Multiple sclerosis is a progressive disease of the central nervous system, in which patches of myelin (the protective covering of nerve fibres) in the brain and the spinal cord are disrupted. The damaged patches are called plaques. The nerves cannot conduct electrical impulses, so functions such as movement and sensation may be lost. Any part of the central nervous system may be affected.

Causes and incidence 

There may be a genetic predisposition, because MS sometimes runs in families. There may also be an environmental cause. It is more common in temperate zones than in the tropics.

Symptoms 

Multiple sclerosis (MS) usually develops between the ages of 20 and 45, and is more common in women. Symptoms depend on the area of the brain or spinal cord that is involved in an attack. Spinal cord damage may cause tingling, numbness, weakness in the extremities, spasticity, paralysis, and incontinence. Damage to white matter (myelinated nerves) in the brain may cause fatigue, vertigo, clumsiness, muscle weakness, slurred speech, blurred vision, facial numbness, or facial pain.

An attack may last for several weeks or months. It is followed by a variable period of remission, in which dramatic improvements may be made. After a remission period, a further attack or a relapse occurs. Most people have mild relapses and long periods of remission (relapsing–remitting MS), with few per-manent effects. Others have a form called chronic–progressive MS, becoming gradually more disabled from the first attack. A few have a form called fulminant MS, which progresses rapidly in the first year of illness.

Diagnosis 

There is no single diagnostic test, but MRI may show damage to white matter in the brain, and a lumbar puncture may show abnormal proteins in the fluid around the spinal cord. Evoked response tests on the eyes may reveal disruption of the nerve pathways from the optic nerves.

Treatment 

There is no specific treatment. A short course of corticosteroid drugs may reduce the severity of relapses, while beta interferon can lengthen the time between attacks; however, these drugs do not improve the outlook. The use of rehabilitation, physiotherapy, and occupational therapy is essential so that people can carry out daily activities more easily. Some people try remedies such as taking sunflower seed oil, following a gluten-free diet, hyperbaric oxygen therapy, or having various vaccines. To date, however, there is no evidence that any of these measures are beneficial.

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Mulitple sclerosis in detail - non-technical

Multiple sclerosis and demyelinating disorders of the central nervous system - in detail - technical

Essentials

Central pontine myelinolysis—often associated with hyponatraemia, or correction of hyponatraemia (see Chapter 21.2.1), the fully evolved clinical picture is of flaccid paralysis with facial and bulbar weakness, disordered eye movements, loss of balance, and altered consciousness.

Leucodystrophies—characterized by noninflammatory demyelination, many of these conditions result from mutations affecting genes involved in myelin biology. They need to be considered in young adults with atypical syndromes combining physical and intellectual deficits, sometimes with peripheral nerve involvement, in whom imaging shows confluent lesions confined to white matter. These include (1) diffuse sclerosis (Schilder’s disease), (2) Krabbe’s disease, (3) adrenoleucodystrophy, (4) metachromatic leucodystrophy, (5) Pelizaeus–Merzbacher disease, and (6) adult-onset dominant leucodystrophies.

Introduction

A distinguishing feature of vertebrate development is the formation of compact glial-derived myelin ensheathing processes around axons. Myelin formation by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) has allowed the development of sophisticated and compact neural systems. Evolutionary advantage, however, is not without its drawbacks. Several diseases, inherited and acquired, loosely grouped under “demyelination” represent processes where the oligendrocyte–myelin unit appears to be the primary target, notwithstanding the intimate relationship and dependency between glia and axons.

Clinicians suspect demyelination when episodes reflecting damage to white matter tracts within the CNS occur in young adults. The paucity of specific biological markers of discrete demyelinating syndromes places an emphasis on clinical pattern—temporal and spatial—when classifying demyelining disorders. The diagnosis of multiple sclerosis, the most common demyelinating disorder, becomes probable when these symptoms and signs recur, affecting different parts of the brain and spinal cord. Other important demyelinating diseases include postinfectious neurological disorders (acute disseminated encephalomyelitis), metabolically mediated demyelination (central pontine myelinosis), and inherited leucodystrophies that may present in childhood or adulthood. Accepting differences in mechanism, presentation, and treatment, two observations can usefully be made when classifying demyelinating disorders based on presence or absence of inflammation and extent of focal versus diffuse demyelination. Multiple sclerosis is prototypic of the former and dysmylinating disorders such as leucodystrophies are representative of the latter.

Neurobiology of demyelination

Origin of oligodendrocytes

Oligodendrocytes synthesize and maintain membrane that is continuous with axonal ensheathing compact myelin. In contrast to neurons, oligodendrocytes are predominantly specified postnatally and continue to divide and migrate as oligodendrocyte precursor cells (OPCs). Identification of the OLIG genes has significantly advanced our understanding of the molecular regulation of developmental and adult oligodendrogenesis. In addition to its established role in specifying neurons and OPCs in the developing CNS, emerging evidence implicates Olig in self-renewal of neural stem cells and adult oligodendrogenesis in the normal and injured brain. These findings, together with accumulated insights into the proliferative, migratory and survival requirements of OPCs, have resulted in the oligodendrocyte lineage being the best characterized of all neural cells and offering potential neuroprotective therapeutic targets in the context of demyelinating disease.

Myelination

Myelination occurs when the membranous processes of mature oligodendrocytes contact and ensheathe axons. The result is compaction of myelin sheaths at two points of apposition, apparent on ultrastructural analysis as major and minor dense lines. Myelin is predominantly composed of lipids (70–80% dry weight; cholesterol, phospholipid, and galactolipids) and protein (20–30% dry weight). The major myelin-specific lipid, galactocerebroside, can be used to identify myelinating glia. The major proteins are proteolipid protein (PLP), myelin basic protein (MBP), and myelin-specific enzyme 2′,3′-cyclic nucleotide 3′-phosphohydrolase (CNP).

