Multiple sclerosis

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Multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, with a lifetime prevalence of approximately 1 in 800. It typically presents between the ages of 20 and 40 and two-thirds of patients are female. Although the course is highly variable, MS is a progressive and incurable disease. It is responsible for a considerable burden of long-term neurological disability and is the most common chronic neurological disorder in young adults.

Demyelination

Axonal myelination is discussed in Chapter 5. The term demyelination refers to the loss of normally formed myelin and can be classified as primary or secondary:

Primary demyelination is selective loss of myelin with relative preservation of axons. Multiple sclerosis is the most common and important cause.

Secondary demyelination is degeneration of the myelin sheath following axonal loss.

It is important to distinguish demyelination (loss of structurally normal myelin) from dysmyelination in which the myelin sheath is not normally formed in the first place. Conditions characterized by dysmyelination are usually due to a metabolic abnormality or enzyme deficiency and are often inherited (Clinical Box 14.1).

Clinical Box 14.1: Leukodystrophies

The leukodystrophies are a large group of cerebral white matter diseases (Greek: leukos, white) caused by abnormal myelin formation in the brain and spinal cord. These conditions usually present in infancy or childhood with developmental delay or progressive neurological deterioration and there may be gradual regression of cognitive, language or motor abilities in a previously normal child. Neuroimaging confirms abnormal cerebral white matter. Most of the leukodystrophies are genetic in origin and may show a recessive, dominant or X-linked pattern of inheritance.

Key Points

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the CNS. It typically presents between the ages of 20 and 40 and two-thirds of patients are female.

MS is the most common and important cause of primary demyelination, which is characterized by loss of structurally normal myelin with relative preservation of axons.

Secondary demyelination is degeneration of the myelin sheath as a result of axonal loss. In dysmyelination (e.g. in the leukodystrophies) myelin formation is abnormal.

Clinical features of MS

Multiple sclerosis is usually a relapsing-remitting disorder. Each clinical episode (or relapse) is caused by a focus of demyelination in the brain or spinal cord, which is referred to as a plaque. When a relapse occurs, symptoms typically develop over a few days and gradually resolve over a number of weeks, as the inflammation subsides and the plaques remyelinate to a greater or lesser degree.

Common symptoms

Although plaques can occur anywhere in the brain or spinal cord, including the central visual pathways, some sites are more likely to be affected than others. This means that certain symptoms and signs are more common (Fig. 14.1). The most frequently encountered presenting features are weakness in one or more limbs (40% of cases) and optic neuritis (up to 25% of cases; discussed below).

Loss of vision

Inflammatory demyelination of the optic nerve (termed optic neuritis) is common in MS. This causes blurred vision in one eye, with reduced light and colour perception, combined with retrobulbar pain (discomfort behind the affected eye, exacerbated by movement). In some cases there is a blind spot or scotoma (Greek: scotos, darkness). Symptoms usually resolve completely within a few weeks, but there may be a persistent afferent pupillary defect (Clinical Box 14.2). Optic neuritis can occur as an isolated phenomenon, but 75% of affected individuals will eventually develop multiple sclerosis. Another common visual problem in MS is discussed in Clinical Box 14.3.

Clinical Box 14.2: Relative afferent pupillary defect

The pupillary light reflexes (see Ch. 3, Clinical Box 3.11) are often abnormal in patients with MS. Loss of myelin in the optic nerve may reduce the afferent drive to constrict the pupils when light is shone into the affected eye, causing a relative afferent pupillary defect (RAPD). This is demonstrated using the swinging light test. A pen torch shone into the normal eye causes strong constriction of both pupils. Quickly swinging the light across to the abnormal eye generates a weaker afferent drive to the pupil constrictor muscles (relative to the good eye) and both pupils paradoxically dilate slightly in response to the torch beam.

Clinical Box 14.3: Internuclear ophthalmoplegia

This is an eye movement abnormality that is caused by a small brain stem lesion that interrupts the connection between the lateral gaze centre (close to the abducens nucleus, CN VI, in the pons) and the oculomotor nucleus (CN III, in the midbrain). Interruption of the medial longitudinal fasciculus (MLF) causes failure of adduction in the affected eye on attempted contralateral gaze, illustrated in Fig. 14.2. It is important to note that the figure is a schematic representation and that in reality the two fasciculi lie close to each other on either side of the midline. This means that it is possible for a single lesion to interrupt both sides at once, leading to failure of adduction in both eyes (on attempted left and right lateral gaze).

Fig. 14.2 Internuclear ophthalmoplegia.
In this person left lateral gaze is normal **(A)** but on attempted right lateral gaze, the left eye fails to adduct **(B).** This is due to a lesion in the left MLF **(C)** which prevents the right lateral gaze centre from communicating with the opposite oculomotor nucleus (which it needs to do to recruit the medial rectus muscle).

Pain and fatigue

Up to 90% of people with MS suffer from chronic fatigue, which is characterized by overwhelming mental and physical exhaustion (regarded by many patients as one of the most disabling features). Painful symptoms may include neuropathic-type burning and gnawing pains in the extremities (e.g. the hands and feet). Some patients experience trigeminal neuralgia, characterized by stabbing facial pains in the territory of the trigeminal nerve. This is extremely unpleasant and is sometimes called ‘the suicide disease’. Chronic pain may also result from muscle spasms and contractures.

Paroxysmal symptoms

Paroxysmal sensory and motor symptoms are common in MS, such as temporary episodes of slurred speech, incoordination, muscle spasms or painful stabbing sensations. These may be due to abnormal electrical impulses in acutely demyelinating lesions. Another characteristic feature is Lhermitte’s phenomenon. This is a sudden shooting pain elicited by neck flexion that may be described as an electric shock passing down the spine and radiating to the legs. It is caused by cervical cord demyelination and is virtually diagnostic of multiple sclerosis.

