Chapter 23 - Demyelinating diseases of the nervous system

Introduction

This group of diseases (see Table 23-1) is characterized by lesions that are associated with loss of myelin with relative sparing of axons. There are many type of disease that damage myelin in concert with the destruction of axons. However, these conditions are not considered "demyelinating" due to their nonspecific and secondary effects on myelin. Additionally, there are metabolic disorders of myelination characterized by the accumulation of abnormal breakdown products. These are considered to be "dysmyelinative" disorders, or leukodystrophies (i.e., metachromatic leukodystrophy, Krabbe's disease) and not demyelinative even though both conditions tend to strike white matter pathways.

Central nervous system myelin and peripheral nervous system myelin are antigenically different (as befits the fact that CNS myelin derives from oligodendroglia and PNS myelin comes from Schwann cells). Therefore, some demyelinating disorders attack the central nervous system (the prototype is multiple sclerosis), while others affect the peripheral nervous system (the prototype being Guillain-Barre syndrome).

Peripheral Nervous System (PNS)

Guillain-Barre Syndrome

There is evidence that the Guillain-Barre Syndrome (GBS) is mediated by immune attack on peripheral nerve myelin. In this condition, peripheral nerves (actually, usually at the level of the proximal nerve roots) show inflammatory infiltrates with cells involved in cell-mediated immunity. Because cell mediated immunity is involved, the condition appears to depend more on local cytokine production than the development of circulating antibodies. Nonetheless, plasmapheresis (which removes significant amounts of circulating antibodies) and human immune globulin infusions (which modulate the immune system by unclear mechanisms) are capable of limiting the acute damage in the condition (these help only if done early in the clinical course). The major pathologic changes, as would be expected with an autoimmune disease, include perivascular inflammatory infiltrate, along with demyelination in the affected nerve roots and nerves. There is usually relatively little damage to underlying axons unless the inflammatory reaction is dramatic.

GBS is a dramatic acute demyelinating neuropathy with rapid onset (hours to days). This usually produces weakness of the extremities and axial musculature, which can evolve to respiratory motor failure and asphyxiation if support is not available. Prior to availability of artificial respiratory support, the mortality rate was 60%. Involvement of the autonomic nervous system also may occur indicating an axonal involvement and, indeed, there is a form of GBS in which axonal involvement predominates (particularly in the Eastern Asia). Autonomic involvement may lead to threatening blood pressure irregularities and cardiac arrhythmias. This condition often involves the largest sensory nerve fibers as well. Because the largest, most heavily myelinated sensory fibers are the muscle stretch fibers, and since these fibers and the motor axons are direct parts of the reflex arc, deep tendon reflexes are almost always lost very early in the course of the condition, even in muscles that are not yet clinically weak. As the condition progresses, there can be sensory change, as well (usually numbness and tingling), but the picture is usually dominated by flaccid weakness. Although the most common presentation is with an ascending paralysis, rarely, it can begin by affecting cranial muscles. Diagnosis can be aided by CSF evaluation, which shows high protein levels, with very few actual inflammatory cells (usually not above the upper limit of normal). This has been termed "cytoalbuminologic dissociation."

There is an experimental model for this condition (experimental allergic neuritis). A prior, usually upper respiratory, infection with one of a variety of agents was the original reason for implicating an immune mechanism. More recently, it has been recognized that preceding diarrheal illness due to campylobacter infection can also trigger it. The putative mechanism for the condition is "molecular mimicry" with either the microbe itself or the changes in body cells produced by infectious agents producing an immune reaction that finds similar epitopes expressed on the Schwann cell.

