Edward K. Lew and Don W. Penney
The term demyelinating disease is applied to a group of central nervous system (CNS) diseases that affect the myelin sheath but largely spare the axon. The major subgroups of demyelinating disease have been classified as follows: Group 1, demyelinating disease in which a disease process of exogenous origin affects and destroys normally formed myelin sheaths; and Group 2, dysmyelinating disease in which defective formation of myelin exists as a result of an inborn error of metabolism. This error of metabolism is usually a genetically determined enzymatic disturbance.
Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the CNS, affecting more than two million people worldwide. More than 400,000 people are affected in the United States. The disease occurs with an incidence of about 7 per 100,000 per year and a lifetime risk of 1 in 400. MS is a disease of young people, typically aged 18 to 50 years. MS is uncommon in children <10 years of age and usually presents before the age of 55. The onset tends to be earlier in women than in men. The female to male ratio is approximately 2:1. MS is more frequent in Caucasians of northern European origin and less common in Africans, Asians, and Mediterranean populations.
Although the cause of MS remains unknown, there appears to be an interaction between undefined environmental factors and genetic susceptibility to produce an inflammatory autoimmune response mediated by autoreactive T cells directed against components of myelin. Direct proof of an autoimmune cause is lacking, however, and no specific autoantibody or autoreactive T cell directed against a self-antigen in the CNS can passively transfer MS to experimental animals.
The name multiple sclerosis speaks to the multitude of lesions throughout the CNS that have a sclerotic appearance on pathological specimens. Clinically, the manifestations of MS result from disruption and abnormal transmission of nerve impulses within the CNS by focal areas of demyelination.
MS is most often characterized by exacerbations of acute or subacute onset that last for days to months. Exacerbations are more commonly manifested by the reappearance of previous signs and symptoms than by the development of new ones. Recovery between exacerbations may be complete or incomplete. Relapsing, remitting disease refers to a situation in which the clinical course between exacerbations is stable. In general, a pattern of intermittent exacerbations is more common in the earlier stages of the disease, whereas progressive deterioration, with or without superimposed exacerbations, is more common in the later stages (secondary progressive course). A small percentage of patients experience disease progression from the onset, with or without superimposed exacerbations (primary progressive and progressive relapsing disease, respectively) (1).
CLINICAL PRESENTATION
The classic clinical picture of MS is that of multiple neurologic symptoms disseminated in space and time. The diagnosis of MS cannot definitely be made in the emergency department (ED). When symptoms first appear, they often develop steadily over days. Visual complaints often occur early. Symptoms such as blurring of vision, alteration in visual acuity and diplopia are common. Up to 40% patients with MS have optic neuritis, but up to 40% of patients with optic neuritis do not go on to develop MS. No single clinical feature or diagnostic test is sufficient for a final diagnosis, although some are relatively characteristic.
The diagnosis of MS continues to focus on objective demonstration of dissemination of lesions in time and space. This temporal perspective is generally unavailable to the emergency physician seeing the patient at only one point in time. In addition, diagnostic test results that enhance the confidence of a clinical diagnosis of MS are often not immediately available in the ED. Ultimately, the diagnosis of MS is a life-altering condition that imposes a significant psychological burden and should therefore not be made without a substantial degree of certainty.
The nature of the deficit depends on the anatomical location of the demyelinating lesion and its size and age (acute vs. chronic). The demyelinating process can also result in the generation of ectopic impulses, abnormal transmission of impulses between neighboring nerve fibers, and increased mechanical sensitivity. These phenomena are the basis for the generation of symptoms such as Lhermitte sign (an electric shock-like, tingling, or vibrating sensation in the torso or extremities that is produced by flexion of the neck against resistance), flashes of light on eye movement (phosphenes), and paroxysmal symptoms such as trigeminal neuralgia, ataxia, and dysarthria or painful tetanic posturing of the limbs triggered by touch or movement. Conduction in partially demyelinated axons fails with an increase in temperature, giving rise to characteristic worsening of symptoms with a rise in temperature as may occur with exercise or a warm bath (Uhthoff phenomenon) (1). Demyelination can occur anywhere within the CNS and the possible clinical manifestations of MS are therefore extremely varied. However, MS lesions have a predilection for certain sites, resulting in a relatively limited distribution of typical initial symptoms (2). Although no symptoms or neurologic findings are pathognomonic, some are characteristic and should heighten the clinician’s diagnostic suspicions. The majority of patients present with one or more of the following signs and symptoms (see Table 161.1 for the common initial symptoms of MS).