Cognitive and emotional changes

Cognitive, emotional and behavioural changes occur in at least 40% of patients with MS. There may be subtle disturbances in frontal executive function (e.g. attention, working memory, decision-making; see Ch. 3) and a small proportion of patients develop more severe cognitive decline or even dementia (Ch. 12). Euphoria is often described, but depression is more common (seen in up to 50% of patients) and the risk of suicide is also increased. Psychotic features (delusions and hallucinations) are rare.

Key Points

MS is usually a relapsing-remitting disorder and each clinical episode is caused by a focus of demyelination (or plaque) within the brain, spinal cord or central visual pathways.

Common features include: optic neuritis, pain and fatigue, problems with bowel, bladder and sexual function and various paroxysmal symptoms (e.g. dysarthria, ataxia, Lhermitte’s phenomenon).

Nine out of ten people with MS suffer from chronic fatigue, which is one of the most disabling symptoms. Psychological features including anxiety and depression are also very common.

Symptoms are often exacerbated by an increase in temperature (Uhthoff’s phenomenon) which is thought to prolong sodium channel inactivation, leading to axonal conduction failure.

Course and progression

The course of MS is highly variable and difficult to predict in a particular individual. The main clinical patterns are illustrated in Figure 14.3 and discussed further below.

Fig. 14.3 Clinical patterns of multiple sclerosis.

Relapsing-remitting MS

Multiple sclerosis most often follows a relapsing-remitting course (85% of cases) and this is sometimes referred to as the Charcot variant. In this classic form of the disease, long periods of stability (remissions) are punctuated by discrete episodes of neurological dysfunction (relapses) followed by partial or complete recovery. A relapse is defined by new neurological symptoms or signs that are present for at least 24 hours and are not associated with a fever. One in five patients will experience this form of the disease for at least 20 years (benign MS) but most will eventually convert to a phase of gradual functional decline.

Secondary progressive MS

Individuals with relapsing-remitting MS who convert to a state of progressive decline are said to have secondary progressive disease. This is characterized by gradual accumulation of permanent neurological deficits. In addition to the steady functional decline, acute exacerbations or ‘flare ups’ may also continue. This is referred to as progressive-relapsing MS. The proportion of patients converting from relapsing-remitting to secondary progressive disease is around 50% at 10 years and more than 90% at 30 years.

Primary progressive MS

In primary progressive MS (which occurs in 10–15% of patients) there is steady functional decline from the start of the illness, with gradual accumulation of irreversible neurological deficits. Males and females are equally affected and age at onset is about ten years later than in relapsing-remitting disease, which coincides with the typical age of conversion from relapsing to secondary progressive MS. The most severe subtype is acute multiple sclerosis, also known as the Marburg variant. This is a rare, hyperacute form of MS that usually leads to death within six months (sometimes after only a few weeks).

Key Points

The course of MS is highly variable, but a classical relapsing-remitting pattern (Charcot variant) is seen in 85% of cases and this lasts for more than two decades in 20% of people (benign MS).

Most patients eventually convert to a state of steady functional decline (secondary progressive MS). This occurs in 50% of people within 10 years and 90% at 30 years.

In primary progressive MS (seen in 10–15% of patients) there is steady functional decline from the start of the illness.

Diagnosis and management

Diagnosis of MS requires the demonstration of demyelinating central nervous system lesions that are disseminated in both space and time (i.e. more than one clinical episode, affecting at least two regions of the brain, spinal cord or visual pathways). There is no cure at present but a number of disease-modifying agents are available that may reduce relapse frequency and severity (see below).

Diagnosis

The diagnosis of multiple sclerosis is primarily clinical, but is confirmed and supported by neuroimaging, serological testing and electrophysiology.

Neuroimaging

The most sensitive method for demonstrating MS lesions is magnetic resonance imaging (MRI), which shows ten times more plaques than clinical episodes (since most lesions are clinically silent).

Demyelinating lesions are well-demonstrated on T2-weighted MRI scans, which highlight increased water content or decreased myelin (fat) content. However, since MS plaques tend to be periventricular, the T2 hyperintensity of normal CSF may make them more difficult to see. This is overcome using a fluid attenuation inversion recovery (FLAIR) sequence, which is similar to T2 but with a suppressed CSF signal (Fig. 14.4).

Fig. 14.4 An axial, T2-weighted MRI scan (A) and a fluid attenuation inversion recovery (FLAIR) sequence (B) in a patient with multiple sclerosis.
There are numerous plaque-like lesions in the periventricular white matter, best seen on the FLAIR sequence [see text for explanation]. Courtesy of Dr Andrew MacKinnon.

In patients with clinically definite multiple sclerosis, MRI shows multifocal white matter abnormalities in 95% of cases. Administration of the MRI contrast agent gadolinium is useful for demonstrating acute (active) lesions. This correlates with breakdown of the blood–brain barrier (see Ch. 5) in areas of active inflammation and demyelination.

Oligoclonal bands

The CNS inflammatory response in multiple sclerosis is associated with synthesis of antibodies (immunoglobulins) in the brain and spinal cord. It is therefore possible to detect antibodies in the CSF that are not present in peripheral blood. A sample of CSF is obtained by lumbar puncture (see Ch. 1, Clinical Box 1.3) and a specimen of venous blood is taken at the same time, for comparison. The two specimens are run on an electrophoretic gel to look for bands indicating the presence of type G immunoglobulins (IgG) that are only present in the CSF (which is indicative of CNS inflammation). These are known as oligoclonal bands (OCBs) and are found in 90% of people with MS (Fig. 14.5).

