Multiple Sclerosis and Demyelinating Conditions

Genetics

Monozygotic twins with multiple sclerosis show a concordance rate of between 15 and 50%, compared with only 3 to 5% concordance in dizygotic twins, consistent with a strong but incomplete role for genes in causing multiple sclerosis. The lifetime risk is increased to 2 to 4% in individuals with a first-degree relative with multiple sclerosis, compared with the general population risk of 0.1%. In addition, between 10 and 20% of patients have a first-degree relative with another autoimmune disease, commonly rheumatoid arthritis, systemic lupus erythematosus, or autoimmune thyroid disease. Psoriasis ( Chapter 405 ) and inflammatory bowel disease ( Chapter 127 ) also may be more common in patients with multiple sclerosis. Genetic modeling of the disease strongly argues against a single gene and suggests that many different genes predispose to multiple sclerosis and account for its many phenotypes and its overlap with other autoimmune diseases. Linkage and association studies have identified the human leukocyte antigen (HLA) or major histocompatibility complex (MHC) region on chromosome 6p21 as one genetic determinant for multiple sclerosis. The MHC class II region, involved in presentation of antigen to CD4 ⁺ T cells, is the most strongly associated locus. The HLA-DR2 allele and, more specifically, the molecular haplotype HLA-DRB1∗1501 allele have repeatedly been implicated. Multiple single-nucleotide polymorphisms (SNPs) in the interleukin-2 (IL-2) receptor-α gene and the IL-7 receptor-α gene also appear to be associated with a higher risk for multiple sclerosis. Over 200 other gene SNPs have been identified, most of which are related to immune function. Although patterns are emerging to suggest dysregulation of differing immune cell subsets, the associations to date are not strong enough to have clinical predictive value.

Pathology

Most cases are characterized by multifocal areas of demyelination and gross gliotic scar in the brain and spinal cord. Classic locations of these lesions, called plaques are the optic nerves, periventricular white matter, deep white matter, juxtacortical white matter, corpus callosum, cerebellar peduncles, and dorsolateral spinal cord. However, there is a bias toward recognition of lesions in white matter because of the relative ease of detecting demyelination and inflammation in white compared with gray matter by magnetic resonance imaging. Indeed, more recent pathologic studies have confirmed demyelination, neuritic damage, and atrophy in the cerebral cortex (pial surface and intracortical or juxtacortical) and deep gray matter structures, especially the thalamus. At the microscopic level, one usually sees multiple areas of perivenular inflammatory cell infiltrates with extravasation into the surrounding tissue parenchyma. In the acute active plaque, CD4 helper T (T _H ) cells are prominent in the perivenular areas. Pro-inflammatory cytokines released from T _H 1 (interferon-γ [IFN-γ]) and T _H 17 (IL-17, tumor necrosis factor [TNF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) cells are thought to mediate damage. Increasingly, large numbers of CD8 cytotoxic T cells have been documented in brain tissue, especially in the parenchyma, and these cells may mediate direct damage to axons and oligodendrocytes through release of proteases such as granzyme B. Most parenchymal inflammatory cells, especially in chronic plaques, are CD68 ⁺ macrophages and microglia. In addition to the influx of circulating immune cells, prominent astroglial activation and in some cases oligodendrocyte precursor cell differentiation occur in response to injury. Over time, the inflammation becomes less prominent in the center of the plaque, but a chronic active rim of inflammation with microglial activation exists at a well-demarcated border between abnormal and normal unharmed myelin. This characteristic of multiple sclerosis is seldom seen in other disorders of myelin. Although oligodendrocytes may survive, proliferate, and result in partial remyelination (shadow plaques) in some early cases, this process is hardly ever complete in multiple sclerosis. Over time, remyelination is less successful, and oligodendrocyte precursor cells appear unable to differentiate into mature myelinating oligodendrocytes.

The number of damaged axons correlates with the extent of inflammation. Further, axonal damage and even neuronal apoptosis and loss are seen in the cortex and retina. Atrophy of both the brain and spinal cord, which occurs more rapidly in multiple sclerosis than in normal aging, reflects loss of both myelin and axons.

Seroconversion, especially to Epstein-Barr virus, ^, has been associated with a 32-fold increased risk of developing multiple sclerosis, and it may be a necessary trigger, perhaps through molecular mimicry, but is not sufficient for disease. Differential expression of human herpesvirus type 6, which is acquired by most people in childhood, has been noted in oligodendrocytes of patients with multiple sclerosis, but whether this virus is a cofactor in demyelination or just a bystander remains unclear. Evidence suggests the possibility that the earliest event may be an insult to the oligodendrocytes, with subsequent activation of resident immune cells and secondary recruitment of other immune cells only at later stages.

