Multiple sclerosis is an immune-mediated inflammatory demyelinating disease of the central nervous system whose cause and pathogenesis are still unclear. Both genetic and environmental factors seem to influence susceptibility to the disease. With an incidence of 2 to 10 cases per 100,000 persons per year (in the United States, Canada, and Europe), MS is a relatively uncommon disease, but because it usually begins early in life it is a major cause of disability in young adults.¹

The classic lesion of MS is the plaque, seen in the white matter of the brain or spinal cord. In the acute phase, plaques show a combination of inflammatory cell infiltration, extensive demyelination, and some degree of axonal damage. White matter lesions are typically found in the periventricular region, corpus callosum, centrum semiovale, deep white matter, and basal ganglia.² More recently, histopathology and imaging have shown that gray matter lesions are common even in early MS and may be critical to the progression of disease. Gray matter lesions can be found in the cerebral cortex, deep structures such as the thalamus, the cerebellum, and the gray matter of the spinal cord. They are difficult to detect without specialized magnetic resonance imaging (MRI) sequences such as double inversion recovery. Although they do show demyelination, gray matter lesions are not marked by massive inflammatory infiltration
or evidence of blood-brain barrier (BBB) breakdown; the inflammatory cells in these lesions may derive from the meninges or choroid plexus and enter from the cerebrospinal fluid (CSF) via the pial surface or ventricles.³

It is clear that MS lesions are often asymptomatic. Autopsy studies show that some persons have central nervous system (CNS) lesions consistent with MS and no clinical evidence of disease. Patients presenting with what appears clinically to be a first attack of demyelination (clinically isolated syndrome, or CIS) are often found to have multiple old plaques on MRI without any prior history of neurological disease. Repeat imaging of patients in the relapsing phase of MS shows that new lesions appear at a rate 5- to 10-fold greater than in clinical relapses.

Advanced MS is also associated with diffuse atrophy of the brain and spinal cord, which is closely correlated with disability. The connection between the acute lesions of MS and later atrophy is unclear.

The median age of onset of multiple sclerosis is approximately 30 years, although the disease can begin anywhere from early childhood to the seventh decade of life. For approximately 85% of patients with MS, the disease will begin with a relapsing-remitting pattern. The hallmark of relapsing-remitting MS (RRMS) is the relapse (also called attack or exacerbation), defined as an episode of neurological dysfunction lasting at least 24 hours and not associated with fever or infection. Attacks develop over a period of hours to days and resolve over weeks to months. They are currently believed to be episodes of acute demyelination. On average, patients with RRMS will have a clinically apparent relapse every 2 years; more frequent assessment of patients tends to yield higher estimates of relapse rate. Relapses tend to be more frequent early in the disease and wane over time. Each relapse may have complete clinical resolution, or there may be permanent sequelae. In the relapsing-remitting phase, there is relatively little disease progression between acute relapses.⁴,⁵,⁶

Some clinical features at the very beginning of the disease, for example, residual deficit after the first relapse and number of relapses during the first 2 years, correlate with a shorter time to reach disability milestones during the relapsing-remitting phase. By contrast, relapses over the remainder of the relapsing-remitting phase appear to have little effect on the speed at which disability accumulates.

Most patients with RRMS will, after 10 to 20 years, gradually transition to a secondary progressive phase, dominated by steadily worsening disability with few or no relapses. By 9 years after disease onset, only half of patients will still have relapses. The frequency of relapses and rate
of accumulation of disability during the relapsing-remitting phase vary tremendously from patient to patient. However, once relapsing patients reach an Extended Disability Status Scale (EDSS) score of 3 or begin a progressive phase, they enter a period of steady decline, which is similar from patient to patient and only weakly influenced by the speed of the relapsing-remitting phase.⁷

About 15% of patients will present with primary-progressive MS (PPMS), characterized by slowly worsening disability from the onset of the disease. The distinction between RRMS and PPMS is made exclusively by history; there are no examination or imaging findings that distinguish the two variants. The most common presentation of PPMS is a gradually worsening spinal cord syndrome with spastic paraparesis and no clear sensory level.

