Therapeutic Decision Making in a New Drug Era in Multiple Sclerosis

B. Mark Keegan, MD, FRCP(C)


Semin Neurol. 2013;33(1):5-12. 

In This Article

Making the Correct Diagnosis

The first and most critical decision in making the appropriate recommendations for patients with possible multiple sclerosis is clarifying the exact diagnosis. Fig. 1 demonstrates a three-step approach in addition to published formal guidelines regarding diagnosis of multiple sclerosis, such as the revised McDonald diagnostic criteria.[1]

Figure 1.

A simplified three-step method to diagnose multiple sclerosis (MS). CSF, cerebrospinal fluid.

The first step in a simplified diagnostic process is identifying what may be termed the classical cardinal clinical features that are highly suggestive and particularly informative of a possible diagnosis of multiple sclerosis. For example, one common heralding clinical MS symptom is inflammatory optic neuritis. This typically presents with painful monocular visual loss that usually worsens over hours to days. The maintenance of visual impairment may last for days to weeks, and then improve, often with complete clinical recovery either spontaneously or with the use of high-dose intravenous or oral corticosteroids.[2,3] Other classical cardinal features include painless binocular diplopia, hemiparesis, hemisensory deficit, or symptoms of acute myelopathy with a spinal sensory level, paraparesis and quadriparesis, and bladder and/or bowel disturbance, all lasting at least 24 hours but generally days to weeks in duration. Insidiously progressive symptoms of gait impairment due to a progressive myelopathy over many months and years are common features of primary or secondary progressive forms of multiple sclerosis (primary progressive MS [PPMS], secondary progressive MS [SPMS]). Mild memory impairment and fatigue are both extremely common in MS, but are typically not considered highly defining clinical features as they occur in many conditions and are regarded as being highly prevalent, but rather nonspecific. Occasionally, patients may have primary progressive cognitive dysfunction that is severe,[4] but this is far less common than the symptoms listed above.

Following a comprehensive clinical history and identification of the classical cardinal clinical features of multiple sclerosis, a detailed neurologic examination is required. Although the results of neurologic examination may be complicated to describe, the resultant examination may be simplified by considering three separate results: a normal neurologic examination, an examination highly suggestive of MS as the underlying diagnosis, and an examination that highly suggests an alternative neurologic diagnosis. The first presentation would be that of an entirely normal neurologic examination. It should be noted that the first examination scenario certainly does not rule out multiple sclerosis as an underlying diagnosis as many patients with unequivocal multiple sclerosis will have an entirely normal neurologic examination. The clinical neurologic examination features that would highly suggest, but are in no way definitively diagnostic of multiple sclerosis include signs of optic neuropathy (e.g., central scotoma, acuity loss, color vision impairment and relative afferent pupillary defect), internuclear ophthalmoplegia—particularly bilateral internuclear ophthalmoplegia, cerebellar gait ataxia, upper motor neuron hemiparesis, paraparesis or quadriparesis, and spinal sensory level and other signs of myelopathy with bilateral extensor plantar responses. Finally, neurologic physical examination features that would be more likely diagnostic of other competing neurologic conditions such as fatigable ptosis in myasthenia gravis, or prominent fasciculations of amyotrophic lateral sclerosis need to be ruled out.

The final step includes specific investigations that yield results highly suggestive of multiple sclerosis. The most critical and specific investigations are brain, cervical, and thoracic spine magnetic resonance imaging (MRI). Some patients' evaluations may require only selected components of brain and spinal cord MRI. However, it should be noted that a lumbar spine MRI scan would not be needed in terms of ruling out or in multiple sclerosis, and that thoracic spine neuroimaging can be an important investigation that is often left unpursued. Typical MRI findings include periventricular, juxtacortical, and infratentorial brain lesions and ovoid short segment (less than three vertebral columns) hemicord lesions within the cervical and thoracic spinal cord.[5] Development of new MRI T2 lesions, gadolinium-enhancing T1 lesions, and T1 hypointensities ("black holes"), as well as brain and spinal cord atrophy are further neuroimaging evidence of MS.

Cerebrospinal fluid (CSF) assessment is important in the evaluation of many MS cases to define evidence of an autoimmune, inflammatory process being generated intrathecally.[6] Specifically, identification of elevations in unique CSF oligoclonal bands and immunoglobulin G (IgG) index are considered characteristic, although not diagnostic of, multiple sclerosis. Importantly, CSF abnormalities such as substantial elevations in white blood cell count might indicate an infectious or an alternative chronic inflammatory cause, and marked elevations in protein may occur in compressive myelopathies with CSF block or other infectious and inflammatory diseases.

Neurophysiological evaluation with evoked potentials may still contribute to MS diagnosis.[7] This includes visual evoked potentials to identify conduction deficit in the optic nerves on either side. Somatosensory evoked potentials are occasionally beneficial in identifying impaired central spinal cord conduction. Generally speaking, brainstem auditory evoked potentials have become decreasingly important in the evaluation of multiple sclerosis.

Finally, serological evaluations and further radiologic or other investigations searching for systemic diseases known to be MS mimickers may be required.[8] One general guideline is the number of serological evaluations and other investigations that may be required to make a diagnosis of multiple sclerosis is inversely proportional to the pretest certainty that the diagnosis is multiple sclerosis. This means that in very certain cases, limited or no serological evaluations may be needed. In very challenging cases, where a diagnosis is clearly uncertain, an expanded number of evaluations may be needed to identify infectious, vascular, traumatic, neoplastic, inherited, and other causes that may mimic multiple sclerosis. Detailed evaluations for MS mimickers are beyond the scope of this article.