Visual evoked potentials

Decreased conduction speed in the central visual pathways can be demonstrated in the majority of patients with MS by obtaining visual evoked potentials (VEPs). Scalp electrodes record electrical activity in the occipital cortex in response to a changing visual stimulus such as an alternating chequerboard pattern. The stimulus-response sequence is repeated many times and averaged (to increase the signal-to-noise ratio). This reveals a characteristic positive wave in the visual cortex at 100 milliseconds (the P100 wave) which is delayed by 30–40 milliseconds in 95% of people with MS (Fig. 14.6).

Key Points

Diagnosis of MS is primarily clinical and requires demonstration of CNS demyelinating lesions that are disseminated in both space and time (confirmed by neuroimaging, serological testing and electrophysiology).

MRI (using a T2 FLAIR sequence) is the most sensitive method for demonstrating MS lesions (showing 10× more plaques than clinical episodes, since most lesions are clinically silent). The presence of gadolinium enhancement suggests there is breakdown of the blood–brain barrier.

Other findings in support of the diagnosis include oligoclonal bands (present in 90% of people with MS) and delay in the P100 wave on visual evoked potentials (in 95% of patients).

Management

There is no cure for MS and the treatment is mainly supportive. Acute relapses are usually managed with a 3–5-day course of high-dose intravenous corticosteroids (e.g. methylprednisolone) or sometimes oral prednisolone. This has an immunosuppressive effect that shortens relapses and provides symptomatic relief, but does not improve long-term outcome.

Disease-modifying drugs (DMDs)

Several disease-modifying agents are licensed for use in MS, but are mainly suitable for relapsing-remitting disease, with little effect once the patient has entered the progressive phase. Although disease-modifying agents are not curative, they do reduce relapse frequency and severity by up to two thirds. First-line treatment in MS includes (i) interferon beta and (ii) glatiramer acetate.

Interferon beta

Interferons are cytokines (inflammatory mediators) that influence immune responses and interfere with viral replication. The mechanism of action in MS is not certain, but interferons are known to have immune modulating and anti-inflammatory properties. Neuroimaging studies show that they reduce the number of inflammatory CNS lesions by more than 50%.

Two forms of interferon beta are used in the treatment of MS: Interferon beta-1a (administered by intramuscular or subcutaneous injection) and interferon beta-1b (administered subcutaneously). Side effects include flu-like symptoms (muscle aches, fever, chills and malaise) for 24–48 hours after injection. In the longer term, there is a risk of liver function abnormalities and immunosuppression (reduced white blood cell count). Interferons are not recommended for children or for women who are pregnant or breast feeding.

Glatiramer acetate

This is a synthetic mixture of polypeptides (a copolymer), containing four amino acids that are present in myelin basic protein (glutamic acid, alanine, tyrosine and lysine). It is administered by daily subcutaneous injection. The original rationale for its use was to compete with (or mimic) myelin basic protein but its actual mechanism of action is not certain. It appears to reduce antigen presentation and to promote secretion of anti-inflammatory cytokines from activated immune cells. There are usually no major side effects, in contrast to interferon beta, but this drug is also not recommended for children or for women who are pregnant or breast feeding.

Natalizumab

This is a monoclonal antibody (immunoglobulin G, IgG) which is given by intravenous injection every 28 days. Clinical trials show that it reduces the number of relapses by about two-thirds. Natalizumab recognizes an adhesion molecule called α4 integrin which binds to a vascular cell adhesion molecule (VCAM-1) on endothelial cells. This is designed to prevent leukocytes from binding to blood vessels, reducing the number of chronic inflammatory cells entering the CNS from the bloodstream. Side effects include headache, nausea, vomiting and skin rash. In rare cases it has been associated with an acute white matter disorder: progressive multifocal leukoencephalopathy (PML) (Clinical Box 14.4).

Clinical Box 14.4: Progressive multifocal leukoencephalopathy (PML)

This is a white matter disease associated with immune deficiency, often HIV/AIDS. It is an opportunistic infection caused by reactivation of a papovavirus that infects oligodendrocytes. The infectious agent is called JC virus (John Cunningham virus, named after a patient with PML). The pathological features include demyelination, chronic inflammation and reactive gliosis. Two key cellular elements are: (i) ‘bizarre’ astrocytes with large irregular nuclei; and (ii) transformed oligodendrocytes with large nuclei that stain bluish-purple with routine stains (reflecting alterations in the nuclear DNA). The mortality rate is high and survivors are generally left with severe neurological disabilities.

Fingolimod

This is the first oral agent that has been licensed for the treatment of MS. It has been shown in clinical trials to reduce the number of relapses by around 50%. It works by inhibition of sphingosine 1-phosphate receptors which blocks lymphocyte migration from lymph nodes. However, a number of potentially serious side effects have been described. These include bradycardia, immunosuppression, liver toxicity and allergic reactions. This drug is therefore only used in patients with severe relapsing-remitting MS, particularly people who are not responding to first-line treatments.

Unlicensed drugs

Other drugs that may be useful in the management of MS are the immunosuppressive agent azathioprine and the chemotherapy drug mitoxantrone, but neither of these is licensed in the UK.

Mitoxantrone, in particular, may be beneficial in patients with secondary progressive MS and might also delay the transition from relapsing-remitting to progressive disease. It appears to work by suppressing activity in lymphocytes and macrophages, which are responsible for the immune-mediated attack on myelin (discussed below). In keeping with other anti-cancer drugs, side effects include nausea, vomiting and hair loss; more serious adverse effects sometimes occur, such as cardiotoxicity and bone marrow suppression (carrying a significant infection risk).

Intravenous immunoglobulin (IVIG) is pooled human immunoglobulin G that may be used in patients who are unable to tolerate standard disease-modifying treatments. The mechanism of action in MS is complex and incompletely understood, but is presumed to be immunomodulatory. It can be given to women who are unable to take their normal disease-modifying agents due to pregnancy or breast feeding. This is important, since one in three women experience a relapse in the post-partum period.

