Evaluating a patient with intermittent neurologic symptoms can be a complex process with a myriad of differential diagnosis and diagnostic algorithms. Often times, the nonneurologist will overlook multiple sclerosis (MS) as a differential diagnosis, because traditionally MS has been viewed as a diagnosis of exclusion and other more common etiologies need to be ruled out. Although the diagnosis of MS is still uncommon, it is the most common neurologic disorder of young adults in the United States, affecting nearly 1 million people in the United States and 2.5 million globally, with the median prevalence estimated at nearly 33 per 100,000 globally as of 2013 and continuing to increase.¹ As the prevalence of MS increases, it is important for the nonneurologist to have a basic understanding of a neurologist’s perspective on the evaluation and diagnosis of a patient with a high likelihood for MS. When considering MS as a diagnosis, there are telltale signs and symptoms that should stand out as more disease
specific for MS, involving symptom timeline, magnetic resonance imaging (MRI) findings, physical examination findings, and common laboratory or diagnostic tests, which can help differentiate MS from other common disease mimics. Understanding some of the subtleties and atypical disease presentations can provide a nonneurologist with a valuable skillset to provide an earlier diagnosis and treatment options. Although this chapter is not intended to be a comprehensive reference for physicians, it will surely provide an efficient and effective framework for the evaluation and diagnosis of MS. Let us first start by demonstrating a common clinical scenario that a nonneurologist may encounter, to set the stage for more detailed discussion about further workup and diagnosis.

One of the many difficulties with diagnosing MS lies in the fact that the disease presentation and neurologic symptoms are largely variable between each clinical case, depending on the location and severity of central nervous system (CNS) demyelinating lesions. To date, there are four different clinical phenotypes of MS, each presenting with a slightly different disease course: clinically isolated syndrome (CIS), relapsing remitting (RR), primary progressive (PP), and secondary progressive (SP). To complicate the clinical picture further, three of the phenotypes (RR, PP, SP) are technically classified as either “active” or “not active” and “worsening” or “not worsening”² (see Figure 3.1). Although proper disease classification is not essential for initial diagnostic purposes, it highlights the complexity of disease course and the burden that is bestowed upon the diagnosing physician.

Traditionally, MS has been defined as a diagnosis of exclusion. There is no single test or pathognomonic feature that is specific for MS, and although the advent of MRI has greatly improved ease of diagnosis, MS remains primarily a clinically diagnosed disease. However, in recent years, more concerted efforts have attempted to create more definitive diagnostic criteria for the disease. Since 2001, the McDonald criteria have been used as the gold standard for diagnostic criteria in MS. Over the past 2 decades they have been revised multiple times, most notably in 2010, with more minor clarifications made in 2017 (see Table 3.1) to add specificity to the 2010 criteria and improve diagnostic value.⁴

According to the 2017 criteria (see Table 3.1), for patients with a clinical course that begins with a neurologic attack, MS can be definitively diagnosed in two separate scenarios without the need of additional information. First, if a patient suffers at least two neurologic attacks with objective clinical evidence of at least two CNS lesions. Second, if a patient has at least two clinical attacks, with evidence of one CNS lesion and reasonable historical evidence of a prior attack involving a distinct anatomical region. However, there are other clinical presentations that do require other additional information to make the diagnosis of MS. Before we explain these clinical scenarios, there are specific terms that should first be explained.

Disseminated in Space (DIS): Although there is still some debate, DIS refers to the development of lesions in distinct anatomical locations within the CNS, indicating a multifocal CNS process. It can be demonstrated by one or more T2-hyperintense lesions that are characteristic of MS in two or more of four areas of the CNS: periventricular, cortical or juxtacortical, and infratentorial brain regions and the spinal cord.⁴

Disseminated in Time (DIT): The development or appearance of new CNS lesions over time. This can be demonstrated by the simultaneous presence of gadolinium-enhancing and nonenhancing lesions at any time or by a new T2-hyperintense or gadolinium-enhancing lesion on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI.⁴

In addition, the 2017 criteria provided further explanation for CIS, and understanding the nuances of this definition is important in the diagnostic algorithm of MS. CIS can be defined as a monophasic clinical episode reflecting a focal or multifocal inflammatory demyelinating CNS event, developing acutely/subacutely, lasting at least 24 hours, in the absence of fever or infection, in a patient not known to have MS. If the patient eventually satisfies the diagnostic criteria for MS, the Clinical Isolated Syndrome will be known as the patient’s first attack/relapse.⁴

According to the 2013 revised classifications of MS phenotypes, the disease onset can be defined by MS with an attack onset or a progressive course onset.² Diagnosing patients with the PP subtype of MS, which is defined by its progressive disease course, also has its own unique diagnostic criteria (see Table 3.2).

Identifying signs and symptoms can often be difficult, as the disease process can be subtle and occur over a long time period, with large gaps between initial symptoms. Patients will often forget or downplay symptom significance, and it can be crucial for practitioners to ask detailed questions to elicit all necessary information. Furthermore, a detailed review of systems is often extremely valuable for collecting vital information. Often times, patients present to clinic for further evaluation after symptoms have already started to affect work performance, daily function, or quality of life. Identifying disease symptoms and establishing an accurate timeline of events is an essential step that will dictate further diagnostic workup and aid in quicker diagnosis and earlier treatment. Table 3.3 is a brief summary of common presenting symptoms for MS. This is by no means a comprehensive list but rather includes major neurologic red flags that a practitioner should identify. Furthermore, these symptoms can also be present in many other diseases and in a large severity spectrum, which will be discussed in the next section.