Identifying the Clinical Course of Multiple Sclerosis

After ruling out potential MS mimickers that may complicate a confident diagnosis of MS, the clinician must then identify the MS clinical course. The patient's current MS clinical course is critical to assess whether currently available immunotherapies will reliably benefit the patient (i.e., those with clinical and or radiologic evidence of relapsing inflammatory MS). Clinical course presentations of MS-related disease range from solely MRI findings without any prior history of clinical attacks or neurologic abnormalities (radiologically isolated syndrome [RIS]) to single attack (clinically isolated syndrome [CIS]) to multiple clinical attacks with maintained stability between attacks (relapsing remitting MS [RRMS]) and those without clinical attacks, but predominantly or only progressive neurologic worsening more consistent with neurodegenerative diseases (PPMS and SPMS).

Radiologically Isolated Syndrome

One clinical scenario arising in the evaluation of MS is that of a patient without characteristic clinical cardinal symptoms or signs of MS attacks or of progressive MS. Also described as "asymptomatic" MS or "radiologic onset" MS, these patients have MRI done for alternative reasons than MS (e.g., migraine, controls for MRI research investigations), but are found to have lesions highly typical of MS on neuroimaging. MRI findings may even fully satisfy the Barkhof-Tintore radiologic diagnostic criteria of MS and may include asymptomatic spinal cord lesions and abnormalities on CSF examination consistent with MS (elevated unique CSF oligoclonal bands and/or IgG index). Patients with RIS are at risk to have a future clinical attack diagnostic of MS of ~ 30% over 5 years [9,10] and higher in those with asymptomatic spinal cord lesions.[11] Given the uncertainty in confirming later diagnosis, and importantly, prognosis in these cases, currently most clinicians do not recommend immunomodulatory medications be initiated unless multiple new lesions are developing rapidly over time or alternatively, a definite clinical attack occurs diagnostic of relapsing remitting MS (RRMS).

Clinically Isolated Syndrome

Clinically isolated syndrome is the term given the clinical course where patients have experienced only one characteristic clinical attack of demyelination (e.g., new-onset optic neuritis, cerebral demyelination, brainstem syndrome, or acute myelopathy).[12] This entity has been extensively studied, and it is clear that the risk to develop MS depends upon MRI findings at CIS onset.[13] The risk for patients with ≥ 2 lesions are at high risk to develop RRMS based on either a new relapse characteristic of MS or new MS MRI lesions. Those with one or no accompanying MRI lesions are at lower risk for future RRMS; in fact, those with the low-risk profile that later develop RRMS appear to have a relatively less severe later clinical course. The diagnosis of CIS has been curtailed by the most recent revision to the diagnostic criteria for MS that allow a diagnosis of RRMS at the time of a single clinical attack when there is MRI evidence of both new (gadolinium-enhancing T1 lesions) and old (nongadolinium-enhancing T2 lesions) lesions simultaneously appearing that satisfy criteria for dissemination in time.[1]

Treatment with either β interferons or glatiramer acetate may be considered for CIS patients with high-risk abnormal MRI at onset as described above. These agents have been shown to reduce the short-term likelihood of further new MRI lesions and development of further clinical attacks diagnostic of RRMS.[14,15,16]

Relapsing Remitting Multiple Sclerosis

RRMS is the most common clinical scenario encountered and the most common indication for immunomodulatory MS therapies. At least 85% of MS patients present with this clinical course, which is confirmed by either two or more clinical attacks or a single clinical attack accompanied by MRI evidence of inflammatory disease activity disseminated in time and space within the central nervous system. It is important to distinguish RRMS from SPMS. RRMS displays complete clinical stability between relapse-related attacks and any clinical impairment comes exclusively from relapse-related, acute inflammatory disease. Occasionally, clinical evidence of relapses is lacking and MRI findings may aid in assessing an ongoing inflammatory activity contributing to clinical worsening. Progressive clinical worsening of impairment that is not due to acute inflammatory disease (clinical attacks and/or prominent new MRI activity) suggests SPMS.

Secondary Progressive Multiple Sclerosis

A majority of RRMS patients develop insidiously progressive impairment typically many years following disease onset. A progressive myelopathic course is the most common clinical manifestation, although progressive ataxia or cognitive impairment can alternatively be seen. This progressive clinical worsening comes in the absence of noticeable inflammatory activity (i.e., clinical relapses and/or new MRI lesion development). Overall, the most substantial degree of MS-related morbidity is due to progressive forms of MS. Documentation of at least one definite clinical MS attack in the past (many have had multiple attacks) distinguishes SPMS from PPMS. Currently available MS therapies do not appear to have any robust effect on purely progressive SPMS, while there may be some rationale for medications in those SPMS patients with ongoing relapses or substantial ongoing accrual of new MRI inflammatory lesions.

Primary Progressive Multiple Sclerosis

PPMS patients present with progressive myelopathic gait dysfunction, cerebellar ataxia, or cognitive impairment without clear history of any clinical attacks.[17] The revised McDonald criteria requires that the clinical progression must be of at least 1 year's duration and be accompanied by a combination of brain and spinal cord MRI abnormalities and/or CSF examination consistent with MS. Obvious inflammatory activity is lower in PPMS patients as evidenced both by the lack of clinical relapses as well as the relative paucity of MRI lesions compared with RRMS and SPMS. Currently, there are no immunomodulatory medications approved by the U.S. Food and Drug Administration (FDA) for PPMS.[18] Occasionally, however, particularly in young patients, a progressive clinical course may be accompanied by MRI findings of marked, acute inflammatory changes with numerous gadolinium-enhancing T1 and new T2 lesion accumulation. It is considered that perhaps these patients have an inflammatory MS that could be considered for immunomodulatory MS medication initiation.