclerotic plaques (or scars) for which MS is named, this disease is characterized by diverse symptoms for each patient that cause varying degrees and progression of disability, from full to partial paralysis, cognitive disabilities, and impairments in vision, speech, or elimination.1 Accurately diagnosing MS as early as possible is crucial for slowing disability and disease progression through the use of disease-modifying therapies. Three keys to diagnosing MS include recognizing common symptoms, administering appropriate tests, and excluding other conditions.
Recognizing Common Symptoms
To diagnose MS, clinicians must start with a thorough patient history and physical exam, looking for current neurologic symptoms or a previous attack.3 The most common symptoms in MS are sensory motor problems, with about one-third of patients describing symptoms such as numbness or tingling in the arms and legs, an electric current sensation down the back or legs, or useless hand syndrome.4 Additionally, patients often report vision problems, particularly vision loss or eye movement disorders, and slow progressive or acute motor deficits.4 Symptoms seen in less than 5% of patients at onset include bladder dysfunction, heat intolerance, paroxysmal symptoms, pain, movement disorders, and dementia.4 Most symptoms are the result of new lesions in specific areas of the CNS (AV 1).1
An indication of a first attack, or clinically isolated syndrome (CIS), is an acute inflammatory demyelinating event in the CNS (eg, an attack of optic neuritis or weakness on one side) lasting at least 24 hours, without evidence of infection, fever, or encephalopathy.5 This first attack can be patient-reported or clinician-observed.5
Administering Appropriate Tests
Magnetic resonance imaging (MRI). To diagnose clinically definite MS (CDMS), patients with one CIS formerly were required to wait for an observable second event to indicate new neurologic symptoms. However, the 2010 revision of the McDonald MS diagnostic criteria,5 which has been shown to have an 86% rate of sensitivity and 93% rate of accuracy, enables clinicians to diagnose MS in patients with a CIS in 1 visit using MRI scans.6 In conjunction with a thorough patient history, an MRI can show evidence of lesions as disseminated in time and space, both requirements that must be met in order to receive an MS diagnosis.
To identify lesions in the brain, T1- and T2-weighted images are 2 types of MRI scans commonly used. According to the updated criteria, T2 lesions disseminated in space (ie, in more than one area) must appear in at least 2 of these 4 CNS areas: periventricular, juxtacortical, infratentorial, or spinal cord.5 A lesion found in the corpus callosum is also indicative of MS because few other conditions attack that area of the brain (AV 2). Gadolinium may be injected to enhance areas of inflammation on the MRI scans, but it is not required here.5
Lesions disseminated in time (ie, occurring at different points in time) can be demonstrated in a few ways. A patient may have 1 lesion at baseline and then, on follow-up MRI, have a new T2 and/or gadolinium-enhancing lesion. Or, a patient could have the simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time.5 Since MRI scans can show both old and new lesions in the CNS, clinicians can confirm lesions at 2 different times through the patient history and an MRI during 1 visit. For some patients, however, additional diagnostic visits may be necessary.
When diagnosing MS and determining patients’ prognoses, MRI scans can aid in predicting patients’ conversion to MS and long-term disability. For example, in a 14-year longitudinal study7 of patients with a CIS, CDMS developed in 88% of patients with abnormal MRI results at baseline but in only 19% of patients with normal MRI results. Of the 17 patients with more than 10 lesions at baseline, 15 developed CDMS. Thus, the number of lesions at first presentation indicates patients’ risk of conversion from CIS to CDMS. Additionally, patients with more and larger lesions developed worse disability than those with fewer and smaller lesions.7
Cerebrospinal fluid (CSF). Although no test alone can confirm or rule out an MS diagnosis, a CSF analysis can supplement other diagnostic procedures. The CSF of patients with MS often contains elevated levels of IgG antibodies and a group of proteins called oligoclonal bands. In addition to having lesions in the brain (≥ 1) or spinal cord (≥ 2) areas, a positive CSF can be used to diagnose primary progressive MS, according to the updated McDonald criteria.5 Further, the presence of CSF abnormalities can also confirm inflammation, which may be helpful in ruling out other disorders.1 However, a negative CSF does not rule out MS, since up to 10% of MS patients do not show CSF abnormalities.8
Visual evoked potential (VEP). The VEP test is used to find impairment and detect demyelination along optic nerve pathways, and it may reveal problems even before the patient has experienced visual symptoms. Because 20% of patients with MS initially present with optic neuritis, 50% of whom develop MS within 15 years,9 the VEP can be a useful and supplemental diagnostic tool. Clinicians should be aware that patients with MS may or may not experience eye pain, which can range from dull and aching to sharp and piercing.