Typically, after a period of progression that can last a week or two, the condition stabilizes and then spontaneously improves (with proliferation of the Schwann cells and reconstitution of the myelin sheath). This improvement occurs over weeks to months and many patients, even those who are severely affected, recover completely. The more severe the symptoms and the older the patient, the more likely there is to be residual damage. The more severe the actual damage to underlying axons (as a byproduct of a severe immune attack on the myelin sheath) the more likely there is to be residual. Electromyography is able to determine how much axonal damage there has been.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

This condition is due to a chronic immune attack on the peripheral myelin. It is usually more insidious than Guillain-Barre syndrome and it also responds better to immune modulating treatments. Not only does it get better with plasmapheresis and human immune globulin infusions, but it also responds to immunosuppressant medications, including Prednisone. However, in distinction to GBS, the condition relapses off of immunosuppressants and also can have some spontaneous waxing and waning of symptoms. The diagnosis of the condition can be tricky especially at the onset. As with GBS (and for the same reason) it often abolishes reflexes even in clinically unaffected muscles. Also, CSF shows very high protein (often higher than with GBS) with few actual inflammatory cells.

Central Nervous System (CNS)

Multiple sclerosis

Multiple sclerosis has been defined as "multiple white matter lesions separated in space and time". The lesions of multiple sclerosis (MS) the lesions are scattered in the white matter, but often clustering near the ventricles. They are variable-sized, well-circumscribed plaques of demyelination. They may occur anywhere within the white matter of the central nervous system. Peripheral nerves are not involved. Lesions of the optic nerves are common (remember that the optic "nerve" is really an extension of the CNS and not a peripheral nerve). The demyelinative lesions are typically associated with perivascular mononuclear cell infiltration, but the pathologic picture, as well as the time course of the illness, differs from that seen in experimental allergic encephalomyelitis (see below).

Clinical findings: MS is uncommon in children under the age of ten, and it usually presents before the age of 55. It is slightly more prevalent in women than men. The clinical pattern appears in three main types: relapsing-remitting multiple sclerosis (RRMS); secondary progressive MS (SPMS); and primary progressive MS (PPMS). The most common of these types is RRMS in which symptoms typically develop subacutely (over hours to days), with subsequent stabilization and gradual improvement over weeks to months. Patients may return to normal or may be left with a residual. Imaging may show new lesions or reactivated lesions (by the presence of contrast enhancement on MR scanning) during the exacerbation, although it is rare that you are able to visualize the actual lesion causing the symptoms. Although the substrate for demyelination is an immune attack on the oligodendroglia (with a block of nerve conduction due to the loss of myelin), presumably the main substrate for remission is the ability of these glia to remyelinate the axons if they are not too severely damaged. There may be some recovery on the basis of compensation as well as the ability of surviving axons to assume the lost functions. Unfortunately, all of these recovery mechanisms have severe limitations and residual dysfunction results from inadequate recovery. As lesions accumulate, remissions are less complete. Eventually there are so many lesions that new ones are not apparent clinically as discrete events. The disease's course is then steadily progressive in the "secondarily progressive" form. Rarely, the disease progresses relentlessly right from the start (with no exacerbations/attacks). This condition may actually be pathophysiologically distinct from RRMS and SPMS since it does not appear to respond to treatments that do affect these patterns of disease. This remains to be clarified.

The nature of the deficit depends on the location and size of the demyelinating plaque. Certain locations are especially common. Lesions in the optic nerve produce optic neuritis. If the plaque involves the optic disk, edema is seen on funduscopic examination (optic papillitis); if it involves the nerve behind the disk, there are no acute changes on funduscopic examination (retrobulbar neuritis). In either case, optic atrophy often develops with time, though it is not apparent before about two weeks after the symptomatic onset. Acute optic neuritis is usually associated with pain on eye movements (due to irritation of the optic nerve), and there is some visual field defect (usually a central or paracentral scotoma). Although 40% of persons with MS have optic neuritis, up to 40% of patients with optic neuritis do not go on to develop MS (some of these may actually have ischemic optic nerve disorders, while others have what has been termed a "clinically isolated syndrome", where symptoms remain in one location).

The medial longitudinal fasciculus is a tract that is occasionally involved by demyelinating plaque, producing unilateral or bilateral internuclear ophthalmoplegia (see Chap. 4). During attempted lateral gaze there is paresis of the medial rectus (insufficient adduction) and nystagmus of the abducting eye. However, convergence movement of the medial rectus is usually spared. Internuclear ophthalmoplegia is almost always due to demyelination, but it can rarely be seen in persons with vascular disease (especially the elderly) and very rarely results from tumor in the fourth ventricle or other inflammatory conditions.

