Paraclinical tests including CSF examination and evoked potentials are frequently abnormal in patients with MS. Under prior diagnostic criteria [1, 5, 6], these ancillary tests were incorporated into diagnostic criteria for relapsing MS, and could be helpful for establishing a diagnosis if space and time requirements were not met clinically. Typically, CSF shows evidence of intrathecal synthesis of IgG as indicated by the presence of oligoclonal bands or elevated IgG index. Testing for oligoclonal bands, meaning two or more IgG bands in the CSF that do not appear in the serum, is a sensitive screening tool for MS and is reported to be positive in over 95 % of patients with MS [16], although in the authors’ experience, using commercial laboratories, this seems to be true in perhaps 60–70 %. However, this finding is nonspecific and can be seen in a host of inflammatory, infectious, neoplastic, hereditary, and vascular disorders. An elevated IgG index (CSF IgG–CSF albumin ratio compared to the serum IgG–serum albumin ratio) is similarly elevated in about 70–80 % of patients with MS, but rarely in oligoclonal band-negative patients [16, 17].

However, reliance on MRI has increasingly replaced the role of paraclinical testing for diagnosing relapsing MS (positive CSF can still be used to meet criteria for diagnosis of MS with progression from the start). However, these tests may be particularly useful in certain circumstances. In the scenario where a patient has CIS but does not meet MS criteria either clinically or via MRI, CSF with positive immunological markers can be helpful at predicting future conversion to MS independent of MRI characteristics [18, 19] and may influence the decision on whether to begin immunomodulatory treatment.

Perhaps most importantly, CSF analysis can be useful in ruling out alternative disease etiologies. The diagnosis of MS is often challenging because of the requirement that no better explanation for the neurologic symptoms be available. The extent and nature of additional testing that should be undertaken is highly case dependent. CSF analysis may be useful in excluding infectious or neoplastic etiologies. CSF that is highly cellular (>50 white blood cells [WBCs]/cubic μL) has a neutrophilic predominance, or a protein concentration greater than 100 mg/dL should raise suspicion for an alternative process.

Though less sensitive than MRI and no longer incorporated in diagnostic criteria, evoked potentials may be used to detect evidence of subclinical demyelination [20, 21]. Visually evoked potentials may show conduction delays and conduction blocks of the P100 potential in up to 75 % of patients with MS [22]. The N13 and N20 potentials of the median nerve and the P37 potential of the tibial nerve may be prolonged in somatosensory evoked potentials. Wave I–V latency may be prolonged in brainstem auditory-evoked potentials.

The most widely used scale for the measurement of the severity of neurologic disability in patients with MS is the Kurtzke Expanded Disability Status Scale (EDSS) [23]. This nonlinear ordinal scale rates patients on overall disability level in 0.5-point intervals ranging from 0 (no disability) to 10 (death due to MS) using a combination of neurologic signs, patient-reported symptoms, and measures of ambulation. It includes measures of severity of disability on seven functional/anatomic systems: visual, brainstem, pyramidal, cerebellar, sensory, bowel and bladder, and cognitive. Scores on these functional systems are combined in a non-additive way, along with measures of ambulation and reports of activities of daily living to obtain an overall EDSS score. Patients obtain scores of 0–3.5 based on combinations of functional system impairments, scores of 4.0–7.0 based primarily on limitations in ambulation, and scores of 7.5–10 based primarily on reports on activities of daily living. The EDSS is an imperfect measure for several reasons including its nonlinear nature (quantitative differences between consecutive scores are not equal or well-defined), strong emphasis on ambulation, and limited reliability and sensitivity to clinical change in the mid to upper ends of the scale [24, 25]. Despite these limitations, the EDSS is the most frequently used endpoint measure in MS clinical trials.

The Multiple Sclerosis Functional Composite (MSFC) is another frequently used measure of disability in clinical trials [26]. Objective quantitative measures of three different functional domains are assessed; lower extremity function/ambulation is measured by a timed 25-foot walk test; upper extremity function is measured by a 9-hole peg test; and cognition is measured by a 3-second paced auditory serial addition task. Scores on each measure are converted to standard scores (z-scores) and averaged to form a single MSFC score. This measure addresses some of the limitations of the EDSS by placing less emphasis on ambulation, having improved psychometric properties, and being more sensitive to small clinical changes. Limitations include the fact that vision and bowel/bladder function are not assessed.