Some pathologists think that four distinct subtypes of multiple sclerosis can be discerned, thereby allowing patients to be classified with differing pathologic categories rather than just describing the evolution of lesions over time. Type I lesions are characterized by typical perivenular inflammatory infiltrates consisting mainly of T cells, with early preservation of oligodendrocytes. Type II lesions are similar to type I but have an additional humoral component with immunoglobulin G (IgG) deposition and complement activation. Type III lesions are distinguished by not being based around venules and by prominent loss of myelin-associated glycoprotein, with evidence for oligodendrocyte apoptosis. Type IV lesions have inflammatory infiltrates more similar to those in types I and II but also have oligodendrocyte loss as in type III. These varying pathologic features may begin to explain clinical subtypes of the disease.

Pathogenesis

It remains possible that the autoimmune hypothesis is wrong and that the inflammation observed in multiple sclerosis is secondary to an as yet uncharacterized primary degenerative process. Proponents of this theory cite evidence from pathologic features of hyperacute cases, in which the oligodendrocytes appear to die before any systemic immune response occurs, as well as recent data revealing neuronal and axonal death or demyelination in the absence of inflammation.

Macrophages and microglia, which make up the majority of cells within the parenchymal infiltrate in chronic multiple sclerosis plaques, are potent antigen-presenting cells and express HLA and costimulatory molecules. Activated macrophages and microglia also have effector functions, including release of cytokines that are partly (IL-6, TNF-α) or completely distinct from the T cells (IL-1β, IL-12, and IL-23). In high concentrations, these cytokines may damage oligodendrocytes and neurons and activate T cells. Reactive astrogliosis, which is also a hallmark of multiple sclerosis plaques, is characterized by loss of homeostatic astrocytic function and gain of neurotoxic properties.

Presenting Symptoms

Multiple sclerosis, which can manifest in many ways across a broad age range, may initially masquerade as a variety of different illnesses ( Table 380-2 ; see Table 380-1 ). In a classic presentation, a young person, more often a woman, will have the acute to subacute onset of impaired vision or sensation. Fatigue, depression, bladder urgency, weakness, impaired balance, and impaired coordination also are common symptoms. The often remarkably mild nature of the first symptoms frequently dissuades the patient from seeking medical attention or is insufficiently impressive to stimulate the physician to order diagnostic tests. Furthermore, patients may initially have few objective neurologic findings, especially between attacks.

Paresthesias of a limb that are circumferential and do not follow a dermatome suggest a spinal cord lesion; these symptoms often manifest distally and then ascend to involve more proximal parts of the limb, spread to the contralateral limb, or progress from a leg to an arm. Similarly, bandlike painful sensations around a limb or the torso also suggest a myelopathic process.

Incomplete transverse myelitis is a focal (partial) spinal cord syndrome that is usually inflammatory and does not follow vascular territories. It is a common presentation of multiple sclerosis.

Lhermitte sign, an electrical sensation moving down the spine into the limbs on flexion of the neck, is characteristic of cervical myelitis from any cause, including multiple sclerosis. Frank loss of sensation is less common as an early symptom or sign but is seen in more advanced cases. Burning, electrical, or deep aching sensations are also common in multiple sclerosis.

Sensory Abnormalities

On examination, the most common sensory findings are loss of vibration perception, most prominent in the feet, and incomplete spinal cord levels to pinprick or vibration, which are often more notable in a graded fashion rather than at a distinct level. Such sensory levels may be asymmetrical and differ by sensory modality because of isolated demyelination in the dorsal columns compared with the spinothalamic tracts. Patchy or seemingly nonanatomic focal areas of impaired sensation can occur, and some patients describe bizarre sensations such as water dripping or bugs crawling on an area of the body.