Long-term supportive care

Much of the long-term treatment for multiple sclerosis is supportive and aims to manage chronic symptoms such as fatigue, pain, muscle spasms and problems with bladder, bowel or sexual function:

Neuropathic pain can be very troublesome and is managed with a number of agents including the anti-epileptic drugs gabapentin and carbamazepine (see Ch. 11).

Extreme tiredness often responds to the Parkinson’s disease drug amantadine (the stimulant effect is mediated by increased dopamine release at central synapses) (see Ch. 13).

Mood disorder is common in patients with multiple sclerosis and can be treated with antidepressants or anxiolytics, in combination with counselling or cognitive-behavioural therapy.

Muscle spasms, musculoskeletal pain and spasticity may be improved by physiotherapy or a muscle relaxant such as baclofen, gabapentin, dantrolene or a benzodiazepine (see Ch. 7).

Bladder problems such as detrusor hyperactivity can be treated with antimuscarinic agents such as oxybutynin or tolterodine which relax smooth muscle of the urinary bladder; nocturia (increased urination during the night) may be treated by desmopressin (antidiuretic hormone).

Constipation can usually be managed with dietary measures such as increased consumption of fruit and fibre. In some cases aperients (laxatives) or stool softeners may be appropriate.

Epilepsy is also more common in patients with MS and this can be managed with anti-epileptic drugs if necessary (Ch. 11).

Careful attention to these long-term problems may have a considerable impact on quality of life and co-operation between the neurologist, family doctor and specialist team members (including nurses, physiotherapists and occupational therapists) is highly beneficial.

Key Points

Acute MS relapses are treated with intravenous methylprednisolone (or oral prednisolone). This shortens relapses and provides symptomatic relief, but does not improve long-term outcome.

First-line disease-modifying treatment for MS includes: (i) interferon beta (an inflammatory mediator that has immune-modulating and anti-inflammatory properties); and (ii) glatiramer acetate (a polypeptide copolymer mixture with an uncertain mechanism of action).

Other disease-modifying agents include natalizumab and fingolimod (which prevent leukocyte migration into the brain) and immunomodulating or immunosuppressive agents such as mitoxantrone (a chemotherapy drug) and intravenous immunoglobulin (IVIG).

Long-term supportive care aims to address chronic pain, fatigue, mood disorder, muscle spasms and problems with bowel, bladder or sexual function.

Pathological features

Post-mortem examination of the brain in a person with longstanding multiple sclerosis mainly shows chronic (old) plaques, but acute lesions are occasionally encountered.

MS plaques

In fresh post-mortem brain tissue, chronic plaques appear as sharply demarcated areas that lack normal myelin, giving them a salmon-pink appearance (Fig. 14.7). This is in contrast to acute plaques which have a yellowish colour due to the high lipid content. The presence of gliosis (‘glial scarring’; see Ch. 8) gives plaques a firm or sclerotic consistency, from which the name multiple sclerosis is derived (Greek: sklerōs, hard). After the brain has been preserved, plaques have a greyish appearance (Fig. 14.8).

Fig. 14.7 Fresh post-mortem brain specimen in multiple sclerosis showing salmon pink plaques in the periventricular white matter. From Stevens and Lowe: Pathology 2e (Mosby 2000) with permission.

Fig. 14.8 Sharply defined plaques of demyelination in (A) the periventricular white matter and (B) the brain stem.
In this case the brain has been preserved in formaldehyde prior to slicing. From Prayson, R: Neuropathology (Chuchill Livingstone 2005) with permission.

Plaque distribution

Plaques can occur anywhere in the brain or spinal cord, but they are most often found in the periventricular white matter. They are typically between 2–10 mm in diameter and have a well-defined margin (Fig. 14.9). Plaques also frequently occur at grey–white matter junctions (especially at the border between the cerebral cortex and subcortical white matter) and within the cortex itself, which also contains myelinated axons. In advanced cases extensive white matter loss may be associated with marked compensatory dilation of the ventricles, termed hydrocephalus ex vacuo. In a subset of patients, plaques are found only in the optic pathways and cervical spinal cord (Clinical Box 14.5).

Clinical Box 14.5: Devic’s disease

Devic’s disease or neuromyelitis optica is an inflammatory demyelinating disorder that affects the cervical spinal cord (causing tetraplegia) and optic nerves (leading to impaired vision or blindness). It can be monophasic, recurrent or relapsing-remitting and may be regarded as a variant of multiple sclerosis or as a separate disease. In a proportion of cases there is an antibody-mediated autoimmune response to the membrane water channel aquaporin-4. Devic’s disease can be managed with immunosuppressive agents including corticosteroids, but cannot be cured.

Fig. 14.9 Appearances of a typical MS plaque with (A) a routine, haematoxylin and eosin or H&E stain and (B) with the myelin stain Luxol fast blue (LFB).
Note the sharp peripheral margin with the surrounding normal white matter. From Stevens, A, Lowe, JS and Young: Wheater’s Basic Histopathology 4e (Churchill Livingstone 2002) with permission.

Acute and chronic plaques

The microscopic appearance of MS plaques depends on whether they are acute or chronic. Acute plaques are cellular, with sheets of foamy macrophages containing lipid-rich myelin debris and perivascular cuffs of lymphocytes. Importantly, there is relative preservation of axons.

Chronic plaques may be active or inactive. Chronic active plaques have a cell-poor centre which is gliotic (with numerous astrocytic processes) but shows little inflammation. This is surrounded by a peripheral margin of activity at the interface with healthy myelin. The rim of active demyelination contains macrophages and lymphocytes. Chronic inactive plaques are similar, but lack the peripheral rim of demyelination. Some histological patterns are associated with a particular MS variant (Clinical Box 14.6).