Myelination corresponds to the formation of segments of compact myelin around axons. Each high resistance myelin segment is separated by the unmyelinated high conductance node of Ranvier. This specialized structure, characterized by clusters of voltage-gated sodium channels, allows impulse propagation by saltatory conduction, which is more rapid, energy and space efficient than propagation along unmyelinated axons. Myelinated internodal segments contain dispersed sodium channels at a much lower density insufficient to support conduction.

Pathophysiology of demyelination

Demyelination results in predictable electrophysiological consequences including impaired saltatory conduction, decreased conduction velocity, variable degrees of conduction block, and inappropriate sensitivity to changes in temperature or mechanical displacement. Clinical manifestations of demyelination are less easily predicted. They are proportionate to the degree of redundancy in individual systems and tracts, the involvement of some being easily exposed whereas others appear able to absorb a greater degree of damage without function being impaired. As with many disorders of the nervous system, the clinical symptoms and signs may be negative (loss of function) or positive (spontaneous, involuntary and paroxysmal): either category may be equally disabling.

Partially demyelinated axons cannot transmit fast trains of impulse, which may explain symptoms that reflect physiological fatigue. Depolarization may traverse the lesion, but at reduced velocity, accounting for the characteristic delay in arrival of potentials evoked by sensory stimuli and recorded over appropriate cortical receptor zones. Partially demyelinated axons may discharge spontaneously, explaining distortions of sensation reported by many patients. Increased mechanical sensitivity manifests as movement-induced symptoms, including flashes of light on eye movement, and the electric sensation that spreads down the spine, limbs, or anterior chest wall after neck flexion—Lhermitte’s symptom and sign. Increased temperature sensitivity, with a reduction in the safety factor for conduction in partially demyelinated axons, explains the temporary increase in severity of pre-existing symptoms experienced by many patients after exercise or immersion in hot water. Cold, by contrast, may improve performance. Ephaptic transmission occurs between neighbouring and partially demyelinated axons, giving rise to paroxysmal symptoms of demyelination usually manifesting as trigeminal neuralgia, ataxia, and dysarthria, or tonic brainstem seizures. These are often triggered by touch or movement.

There are several mechanisms of symptom recovery early in the course of multiple sclerosis. These include the resolution of conduction block in nerve fibres which were never demyelinated, re-establishment of conduction in persistently demyelinated axons, functional reorganization of surviving pathways, and remyelination.

Onset and recovery of conduction block and clinical impairments match the phase of acute inflammation. Transient symptoms depend on reversible conduction block caused by direct action of cytokines and inflammatory mediators (especially nitric oxide) on normal or hypomyelinated axons. Function may be restored after demyelination by an increase in number and rearrangement of sodium channels along denuded axons, providing a variety of alternative patterns of ordered or partially disordered conduction. But channel reorganization can also be maladaptive, with the energy compromised demyelinated axon appearing vulnerable to sodium channel dependent axonal degeneration. Experimentally, remyelinated axons restore conduction of the nerve impulse and motor function. Together these observations suggest sodium channel blockade and promotion of remyelination as plausible neuroprotective strategies.

Inflammation, neurodegeneration, and remyelination

Demyelinating disease includes conditions in which myelin fails to develop (leucodystrophies) or is lost through inflammatory (multiple sclerosis and related conditions) or metabolic (central pontine myelinolysis) mechanisms. Outstandingly the most common group is multiple sclerosis, histologically characterized by breakdown of the blood–brain barrier and multifocal inflammatory plaques. In all but the most severe forms, perivascular inflammation evolves through stages of acute axonal injury, demyelination, oligodendrocyte depletion, remyelination, astrocytosis, and chronic neurodegeneration. The order and relationship of these separate components is still debated. The resulting plaques are widely distributed, but concentrated around venous networks, the ventricles, and in the corpus callosum, the optic nerve, brainstem, and cervical cord.

Although the precise pathogenesis of inflammatory-mediated demyelination is unknown, it is widely believed to be consistent with a T-cell mediated autoimmune process. It depends on the movement of activated T cells from the periphery into the CNS. The basis of peripheral activation and the precise role and subsequent relationship between the innate and adaptive immune system in initiation and maintenance of CNS autoimmunity is unclear. Furthermore, recent experimental, clinical, and pathological insights emphasize the complex interplay between T cells (including regulatory T cells), macrophages or microglia and humoral and complement effector systems in propagating and amplifying tissue damage.

Activated T cells that encounter antigen persist within the nervous system. Recruitment of lymphocytes across the blood–brain barrier is mediated by adhesion molecules and chemokines, the latter also being important in mediating migration of inflammatory cells within the CNS. Once within the CNS, activated T cells specific for putative central antigen(s) initiate a cascade of events, including secretion of pro-inflammatory cytokines, local activation of microglia and production of immunoglobulins that together culminate in damage to the myelin–oligodendrocyte unit. Together, these inflammatory processes lead to disruption of the myelin membrane with increased spacing, vesicular disruption, splitting, vacuolation, and fragmentation of the lamellae. This immunological formulation belies pathological heterogeneity and the complexity of evolution seen in inflammatory demyelination.

Originally, it was proposed that individual patients conform to one of four patterns: T cell infiltrates and macrophage associated tissue injury (pattern 1); antibody and complement-mediated immune reactions against cells of the oligodendrocyte lineage and myelin (pattern 2); hypoxia-like injury, resulting either from inflammation-induced vascular damage or macrophage toxins that impair mitochondrial function (pattern 3); and a genetic defect resulting in primary susceptibility of the oligodendrocytes to immune injury (pattern 4). The evidence for pathological heterogeneity—as opposed to complexity—has recently been challenged. Rather, the various pathological features are now seen as stages in the development of an ubiquitous pathological end-game in which apparent heterogeneity may disappear over time as different pathways converge on one general mechanism of demyelination—the presence of complement, antibodies, and Fc gamma receptors in phagocytic macrophages indicating that antibody—and complement-mediated myelin phagocytosis is the dominant mechanism of demyelination in established multiple sclerosis. The focus on inflammation and demyelination had until recently obscured the extent and significance of neuronal and axonal injury. Axonal injury is present at all stages of multiple sclerosis. Multiple mechanisms have been implicated, contingent on stage and pattern of disease; early axonal injury evident by axonal transection and accumulation of amyloid precursor protein tends to occur when inflammatory demyelination is prominent. Whether specific immune mediated axonal injury also occurs over and above nonspecific inflammatory collateral damage is unclear. Similarly, it is uncertain if axonal loss in normal appearing white matter merely reflects axon dropout due to time-delayed Wallerian degeneration. Chronic axonal attrition observed in the inflammatory quiescent chronic demyelinated lesion, along with other observations, implicates loss of myelin-derived signals as central to the mechanism of progressive neurodegeneration.