TABLE 161.1
Common Initial Symptoms of Multiple Sclerosis
Decreased visual acuity and symptoms related to oculomotor dysfunction are among the most common initial presenting symptoms of MS. Optic neuritis characteristically presents with subacute monocular loss of vision although simultaneous or sequential loss of vision can occur in both eyes. Visual loss typically progresses over days to 2 weeks and is accompanied by headache or retroorbital or periocular pain in most but not all cases that may be exacerbated by movement of the eye. Maximal loss of visual acuity varies from blurring to absence of light perception in the affected eye. Alteration of color vision and visual field defect may occur. Slit lamp exam is usually normal but occasionally may reveal cells and flare in the anterior chamber. The optic disc appears swollen on initial presentation in 36% to 58% cases. An afferent pupillary defect (Marcus Gunn pupil) consisting of diminished response to a direct light stimulus and a normal consensual response to a light stimulus in the opposite eye may be noted. Approximately 50% to 60% of patients with optic neuritis will have periventricular white-matter abnormalities consistent with demyelination on an initial magnetic resonance imaging (MRI) scan. Optic nerve involvement may remain as an isolated manifestation, but if demyelination is found on MRI as well, 72% of those patients will convert to MS within 15 years, in contrast to 25% of those with a normal MRI (3,4).
Nystagmus and diplopia occur commonly in patients with MS. The finding of internuclear ophthalmoplegia (INO), especially in a young adult, is very suggestive. This form of dysconjugate gaze, localized to the medial longitudinal fasciculus (MLF) of the brainstem, involves limited adduction of one eye and nystagmus in the abducting eye on lateral gaze. Although there are other potential etiologies for INO, such as ischemia and neoplasm, these are much less common.
Sensory symptoms are among the most common presenting symptoms of MS and include numbness, tingling, pins and needles, tightness and coldness of the limbs or trunk. Radicular pain and itching in a dermatomal distribution can occur. Symptoms are variable in distribution and can be referable anatomically to the spinothalamic, posterior column and dorsal nerve root or can occur distally in the extremities or in a patchy distribution. Motor weakness may occur as paraparesis, hemiparesis, or monoparesis and is generally accompanied by signs of upper motor neuron dysfunction (e.g., hyperreflexia, hypertonia, and positive Babinski sign) (1). Transverse myelitis can be the initial neurologic event. Symptoms include ascending weakness and numbness below the level of the lesion.
The brainstem can be affected by MS plaques. Neuroanatomically, both ascending and descending tracts are found within the brainstem in close proximity. Corticospinal, corticobulbar, spinothalamic, lemniscal, vestibular and cerebellar tracts, and interneural pathway connections can be affected. Likewise, 11 of the 12 cranial nerves have either nuclei in the brainstem or synaptic connections within the brainstem.
Patients with Known Multiple Sclerosis
In most cases, the natural history of MS is characterized by episodes of neurologic dysfunction alternating with periods of stabilization or remission of symptoms. Common signs and symptoms of chronic disease are listed in Table 161.2. Patients with known MS may present to the ED because of an exacerbation of previous deficits, because of the development of new deficits, or because of medical complications of the disease.
TABLE 161.2
Common Chronic Problems of Multiple Sclerosis
Factors that have been cited as having an association with occurrence of MS exacerbations are infection (including minor respiratory infections and gastrointestinal infections), and the postpartum period. Pregnancy itself has not been associated with an increase in frequency of attacks (1,5).
Common secondary complications in patients with MS are pneumonia, infections of the urinary tract, septicemia, respiratory failure, pulmonary embolism, bladder and renal calculi, and pressure ulcers of the skin (2). Elevated body temperature, occurring as a result of infection or because of exposure to heat, can be associated with a transient increase in neurologic symptoms (Uhthoff phenomenon). Exacerbations that include dysphagia can result in aspiration pneumonia.
