Multiple Sclerosis and Other Autoimmune Diseases of the Central Nervous System

8.3 Other Autoimmune Diseases of the CNS

Ups and Downs

In the spring of 1970, the patient, who was then 30 years old, noticed a tingling in her left big toe. Over the next 3 days, this sensation spread into her entire left leg and then into her right leg as well, and she then developed numbness all over her trunk. Her gait was unsteady, she very rapidly became fatigued, and she had trouble holding her urine from the moment she felt the urge to urinate. These problems all resolved spontaneously in the ensuing weeks, and she ascribed no special importance to them. Six months later, however, her right eye began to hurt, and the vision in that eye became blurry. Once again, the problem resolved spontaneously in about 10 days, and she did not consult a doctor.

In 1973, she had marked difficulty walking for 2 months; practically as soon as this problem improved, she began to see double and was dizzy. These problems, too, got better in about a month, but, in the meantime, she had finally seen a doctor. In the light of her current problems, her past history, and the clinical and laboratory findings (in particular, the visual evoked potentials and the cerebrospinal fluid [CSF] findings), the doctor diagnosed multiple sclerosis (MS).

Over the following years, she had multiple episodes of sensory disturbance on the upper or lower limbs, unsteady gait, and (once) double vision. She often felt uncommonly tired. She sought psychiatric treatment twice for depression. As a rule, each episode resolved within a few weeks or, at most, months, sometimes spontaneously and sometimes after infusions of adrenocorticotropic hormone or corticosteroids.

In the late 1980s, her gait gradually worsened. She no longer experienced any improvement between episodes or any asymptomatic periods, as she had in the past. She became depressed again and gave up her job as a schoolteacher. In 1987, she could still walk 500 m unaided; from 1995 onward, she needed a cane at all times. She was hospitalized twice for urinary tract infections with high fever. Each time, during the febrile phases, her gait transiently worsened to the point that she was totally unable to get out of bed and walk. Two or three years later, she could no longer leave the house without her husband’s help, and was dependent on a wheelchair. Now, in 2015, the patient is 75 years old and can help her husband cook dinner from a seated position in her wheelchair. She can pull herself from bed into the wheelchair with difficulty, but she needs help to get dressed and undressed, or to use the toilet.

This case illustrates the typical clinical features and long-term course of MS arising in a young woman. At first, relapsing and remitting disturbances of sensory and motor function and coordination are characteristic, as is transient cranial nerve dysfunction. Phases of abnormal fatigue and depression are common as well. Over time, “classic” relapses become less frequent and are replaced by the slow progression of neurologic deficits—usually a gradually worsening gait impairment. Only half of all patients can still walk 25 to 30 years after the onset of the disease. If the first symptoms arise when the patient is older, less time generally elapses before the phase of secondary progression begins. At present, the most important ancillary diagnostic study for MS is magnetic resonance imaging (MRI). Immune-modulating treatment lessens the frequency and severity of relapses. Over the long term, the result is less severe permanent disability and a better quality of life.

8.1 Fundamentals

Key Point

MS is the most common autoimmune-mediated disease of the central nervous system (CNS). Other autoimmune diseases are much rarer; these include neuromyelitis optica (NMO) and acute disseminated encephalomyelitis (ADEM). The latter primarily affects children and is usually precipitated by a viral infection.

Systemic autoimmune diseases can also affect the CNS and manifest themselves with neurologic symptoms and signs. Further important differential diagnoses of MS include vascular leukoencephalopathy (see section ▶ 6.5.6, ▶ 6.5.6.3, and section ▶ 6.12.5) and the leukodystrophies (see ▶ Table 6.23).

8.2 Multiple Sclerosis

**Table 8.1** Clinical features of multiple sclerosis
Symptoms and signs	Remarks
Repeated episodes	At varying temporal intervals After each episode, either complete recovery or residual deficit
Diverse sites in CNS affected	Multiple, distinct CNS sites can be involved in a single episode Different episodes generally involve different sites Rarely, successive episodes may have similar clinical manifestations (particularly with spinal cord lesions)
Progressive neurologic impairment	In relapsing–remitting type, cumulation of residual deficits In primary progressive type, steady progression without episodes (particularly in late-onset disease)
Abbreviation: CNS, central nervous system.