Visual Effects

Optic neuritis ( Chapter 392 ) is a classic manifesting syndrome, typically with visual symptoms in one eye. In optic neuritis, patients often complain of pain over the temporal eyebrow and worsening on lateral eye movement. The visual impairment may be described as looking through frosted glass or a veil. The scotoma or area of greatest loss often can be mapped in a centrocecal distribution (central focal point to the blind spot laterally), which in mild cases may be evident only as desaturation to red color using the head of a pin. More severe cases may result in total loss of light perception. In most acute cases of optic neuritis, the inflammation is retrobulbar (behind the disc), so no immediate changes are visible on the optic disc, thereby leading to the aphorism “the patient sees nothing, and the doctor sees nothing.” However, there should be a relative afferent papillary defect (Marcus-Gunn pupil; Chapter 392 ) with paradoxical dilation of the affected eye to direct light on swinging a flashlight from the unaffected eye in which consensual constriction was induced. In cases of bilateral optic neuritis (new or old), this abnormality may not be seen. Patients usually spontaneously recover substantial vision after weeks to months. Later, the optic disc may become pale, especially in the temporal region, a finding reflecting damage to the axons following inflammation and demyelination, even with recovery of normal visual acuity. Patients often have more subtle chronic visual impairment for colors, low-contrast visual acuity, and contrast sensitivity. Visual testing using low-contrast letter acuity charts commonly reveals substantial visual loss after clinical optic neuritis, which manifests clinically as nyctalopia (night blindness).

Visual impairment from impaired tracking of eye movements owing to brain stem or cerebellar disease most commonly occurs in the setting of an acute lesion affecting the medial longitudinal fasciculus, which is the neurologic pathway that yokes the eyes together on lateral saccades. Patients may experience frank diplopia or just blurred vision, especially when they look off to one side rapidly, such as when looking over one’s shoulder while driving. The neurologic sign of this problem is called internuclear ophthalmoplegia ( Chapter 392 ) and manifests as slowed or absent adduction of one eye with abducting nystagmus of the other eye. It may occur bilaterally or may exist in milder forms, such that the adduction lag is imperceptible to the human observer. Blurred vision from cerebellar damage with nystagmus is very common and is often worse on extreme lateral or vertical gaze. Oscillopsia, which is the sensation that the environment is moving when it actually is not, is another symptom of impaired cerebellar coordination of the eyes. Saccadic eye movement or loss of smooth pursuit is common in multiple sclerosis and also can be seen in numerous neurologic conditions or with aging.

Motor Symptoms

The most common motor symptoms of multiple sclerosis are weakness and impaired coordination, in a leg, with ascending involvement from distal to proximal and commonly spreading to the contralateral leg or ipsilateral arm. The lesion causing these symptoms is more commonly in the cervical spinal cord rather than the thoracic spinal cord, even when the first sign is partial footdrop. It is likely that axons that must conduct impulses over the longest distance (entire length of the spinal cord) from a site of inflammatory demyelination will become symptomatic before axons delivering signals to closer synapses (adjacent anterior horn cells in the cervical cord). Clinically, the weakness may be severe and may result in an obvious paralysis or be so subtle as to be undetectable. Heat-induced fatigue and weakness, as manifested by focal symptoms (slapping of a foot or dragging a leg) occurring after 15 to 20 minutes of exercise and resolving with rest, are characteristic of early demyelinating disease. The early absence of associated hyperreflexia and plantar extensor responses (Babinski sign) may make it difficult to document corticospinal tract involvement. Later, in more established multiple sclerosis, classic corticospinal tract signs are often evident and manifest clinically as spastic gait (either hemiparetic or paraparetic), muscle cramps, and clonus (sustained reflex loop), sometimes occurring with positional changes and mistaken for signs of a cerebellar tremor. Some patients will lose reflexes.

Ataxia may occur as a result of impaired delivery of sensory information up the spinal cord or from demyelination of cerebellar pathways in the brain stem or cerebellum. Often, the two are mixed and may be confounded further by visual loss and impaired ability to compensate by fixing on the environment; this combination commonly causes dizziness in crowds, in which fixation may be further obscured. Appendicular dysmetria resulting in tremor on reaching for an object is a common cause of impaired coordination and dexterity. Lower extremity and truncal ataxia may result in a wide-based (drunk) gait. Other movement disorders, such as postural tremor and titubation (head tremor), are much less common. Myokymia (wormlike muscle movements) under the skin, especially around the face, however, is fairly common. Pseudoathetosis and parkinsonism can be seen in severe cases.

Cognitive and Behavioral Symptoms

Over 50% of patients with multiple sclerosis experience bouts of moderate-to-severe depression ( Chapter 362 ). There is also increased incidence of bipolar disease, which may manifest after treatment of depression or treatment with corticosteroids. Pseudobulbar affect, either pathologic laughing or crying, is seen in patients with more advanced disease. Numerous cognitive symptoms, including short-term memory loss, word-finding difficulty, trouble with multitasking, and cognitive fatigue, may be mistaken for depression but are well-recognized primary symptoms of multiple sclerosis pathology. Most patients do not progress to dementia ( Chapter 371 ), but cognitive and behavioral impairments are major causes of loss of employment and quality of life.