Recognition that neurodegeneration is the dominant pathological substrate of progressive disability raises the fundamental and as yet unanswered question of the relationship between inflammation—clinically manifest as relapse—and neurodegeneration. A widely held position, accepting that an independent axonal vulnerability may pre-exist for genetic and other reasons, is that inflammation primes and/or maintains neurodegeneration.

It has long been known that acute lesions frequently show an increase in numbers of oligodendrocyte precursors and may undergo remyelination evident as shadow plaques. Remyelination, found at all stages of disease, is histologically identified by inappropriately thin myelin lamellae, with a short internode and widened nodes of Ranvier. The finding that remyelination is associated with negligible axonal injury compared to inactive demyelinated plaques suggests remyelination is neuroprotective. The source of remyelinating cells is presumed to be the oligodendrocyte progenitor which is found in the lesions of multiple sclerosis, although recent evidence also suggests a role for adult stem cells derived from the subventricular zone.

Isolated demyelinating syndromes

The clinical expression of demyelination may be focal and monophasic. Multiple sclerosis, in contrast, is both multifocal and multiphasic. Notwithstanding that a monophasic event may occasionally appear disseminated in time, the distinction between multiple sclerosis and isolated demyelinating disorders can only be reliably made when more than one episode has occurred, affecting two or more sites, and not merely on the basis of anatomical dissemination of lesions. Longitudinal studies show that inclusion of imaging criteria increases precision in predicting likely conversion of clinically isolated syndromes to multiple sclerosis. Emerging evidence that treating high risk patients with disease modifying agents may delay conversion emphasizes the value of early accurate diagnosis.

Acute disseminated encephalomyelitis

Typically, acute disseminated encephalomyelitis, a monophasic illness, develops within days or a few weeks after an infectious illness, or more rarely following vaccination. It is usually but not invariably a disease of children and often has an explosive onset. Formerly, acute disseminated encephalomyelitis affected 1 in 1000 children with exanthematous illnesses, the risk being slightly lower following pertussis and scarlet fever than measles and rubella, but these childhood illnesses, and hence their complications, are now less prevalent. A greater variety of causative organisms has been implicated in adult-onset acute disseminated encephalomyelitis, but in both groups a presumptive diagnosis often has to be made in the absence of an identifiable preceding infection.

In the absence of biological markers, diagnosis is based on the combination of clinical, radiological, and laboratory investigations in the appropriate demographic context. However, an absence of lesion accrual upon serial imaging is sometimes required to exclude multiple sclerosis. The disorder is usually diffuse, and with a cerebral–encephalopathic flavour, but the clinical manifestations may be restricted to the brainstem, optic nerves, or spinal cord. About 50% of cases occurring after varicella infection present with a pure cerebellar syndrome. Headache, drowsiness, meningeal irritation, signs of systemic infection, focal or generalized fits, and combinations of lesions indicating damage to the cerebrum, optic nerves, brainstem, or spinal cord evolve over the course of a few days. The cerebrospinal fluid contains a mixture of polymorphonuclear cells and lymphocytes with raised protein and slight reduction in glucose; oligoclonal bands may be present. Although there is an appreciable mortality, most patients survive, sometimes with persistent neurological deficits. MRI shows changes similar to those occurring in multiple sclerosis, including gadolinium enhancement, but the lesions are more extensive, asymmetric, and frequently involve grey matter of thalamus and basal ganglia; they persist long after recovery of the clinical illness.

The hyperacute form of acute disseminated encephalomyelitis (Hurst’s disease) starts with headache and progresses over hours to disorientation, confusion, drowsiness, and coma; events move quickly and the illness often proves fatal before the diagnosis has been established. The combination of pyrexia and a marked cerebrospinal fluid pleocytosis with a predominantly neutrophil response mimics pyogenic infection of the CNS, but the course is not influenced by antimicrobial treatment. Occasionally, the clinical and pathological features of acute haemorrhagic leucoencephalitis are focal and suggest a rapidly expanding tumour or herpes simplex encephalitis.

There is no evidence based standard treatment for acute disseminated encephalomyelitis. However, outcome is probably influenced by early use of high-dose intravenous steroids, but—anecdotally—there may be a more favourable response to intravenous immunoglobulin or plasmapheresis.

Some patients recovering from the initial attack subsequently relapse. In others, although the illness remains monophasic, separate sites are involved sequentially over several weeks, but the disorder does not recur. Sometimes the illness is subsequently shown to be the encephalopathic presentation of multiple sclerosis, which then follows the typical relapsing–remitting course. The nosological status of multiphasic disseminated encephalomyelitis—based on a history of episodes and atypical imaging appearances for multiple sclerosis—has not gained general acceptance.

Postvaccinial encephalomyelitis has become a rare disorder, with the definitive series collected several decades ago when vaccination against smallpox was necessary. The illness develops within 2 to 3 weeks of vaccination, with a skin rash and systemic symptoms, followed by cerebral or myelitic signs that usually recover spontaneously in due course.

Optic neuritis

Optic neuritis presents with pain on eye movement, followed by subacute visual loss which evolves over hours or days, sometimes to complete blindness; patients may be aware of selective loss of colour vision and flashes of light (phosphenes) on eye movement. Other signs of optic neuropathy at presentation include afferent pupillary defect and visual field loss. The pain disappears within a few days; vision begins to improve within 4 weeks and does so in 90% of patients over months, but defects of colour perception frequently persist.