MS symptoms can be worsened in the presence of infection or other physiologic stress, a situation referred to as a pseudorelapse.³,⁴ Worsening of symptoms via increased body temperature (Uthoff phenomenon) may underlie some of these episodes. Classical pseudorelapses are exacerbations of previous symptoms and typically include worsened generalized fatigue and spasticity. In the emergency department (ED), any patient with MS with worsened symptoms should be screened for infection, especially of the respiratory and urinary tract. The presence of a plausible infectious process, along with an MRI showing no acute lesion, is generally taken to diagnose a pseudorelapse. Occasionally, patients with known MS will also present with psychologically based symptoms in the setting of depression or severe life stresses.⁸

However, some caution is justified in making the diagnosis of pseudorelapse. There is evidence that new MS lesions can be triggered by infection, so the presence of a urinary tract infection (UTI) or viral respiratory illness does not in itself exclude a true relapse. Furthermore, current MR technology does not detect all acute lesions; gray matter lesions, for example, are not well seen without specialized sequences. Given that MRI lesions accumulate at a rate at least 5 to 10 times greater than clinical relapses, it seems likely that some true attacks are misdiagnosed as pseudorelapses.

A single focal attack of demyelination does not in itself constitute MS. The diagnosis of MS requires the demonstration of CNS lesions disseminated in both space and time, based on either clinical findings alone or a combination of clinical findings and MRI or CSF-specific oligoclonal bands
(OCBs).⁹ The initial presentation of MS may be a CIS, that is, an attack compatible with MS but not yet fulfilling diagnostic criteria. For patients with a CIS and an otherwise normal MRI, the long-term likelihood (>10 y) of developing MS is approximately 20%.

Just as there are no clinical presentations that are unique to MS, any of the manifestations of MS can be an initial presentation. Common presenting syndromes include optic neuritis, spinal cord sensory or motor symptoms, transverse myelitis, and brainstem and cerebellar syndromes.

Although computed tomography can sometimes demonstrate MS lesions, MRI is currently the imaging modality of choice. In many cases, MRI can establish a diagnosis of MS at the time of the first attack by demonstrating not only the acute lesion but also additional lesions disseminated in both time and space. On MRI, brain lesions appear ovoid in shape and are typically aligned at right angles to the corpus callosum, forming a pattern on sagittal imaging referred to as “Dawson fingers.” The most valuable sequences are T2/T2-fluid attenuation inversion recovery, used to identify old (chronic) lesions, and contrast-enhanced T1, which detects breakdown of the BBB associated with acute white matter lesions. Enhancement typically resolves within a month, usually leaving a T2-hyperintense lesion that persists indefinitely. T2 lesions that are hypointense on T1 (“black holes”) are thought to represent areas of severe white matter destruction and axonal loss. Diffuse brain and spinal cord atrophy are also commonly seen in advanced MS and correlate more strongly with clinical disability than does total lesion burden. Spinal cord lesions are common in patients with MS, although isolated spinal involvement is uncommon.¹²,¹³

All patients with suspected MS should have MRI of the brain with and without contrast. Neurology consultation can help choose appropriate imaging to maximize diagnostic yield.

Activation of an IgG (humoral) immune response leads to the appearance on electrophoresis of multiple distinct bands of IgG corresponding to the activation of multiple B cell clones. This response can be seen in a variety of systemic infectious, inflammatory, and neoplastic diseases. OCBs found
in the CSF and not in the serum indicate an immune response originating within the CNS. This is seen not only in MS but also in meningitis, neurosyphilis, progressive multifocal leukoencephalopathy (PML), tumors, and many other CNS disorders. CSF-specific OCBs are found in up to 95% of patients with clinically definite MS.¹⁴

Before the advent of MRI, OCBs were a vital factor in establishing dissemination in time for the diagnosis of MS. One meta-analysis found that the presence of OCBs in a patient with a CIS was associated with an odds ratio of approximately 10 for the development of MS. In the MRI era, OCBs are often unnecessary for diagnosis. The neurology consultant should decide whether lumbar puncture for OCBs is needed, and because the results will not be immediately available to influence management, the test is most appropriately performed when the patient is admitted.

The differential diagnosis for a young adult who presents with a classic history of two or more acute episodes of neurological dysfunction with at least partial resolution is limited. For patients with a single attack of CNS disturbance, the differential is broad and includes many infectious, inflammatory, ischemic, neoplastic and genetic disorders.¹⁵ Given the complexities of the differential and the profound consequences of a diagnosis of multiple sclerosis, emergency medicine (EM) clinicians would be prudent to ask for neurology consultation to help with the evaluation of these patients.

A number of clinical “red flags” suggest that a diagnosis other than MS should be considered. Hyperacute onset of symptoms (over seconds to minutes) or very short duration (minutes to hours) suggests an ischemic or hemorrhagic lesion, seizure, or syncope. Diffuse encephalopathy with confusion or depressed level of awareness points toward a systemic process (toxic or metabolic) or a multifocal CNS disorder such as encephalitis, vasculitis, or posterior reversible encephalopathy syndrome.