Damage to spinal cord pathways (myelopathy) is yet another common presentation. This can include damage to descending motor pathways, producing spastic hemiparesis or damage to sensory tracts (usually the dorsal columns). In the latter case, paresthesias may be very distressing. The cerebellar connections can be affected with incoordination of the limbs, ataxia and dysarthria (scanning speech or "drunken speech). Tic douloureux (trigeminal neuralgia) sometimes occurs, and MS must be a consideration in a young patient with this presentation. Lhermitte's symptom, an electric or tingling sensation referred to the trunk and limbs during neck flexion (chin on chest), was first described in association with multiple sclerosis. It is presumed to be caused by stretch of damaged dorsal columns, depolarizing axons (see Chap. 1). Although this can appear with other intrinsic and occasionally extrinsic spinal cord lesions, it is most commonly seen with multiple sclerosis. The vestibular system may result in imbalance, but usually vertigo (if present) is mild, while nystagmus can be severe and bizarre. Certain nonspecific symptoms are quite common, including fatigue. However, it is important to consider alternative explanations for this before ascribing symptoms to this mechanism.

There are some symptoms that rarely occur with MS. For example, hearing is unaffected by MS. Lower motor neurons are very rarely affected (and then only in advanced MS). Aphasia is also quite rare. Patients with MS usually have intact intellect at the beginning, but progressive and severe subcortical hemispheric white matter lesions may result in dementia late in the course.

Diagnosis: The diagnosis of MS is strongly suggested when a person in the appropriate age range has evidence of lesions of white matter separated in space and time. There are several conditions that should at least be considered before making the diagnosis. Multiple emboli and vasculitis can result in small infarcts that can appear as white matter damage on MRI scans. Central nervous system sarcoidosis (an idiopathic, steroid-responsive inflammatory condition) can produce reversible optic neuritis and other CNS signs. Whipple disease also has a tendency to result in inflammatory lesions, along with unusual eye movements due to midbrain involvement. Vitamin B12 deficiency is suggested by dementia, spasticity, and posterior column findings. Meningovascular syphilis, a rare but reemerging entity, can give rise to multifocal CNS damage due to multifocal meningeal vascular inflammation. CNS Lyme disease can also produce multifocal disease, probably due to vasculitis. An additional concern is that single lesions (by definition, not MS) can affect several different neurological systems. For example, a patient may have cerebellar ataxia and spastic paraparesis that could both result from a single lesion compressing the rostral spinal cord and the cerebellum at the level of the foramen magnum. Fortunately, magnetic resonance imaging (MRI) (see Chap. 11) is particularly good at detecting such lesions (although they were difficult to see with older technology, such as the CT scan). On the other hand, if that person also had optic neuritis or hemiparesis involving the face, one lesion could no longer explain the findings. A history of remissions and exacerbations also helps in the diagnosis of MS, but it must be remembered that the symptoms of neoplasms commonly fluctuate to some degree.

To evaluate for the potential for other conditions, it would be appropriate to consider several blood tests in the initial evaluation of the patient with suspected MS. These tests include complete blood count (CBC), antinuclear antibodies (ANA), serum test for syphilis (RPR, VDRL, etc.), fluorescent treponemal antibody test (FTA), Lyme titer, ESR and, possibly, angiotensin converting enzyme level (a test for sarcoidosis). Imaging (MRI if at all possible) should be performed to rule out alternative diagnoses and because MRI can provide information about dissemination of disease. Over 90% of patients with MS have abnormalities on the MRI scan. Multifocal white matter disease of MS is easily observed but not easily differentiated from vascular lesions, gliotic scars or other forms of inflammation (see Chap. 11). As yet, there are no entirely pathognomonic criteria for MS on an MRI scan, but McDonald criteria are used in research studies. Spinal fluid examination may show evidence of immunologic activity in the CNS: slight elevation of mononuclear white blood cells (pleocytosis) is often found, and CSF oligoclonal IgG bands and increased globulin to albumin ratio can be found in 90% of cases. There may also be an increase in CSF myelin basic protein levels, which is evidence of actual damage to myelin. Evidence of subclinical demyelinated lesions can be provided by MRI, visual, somatosensory, or brain stem auditory evoked responses. The "hot bath test" is an historically interesting test. A hot bath often amplifies symptoms and worsens deficits by raising body temperature (which slows conduction in demyelinated plaques).