When making a diagnosis of MS, it is important that the physician is supportive and provides education and counseling about the new diagnosis. Patients will naturally ask about their prognosis; although it may be difficult to predict the course of a given individual, an element of hope should always be emphasized. The physician can state that many patients do quite well and there are a significant number of effective medications that were not available as recently as a generation ago. Emphasizing that establishing the diagnosis provides an opportunity to intervene before significant (or any) disability develops may also be helpful. Referrals to mental health professionals can be extremely useful for issues such as anxiety or depression surrounding the diagnosis, and social workers can aid in matters such as issues of disclosure or, when appropriate, disability accommodations. Patients should also be counseled regarding reliable sources of information and should be urged to avoid unfiltered sources, particularly from the internet, which tend to portray worst-case scenarios and provide misleading, or potentially dangerous, advice. Patients can be referred to resources such as the National MS Society (in the United States) or the MS International Federation as reliable, balanced sources of information should they have questions. These societies can also assist in locating resources such as support groups, MS-specific exercise groups, and mental health professionals familiar with MS.

Patients should be counseled about the relapsing nature of the disease. They should be instructed to contact their physician if they experience new neurologic symptoms that last for over 24 h as this may be a relapse and may warrant an intervention such as steroids. Brief, transient symptoms do not usually indicate an acute MS exacerbation. Patients should be warned that prior or existing symptoms may resurface or worsen should they become overheated, tired, or ill, and that this is a transient physiologic phenomenon rather than meaningful new disease activity.

Patients almost inevitably have questions regarding what lifestyle modifications, if any, they should be undertaking. For those patients who smoke, this is a good opportunity to emphasize smoking cessation and the information that smoking is specifically “bad for MS” may be a powerful motivator for quitting. Patients should also be advised to supplement their vitamin D intake so as to keep it within a normal range. Patients should be counseled that, despite many claims, there are no particular dietary modifications that have been proven to help patients with MS and that a well-balanced, heart-healthy diet and an active lifestyle are recommended for patients with MS, as they are for the rest of the population. It may also be helpful to advise the patient not to allow MS to dominate his or her life in ways that are not necessary. Nonetheless, if a patient states that a particular dietary or lifestyle intervention (i.e., gluten-free diet, vegetarian diet, and water aerobics) is helpful with subjective symptoms (fatigue, pain, and stiffness), this decision should be supported, provided the intervention is not otherwise unhealthy.

Part of what makes the diagnosis of MS so challenging is that a diagnosis requires that no better explanation for the neurologic symptoms be available. The extent and nature of additional testing that should be undertaken is highly case dependent. When a patient presents with a typical relapsing course of characteristic symptoms and with typical MRI findings, little, if any, additional testing is necessary. However “red flags” in the clinical history, radiologic findings, or CSF could necessitate an extensive workup. In general, the differential diagnosis for MS is broad and includes infectious, vascular, neoplastic, genetic, and toxic/metabolic diseases as well as other non-MS idiopathic demyelinating disease such as neuromyelitis optica (NMO) and acute disseminated encephalomyelitis (ADEM).

Typical MS presentations include myelitis, brainstem or cerebellar syndromes, and optic neuritis (ON). MS myelopathy typically presents as a subacute partial myelitis with evolution of sensory and/or motor symptoms over hours to a few days. Lesions to the dorsal cord, the most typical cord location, may or may not be associated with a Lhermitte’s sign (or the barber chair phenomenon), an electric sensation traveling down the back and/or limbs elicited by neck flexion. Radiologically, spinal cord lesions are typically short, extending the length of no more than two spinal segments. When MS presents as a posterior fossa syndrome, typical presenting signs include internuclear ophthalmoplegia, sixth nerve palsies, facial numbness, vertigo, ataxia, and/or dysarthria. The ON of MS is typically unilateral and mild-to-severe (though rarely so severe as to eliminate all light perception); decreased acuity is usually associated with a cecocentral scotoma and decreased color saturation. ON is usually associated with pain on eye movements. Upon examination, an afferent pupillary defect is frequently seen (though it may be absent if the ON is mild or if the other eye was previously affected). The optic disc is typically normal in appearance though it may initially appear swollen. Hemorrhages and exudates are rare, as is optic pallor on initial presentation.

Regardless of the type of presenting syndrome, MS relapses have a natural history in which the symptoms evolve over hours to days, reach their peak, and then begin to stabilize or remit. On MRI, the acute lesion may enhance for up to 4–6 weeks and then leave a T2 hyperintense lesion. Clinical evolution over a different time course (hyperacute or slowly progressive) or persistent contrast enhancement on MRI are often clues to an alternate diagnosis. Below are some of the most frequent presenting MS syndromes and some atypical features that could alert one to an alternate diagnosis (Tables 3.2, 3.3, 3.4 and 3.5).