Outside the paediatric population, optic neuritis is usually monocular; bilateral simultaneous loss, and progressive visual failure suggest alternative diagnoses. Transient visual loss, mimicking optic neuritis, also occurs in ischaemic optic neuropathy, sarcoidosis, and lupus, and a family history should be taken since the presentation of visual failure in Leber’s hereditary optic neuropathy is similar to bilateral sequential optic neuritis in men.

The lesion responsible for optic neuritis can be imaged in vivo; inflammation within the intracanalicular portion of the nerve and long lesions are associated with delayed or incomplete recovery of vision. Correlations between imaging, symptoms, and neurophysiological changes indicate that the visual deficits in optic neuritis arise at the time of altered blood–brain barrier permeability. They are associated with conduction block and precede demyelination or axonal degeneration. In this regard, the increasing availability of optical coherence tomography is valuable as this provides a noninvasive quantitative measure of retinal nerve fibre loss, of particular interest given the association of neurodegeneration with progression.

Corticosteroids accelerate recovery but do not influence long-term outcome or alter conversion to clinically definite multiple sclerosis. Current practice tends to reserve intravenous methylprednisolone for optic neuritis in the setting of pre-existing abnormal function of the nonaffected eyes.

Acute demyelinating optic neuritis is a first manifestation of multiple sclerosis in up to 20% of patients. Brain MRI findings at presentation are invaluable in predicting conversion to clinically definite multiple sclerosis following optic neuritis. Long-term follow up of patients initially enrolled in trials to evaluate the utility of corticosteroids in optic neuritis has shown that an abnormal MRI brain scan is associated with 56% risk at 10 years compared to 22% with a normal scan. Studies that also included other isolated syndromes suggest an abnormal brain MRI predicts a conversion risk of 82% at 10 years. The presence of oligoclonal bands on cerebrospinal fluid electrophoresis during the acute phase is also a significant risk factor. An early MRI brain scan is recommended at presentation of optic neuritis in view of evidence that early treatment with β-interferons delays conversion of high risk (associated abnormal brain MRI) isolated optic neuritis to clinically definite multiple sclerosis.

Transverse myelitis

The spinal cord is vulnerable to postinfectious inflammatory damage, but as with acute disseminated encephalomyelitis in adults, the precipitating cause is often not identified. Transverse myelitis presents with pain at the site of the lesion, followed by weakness in the legs, sensory symptoms, and sphincter involvement. The weakness increases and the clinical picture is that of spinal shock—features rarely seen in acute cord lesions due to multiple sclerosis. Sphincter control is lost, but patients usually have difficulty in emptying rather than filling the bladder, unlike those with multiple sclerosis. Partial cord lesions are more typical of multiple sclerosis.

The need to exclude a structural abnormality in patients with transverse myelitis means that many patients undergo radiological investigation, which may demonstrate cord swelling. The spinal fluid shows an increased mononuclear cell count, numerically intermediate between the marked pleocytosis of acute necrotizing myelitis and the marginal abnormalities seen in multiple sclerosis; total protein is raised and oligoclonal bands may be present on electrophoresis, but the glucose is usually normal. Transverse myelitis is more common in adults than children; there is a high frequency of persistent disability, but a much lower conversion to multiple sclerosis than following optic neuritis.

Acute necrotizing myelitis causes rapidly progressive flaccid areflexic paraplegia with anaesthesia and loss of sphincter control. The intensity of inflammation results in severe pain with meningism, pyrexia, and systemic symptoms. The condition mimics cord compression, and the cerebrospinal fluid changes often resemble pyogenic or tuberculous infection of the CNS. For these reasons, treatment with high-dose intravenous steroids, which may usefully influence mortality and limit long-term disability, is often withheld. Acute necrotizing myelitis has been described in association with herpesvirus infection, and as a complication of acute lymphocytic leukaemias, lymphoma, carcinoma, and AIDS.

Devic’s disease (neuromyelitis optica)

Devic’s disease is an inflammatory demyelinating disorder characterized by severe optic neuritis and myelitis, occurring simultaneously or sequentially and in either order, these components usually separated by weeks or months, and one or other recurring so that the illness frequently follows a relapsing course. Cellular reaction in the cerebrospinal fluid more usually involves polymorphonuclear cells than lymphocytes, but often lacks oligoclonal bands. MRI brain findings are typically normal at onset, although asymptomatic cerebral white-matter abnormalities tend to emerge in later disease. The spinal lesion is long, extending over three or more vertebral segments, in contrast to the several short asymmetric lesions which characterize spinal MRI in multiple sclerosis. Recovery from attacks is generally incomplete and disability due to the impact of incomplete recovery from individual episodes usually emerges over time. This contrasts with multiple sclerosis where recovery from relapses is more complete but disability follows the onset of the secondary progressive phase that is typically much later in disease course and independent of relapses.

Together with these clinical and paraclinical features, the recent identification of a highly specific and sensitive auto-antibody (NMO-IgG) against the water channel aquaporin-4 antigen has clarified the relationship between neuromyelitis optica and multiple sclerosis. Demyelinating disease often follows an optico-spinal pattern in Japanese and African patients, where multiple sclerosis is otherwise rare. But, even with the use of biomarkers, the distinction from multiple sclerosis can still be confusing. Although the contribution of NMO-IgG to the pathogenesis of tissue injury is unknown, neuromyelitis optica is characterized immunohistologically by immunoglobulin and complement deposition—as in the so-called pattern II subset of pathology described in active multiple sclerosis. These insights have led to encouraging observational studies that recommend prompt use of plasma exchange and corticosteroids with subsequent maintenance immunosuppression. Similar findings have emerged from open label studies of the humanized monoclonal antibody Rituximab that selectively depletes B lymphocytes.