Fatigue is a common complaint of patients with MS. It typically increases with exercise, heat exposure, or as the day progresses. Spasticity, a manifestation of upper motor neuron disease, is characterized by increased muscle tone, hyperreflexia, decreased mobility, painful muscle spasms, and weakness. There is conflicting evidence as to whether seizures occur more frequently in MS patients than in the general population. When seizures occur, they should not be attributed to MS until other causes have been ruled out. Similarly, aphasia and dementia should prompt a search for alternate causes.
Major depression has a lifetime occurrence of 50% in patients with MS. A recent critical review did not find adequate evidence to substantiate concerns that newer disease-modifying agents for the treatment of MS might be associated with an increase in the incidence of depression or worsening of depressive illness. Treatment of depression with usually psychotherapy and pharmacotherapy are often effective (6).
DIFFERENTIAL DIAGNOSIS
As previously noted, the diagnosis of MS is generally a clinical diagnosis that is made over a prolonged period of observation and is supported by laboratory and MRI data. There must be a minimum of two separate clinical episodes suspicious for an MS attack separated over a period of time with evidence of two separate CNS lesions. It is imperative that the diagnosis is made only after confirmation of all data in support of the diagnosis and that all other potential diagnoses are ruled out. There is no single test that provides a definitive diagnosis.
The differential diagnosis of an acute neurologic deficit is broad and includes the intracranial and spinal cord processes listed in Table 161.3. Some of the more common diseases capable of causing multifocal CNS lesions disseminated over time are systemic lupus, Lyme disease, sarcoidosis, and CNS vasculitis. Because MS is a disease that is confined to the CNS, patients generally lack the rheumatologic and constitutional symptoms and laboratory abnormalities that are present in many of these other disease states. Spinal cord compression by mass lesions or hematomas must be considered in the patient who presents with symptoms referable to the spinal cord. The differential diagnosis of transverse myelitis includes both infectious (e.g., herpes simplex) and postinfectious causes. Optic neuritis may be caused by syphilis, demyelination following vaccination or viral infection, sarcoidosis, systemic lupus erythematosus, herpes zoster, and diabetes mellitus.
TABLE 161.3
Differential Diagnosis of Acute Focal Neurologic Deficit
ED EVALUATION
The diagnosis of MS requires the demonstration of focal neurologic signs and symptoms scattered over time and space. When faced with a patient with one or more focal neurologic deficits in whom MS is suspected, a critical task of the ED provider is the exclusion of other disease entities that may mimic the diagnosis and require specific immediate treatment. The definitive diagnosis of MS is most appropriately left to the neurologist in the non-ED setting.
Just as no neurologic findings are pathognomonic for MS, no laboratory test is universally diagnostic. Diagnostic evaluations used to confirm the diagnosis in situations in which the diagnosis cannot be made definitively on clinical grounds include visualization of anatomic dissemination of lesions in time and space with MRI of the brain and spinal cord; assessment of inflammatory and immunologic dysfunction through cerebrospinal fluid (CSF) examination; and demonstration of alteration of conduction in a pattern consistent with demyelination through the use of evoked potentials (EPs) as outlined by the McDonald criteria for the diagnosis of MS (1,7,8).
MRI is the most sensitive and specific test used to make the diagnosis of MS (9). T2-weighted brain imaging is superior in sensitivity to contrast-enhanced computed tomography (CT). More than 90% of patients with MS have MRI abnormalities, but there are no findings that are entirely pathognomonic for MS. Because myelin has a relatively short T2 and T1 relaxation times due to its lipid content, normal myelin is hypointense to gray matter on T2-weighted images and hyperintense on T1-weighted images. In MS, there is a reduction in myelin content; as a result white matter becomes less hydrophobic and takes on more water. A decrease in myelin and an increase in water content prolong the relaxation times of both T1- and T2-weighted images, resulting in more signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images, and less signal on T1-weighted images.