Key Point

MS typically arises in young adults (women more often than men). It is a chronic disease of the CNS (i.e., the brain and spinal cord) that causes the loss of axons and neurons. If untreated, it almost always leads to severe disability. Autoimmune processes involving autoreactive lymphocytes play a major role in its pathogenesis. The disease often manifests itself in episodically occurring neurologic deficits that arise over a few hours or days, and then subside: this is the typical relapsing–remitting course of MS. As the disease progresses, the episodes often leave residual deficits behind, and these accumulate over time. The relapsing MS usually undergoes a transition to secondary progressive MS, in which there is progressive disability, with or without discrete episodes of worsening. A primary progressive course—usually involving spasticity and paralysis—is rarer. The symptoms and signs of MS are highly diverse because of the involvement of many different areas of the CNS and the variable dynamics of disease progression.

“Disseminated encephalomyelitis” is a synonym for MS. In French, the disease is called “sclérose en plaques,” as it was named by Charcot; related terms are used in the other Romance languages.

Epidemiology The incidence of MS in temperate zones is 4 to 6 new cases per 100,000 persons per year and the prevalence is approximately 120 per 100,000. The disease becomes more common with increasing distance from the equator and is thus particularly common in northern Europe, Russia, the northern United States., Canada, New Zealand, and southern Australia. Women are affected twice as commonly as men. Relatives of MS patients have an elevated risk of developing the disease; the risk is 3% for siblings and 30% for monozygotic twins. The initial attack usually occurs in the third decade, and only rarely in a child or older adult. The primary progressive form of MS is of later onset, usually after age 40 years.

Note

In developed countries, MS is the most common disease of the nervous system that arises in young adults and causes permanent disability. For older adults, the most common cause of permanent neurologic disability is ischemic stroke.

Pathologic anatomy There are disseminated foci of demyelination in the CNS, which are associated with the destruction and loss of myelin sheaths, axons, and neurons. Local, reactive gliosis is found at the sites of older foci. Thus, “sclerosis” develops at “multiple” locations, giving the disease its English name.

Etiology and pathogenesis The cause of MS is unknown; genetic factors, environmental influences, and disturbances of the immune system all play a role in its pathogenesis. It is not currently known whether MS is a heterogeneous disease with a complex pathogenesis or, alternatively, a unitary disease whose complex pathogenesis gives it a heterogeneous appearance. It has often been hypothesized that viruses are etiologic factors for MS, precipitating the disease either by infecting neurons directly or by serving as antigens that call forth an uncontrolled immune response. It is clear, in any case, that autoimmune processes with autoreactive T-lymphocytes and monocytes play a role in the pathogenesis of the disease and cause episodes of inflammation and demyelination.

Experimental allergic encephalomyelitis (EAE) in mice is a laboratory model for MS. In EAE, the inflammatory cells form nitrogen oxides that act as toxic free radicals, promoting apoptosis and leading to the destruction of neurons, axons, and glia. After numerous prolonged episodes of inflammation, more and more neurons, myelin sheaths, axons, and glia are lost. The body’s intrinsic repair mechanisms cannot keep up with the destructive process.

In the early stages of MS, foci of inflammation and demyelination arise in the cerebral white matter and, to a lesser extent, in the gray matter as well. In the first few years of the disease, these inflammatory cellular autoimmune mechanisms play the most important role. The more active these mechanisms are, the more axons and neurons are lost, and the more sclerotic glial scarring takes their place. Cumulative scarring over the course of the disease leads to progressive atrophy of the brain and spinal cord, with increasing involvement of the cerebral gray matter (see ▶ Fig. 8.4).

Course The temporal course of MS ( ▶ Fig. 8.1) can be of four main types:

Relapsing (or “relapsing–remitting”) type: characterized by the episodic appearance of new neurologic deficits, which can then remit completely or almost completely, leaving residual deficits of greater or lesser severity, without any progression of disease between the episodes.
Secondary progressive type: episodic worsening at first, followed by steady progression (possibly punctuated by further episodes).
Primary progressive type: steady progression from the beginning, most commonly seen in older patients with spastic-paraparetic MS.
Progressive relapsing type: steady progression with interspersed episodes of acute worsening, from the onset of the disease onward.

Note

In the initial years of the disease, autoimmune inflammatory processes are the most important factors causing the clinical manifestations and relapsing episodes; in the later years and decades, degenerative processes, with loss of axons and neurons, play the main role ( ▶ Fig. 8.2).

Clinical features and neurologic findings The general clinical features of MS are summarized in ▶ Table 8.1.

Fig. 8.1 The temporal course of multiple sclerosis: four major types. (Reproduced from Mattle H, Mumenthaler M. Neurologie. Stuttgart: Thieme; 2013.)

Fig. 8.2 Increasing brain atrophy as multiple sclerosis progresses, with increasing disability. CIS, clinically isolated syndrome; RRMS, relapsing–remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. (Reproduced from Mattle H, Mumenthaler M. Neurologie. Stuttgart: Thieme; 2013.)