Isolated brainstem syndromes

The clinical symptoms and signs of isolated brainstem syndromes typically consist of disequilibrium, disturbed eye movements, facial numbness, and dysarthria, but there may be severe headache, which rightly leads to early investigation to exclude a structural lesion. Most patients progress to clinically definite multiple sclerosis. As with other isolated demyelinating syndromes, abnormal MRI outside the affected site at presentation is a risk factor for clinical conversion.

Multiple sclerosis

Aetiology

The aetiology of multiple sclerosis involves an interplay between genes and the environment. It is a disease of northern European people and occurs less frequently in other racial groups with a modest female predominance. The familial recurrence rate is approximately 15%. Meta-analysis amongst relatives of probands from three population-based series shows that the age-adjusted risk is highest for siblings (3%), then parents and children (2%), with lower rates in second- and third-degree relatives. Recurrence in monozygotic twins is around 35%. Conversely, the frequency of multiple sclerosis in adoptees is similar to the population risk for Europeans. The age-adjusted risk for half-siblings is intermediate between social and biological relatives. Recurrence is higher in the children of conjugal pairs with multiple sclerosis (age-adjusted 20%) than the offspring of single affecteds (2%).

Population studies demonstrate an association between the linked class II MHC alleles (DR15 and DQ6) and their corresponding genotypes. Extensive searches, using association and linkage studies over many years, had—until recently—yielded very few additional candidates for susceptibility. However, large-scale genome wide association studies have begun to identify further genes that, individually, confer a modest increase in risk; these include the interleukin receptor related genes IL2RA and IL7RA and, perhaps more provisionally, HLA-C, TYK2, and CD58. This approach is likely to deliver further genes. The functional property of each of these newly identified genetic risk factors reinforces the idea that multiple sclerosis is an auto-immune disorder and offers a rational pathway for further studies of disease mechanisms and immunological treatments. Studies of concordance in multiplex families show that genetic factors influence the risk of progression but the responsible loci are not identified. It is assumed, but without any evidence to date, that there are also pharmacogenomic effects that determine the response to treatment. Genetic analysis may also contribute to the debate on whether multiple sclerosis is one disease. Mutations of mitochondrial DNA are responsible for a multiple sclerosis-like illness characterized by disproportionate involvement of the anterior visual pathway, although mitochondrial genes do not contribute generally to susceptibility in multiple sclerosis. A major part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity.

The distribution of multiple sclerosis cannot be explained only on the basis of population genetics. In white South Africans and in Australia, prevalence rates are half those documented for many parts of northern Europe. There is a gradient in frequency, in both Australia and in New Zealand, that does not follow genetic clines. The risk is higher for English-speaking white people migrating into South Africa as adults than in childhood. Multiple sclerosis occurs at a low frequency in the Caribbean population, but the risk increases substantially in their first-generation descendants raised in the United Kingdom. Over and above the effect of racial predisposition, migration influences distribution of the disease. Surveys of multiple sclerosis have prompted speculation on the occurrence of post-Second World War epidemics in Iceland, the Orkneys and Shetlands, and the Faroes, but others prefer the interpretation that these merely reflect improved case recognition.

The widely accepted formulation that multiple sclerosis is the outcome of unknown environmental factors conditioned by age of exposure acting on a genetically vulnerable population has led to a largely unrewarding search for such environmental agents. The risk of developing multiple sclerosis is increased for individuals exposed to measles, mumps, rubella, and Epstein–Barr virus infection relatively late in childhood or adolescence. These studies suggest that an age-linked period of susceptibility to viral exposure exists in those who are constitutionally at risk of developing the disease. But, noting the association with latitude, it has been suggested that the environmental effect is conferred by variable light exposure and vitamin D status rather than microbes.

Clinical symptomatology

Special senses

Visual involvement is almost invariable and most commonly affects the optic nerve (see above). The postchiasmal visual pathway is occasionally involved, resulting in hemianopic field defects. Deafness occurs in multiple sclerosis, sometimes at presentation. Feelings of unsteadiness are common. Acute brainstem demyelination causes severe positional vertigo, vomiting, ataxia, and headache. Taste may be subjectively abnormal, but ageusia is rarely described. Anosmia is reported in a high proportion of asymptomatic patients examined with more than usual thoroughness.

Motor symptoms and signs

Impaired mobility affects most patients with multiple sclerosis, usually as a result of spinal disease. Movements are slow, weakness differentially affecting extensors in the arms and flexors in the legs, and there are the expected signs of upper motor neuron lesions. Spasticity may be more problematic than weakness, and all aspects of immobility are frequently complicated by fatigue. Cerebellar involvement causes incoordination of speech, bulbar control, eye movements, the individual limbs, or balance, usually in combination with corticospinal damage. Damage to the superior cerebellar peduncle or red nucleus produces a disabling proximal wild flinging tremor, and many other movement disorders have been described. Lower motor neuron signs occur when there is extensive demyelination adjacent to the dorsal root entry zone.

Sensory symptoms and signs

Altered sensation occurs at some stage in nearly every patient with multiple sclerosis. Damage to the posterior columns in the cervical cord produces tight, burning, twisting, tearing, or pulling sensations, which are usually unpleasant. Associated loss of proprioception severely compromises function. Spinothalamic tract involvement leads to loss of thermal and pain sensation. Nonspecific tingling without accompanying signs is often described, and the commonest physical sign found in the absence of symptoms is impaired vibration sense in the legs.

Demyelination of the dorsal or lumbar segments of the spinal cord produces paraesthesias and numbness in the legs, ascending to the trunk, and sometimes associated with sacral sparing, although a characteristic sensory syndrome seen in patients with multiple sclerosis is numbness of the perineum and genitalia with disturbed sphincter function.