Etiology: Autoimmune and infectious mechanisms have received the greatest amount of attention recently. Genetic susceptibility to MS is suggested by finding certain histocompatibility antigens over-represented in patients with MS. This appears to convey risk rather than be causative, however. The spinal fluid changes noted above indicate production of immunoglobulins in the CNS. Recent studies have demonstrated reduction in the number of suppressor cells (that normally inhibit immune responses) immediately prior to exacerbations of MS.

An infectious etiology has been suggested by the following evidence:

  1. The distribution of MS is very non-uniform. Temperate climates have a higher incidence than warm climates, but the disease is uncommon in Japan. In the Orkney and Shetland islands, north of Scotland, the incidence is extremely high: 1 in 300 persons are affected. Not far away, however, in the Faroe Islands, the disease was unknown until British troops arrived during World War II.
  2. Epidemiologic studies suggest that MS is often acquired in childhood or adolescence. Moving from a high-risk to a low-risk area after the age of 15 does not appear to reduce one's chances of developing MS.
  3. There is an increased incidence of measles antibody titers in persons with MS.
  4. However, there have been extensive and, to date, unsuccessful investigations to attempt to detect active infection.

These findings strongly implicate an environmental factor, probably infectious; however, the identity of the factor is presently unknown. Additionally, it appears that whatever triggers the immune reaction that is active during MS does not appear to be present at the time of diagnosis. It is likely that both infectious and immune mechanisms contribute to the pathogenesis of MS. A viral infection may trigger an inappropriate immune response with antibodies to a common virus-myelin antigen.

Prognosis: The course varies from a few months ("acute MS") to more than 50 years, with the average survival after diagnosis being 15 to 20 years. Death is usually from superimposed infection and not due to the effects of the disease itself.

Demyelinating on an allergic basis

Experimental allergic encephalomyelitis (EAE) is the model for this group of demyelinative disorders. This is a rare disease, clinically, but it is a commonly used experimental model for investigation of demyelination and illustrates the results of immune attack on neural tissue. EAE develops several days after an animal is inoculated with central nervous system (CNS) myelin basic protein accompanied by Freund's adjuvant. The CNS becomes peppered with lesions consisting of perivenous lymphocytic infiltration and demyelination. These lesions are similar pathologically to these seen in a naturally occurring (rare) human disease, acute disseminated encephalomyelitis (ADEM). This disease may occur following various viral infections or following vaccinations (and hence is also called postinfectious or postvaccinal encephalomyelitis). In some instances, this disease can be shown to relate to hypersensitivity to CNS myelin. Acute hemorrhagic encephalomyelitis is currently thought to be merely a more fulminant variety of ADEM, in which necrosis of vessels leads to superimposed hemorrhage.

Reference

Questions

Define the following terms:

demyelination, Guillain-Barre syndrome, multiple sclerosis, Schwann cell, oligodendrocyte, cytoalbuminologic dissociation.
Demyelination is an inflammatory attack on myelin.
Guillain Barre syndrome is a monophasic illness characterized by a cell-mediated immune attack on peripheral nervous system myelin.
Multiple sclerosis is a condition characterized by inflammatory, demyelinating lesions in the central nervous system separated in space and time.
The Schwann cell is the cell in the peripheral nervous system that creates myelin.
The oligodendrocyte is the glial cell in the central nervous system that creates myelin.
Cytoalbuminologic dissociation is the finding of high protein in the cerebrospinal fluid without many (usually less than 6) white blood cells. This is a characteristic of Guillain-Barre syndrome but is not completely diagnostic.


23-1. What is a good working definition of multiple sclerosis?

Answer 23-1. Multiple sclerosis is defined as multiple inflammatory white matter lesions separated in space and time.