Laboratory tests. While an MRI scan showing CNS lesions is always needed for an MS diagnosis, laboratory tests may be helpful for ruling out other conditions that can mimic MS, such as lupus erythematosus, infections, hereditary diseases, and even vitamin and mineral deficiencies. A few tests that clinicians can administer during the differential diagnosis include a complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, antinuclear antibody test, B12/folate levels, and Lyme disease test. Based on the patient’s history and physical examination, clinicians should determine the most appropriate lab tests to order, since doing a complete work-up is expensive and time-consuming.
Excluding Other Conditions
If a patient is suspected to have MS, several conditions may need to be excluded before making a definitive diagnosis (see Differential Diagnosis). To help clinicians assess patients whose MRI findings are abnormal, the European group, MAGNIMS, convened to define MRI red flags, or features atypical for MS but suggestive of another diagnosis (Table 1).10 For example, an MRI with T2 lesions of the temporal pole, U-fibers at the vertex, and external capsule or insular regions indicates CADASIL, an inherited cerebrovascular disease, rather than MS.10 Instead of assuming a diagnosis of MS based on MRI findings but no better explanation for symptoms, clinicians can use MRI red flags to reduce misdiagnosis and subsequently direct patients to appropriate treatment for the correct condition.10
In addition to MRI red flags, clinical red flags may also indicate an alternative diagnosis. For example, bone lesions are a clinical red flag for histiocytosis or Erdheim Chester disease, while peripheral neuropathy could stem from B12 deficiency, adrenoleukodystrophy, metachromatic leukodystrophy, and Lyme disease.11 Clinicians should be alert to red flags and refer challenging cases to a specialist.
Patients who experience atypical symptoms are likely to have a condition other than MS. In a study12 of patients referred with suspected MS (AV 3),12 atypical symptoms had higher sensitivity (84%) and specificity (90%) for refuting an MS diagnosis versus the presence of red flags (47% and 88%, respectively). This study shows the importance of recognizing atypical symptoms or unusual MRI findings in patients with CIS or suspected MS and following up with additional testing or referrals where necessary.
An accurate and timely diagnosis of MS can enable clinicians to initiate treatment as soon as possible to slow patients’ disease progression. Based on the patient’s history and examination, clinicians should focus questioning and testing on common symptoms stemming from inflammation in the CNS. If the patient appears to have had a CIS, an MRI scan can confirm lesions in time and space. The next step is to administer additional tests if the diagnosis is not clear or if the patient has atypical symptoms or red flags that indicate other conditions. Getting a second opinion or examining the patient a second time can help in difficult cases.
- Look for typical and atypical symptoms of MS
- Make a clinical diagnosis of MS based on a thorough patient history and examination along with MRI scan to assess lesions disseminated in time and space
- Order tests as appropriate to the individual and know the red flags to help you rule out other conditions
- CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
- CDMS = clinically definite multiple sclerosis
- CIS = clinically isolated syndrome
- CNS = central nervous system
- CSF = cerebrospinal fluid
- IgG = immunoglobulin G
- MAGNIMS = Magnetic Resonance Network in Multiple Sclerosis
- MRI = magnetic resonance imaging
- MS = multiple sclerosis
- VEP = visual evoked potential
- 1. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359(9313):1221–1231. PubMed
- 2. Multiple Sclerosis Foundation. Facts about MS. http://www.msfocus.org/Facts-about-MS.aspx. Updated 2013. Accessed May 19, 2014.
- 3. Poser CM, Brinar W. Diagnostic criteria for multiple sclerosis: an historical review. Clin Neurol Neurosurg. 2004;106(3):147–158. PubMed
- 4. Paty DW. Initial symptoms. Burks JS, Johnson KP, eds. Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation. New York, NY: Demos; 2000:75–76.
