Multiple Sclerosis
Alexandra Degenhardt
▪ INTRODUCTION
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of uncertain etiology involving the central nervous system (CNS). In 70% to 85% of cases the initial course is relapsing-remitting (RRMS), in which episodes of subacute neurological deterioration (relapses) are followed by complete or near-complete recovery over weeks to months. Relapses must last for at least 24 hours, be separated in time by at least 1 month, and involve separate lesions in the CNS.
In 15% to 30% of cases, the initial course is predominantly one of progressive neurological deterioration (PPMS) without distinct relapses. Approximately 70% of patients with RRMS transition to a progressive course within 25 years, which is termed secondary progressive multiple sclerosis (SPMS).
KEY POINTS
1. Of MS cases, 80% are relapsing-remitting, 70% of these transition to a progressive course within 25 years termed SPMS.
2. Of MS cases, 20% are primarily progressive.
▪ SYMPTOMS AND SIGNS
General
Typical symptoms during relapses may include any of the following: hemiparesis, paraparesis, monoparesis, numbness, paresthesias, ataxia, diplopia, and vertigo. Additional symptoms that are often troublesome and persistent include pain, fatigue, depression, and cognitive and urinary dysfunction. Cognitive impairments usually involve executive functions and short-term memory. Urinary dysfunction often begins with urge incontinence (detrusor hyperreflexia) and later progresses to dyssynergia (in which the bladder contracts against the closed sphincter), or urinary retention secondary to detrusor flaccidity or a hyperactive sphincter.
On examination, there are signs referable to the CNS consistent with the patient’s symptoms, such as weakness in an upper motor neuron pattern, ataxia, and sensory loss. Upper motor neuron signs of the CNS include increased tone, hyperreflexia, the extensor plantar response, clonus, and weakness (involving shoulder abduction, elbow, hand and finger extension, flexion of the hip and knee, and dorsiflexion). Characteristic signs include Lhermitte’s sign (neck flexion elicits a shooting unpleasant sensation down the spine), Uhthoff’s phenomenon (exerciseor heat-induced worsening of symptoms), Marcus Gunn pupil (dilation of the affected pupil during the swinging flashlight test), and internuclear ophthalmoplegia (paresis of the adducting eye on conjugate lateral gaze with nystagmus of the abducting eye). The degree of disability on the neurological examination is quantified by the Expanded Disability Status Scale (Table 19.1).
TABLE 19.1 THE EXPANDED DISABILITY STATUS SCALE (EDSS) | ||||||||||||||||||||||||||||||||||||||||||||
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Psychiatric Symptoms
Depression and anxiety are more common in MS than in most chronic diseases, including most neurological disorders. The prevalence of depression in patients with MS is 14%, with a lifetime prevalence of 50%. Anxiety is common, with a prevalence of 34% in patients attending an MS clinic and 40% of partners with anxiety. Anxiety disorders more common in MS than in the general population include panic disorder (10% versus 3.5%), obsessive-compulsive disorder (8.6% versus 2.5%), and generalized anxiety disorder (18.6% versus 5.1%). Patients with anxiety were more likely to be women, abuse alcohol, report higher levels of stress, and have a history of depression.
Patients with both depression and anxiety are at highest risk for attempting suicide. Of note, the incidence and degree of depressive symptoms correlate with greater cognitive impairments
and modestly with brain atrophy. Suicide is thought to be the cause of 15% of deaths in MS; 6.4% of patients will attempt to commit suicide during their lifetime. Suicidal intent occurs in 28.6% of patients during their lifetime. The greatest risk factors include depression, alcohol abuse, and living alone.
and modestly with brain atrophy. Suicide is thought to be the cause of 15% of deaths in MS; 6.4% of patients will attempt to commit suicide during their lifetime. Suicidal intent occurs in 28.6% of patients during their lifetime. The greatest risk factors include depression, alcohol abuse, and living alone.
Medications used to treat MS are associated with a variety of psychiatric symptoms. High-dose steroids can cause mania, increased energy, insomnia, and euphoria. Depressive symptoms can occur with the abrupt tapering of steroids or their chronic use. The interferons used to treat MS are associated with a worsening of preexisting depression, but not clearly with the development of depression.
KEY POINTS
1. On examination, one can find upper motor neuron patterns of weakness, dermatomal and patchy sensory loss, hyperreflexia, Lhermitte’s sign, Marcus Gunn pupil, and internuclear ophthalmoplegia.
