1. 
   

   What are the major disease manifestations and complications of multiple sclerosis?

   
   
2. 
   

   How are exacerbations of multiple sclerosis treated?

   
   
3. 
   

   What are treatment options for complicating symptoms of multiple sclerosis, such as fatigue, bladder dysfunction, and spasticity?

   
   
4. 
   

   What disease-modifying agents are available to treat multiple sclerosis? What are their major toxicities?

Multiple sclerosis (MS) is an autoimmune, T-cell-driven disease of the central nervous system characterized initially by demyelination and, eventually, by axonal destruction and neuronal loss. It is the most common neurologic disease in young adults.

The peak age of onset between 20 and 40 years, and it has a twofold higher incidence in women. It has long been observed that latitude of residence in childhood is a risk factor for the development of the disease. MS is rare in equatorial areas, and the prevalence rises sharply with increasing distance from the equator. The relation of MS prevalence to latitude and altitude suggests that increased sun exposure in childhood protects against MS, but more recent work favors a genetic predisposition to MS that is geographically clustered.

Genetic factors play a major role in the development of MS, and a family history is common. The major histocompatibility complex allele HLA-DRB1*1501 and two cytokine receptor genes, the interleukin 7 receptor alpha chain gene (IL7RA) and the interleukin 2 receptor alpha chain gene (IL2RA), have been implicated. Susceptibility to MS is likely polygenic, with the contribution of most genes to MS risk being relatively small. Clusters of MS cases have suggested an infectious trigger, although the search for a specific viral or bacterial cause of MS has been thus far fruitless.

Symptoms

Multiple sclerosis is characteristically a relapsing and remitting disease, but there is great variation in its course. Common presenting symptoms of MS are summarized in Table 213-1. Weakness, numbness, or both in one or more limbs are common first symptoms. Patients may have paresthesias in the extremities or a band-like tightness around the trunk or limbs. The legs may feel heavy or difficult to control. Neck flexion may cause a sensation of electric shocks in the shoulders, back, and occasionally in the thighs. This finding, known as the Lhermitte sign, may also be present in cervical spondylosis, vitamin B12 deficiency, radiation myelopathy, and other conditions affecting the cervical spine.

Certain acute or subacute clinical syndromes are particularly characteristic of MS, although they also occur in association with other diseases of the nervous system. Optic neuritis most often presents with a deep aching sensation in the eye for a day or two, followed by rapid visual loss over several days or less. It is usually unilateral, but may be bilateral or sequential. Swelling of the optic nerve head (papillitis) is seen in 10% of patients, the majority of cases being retrobulbar and, therefore, having a normal disc head. In acute myelitis, patients develop paraparesis or paraplegia over hours to days, with extensor plantar responses, ascending paresthesias, a sensory level on the trunk, and impaired sphincter function. Cerebellar ataxia and brainstem syndromes are also frequent. Sphincter dysfunction, especially urinary urgency, is common as the disease progresses.

Signs

Common examination findings include hyperreflexia, extensor plantar responses, lower-extremity ataxia, impaired rapid alternating movements, and loss of vibration and proprioception. Evidence of optic neuropathy may be present, either obvious (visual loss) or subtle (afferent pupillary defect). Previous episodes of optic neuritis cause optic nerve atrophy. Somewhat less frequent findings include nystagmus, intention tremor, spasticity, dysarthria, and paraparesis. Unilateral internuclear ophthalmoplegia is another characteristic finding but is not common.

At first, most patients (85%) fall into the category of relapsing-remitting MS, undergoing periodic symptomatic flares (relapses) with incomplete recovery (remission). Emotional stress and infections have tentatively been associated with flares. The postpartum period is another frequent time of relapse; MS often abates during pregnancy. In 10% of patients, the disease has little response to treatment and a progresses inexorably from the onset (primary progressive MS). A minority (5%) have “benign” MS, with few relapses and little disease progression 10 to 15 years after diagnosis. Most patients with relapsing-remitting MS eventually develop a secondary progressive course characterized by steady neurologic deterioration and pathologically, by a progression from demyelination to neuronal loss. The cervical cord is particularly prone to disease in these cases.

The diagnosis of MS requires evidence of dissemination of disease in both space and time, although the time-honored requirement for the occurrence of clinical relapses has been replaced by imaging evidence of lesions of varying ages and in several central nervous system locations (Table 213-2). The major diagnostic test for MS is now magnetic resonance imaging (MRI). Typical lesions on MRI are bright on T2-weighted and fluid-attenuation inversion recovery (FLAIR) images, consistent with high water content (Figure 213-1). Early lesions are isodense on T1-weighted images and display enhancement with gadolinium, but more advanced ones may be T1 isodense, indicating necrosis (“black holes”). Typical locations include the periventricular regions, corpus callosum, cerebellar peduncles, and spinal cord.

Lumbar puncture is helpful but not mandatory for the diagnosis of MS. The cerebrospinal fluid (CSF) may display a minimal increase in lymphocytes (< 50/mm3

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