Clinical Box 14.6: Balo’s concentric sclerosis

Balo’s concentric sclerosis is a histological variant of MS which used to be regarded as a distinct form of the disease. Histological examination of the brain shows sharply defined concentric rings of demyelination alternating with bands of unaffected myelin, giving an ‘onion-skin’ appearance (Fig. 14.10). This was previously only diagnosed at post-mortem examination and was thought to be associated with an invariably aggressive (usually fatal) clinical course. However, it is now possible to identify Balo’s disease in life using modern neuroimaging methods, which suggests that this pattern of demyelination is much more common and not necessarily aggressive.

Fig. 14.10 Balo’s concentric sclerosis.
The presence of multiple concentric rings of demyelinated and myelinated axons creates an ‘onion skin’ appearance [section of cerebral hemisphere; Loyez stain], in which myelin appears black. From Ellison, D and Love, S: Neuropathology 2e (Mosby 2003) with permission.

Remyelination

After the inflammation has subsided, approximately 20% of MS plaques remyelinate to form a ‘shadow plaque’ (Fig. 14.11). However, remyelination is often partial or inadequate, with thinner than normal myelin sheaths and shortened internodal segments.

Remyelination relies on recruitment from a pool of oligodendrocyte precursor cells (OPCs). These cells migrate towards regions of demyelination before proliferating and differentiating into mature oligodendrocytes that are able to invest the denuded axons with a new myelin sheath.

Remyelination is more common in early MS lesions and is less likely in old (chronic) lesions. Inadequate remyelination may contribute to the gradual development of permanent neurological deficits in progressive disease, but the reason for myelination failure is not fully understood.

Failure of remyelination

Remyelination may be prevented by on-going inflammation and continued demyelination. In older plaques, the presence of glial scarring (see Ch. 8) may also be a factor. This is characterized by a dense meshwork of astrocytic processes at the centre of the lesion which may physically prevent inward migration of oligodendrocyte precursor cells.

Remyelination failure might also reflect OPC depletion, although successful recruitment and proliferation of progenitor cells has been demonstrated in some animal models, in which failure of OPC differentiation appears to be the most important factor.

Expression of certain cell-surface molecules on demyelinated axons may actively inhibit remyelination. These include the polysialylated form of neural cell adhesion molecule (NCAM). Other inhibitory molecules are present in the extracellular matrix and in association with astrocytic processes (in areas of glial scarring).

Oligodendrocyte precursor cells express Notch receptors at the cell surface. These are stimulated by extracellular ligands such as the protein jagged (which is known to be present in MS plaques). The notch-jagged interaction inhibits differentiation of OPCs to mature oligodendrocytes and contributes to remyelination failure. Notch inhibitors are therefore potential disease-modifying agents in MS.

Key Points

Pathological examination of the brain in MS shows acute, chronic active and chronic inactive plaques, which are 2–10 mm in diameter and often occur in the periventricular white matter.

After the inflammation has subsided, approximately 20% of plaques remyelinate (particularly in the earlier stages of MS) to produce a partially remyelinated shadow plaque.

Remyelination depends on the recruitment, proliferation and differentiation of oligodendrocyte precursor cells (OPCs).

Failure of remyelination may be due to ongoing inflammation, the presence of an astroglial scar or failure of OPC differentiation. In the CNS, remyelination appears to be actively inhibited.

Aetiology

The cause of multiple sclerosis is not known, but it is widely believed to result from an interaction between genetic and environmental factors and may be triggered by exposure to a virus infection.

Genetic and immunologic factors

MS cannot be inherited in a simple Mendelian fashion and there are no familial forms. Nevertheless, concordance is around 25% in identical twins, compared to around 5% for fraternal twins and siblings – and the risk is up to 20 times higher in first-degree relatives of people with MS.

Familial clustering is likely to be due to a number of unknown susceptibility genes, but candidates have been difficult to identify. This is probably because the genetic effects are small and involve multiple genes, each making a modest contribution to overall risk.

Robust associations have only been found with certain human leukocyte-associated antigen (HLA) genes, particularly within the class II region of the major histocompatibility complex (MHC) of antigens on chromosome 6. The most consistently implicated subtype in Caucasians (the population at greatest risk) is HLA-DRB1*15 (HLA-DR15 haplotype). In other populations, different HLA types may be more important and the estimated contribution to overall genetic susceptibility varies from 20–50%.

Environmental factors

The prevalence of multiple sclerosis varies with distance from the equator (Fig. 14.12). Equatorial regions tend to have comparatively low prevalence rates, whereas more temperate areas to the north and south have a progressively greater incidence. Some of the highest recorded rates of MS have been identified in the northern part of Scotland and in North America.

Fig. 14.12 Geographical distribution of multiple sclerosis risk.
Individuals who are closer to the equator below the age of 15 years are at a lower risk of MS in adulthood, regardless of subsequent migration.

Migration studies

Geographic risk in MS relates to location before puberty (under the age of 15) and individuals who migrate after this age carry the risk of their original location. This may reflect exposure to an environmental agent (such as a virus) during a critical time-window prior to puberty. The time frame coincides with maximal development and involution of the thymus gland. This is the site of T-cell (thymus cell) maturation and the deletion of potentially auto-aggressive cells by apoptosis (see Ch. 8).

Sunlight and vitamin D

Proximity to the equator may reduce MS risk as a result of increased sunlight exposure. This could reflect a lower chance of encountering a particular pathogenic virus (since viruses are destroyed by ultraviolet radiation in sunlight) or higher levels of vitamin D (in keeping with research showing that supplementation may reduce relapse frequency). There is also a month of birth effect: in the Northern Hemisphere more people with MS are born in the spring than the autumn. This phenomenon may be related to maternal sunlight exposure or vitamin D status.

Viral and other infections

A number of infectious agents have been proposed as the cause of multiple sclerosis, including Epstein–Barr virus (EBV), human herpes virus 6 (HHV-6) and many of the immunological features of MS are suggestive of a virally mediated process.