- 5. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. PubMed
- 6. Runia TF, Jafari N, Hintzen RQ. Application of the 2010 revised criteria for the diagnosis of multiple sclerosis to patients with clinically isolated syndromes. Eur J Neurol. 2013;20(12):1510–1516. PubMed
- 7. Brex PA, Ciccarelli O, O’Riordan JI, et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002;346(3):158–164. PubMed
- 8. National Multiple Sclerosis Society. Cerebrospinal fluid (CSF). http://www.nationalmssociety.org/Symptoms-Diagnosis/Diagnosing-Tools/Cerebrospinal-Fluid-%28CSF%29. Accessed May 19, 2014.
- 9. Voss E, Raab P, Trebst C, et al. Clinical approach to optic neuritis: pitfalls, red flags and differential diagnosis. Ther Adv Neurol Disord. 2011;4(2):123–134. PubMed
- 10. Charil A, Yousry TA, Rovaris M, et al. MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation.” Lancet Neurol. 2006;5(10):841–852. PubMed
- 11. Miller DH, Weinshenker BG, Filippi M, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler. 2008;14(9):1157–1174. PubMed
- 12. Kelly SB, Chaila E, Kinsella K, et al. Using atypical symptoms and red flags to identify non-demyelinating disease. J Neurol Neurosurg Psychiatry. 2012;83(1):44–48. PubMed
From the Series:
Supported by educational grants from EMD Serono and Genzyme, a Sanofi Company.
CME Background Information
Supported by educational grants from EMD Serono and Genzyme, a Sanofi Company.
Participants may receive credit by reading the activity, correctly answering 100% of the questions in the posttest, and completing the evaluation.
After completing this educational activity, you should be able to:
- Diagnose and counsel a patient with clinically isolated syndrome or MS
- Recognize common symptoms and signs of MS
- Recognize and interpret brain MRI findings in MS patients
The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure are as follows:
Dr Levin is a consultant for Merck and Gerson Lehrman, holds a patent titled Biomarker for Neurodegeneration in Neurologic Disease, and owns A1 Brain Diagnostics.
Dr Jackson is a consultant for DepoMed, Pamlab, and Sunovion; has received honoraria from Otsuka; and is a member of the speakers’ bureaus for Pamlab and Sunovion.
The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
The American Academy of Physician Assistants (AAPA) accepts certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by ACCME or a recognized state medical society. Physician assistants may receive a maximum of 0.5 hours of Category I credit for completing this program.
To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.
Release, Review, and Expiration Dates
This Neurology Report was published in July 2014 and is eligible for AMA PRA Category 1 Credit™ through July 31, 2017. The latest review of this material was May 2014.
Statement of Need and Purpose
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by diverse symptoms, an unpredictable course, and a highly variable prognosis. Functional disabilities are extremely common in MS, and some individuals may experience full or partial paralysis, cognitive disabilities, or impairments with vision, speech, or elimination. A diagnosis of MS is made based on the patient’s history, the presence of demyelinating lesions on brain or spinal cord MRI scans, and the exclusion of alternative diagnoses, yet many physicians, particularly those in primary care, still have difficulty diagnosing MS because of the heterogeneous nature of the disorder. Most patients who will develop MS initially present with a clinically isolated syndrome (CIS), but progression to clinically definite MS may be delayed or prevented if treatment with a disease-modifying agent (DMA) is initiated early. However, these agents are underused; evidence shows that less than half of patients with MS were prescribed DMAs. Because more than a quarter of patients with MS do not consult or have access to a neurologist, particularly those in rural areas, primary care physicians and other nonspecialists who are likely to provide care to patients with MS need more information on strategies for making an accurate and timely diagnosis of MS and on the importance of early treatment with DMAs. This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on MS.
Disclosure of Off-Label Usage
Dr Levin has determined that, to the best of his knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration–approved labeling has been presented in this activity.
The entire faculty of the series discussed the content at a peer-reviewed planning session, the Chair reviewed the activity for accuracy and fair balance, and a member of the External Advisory CME Board who is without conflict of interest reviewed the activity to determine whether the material is evidence-based and objective.
This Neurology Report is derived from the planning teleconference and live meeting series “Appropriate Management of Multiple Sclerosis in Primary Care: Focus on Rural Health,” which was held from June 2013 to March 2014, and is supported by educational grants from EMD Serono and Genzyme, a Sanofi Company. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.