The neurologic deficits present in each individual patient depend on the number and location of the demyelinating foci. The following are among the more characteristic disease manifestations and physical findings:

Retrobulbar neuritis is usually unilateral. Over the course of a few days, the patient develops an impairment of color vision (red desaturation), followed by impairment of visual acuity. Orbital pain is often present and the patient may see flashes of light on movement of the globe. These problems begin to improve in 1 or 2 weeks and usually resolve completely. The temporal side of the optic disc becomes pale 3 or 4 weeks after the onset of symptoms because of nerve fiber degeneration ( ▶ Fig. 8.3). Retrobulbar neuritis rarely affects both eyes, either at the same time or in rapid succession. If retrobulbar neuritis is an isolated event in a patient otherwise free of neurologic disease, the probability that other clinical signs of MS will appear in the future is roughly 50%. The probability is greater if abnormalities are found in the CSF ( ) or on an MRI scan (see ▶ Fig. 8.6).

Fig. 8.3 Retrobulbar neuritis. (a) MRI: behind the apex of the orbit, the inflamed optic nerve takes up contrast medium, and a short segment of it therefore appears hyperintense (bright). (b) Funduscopy after an episode of left retrobulbar neuritis: the temporal side of the optic disk is pale up to its edge.

Oculomotor disturbances: Diplopia, particularly due to abducens palsy, is a common early symptom. Later, typical findings are nystagmus (often dissociated) and internuclear ophthalmoplegia (see section ▶ 12.3.3, ▶ 12.3.3.3), often without any subjective correlate. Internuclear ophthalmoplegia in a young patient is relatively specific for MS.

Lhermitte sign (positive neck-flexion sign): Active or passive forward flexion of the neck induces an “electric” or tingling paresthesia running down the spine and/or into the limbs.

Sensory disturbances are present in half of all MS patients early on in the course of the disease, often as an initial manifestation. Vibration sense in the feet is impaired in practically all patients from some point in the course of the disease onward. Pain is common, and there is occasionally a dissociated sensory deficit.

Note

Retrobulbar neuritis, oculomotor disturbances, Lhermitte sign, and sensory deficits are common early findings in MS.

Pyramidal tract signs and brisk intrinsic muscle reflexes may also be present early in the course of the disease. The abdominal cutaneous reflexes are absent. Later on, in almost all patients, spastic paraparesis or quadriparesis develops.

Cerebellar signs are practically always present in advanced MS, including impaired coordination, ataxic gait, and, often, a very characteristic intention tremor (cf. ▶ Fig. 3.22).

Gait impairment often becomes severe early in the course of the disease. Typically, the combination of spastic paraparesis and ataxia results in a spastic-ataxic, uneven, uncoordinated, and stiff gait (cf. ▶ Fig. 3.2).

Bladder dysfunction is present in about three-quarters of all patients (generally in association with spasticity); disturbances of defecation are much rarer. Bladder dysfunction is sometimes an early manifestation of the disease. Urge incontinence is highly characteristic, that is, a sudden, almost uncontrollable need to urinate, perhaps leading to involuntary loss of urine. Patients often do not mention bladder dysfunction unless they are directly asked about it.

Ictal phenomena of various types are not uncommon. Epileptic seizures are somewhat more common than in healthy individuals, but less common than in persons with cerebrovascular disease. About 1.5% of persons with MS suffer from trigeminal neuralgia, which may alternate from one side to the other. Acute dizzy spells can occur, as can paroxysmal dystonia, dysarthria, or ataxia. The characteristic so-called tonic brainstem seizures consist of paroxysmal, often painful, tonic stiffness of the muscles on one side of the body. The lower limb is hyperextended and the upper limb flexed (Wernicke–Mann posture). The patient remains fully conscious. Tonic brainstem seizures are often provoked by a change of position; they last less than 1 minute and are followed by a refractory period of a half hour or more in which no further seizures can occur. Tonic brainstem seizures and most other MS-associated ictal phenomena respond to treatment with carbamazepine or other antiepileptic drugs.

Mental disturbances are not severe early in the course of the disease, although sometimes unusually severe fatigue is the main symptom. Later on, however, many patients develop psycho-organic changes, including psychoreactive and depressive disturbances, as a consequence of progressive brain atrophy ( ▶ Fig. 8.4). Psychosis is very rare.

Fig. 8.4 Brain atrophy in multiple sclerosis. The progressive loss of neurons and axons leads, over the years, to brain atrophy that is visible in MRI. In these two axial T2-weighted images obtained from two different patients, the subarachnoid space is wider in a than in b as a result of brain atrophy in a.

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