Organ Dysfunction

Bladder symptoms are extremely common, but often are not volunteered, so specific questions must be asked concerning urinary frequency, urgency, incontinence, or retention. Careful discrimination of a spastic bladder (detrusor muscle spasm) causing incontinence from an atonic bladder or spasm of the external sphincter (the latter two causing retention) leading to overflow incontinence is critical to designing treatment ( Chapter 115 ). Urinary tract infections ( Chapter 263 ) owing to bladder dysfunction may aggravate symptoms of multiple sclerosis.

Bowel dysfunction commonly manifests as constipation ( Chapter 122 ), which may be primary (related to spinal cord involvement) or secondary (related to self-induced dehydration to manage urinary frequency or to side effects of anticholinergic drugs). Bowel incontinence secondary to an incompetent anal sphincter is less common and most often occurs as an isolated episode of fecal urgency, sometimes related to dietary change or diarrheal illness, or as a sequela of prolonged compaction.

Sexual dysfunction is common and underdiscussed in multiple sclerosis. In men, erectile dysfunction is frequent. In women and men, loss of libido and inability to achieve orgasm can occur as a result of medication, loss of sensation, heat-induced worsening of symptoms, physical barriers to intercourse (impaired mucosal moisture, spasticity, and pain), depression, or disorders of body image.

Systemic Symptoms

Fatigue, which is common, may be linked to depression but often occurs independently and can be the most disabling symptom of the disease. A sleep history is important to exclude daytime fatigue resulting from disrupted sleep secondary to pain, cramps, bladder frequency, sleep apnea, periodic limb movements, depression, or disrupted sleep-wake cycles. Daytime fatigue even after a good night of sleep may occur in mid-afternoon and may be described as being “unplugged” or completely drained. Many patients obtain benefit from a short daytime nap.

Sensitivity to heat, which is a classic symptom of multiple sclerosis, occurs only in some patients. Even minor elevations of the body temperature can dramatically worsen symptoms (Uhthoff phenomenon). Some patients complain of worsened symptoms in cold weather, likely related to increased dysfunction of already stiff muscles or signal blockade consistent with the known physiology of nerve conduction, which has an inverted U-shaped temperature versus conduction curve.

Pregnancy

Women with multiple sclerosis may have children, and the activity of disease typically lessens during the course of pregnancy, especially by the third trimester, when the frequency of exacerbations is reduced by approximately two thirds. Relapses are more frequent in the first 6 postpartum months, but no evidence indicates that pregnancy changes the natural history of the disease. Whether breast-feeding alters the course of multiple sclerosis is unclear, but it is contraindicated for patients who resume disease-modifying drugs following delivery.

Types of Multiple Sclerosis

The three major clinical types of multiple sclerosis are relapsing remitting, secondary progressive, and primary progressive. Approximately 85 to 90% of patients present with relapsing-remitting multiple sclerosis, characterized by acute or subacute episodes of new or worsening old neurologic symptoms that increase in severity, plateau, and then partly or completely remit. Patients may have no detectable residual deficit, or they may accumulate significant permanent disability from an attack. Many patients with relapsing-remitting multiple sclerosis will convert to secondary progressive multiple sclerosis after 20 to 40 years. This stage of the disease, which is characterized by at least 6 months of progressive worsening without evidence of a relapse, can be diagnosed with confidence only retrospectively. Some patients with secondary progressive multiple sclerosis also have interposed relapses (called active secondary progressive multiple sclerosis) distinct from their periods of progressive worsening, although these episodes become less frequent with time. Primary progressive multiple sclerosis, which is characterized by progressive deterioration from the onset for at least 1 year without a history of distinct relapses, occurs in approximately 10 to 15% of patients. It is more common in middle-aged men and typically has more involvement of the spinal cord and fewer inflammatory brain lesions.

Acute progressive multiple sclerosis (Marburg disease) causes acute or subacute progressive neurologic deterioration leading to severe disability within days to a month in a patient with no prior history of multiple sclerosis. This rare form of the disease may progress to a quadriplegic, obtunded state with death as a result of intercurrent infection, aspiration, or respiratory failure from brain stem involvement.