Characteristic lesions observed on MRI are plaques typically found in the periventricular region and juxtacortical white matter. MS plaques usually appear as discrete foci, ovoid in shape with well-defined margins. Most are small and irregular, however some of these lesions can coalesce forming larger-sized lesions. Plaques correspond pathologically to multifocal areas of demyelination and perivascular infiltration of lymphocytes, macrophages, and plasma cells. Typical lesions are ovoid and are arranged like fingers radiating away from the walls of the lateral ventricles. In addition, lesions commonly involve the corpus callosum, white matter abutting the temporal horns, trigones of the lateral ventricles, brainstem, cerebellum and spinal cord. Signal enhancement with gadolinium is characteristic of the disruption of the blood–brain barrier that occurs with active inflammatory lesions. The number, size, and distinctive location of areas of increased signal found on MRI help distinguish MS from other neurologic diseases.
MRI is used to monitor the course of the disease and its response to treatment and is useful in identifying alternate diagnoses such as intracranial neoplasm, vascular abnormalities, and spinal cord lesions. A negative MRI does not, however, have sufficient sensitivity or negative predictive value to rule out the diagnosis (10). Diseases that may produce similar lesions include ischemia, systemic lupus erythematosus, Behçet disease, other vasculitides, human immunodeficiency virus (HIV), and sarcoidosis.
Findings on MRI are common in patients with optic neuritis, even when there is no other clinical evidence of MS. MRI has been demonstrated to have prognostic value in predicting conversion from isolated syndromes, such as optic neuritis, myelitis, and INO to MS (3,4).
CSF examination can help to confirm the diagnosis by demonstration of immune and inflammatory mediators of disease. For the diagnosis of MS, CSF abnormality is defined as the presence of oligoclonal immunoglobulin G (IgG) bands different from bands in the serum or the presence of an elevated IgG index (7,8). Oligoclonal bands may be present even when the total CSF IgG content is normal. Studies have shown very poor correlation between the presence of oligoclonal banding and the degree of MS-induced disability. Changes in CSF IgG patterns have found not to be specific for MS. Patients with infection of the CNS, both acute and chronic, and brain neoplasms can also demonstrate changes in immunoglobulin levels. Other common CSF findings include elevated total protein and modestly increased mononuclear cell count (<50 cells/μL). In addition, CSF analysis permits the exclusion of infection as the cause of symptoms.
EPs are electrodiagnostic studies that measure the electrical potentials (voltages) that are evoked in response to the application of brief sensory stimuli. Demyelination causes abnormal axonal conduction that can be picked up on EP testing as abnormal potentials. In the past, prior to the development of MRI, visual evoked potentials (VEPs) were utilized in the diagnosis of MS. VEP often demonstrated a delay in conduction of visual responses from retina to occipital (visual) cortex. These studies were positive in 90% patients with clinically obvious MS. Both VEPs and somatosensory evoked potentials (SSEPs) may also detect subclinical sites of demyelination. This modality falls into the domain of the neurologist and is not part of the ED evaluation.
KEY TESTING
• Thorough neurologic examination
• MRI of brain to aid in initial diagnosis of MS
• Search for infection in patient with established MS
• CBC
• UA
• CXR
ED MANAGEMENT
Treatment of acute exacerbations of MS is most appropriately undertaken in consultation with a neurologist. The anti-inflammatory effects of steroids have traditionally been the primary therapy for relapses in patients with known disease. Corticosteroids shorten the duration of relapses and their short-term morbidity but have not been demonstrated to alter the evolution of the disease or to prevent relapses (1,11,12). There are no rigid guidelines for the use of steroids, but protocols generally include high-dose IV methylprednisolone, 1 to 2 g daily for 3 to 10 days, with or without an oral taper (12). For the rare patients who cannot tolerate corticosteroids or have had a prior poor response, intramuscular adrenocorticotropic hormone (ACTH) is an option. However, there is a significant incidence of weight gain, hypertension, and edema as compared with steroids (11).