2. Depression occurs with a prevalence of 14% in MS clinics and a lifetime prevalence of 50%. The prevalence of anxiety is 34%.
3. High-dose steroids can cause mania, increased energy, insomnia, and euphoria.
▪ MULTIPLE SCLEROSIS VARIANTS
Clinical variants include progressive-relapsing MS (PRMS) and single-attack progressive MS (SAPMS). PRMS is rare. It is primarily progressive at onset with occasional relapses, and appears to have a similar prognosis to PPMS. Single-attack progressive cases demonstrate progression after one relapse and also have a prognosis similar to that of PPMS.
Other variants of MS include Balo’s concentric sclerosis (in which alternating rings of myelination and demyelination are seen on imaging), Marburg’s disease (widespread demyelination that is often destructive, with rapid clinical progression), and tumefactive MS (in which a large single lesion with significant edema is seen on imaging). Neuromyelitis optica, otherwise known as Devic’s disease, is presently considered a separate demyelinating autoimmune disease that involves primarily the optic nerves and spinal cord.
KEY POINTS
1. MS variants include Balo’s concentric sclerosis, Marburg’s disease, and tumefactive MS.
2. Devic’s disease is considered a distinct demyelinating autoimmune disease.
▪ EPIDEMIOLOGY
MS affects more women than men, with a female to male ratio of 1.5:2.4. The mean age of onset is 30 in RRMS and 37 in PPMS. The prevalence of MS is generally higher in northern latitudes, and there is rare familial clustering. The prevalence of MS per 10,000 is 30 to 70 in southern Europe, 100 to 200 in Scandinavia, 100 in the United States, 16 to 30 in the Middle East, and fewer than 10 per 10,000 in Asia, Central America, and most of Africa.
KEY POINTS
1. The female to male ratio is 2:1.
2. The mean age of onset in relapsing MS is 30 years.
▪ ETIOLOGY
Geographic differences in the prevalence of MS appear to be due to an interaction between undetermined environmental and genetic factors. The children of families who migrate from a country with a low prevalence of MS to a country with a high prevalence have an increased risk compared with that of their parents. Moreover, the genetic risk for the children of patients with MS is low, although higher than in the general population. The concordance of MS in dizygotic twins and siblings is 3% to 5% and in monozygotic twins is 20% to 40%. The HLA-DR2 allele increases the risk of MS, and its frequency varies similarly among populations at risk. Further identification of genes is ongoing and most likely involves complex genetic and environmental interactions. Several genetic associations found have included the HLA variables DRB1 *1501, DQA1 *0102, and DQB1 *0602.
KEY POINTS
1. The exact cause of MS is unknown.
2. The concordance of MS in dizygotic twins and siblings is 3% to 5%, and in monozygotic twins it is 20% to 40%.
▪ PATHOLOGY
Plaques of demyelination are found in the CNS, primarily in the perivenular, periventricular, and deep white matter areas, but also in the brainstem and spinal cord. Plaques are infrequently found within the cortex. There is relative preservation of axons, but early axonal transection has been described and may account for progression in the long term. The development of a plaque begins with alteration of the blood-brain barrier. This includes the uptake of water, lymphocytes, antibodies, and cytokines into the brain parenchyma. The active plaque is characterized by abundant proinflammatory cytokines (interleukin-2, interferon-gamma, and tumor necrosis factor-beta), myelin debris, lipid-laden macrophages, and perivascular infiltration of lymphocytes, predominantly T-cells (both CD4+ and CD8+). Reactive astrocytes are also found within the plaque.
Remyelination is thought to occur, as suggested by thinly myelinated axons, but occurs over months. More rapid clinical recovery is due to the reduction in edema, cytokines, and inflammation. In addition, there is proliferation of the sodium channel along demyelinated axons that helps to propagate electrical conduction along the axon. Recent pathological studies suggest that there is heterogeneity among plaques regarding features other than the common T-cell and macrophage infiltration. These differences include the predominance of one of the following: (a) TNF-alpha, (b) IgG and complement, (c) oligodendrocyte dysfunction, or (d) oligodendrocyte apoptosis. The chronic plaque is well demarcated and lacks signs of inflammation, which, if present, are limited to the plaque’s edges. The center of the plaque is characterized by proliferation of astrocytes and absent oligodendrocytes.
KEY POINTS
1. Demyelination is found in the CNS, primarily in the perivenular, periventricular, and deep white matter areas, but also in the brainstem, spinal cord, and occasionally in the cortex.
2. Remyelination occurs over months.
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