23-2. What causes multiple sclerosis?

Answer 23-2. The cause is unknown although the rate is higher in certain families and certain genetic types. It is also higher in certain locations (particularly at higher latitudes), but where you spend your first 15 years appears to determine risk (higher the further away from equator). There is an immune attack on oligodendroglia, although the trigger is not clear.

23-3. Can a patient with a single episode of demyelination be diagnosed with MS?

Answer 23-3. Single episodes cannot be diagnosed as definite multiple sclerosis, although sometimes scans can detect evidence of prior as well as recent events that fulfill criteria.

23-4. What are the patterns of presentation for MS?

Answer 23-4. MS may be relapsing remitting, secondarily progressive, primary progressive or rapidly progressive.

23-5. What are common symptoms of MS?

Answer 23-5. Symptoms are scattered in the nervous system. They often affect optic nerves (vision loss), dorsal columns (loss of sensation), corticospinal tract (spastic weakness), cerebellar pathways (incoordination, dysarthria), medial longitudinal fasciculus (double vision on lateral gaze), spinal trigeminal tract (face numbness or pain) and control of the bladder. Lhermitte sign consists of an electric sensation down back and/or legs with neck flexion. This is due to irritation of cervical spinal cord sensory tracts.

23-6. Are certain portions of the nervous system not affected by MS?

Answer 23-6. MS does not directly damage neuron cell bodies and therefore does not result in basal ganglia symptoms. It does not result in LMN damage, damage to cranial nerve nuclei, or damage to peripheral nerves. It also does not produce aphasia or affect memory (until late in the condition).

23-7. What supportive tests are there for the diagnosis of MS?

Answer 23-7. There are many supportive tests for MS (none is perfect). MRI shows T2 and flair hyperintensities in periventricular distribution in well over 90% of patients. Some of these lesions may be enhancing (if they happened in the last 3 months). CSF shows oligoclonal bands and elevated IgG synthesis in over 80% of patients. Evoked potentials that may show problems with sensory systems that are not known from clinical exam. However, none of these (except serial MRIs) can show whether lesions are separated in space and time.

23-8. What other conditions can produce symptoms similar to MS?

Answer 23-8. You must rule out other conditions producing disseminated lesions such as lupus, Lyme, HIV, sarcoidosis, neurosyphilis, B12 deficiency, brucellosis, HTLV-1.

23-9. What is Guillain Barre syndrome (acute inflammatory demyelinating polyradiculoneuropathy - AIDP)?

Answer 23-9. Guillain-Barre syndrome is a monophasic demyelinating disease affecting peripheral nerves.

23-10. What causes Guillain-Barre syndrome?

Answer 23-10. Guillain-Barre syndrome may be triggered by certain infections. It is a cell-mediated immune attack on nerve roots with a lymphocytic infiltration in perivenous pattern.

23-11. What laboratory findings are supportive of the diagnosis of Guillain-Barre syndrome?

Answer 23-11. CSF shows high protein but few white blood cells (cytoalbuminologic dissociation).

23-12. What is the usual clinical picture for Guillain-Barre syndrome?

Answer 23-12. Symptoms develop over days to weeks, usually resolving over weeks to months. It often proceeds in an ascending fashion though it may even start in the cranial nerves. It can paralyze all muscles (including respiration) and produce autonomic nervous system instability. Reflexes are lost early on, even in clinically unaffected muscles. Autonomic instability can be fatal as can respiratory arrest, infection or pulmonary embolus. Guillain-Barre syndrome does not affect central nervous system. Patients usually recover (about 20% have residual).

23-13. What treatments help in Guillain-Barre syndrome?

Answer 23-13. Treatment with plasmapheresis or human immune globulin infusions may speed recovery. Steroids don't help the conditon.

23-14. What is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)?

Answer 23-14. CIDP is a condition that has an appearance of chronic and demyelination of peripheral nerves. It is associated with subacute weakness and sensory loss and (as opposed to AIDP) responds to steroids and other immunosuppressives (including plasmapheresis and human immune globulin infusion).
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