The bacterial agent Chlamydia pneumoniae has also been implicated – and bacterial infection is known to be associated with some cases of demyelination in the peripheral nervous system (Clinical Box 14.7). Nevertheless, no causative agent has been unequivocally implicated and no microorganisms have been isolated from human tissues.

Clinical Box 14.7: Guillain–Barré syndrome

This is a peripheral neuropathy, also known as acute inflammatory demyelinating polyneuropathy (AIDP) that is characterized clinically by ascending weakness. This means that the lower part of the body is affected first, progressively spreading to involve more proximal muscle groups in the trunk and upper limbs. It can be life-threatening if paralysis reaches the respiratory muscles. In many cases the cause is not known but it is sometimes triggered by an infection and 30% of cases are preceded by an episode of campylobacter enteritis (caused by the bacterium Campylobacter jejuni). The pathogenesis is thought to involve molecular mimicry, in which a cell-surface antigen on the infectious organism is similar to a surface antigen in peripheral myelin, creating an autoimmune inflammatory demyelination. Unlike MS, it is restricted to the peripheral nervous system.

Key Points

The cause of MS is not known, but it is widely believed to result from an interaction between genetic and environmental factors and may be triggered by a virus infection.

MS cannot be inherited in a simple Mendelian fashion, but concordance rates are 5× higher in identical twins and risk is up to 20× higher in first-degree relatives of people with MS.

The most robust association is with human leukocyte-associated antigen (HLA) subtypes and the most consistently implicated subtype in Caucasians (who are at greatest risk) is HLA-DR15.

Prevalence of MS is higher with increasing distance from the equator and migration studies show that location prior to puberty determines adult risk. This may reflect increased risk of encountering a particular virus, but other factors have been implicated including sunlight exposure and vitamin D status.

Animal models of MS

A number of experimental models of CNS demyelination have been developed (which resemble multiple sclerosis to a greater or lesser degree) and have contributed to our understanding of its pathogenesis. Animal models fall into four major categories:

Autoimmune models

The most widely used model of central nervous system demyelination is experimental autoimmune encephalomyelitis (EAE). This system is used to evaluate potential disease-modifying therapies. The experimental animal is injected with homogenates derived from CNS tissue or protein extracts containing myelin basic protein (MBP) or proteolipid protein (PLP).

This induces a T-cell-mediated immune response (often in a rat or mouse, but sometimes in other species including non-human primates). This leads to brain and spinal cord inflammation with blood–brain barrier dysfunction, usually accompanied by demyelination. In particular, the immune response is mediated by helper T-cells, which is the same type of immune response seen in MS. This is accompanied by clinical signs and axonal changes, including conduction block. A criticism of this model is that since it produces a monophasic, post-vaccinial demyelinating disease, it has more in common with acute disseminated encephalomyelitis (Clinical Box 14.8).

Clinical Box 14.8: Acute disseminated encephalomyelitis

This is a self-limiting CNS disorder of childhood that presents with meningism (headache, fever, neck stiffness) and usually occurs 2–10 days after a virus infection or vaccine. Imaging shows bilateral hemispheric white matter changes corresponding to perivenous demyelination and oedema (Fig. 14.13). The clinical course is usually benign, with complete recovery. It is almost always monophasic. A hyperacute variant termed acute haemorrhagic leukoencephalopathy (AHL) or Hurst disease is characterized by widespread haemorrhagic lesions with brisk inflammatory infiltrates and marked brain oedema. This subtype is much more aggressive and usually fatal.

Fig. 14.13 Axial MRI FLAIR images in a boy age 2 years 8 months with acute disseminated encephalomyelitis (ADEM).
There are patchy signal changes widely distributed in the cerebral white matter bilaterally, including diffuse involvement of the internal capsules. Courtesy of Dr Andrew MacKinnon.

Viral models

A number of CNS viruses are known to cause demyelination in humans (such as JC virus in PML; see Clinical Box 14.4). Several animal models have been developed that exploit this phenomenon. Many of the viruses used in these models infect oligodendrocytes and are either directly cytotoxic or induce a cell-mediated immune response against oligodendrocytes.

Chemically-induced models

It is also possible to induce demyelination in experimental animals by systemic or targeted administration of substances that are toxic to oligodendrocytes. Examples include: (i) cuprizone, a copper chelating agent that causes oligodendrocyte death following oral administration; and (ii) ethidium bromide, a DNA-binding agent which can be injected into white matter pathways such as the dorsal columns or cerebellar peduncles.

Chemically-induced demyelination is monophasic and is usually followed by complete remyelination within a few weeks. These systems therefore enable systematic study of the processes involved in demyelination, clearance of myelin debris and remyelination, including OPC recruitment.

Genetic models

A number of models are available in which the experimental animal (usually a rodent) has a myelin gene mutation. These include animals with mutations in genes for myelin basic protein (e.g. Shiverer) and proteolipid protein (e.g. Rumpshaker and Jimpy). Gene knockout animals for myelin components also exist. However, animals with myelin gene mutations typically exhibit abnormal primary myelination (dysmyelination) and are thus more comparable to human leukodystrophies (see Clinical Box 14.1).

Key Points

Animal models of CNS demyelination are useful to investigate the pathogenesis of MS and to test potential disease-modifying therapies. The main types are autoimmune, virus-mediated, chemically-induced and genetic.

The most common animal model of MS is experimental autoimmune encephalomyelitis (EAE) in which the experimental animal is injected with myelin extracts to trigger an immune reaction.

Pathogenesis

Our understanding of disease pathogenesis in MS is derived from a combination of findings in animal models and observations in human disease. Gadolinium-enhanced MRI scans in patients with MS suggest that disruption of the blood–brain barrier (see Ch. 5) may be an early event in acute lesions. Pathological studies confirm increased permeability of cerebral vessels, associated with immune activation of endothelial cells and passage of leukocytes from the bloodstream into the brain tissue.