Autonomic involvement

Autonomic symptoms occur in most patients with multiple sclerosis. Bladder symptoms are most common in women, whereas impotence occurs frequently in males. Loss of inhibition of reflex bladder emptying, normally mediated by cholinergic neurons that contract the detrusor and relax the internal sphincter, results in urgency and frequency with incontinence when combined with immobility. With conus lesions, the problem is impaired bladder emptying. Failure to fill and empty may coexist, resulting in detrusor contractions against a closed sphincter.

Impaired control of the rectal sphincter is much less of a problem than failure of emptying. Some impotent men with multiple sclerosis retain reflex erections, in which case psychogenic factors are often invoked; but erectile failure is usually a manifestation of spinal cord disease. Mechanical difficulties, spasticity, altered sensation, skin excoriation, and indwelling catheters affect sexual performance in both sexes. Other autonomic features in multiple sclerosis occur rarely but include loss of thermoregulation leading to inappropriate sweating, fever, and hypothermia; Horner’s syndrome; abnormalities of cardiac rhythm and vascular responses with acute pulmonary oedema; weight loss; and inappropriate secretion of vasopressin.

Eye movements

Abnormalities of eye movement are frequent in multiple sclerosis. They are often asymptomatic, but may manifest as double vision and oscillopsia. The commonest sign is first-degree symmetrical horizontal jerking nystagmus. Weakness of the lateral rectus is more common than isolated third and fourth nerve palsy. Internuclear ophthalmoplegia is often bilateral and may coexist with gaze paresis to produce the ‘one and one half’ syndrome.

Vertical up-beating nystagmus is always associated with bilateral internuclear ophthalmoplegia. Down-beating nystagmus has other important causes which can be confused with multiple sclerosis. Ocular flutter consists of horizontal saccadic oscillations without an intersaccadic interval. Opsoclonus, in which the movements occur in all directions, is equally disabling. Ocular bobbing describes an initial rapid downward eye movement followed by slow return to the neutral position and denotes cerebellar involvement. Abrupt displacement from the primary position during central fixation (square wave jerks) occurs with severe cerebellar deficits.

Other brainstem manifestations

Facial weakness, indistinguishable from Bell’s palsy, occurs in patients with multiple sclerosis, alone or in association with other signs of brainstem disease including hemifacial spasm and diffuse rippling of muscle fibres (myokymia). Exceptionally, there may be unilateral involvement of the hypoglossal and recurrent laryngeal nerves. Extensive brainstem demyelination may produce disturbances of consciousness and respiratory failure distinct from the narcolepsy syndrome, which is seen more frequently in patients with multiple sclerosis than expected by chance—an observation of immunogenetic interest in view of their shared HLA DR2 association. Occasional manifestations include the locked-in state, persistent hiccup, and the lateral medullary syndrome.

Paroxysmal symptoms are invariably brief but repetitive and usually occur in bouts lasting a few months before remitting. Symptomatic trigeminal neuralgia may begin in the first division or bilaterally, at a younger age than the idiopathic condition, and with associated signs of trigeminal involvement including motor weakness and sensory loss. It is usually associated with demyelinating lesions of the dorsal root entry zone, but may coexist with compression of the fifth cranial nerve by ectatic vessels. Other than trigeminal neuralgia, isolated involvement of the fifth nerve is rare. Paroxysmal dysarthria and ataxia with a clumsy arm, complex disturbances of sensation, and painful tetanic posturing of the limbs lasting 1 or 2 min are often triggered by movement and preceded by positive sensory symptoms on the side opposite to the muscular spasm. These are easily recognized and treated. Bursts of pain and paraesthesias, sensory distortion, itching, cough and hiccup, painful extensor spasm, akinesia, kinesogenic choreoathetosis, and complex gaze palsies—any of which may respond to anticonvulsants, especially carbamazepine—also appear to be paroxysmal manifestations of multiple sclerosis.

Cognitive and affective symptoms

Defects of visual and auditory attention occur in multiple sclerosis, sometimes at an early stage, and these are also detectable in patients with isolated demyelinating lesions. An overall impairment in IQ relates more to duration of disease, and onset of the progressive phase, affecting memory rather than language skills. Specific cognitive deficits due to hypothalamic involvement are sometimes seen, including the Korsakoff state and the syndrome of bulimia, lack of social restraint, mental inertia, and mutism. Psychotic behaviour is rare, but depression occurs more frequently than in patients with comparable neurological disability; hypomania is occasionally seen, but should not be confused with pathological laughter and crying arising from loss of central inhibition of facial and bulbar reflexes in association with extensive brainstem disease.

Rare manifestations

The list of rare clinical manifestations (some already described) includes massive cerebral lesions, aphasia, headache, fever, movement disorders, epilepsy, hypothalamic and pituitary symptoms, respiratory failure, and peripheral neuropathy. Narcolepsy, Sjögren’s syndrome, ankylosing spondylitis, type I neurofibromatosis, and autoimmune thyroid disease have periodically been associated with multiple sclerosis.

Childhood multiple sclerosis

In retrospect, symptoms attributable to recurrent demyelination often affect individuals with multiple sclerosis as teenagers, but onset in the first decade also occurs; 2% of patients with multiple sclerosis present before the age of 10, and up to 10% before 16 years. Individual episodes often centred on optic neuritis and brainstem syndromes can be severe, but the long-term prognosis is surprisingly good. Fever and meningism, impaired conscious level due to cerebral oedema with swollen optic discs, and seizures are regular features and the distinction from acute disseminated encephalomyelitis can often only be made by the later occurrence of remission and relapse. A recent European study of the natural history of childhood onset disease confirms a higher female to male ratio (2.8:1), disease course that is invariably relapsing–remitting, and a delayed time by 10 years to secondary progression compared to adult onset disease. Current international guidelines recommend disease modifying treatment for childhood multiple sclerosis with active relapsing–remitting disease on lines similar to adult patients, with β-interferon being the most common first-line agent.

