Multiple sclerosis (MS) literally means “many scars,” which refers to the lesions that accumulate in the brain and spinal cord throughout the course of the disease. These scars, or lesions, consist mostly of dead nerve cells, whose axons have been denuded of the myelin sheaths that normally protect them and permit the conduction of nerve impulses. MS is a chronic, degenerative disease that usually begins in young adulthood and most visibly destroys muscular control, although many other brain functions are affected. Most people will live with MS for decades after their diagnosis. MS reduces life expectancy after onset (as measured by current diagnostic criteria) by only about 10-15 years, and about half of the patients survive 30 years or more from onset.110THE CLINICAL PICTURE: SYMPTOMS, DISEASE COURSE, VARIATION, AND DIAGNOSIS
Disease Activity and Progression
MS, as defined by ongoing central nervous system (CNS) lesion formation and increasing cumulative damage, is now recognized as a disease that is active in most patients most of the time. Disease activity has reversible and irreversible sequelae; irreversible sequelae ultimately lead to progressive impairment and disability in most patients. MS takes a variety of forms, distinguished by the clinical pattern of disease activity (Table 2.1, Figure 2.1). Accumulated deficit can produce sustained worsening in both relapsing and progressive MS. In relapsing MS, worsening occurs in most patients during acute attacks with incomplete recovery. In progressive MS, the dominant pattern is a gradual accumulation of neurologic deficits, with slow clinical worsening.
Disease activity and progression have both clinical and subclinical components. Clinical disease activity and progression are judged by observation and neurologic examination. Subclinical components refer to pathological changes that are not observable in a clinical examination but are observed using a variety of laboratory tests, predominantly neuroimaging parameters.
Clinical Activity
Relapses. Relapses are variously referred to as acute attacks, exacerbations, or disease flare-ups. They involve the acute, or sudden onset, of focal neurological disturbances. Examples of typical MS relapses include blurring of vision in one eye (optic neuritis), persistent numbness or tingling of a body part (sensory system relapse), weakness of a body part (motor system relapse), or loss of coordination (cerebellar system relapse). Early in the MS disease process, relapses are likely to involve sensory, motor, cerebellar, or visual system abnormalities (Figure 2.2, Table 2.2). Later in the disease process, relapses are likely to involve bladder, bowel, cognitive, and sexual function abnormalities. Acute disease attacks are a characteristic feature of the relapsing-remitting MS subtype. Relapses also occur in patients with progressive relapsing disease and in a number of patients with secondary progressive disease. The only clinical disease subtype in which relapses never occur is primary progressive MS.
Relapses generally consist of three phases. There is a period of worsening, with onset of new deficits or increasing severity of old deficits. This is followed by a period of stability, with no change in deficits. The final phase is the period of recovery, with variable degrees of improvement in deficits. Most patients recover within six weeks, although for some, improvements can continue over months. Recovery can be complete return to baseline status, partial return, or no improvement. However, some degree of improvement is typical, particularly early in the disease. Relapsing patients then remain clinically stable until the next disease attack.
To be considered a relapse, deficits must persist for a minimum of 24 hours. This avoids confusion with deficits lasting only minutes to hours, which are believed to be a consequence of impaired nerve conduction through old lesion areas rather than the formation of a new lesion. Alternatively, new abnormalities that last seconds to minutes, such as Lhermitte’s sign (a tingling sensation radiating down the arms, neck, or back on neck flexion), or paroxysmal attacks (stereotypic neurologic deficits occurring multiple times a day that last less than a minute) are also considered relapses if they occur repeatedly over several weeks. Sequential relapses are considered distinct only when they occur at least 30 days apart with a month of clinical stability in between. Although clinical relapses always produce changes in a patient’s condition, they are not always associated with changes on neurologic examination. Maximal deficit in an MS relapse typically develops over several days but in some cases can develop much faster, over hours or even minutes, or much more slowly, over a period as long as several weeks.
Physiologic factors such as temperature, pH, or electrolyte balance can temporarily disrupt nerve conduction and produce neurologic abnormality. A relapse must be distinguished from a pseudoexacerbation, which is a neurologic deterioration associated with a physiologic change such as infection or fever. This condition can last for days, mimicking a true relapse. Pseudoexacerbation deficits disappear once the precipitating factor has been corrected. They reflect a temporary disruption in nerve conduction, rather than the formation of a new lesion.