A recent Cochrane review comparing different routes of steroid administration (i.e., IV vs. oral) failed to demonstrate a clear advantage of one over the other, giving weight to the notion that oral steroids are an effective alternative to parenteral steroids (13). An exception is in the treatment of optic neuritis. A recent meta-analysis concluded that corticosteroids did not result in an improvement in eventual return to baseline vision, but that IV corticosteroids did result in faster recovery. On the other hand, oral steroids appeared to be associated with more likely recurrences of optic neuritis. Thus, initial treatment with high-dose IV corticosteroids followed by oral formulations is thought to be reasonable (14).
If a relapse is deemed to be corticosteroid-refractory, plasmapheresis can be considered. It has recently been given a Class B recommendation from the American Academy of Neurology (12,15), but is not recommended for the progressive types of MS.
Current research has focused on two areas: (1) preventing disease burden from acute relapses, and (2) stabilizing MS in the long term. Interventions are aimed at suppressing inflammation, limiting demyelination, enhancing remyelination, and improving conduction in demyelinated fibers. As previously noted, some short-term treatments may accelerate recovery from relapses but do not prevent future relapses or eventual disabilities (16). Long-term management typically involves disease-modifying therapies (DMTs). Currently, there are at least eight DMTs approved for MS by the US and European drug-regulating bodies. Interferon-beta and glatiramer acetate are currently the most commonly prescribed agents. The annual relapse rate of patients treated with these drugs is lower than that in those treated with placebo by up to 30% (12,16). Interferon-beta also lowers the progression of disability; glatiramer acetate has not been proven to do so. For the most part, interferons and glatiramer acetate are first-line MS treatments as they have a good safety profile, reasonable tolerability and efficacy, and low toxicity. Nevertheless, their use may be limited by adverse events (such as flu-like symptoms, depression, injection site necrosis, elevated liver enzymes, leucopenia, and anemia) and cost. As always, risk–benefit ratios have to be determined by both physician and patient. Other approved treatments with more potentially serious adverse effects are being studied, including natalizumab, fingolimod, dimethyl fumarate, and teriflunomide (7,16). Therapies currently under investigation include mitoxantrone, alemtuzumab, laquinimod, rituximab, daclizumab, and cladribine (7,16). Administration of disease-altering drugs generally is the domain of the neurologist.
In the patient with known disease who presents with fever, sources of infection should be sought and treated aggressively. Patients with bladder dysfunction are particularly susceptible to urinary tract infection; decubitus ulcers and pneumonia are other common sources of infection that should be considered. Antipyretics should be administered because of the Uhthoff phenomenon. An elevated temperature that is related to heat exposure should be treated by active cooling measures. Table 161.2 lists some of the more common fixed neurologic symptoms of MS along with their treatments.
CRITICAL INTERVENTIONS
• Do not make the initial diagnosis of MS in the ED.
• Initiate high-dose methylprednisolone in the treatment of optic neuritis.
• Diagnose and treat fever in MS patients because elevated body temperature, occurring as a result of infection or exposure to heat, can be associated with a transient increase in neurologic symptoms.
DISPOSITION
The patient with newly onset clinically suspected MS may warrant hospital admission to complete the diagnostic workup, to exclude other causes of signs and symptoms, and to undergo aggressive treatment of debilitating symptoms. For the patient with known MS, determination of the need for hospitalization depends on the general medical condition as well as the neurologic status. Patients may also require hospitalization for medical complications of MS (e.g., infection), for the administration of aggressive treatment of neurologic symptoms, and for the supportive care necessary because of disability during disease exacerbations.
Common Pitfalls
• Failure to identify and treat other disease entities in the patient with known or suspected MS.
• Failure to consider the possibility of intercurrent medical illnesses, especially those that commonly affect the chronically ill neurologic patient (e.g., urinary tract infection, pneumonia, decubitus ulcers).
• Failure to realize that rheumatologic or constitutional symptoms or abnormal laboratory values should call the diagnosis of MS into question.
• Making a diagnosis of MS in a patient with progressive disease at a single site (e.g., spinal) when other diagnoses have not been adequately excluded.
• Failure to consider MS in the young patient presenting with focal neurologic signs and symptoms. The presenting symptoms of MS can be vague and transient, and can seem bizarre. A psychogenic etiology remains a diagnosis of exclusion.
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