Endothelial cells are activated by pro-inflammatory cytokines including interferon-gamma. This leads to upregulation of MHC class II molecules and alterations of cell-surface proteins involved in leukocyte–endothelial interactions, promoting cell adhesion and extravasation of white blood cells. Changes to tight junctions between endothelial cells lead to increased vascular permeability and movement of fluid and immune cells into the brain tissue, causing local oedema (swelling).

Inflammatory cells

Following endothelial cell activation and breakdown of the blood–brain barrier, a mixed inflammatory infiltrate enters the brain that is predominantly composed of macrophages and lymphocytes.

Macrophages

Macrophages (and activated microglia, which are of similar lineage) are the principal cellular mediators of demyelination. These cells actively strip axons of their myelin sheaths and digest its lipid and protein constituents. Myelin debris accumulates within activated macrophages to give a ‘foamy’ appearance (Fig. 14.14).

The number of macrophages is related to lesion activity. As myelin debris is cleared and inflammation subsides, macrophages gradually disappear from the centre of acute plaques, but remain prominent at the peripheral (active) margins of the lesion where there is continued expansion into the surrounding white matter.

T-lymphocytes

Active multiple sclerosis lesions are rich in T-lymphocytes. These can be divided into: (i) helper T-cells which express the cell-surface molecule CD4; and (ii) cytotoxic T-cells which express CD8. The CD4 and CD8 molecules help T-lymphocytes to recognize myelin constituents that have been processed and ‘presented’ to them by antigen-presenting cells (APCs) including activated microglia and macrophages (Fig. 14.15).

CD4⁺ helper T-cells produce cytokines including interleukin-1 and 2 (IL-1 and IL-2), tumour necrosis factor (TNF) and interferon-gamma that are key inflammatory mediators. These molecules play a number of roles including upregulation of cell-adhesion molecules (facilitating leukocyte recruitment) and activation of microglia and macrophages.

CD8⁺ cytotoxic (‘killer’) T-cells are also numerous in acute multiple sclerosis lesions and probably have a more direct role in damaging CNS tissues.

B-lymphocytes

The role of B-lymphocytes (and antibody-producing plasma cells which derive from them) is demonstrated by the presence of IgG oligoclonal bands in the CSF of patients with multiple sclerosis.

Binding of myelin-specific autoantibodies disrupts the myelin sheath and triggers activation of the complement cascade, leading to attachment of proteins called opsonins that attract macrophages and microglia. Macrophages recognize and bind the opsonized myelin via complement receptors on the macrophage plasma membrane, leading to receptor-mediated endocytosis. Disrupted myelin fragments are thereby internalized by the macrophages and digested.

Key Points

Gadolinium-enhanced MRI scans in patients with multiple sclerosis suggest that disruption of the blood–brain barrier is an early event in acute MS plaques.

Endothelial cell activation (e.g. by pro-inflammatory cytokines such as interferon-gamma) is following by a chronic inflammatory infiltrate dominated by macrophages and lymphocytes.

Macrophages (and activated microglia) are the principal mediators of demyelination and are involved in actively stripping and digesting the myelin sheath and its components.

T-lymphocytes (CD4⁺ helper T-cells and CD8⁺ cytotoxic T-cells) are involved in cell-mediated myelin damage whereas B-cells (and plasma cells) produce myelin-specific autoantibodies.

Impact on axonal conduction

In myelinated fibres, voltage-gated ion channels are concentrated at the nodes of Ranvier (Fig. 14.16A). This means that following demyelination, the denuded portion of the axon is unable to transmit action potentials, leading to conduction block (Fig. 14.16B). Partial recovery of function may be possible due to redistribution or insertion of new voltage-gated sodium channels along the internodal region (Fig. 14.16C). However, this permits only continuous (rather than saltatory) conduction, which is considerably slower and much less energy-efficient (see Ch. 6).

Fig. 14.16 Conduction block and recovery of function in demyelinated axons. See text for explanation.

Changes in the excitability and ion channel expression profile within the demyelinated axon can also generate ectopic action potentials. This may lead to ‘positive’ phenomena such as painful sensations or tingling (paraesthesiae). The hyperexcitable axonal segments may also be sensitive to mechanical deformation, which might explain Lhermitte’s phenomenon (discussed above).

Types of active plaque

Studies of post-mortem brain tissue (and diagnostic brain biopsies in living patients) have provided evidence of four distinct patterns in early (active) MS plaques, each with a different pathophysiological mechanism (Fig. 14.17). In a particular patient, all plaques are of the same type.

The basic mechanism in multiple sclerosis (pattern I) is characterized by a T-cell-mediated immune response with macrophage-associated demyelination. This accounts for around 20% of MS cases. In many patients, the basic T-cell response is supplemented by a specific antibody and complement-mediated assault on CNS myelin (pattern II). This appears to be the most common type overall, accounting for more than 50% of cases. It is typified by Devic’s disease and in this particular case the antibodies are raised against the water channel aquaporin-4 (discussed above; see Clinical Box 14.5).

Pattern III is referred to as a distal oligodendrogliopathy because the target is the distal (para-axonal) loop of myelin that lies in intimate contact with the axon (see Fig. 14.18); the oligodendrocyte cell body remains intact, but there is a ‘dying back’ of its processes, with consequent demyelination. There is also evidence of mitochondrial dysfunction in this type of plaque, which has features in common with hypoxic or ischaemic cell death (see Ch. 10). Pattern III is typified by Balo’s disease in which multiple waves of hypoxic-type damage create an onion skin appearance (see Clinical Box 14.6) and accounts for approximately 25% of lesions overall.

Fig. 14.18 An oligodendrocyte process investing part of an axon.
The distal oligodendrocyte process (or para-axonal loop) is indicated. This is the target in ‘dying-back’ oligodendrogliopathy, the characteristic finding in pattern III multiple sclerosis plaques.