Clinical course and prognosis

Most patients (c.80%) present with relapsing–remitting disease. Typically, the illness passes through the three phases of relapse with full recovery, relapse with persistent deficits, and secondary progression. One patient may spend several years or even a few decades in each, whereas another moves rapidly to a condition of fixed progressive disability. About 25% of patients have multiple sclerosis in a form which is not disabling, termed ‘benign’, and they remain ambulant. In 5%, relapses occur frequently and do not recover, leading rapidly to disability and early death from respiratory failure when the medulla is affected and from massive cerebral or spinal demyelination. Up to 15% become severely disabled within a short time. Life expectancy is at least 25 years, and a high proportion of patients die from unrelated causes.

Episodes occur at random frequency but initially average about 1.5 per year and decrease steadily thereafter. Recovery from each attack is invariably slower than onset and may be incomplete. Self-evidently, secondary progressive multiple sclerosis tends to affect whichever system has previously been involved. Progression may follow directly upon a severe relapse and be interrupted by further episodes.

In approximately 20%, multiple sclerosis is progressive from onset. The spinal cord bears the brunt of progressive multiple sclerosis, but optic nerve, cerebral, and brainstem disease may also advance slowly. Primary progressive spinal disease is the usual mode of presentation when multiple sclerosis develops beyond the fifth decade. It is characterized by an absence of acute attacks, with gradual decline from onset, and although cerebrospinal fluid analysis is similar to relapsing–remitting disease there are comparatively greater spinal and fewer brain abnormalities on MRI. Current disease modifying agents have no effect on primary progressive disease.

The prognosis is relatively good when sensory or visual symptoms dominate the illness and there is complete recovery from individual episodes; this pattern is most common in young females. Conversely, motor involvement, especially when coordination or balance is disturbed, has a less good prognosis. The outlook is also poor in older-onset patients who are often males. Frequent, prolonged relapses with incomplete recovery and a short interval between the initial episode and first relapse carry a worse prognosis, but the main determinant of disability is onset of the progressive phase. Most patients develop progressive irreversible disability within 10–15 years of disease onset. Accumulated epidemiological evidence also argues for redundancy of the phenotypic distinction between the various forms of multiple sclerosis upon reaching the stage of fixed moderate deficit. Disability appears to be age dependent and uninfluenced by prior history of relapses. This observation in turn raises unresolved questions around the relationship between inflammation, manifesting as relapse, and neurodegeneration, the primary substrate of progression.

Prospective studies show that 9% of upper respiratory (adenovirus) and gastrointestinal infections occurring in patients with multiple sclerosis are followed by relapse and 27% of new episodes are related to infection. The emerging evidence suggests that disease activity is not increased by vaccination. Relapse rate is affected by pregnancy. There is a reduction in the prepregnancy relapse rate for each trimester, with approximately a threefold higher risk in the puerperium, and the attacks may be more severe. The clinical course is uninfluenced by breastfeeding or epidural anaesthesia. There is no evidence that trauma triggers the first or recurrent clinical manifestations of multiple sclerosis in someone who has the underlying disease process, or alters the course in individuals who have already experienced symptoms.

Laboratory investigations

Multiple sclerosis can reliably be diagnosed using clinical criteria and without laboratory support. There is no single diagnostic laboratory investigation. That said, investigations are now incorporated in revised diagnostic criteria and, under some circumstances, can supplement or replace clinical events. Taken together, laboratory investigations can be used: to demonstrate the anatomical dissemination of lesions; to provide evidence for intrathecal inflammation; to demonstrate that conduction is altered in a form consistent with demyelination; and to exclude conditions that mimic demyelinating disease.

Electrophysiology

Recent demyelination can be detected in clinically unaffected pathways using visual, auditory, somatosensory, central motor, and event-related potentials; their latencies are characteristically delayed whereas, except in acute lesions, the amplitude is unaffected. Evoked potentials add little in situations where the pathway under investigation is clinically affected. Since they provide qualitatively different information, evoked potentials remain useful as an adjunct to diagnosis despite the advent of imaging techniques.

MRI

Recent diagnostic criteria have been revised, permitting MRI-based evidence for dissemination in time and space to allow earlier diagnosis, partly to allow prompt consideration of disease-modifying treatments. The major practical application is in the investigation of individuals early in the course and, especially, those with isolated demyelinating lesions, recurrent episodes at a single site, or progressive disease affecting the spinal cord. In all these situations the first requirement is to exclude a structural lesion, especially since these can present with relapsing symptoms. Imaging any region of the nervous system, clinically affected in isolation, will reliably exclude a structural lesion that might mimic multiple sclerosis and may show changes consistent with focal demyelination, but will not distinguish the syndromes of isolated demyelination from multiple sclerosis. Once the clinically affected part has proved negative for a structural lesion, the diagnosis of multiple sclerosis also requires the demonstration of anatomically separate lesions, ideally with enhancement to identify recent lesions, or the accumulation of new imaging abnormalities over time, even if these are not expressed clinically.

Low-density lesions, corresponding to areas of demyelination, may be seen using contrast-enhanced CT or MRI, and these occasionally are mistaken for cerebral tumour or abscess. More than 95% of patients with clinically definite multiple sclerosis have periventricular lesions, and more than 90% also show discrete white matter abnormalities. Focal demyelination can also be imaged in the optic nerve, brainstem, and spinal cord.

Variations in the imaging protocol are beginning to distinguish separate components of the underlying pathological process. Imaging can distinguish inflammation (gadolinium–DTPA enhancement of T ₁-weighted lesions, indicating that the lesion is of recent origin), demyelination and remyelination (magnetization transfer ratio), astrocytosis (T ₂-weighted lesions, the signal arising from increased water content), and axonal damage (reduction in diffusion tensor imaging anisotrophy and N-acetylaspartate spectra with chemical shift imaging, or the presence of focal atrophy and T ₁-weighted black holes). The evolving lesion starts with increased blood–brain barrier permeability that lasts for up to 4 weeks, and is revealed by demonstration of enhancement after intravenous gadolinium. These lesions may disappear, but reactivation is sometimes seen, the cycles lasting about 8 weeks. Fluid attenuated inversion recovery (FLAIR), proton-density, and T ₂ sequences best demonstrate demyelination. The periventricular lesions, which characterize multiple sclerosis, correlate with areas of persistent demyelination and astrocytosis. A mixture of new, evolving, and recovering lesions may be seen in an individual patient at any one time. Lesions visible on MRI occur about 15 times more frequently than new clinical events. Eventually, there is a reduction in the frequency of new lesions as patients move from the relapsing to the progressive phases of the disease, and evidence for atrophy is then more apparent. The number or volume of lesions correlates poorly—if at all—with disease severity or course, but there is less cerebral involvement in patients who present with primary progressive disease compared with those having similar disability from secondary progression. The imaging abnormalities of multiple sclerosis are not specific and similar changes occur with inflammatory or vascular lesions and with advancing age.