Rarely (in less than 5% of cases) there is a genetic predisposition leading to primary oligodendrocyte degeneration, followed by secondary demyelination (pattern IV).

Key Points

Studies of post-mortem brain tissue and diagnostic brain biopsies in living patients have provided evidence that there are four different types (or patterns) of MS plaque.

The basic mechanism in MS (pattern I) is characterized by a T-cell-mediated immune response (20%) supplemented by an antibody-mediated attack (pattern II) in a further 50% of cases.

Pattern III (25% of cases) is referred to as a distal (dying-back) oligodendrogliopathy in which the distal oligodendrocyte processes are lost, with relative preservation of the cell body. Pattern IV is rare (<5% of cases) and is associated with a mutation that promotes oligodendrocyte apoptosis.

In each of the four patterns, demyelination leads to: (i) conduction failure, associated with ‘negative’ neurological symptoms such as weakness and numbness; and (ii) ectopic action potentials, which leads to ‘positive’ symptoms including pain and paraesthesiae.

Neurodegeneration in MS

In the progressive phase of MS, there is gradual white matter atrophy, with ventricular dilatation and thinning of the cerebral cortex (Fig. 14.19). This is associated with accumulation of permanent neurological disability and is thought to be due to axonal damage and loss of cortical neurons.

Fig. 14.19 Neurodegeneration in multiple sclerosis.
In most patients, the early stages of MS are characterized by a relatively benign relapsing-remitting course with episodes of acute inflammatory demyelination and discrete clinical relapses, often with very good functional recovery. Most patients convert to a progressive phase of neurological decline, characterized by axonal loss (even in the normal-appearing white matter), together with plaques and neuronal loss in the cerebral cortex. The degenerative phase of MS is associated with brain atrophy and dilation of the ventricles.

Axonal damage

Axonal disruption and transection occurs in acute MS plaques and at the peripheral margins of chronic active plaques. In general, the degree of axonal damage correlates with the intensity of inflammation, but axon loss is also present in normal-appearing white matter (NAWM).

Disrupted axons (axon swellings) can be demonstrated using silver stains or by immunohistochemistry for axonal proteins such as neurofilament protein. Immunolabelling for beta amyloid precursor protein (β-APP) is a sensitive method for demonstrating axonal disruption, which is also used in traumatic head injury (see Ch. 9).

In recent years progressive axonal loss has become an increasing focus of research interest and is now regarded as an important cause of long-term neurological disability. Axonal and neuronal damage is likely to be responsible for the cumulative deficits that appear as the patient makes the transition to secondary progressive disease.

Mechanism of axonal injury

The precise cause of axonal loss in MS plaques is not known, but may reflect ‘bystander’ damage to neurons and axons. This refers to injury mediated by cytotoxic molecules including pro-inflammatory cytokines, nitric oxide and other toxic substances released by activated macrophages, lymphocytes and astrocytes during the inflammatory response.

Glutamate-mediated excitotoxicity (see Ch. 8) has also been implicated, with axonal calcium overload as a final common pathway. In experimental models of inflammation, axonal degeneration can be triggered by nitric oxide (which is known to be present in MS plaques and is generated in response to excess glutamatergic stimulation). In addition, the presence of antineuronal antibodies in the CSF of patients with MS raises the possibility of more direct, immune-mediated axonal damage.

Loss of demyelinated axons

In some cases demyelinated axons survive the acute inflammatory response but subsequently degenerate. One reason for loss of chronically demyelinated axons is lack of their normal trophic support from oligodendrocytes. This includes soluble mediators and trophic molecules that are required for continued neuronal survival.

Metabolically active demyelinated axons appear to be most at risk and energy depletion is considered to be an important factor. This may be due in part to redistribution of sodium channels along the internodal segments as a result of demyelination (see Fig. 14.16). This permits impulse conduction across the denuded axonal segments, but makes axonal conduction less efficient and increases axonal energy demands.

If there is inadequate ATP generation (to cope with the increased metabolic demands) then reduced activity of the ATP-dependent sodium–potassium pump may lead to the accumulation of sodium ions within the axon. This leads to impairment of the sodium–calcium exchange pump (which relies on the sodium gradient) with a consequent rise in the axonal free calcium concentration, triggering cell death pathways. Drugs that inhibit voltage-gated sodium or calcium channels may therefore be useful as potential neuroprotective agents in multiple sclerosis.

Cortical demyelination

The cerebral cortex also contains myelinated axons and cortical plaques are present in the majority of patients with MS (Fig. 14.20). Pathological studies in longstanding MS show that more than 25% of the cortex may contain plaques, which are of three types:

Type I lesions affect the lower half of the cerebral cortex and span the cortical–subcortical junction, therefore affecting both grey and white matter.

Type II lesions are small foci of cortical demyelination that surround small blood vessels. They are the least common and probably make a relatively minor contribution to cortical pathology.

Type III lesions consist of large, confluent areas of subpial demyelination that affect the superficial half of the cortex, often spanning several adjacent gyri.

Cortical plaques are not associated with chronic inflammation, which makes them less obvious in pathological preparations. They are also difficult to identify using clinical imaging because there is no associated compromise of the blood–brain barrier (so they do not appear on T2-weighted MRI scans or with gadolinium contrast enhancement).

Pathological studies of cortical plaques show associated axonal degeneration, reduction in dendritic density and neuronal apoptosis, contributing to a greater than 20% reduction in cortical neuronal density in patients with progressive MS. Although chronic inflammatory infiltrates are not seen in association with cortical demyelination, there is prominent microglial activation and these cells (or cytotoxic inflammatory mediators released by them) may be responsible for the neuronal injury.

Key Points

In the progressive phase of MS there is gradual white matter atrophy, with ventricular dilatation and thinning of the cerebral cortex, due to loss of axons and neurons.