Cerebrospinal fluid

Cerebrospinal fluid analysis provides information which is complementary to imaging abnormalities and specifically useful in elderly patients suspected of having multiple sclerosis in whom MRI is less discriminating. The cell count rarely exceeds 50 lymphocytes/ml, even during periods of clinical activity, and is normal in more than 50% of patients. There is a rise in total protein (usually <1 g/litre), with a specific increase in the immunoglobulin concentration and the presence of oligoclonal bands on protein electrophoresis seen in more than 90% of cases, after correction for leakage of serum proteins through the blood–brain barrier, providing evidence for synthesis of immunoglobulin within the CNS. As with the imaging abnormalities, these are sensitive but not specific. Although some antibodies are directed against components of the oligodendrocyte or its myelin membranes, and others recognize extrinsic antigens including viruses, collectively these specificities only account for a minority of the bands.

Differential diagnosis

The commonest error in clinical practice is to make the diagnosis of multiple sclerosis in patients with progressive spinal disease in whom a structural lesion has not been adequately excluded. Rarely, spinal tumours present with intermittent symptoms creating difficulties for the unwary. It is not safe to assume the diagnosis of multiple sclerosis in patients with symptoms and signs restricted to a single site, whatever the clinical course without appropriate investigation. Lesions at the foramen magnum are particularly well placed to cause confusion through appearing to produce evidence for independent spinal and brainstem lesions. Errors also arise with progressive and relapsing manifestations of brainstem or spinal arteriovenous malformations.

Care must be taken in the diagnosis of multiple sclerosis when several members are affected within one family. Hereditary spastic paraplegia mimics familial multiple sclerosis, and this should also be considered in isolated cases of progressive spastic paraplegia when pyramidal manifestations occur in isolation and with disproportionate spasticity. Other familial disorders confused with multiple sclerosis include the hereditary ataxias, adult-onset leucodystrophies, and vasculopathies (CADASIL). Pedigrees with affected males and maternal inheritance may be examples of X-linked adrenoleucodystrophy, and the phenotype of multiple sclerosis occurs in families with the clinical and genetic features of Leber’s hereditary optic atrophy (Harding’s disease).

Clinical, immunological, and imaging abnormalities indistinguishable from multiple sclerosis occur with granulomatous and vasculitic diseases of the brain, especially the cerebral variant of systemic lupus erythematosus which often occurs in the absence of systemic manifestations or informative serology, although headache and prominent cognitive impairment are clues to vasculitic aetiology. Sarcoidosis may present with clinical involvement of the CNS, typical MRI and cerebrospinal fluid abnormalities, and without pulmonary or cutaneous manifestations; uveitis also occurs in multiple sclerosis and so is not necessarily a useful discriminator. Orogenital ulceration in a patient with the clinical manifestations of multiple sclerosis suggests the diagnosis of Behçet’s disease.

Alternative diagnoses need to be considered when multiple sclerosis is diagnosed in African or Asian people in whom progressive spinal disease, sometimes with visual involvement, is more probably due to human T-lymphotropic virus type I (HTLV1) associated tropical spastic paraplegia or neuromyelitis optica (see above). Infections of the nervous system can mimic the isolated demyelinating syndromes and multiple sclerosis. These include tuberculous and other chronic meningitides, and the neurologicalmanifestations of AIDS or Lyme disease; borreliosis can also cause a chronic or relapsing disorder of the CNS, but this is usually preceded by the characteristic painful polyradiculitis and facial palsy that epitomizes Lyme disease. Similarities between multiple sclerosis and neurosyphilis should not be forgotten in the context of opportunistic infection complicating HIV infection. The age distribution and clinical manifestations usually make it easy to distinguish subacute combined degeneration of the spinal cord from multiple sclerosis, but focal spinal lesions, accompanied by Lhermitte’s sign, occur in vitamin B₁₂ deficiency.

Treatment of demyelinating disease

Therapies in multiple sclerosis are aimed at managing individual symptoms, resolving acute attacks, preventing new relapses, limiting disability, and (for the future) preventing progression and repairing the damage.

Symptomatic management

The complex and progressive nature of disability requires a multi-disciplinary approach to patients with multiple sclerosis. Several manifestations of the disease can be treated symptomatically. Urgency and frequency of micturition respond to drugs with anticholinergic activity (oxybutinin or propantheline). A simple means for intermittently reducing urine volume, and hence the desire to micturate, is to use intranasal desmopressin spray. When detrusor and sphincter function become uncoupled, causing impaired filling and a significant residual volume after voluntary voiding, the preferred treatment is clean self-intermittent catheterization, which is easily adopted by motivated patients retaining adequate vision and arm function; it ensures complete bladder emptying often with unimagined advantages to social activities and sleep. Other options include intravesical botox injections to reduce reflex bladder contractions or a suprapubic catheter with closure of the lower urinary tract which is preferable to an indwelling urethral catheter or, worse still, constant dribbling incontinence, which usually leads to skin excoriation. These manoeuvres have largely replaced urinary diversion through an ileal conduit, insertion of an artificial mechanical sphincter, or electrical stimulation of the spinal nerve roots in an attempt to synchronize sphincter contraction and relaxation.

Constipation in multiple sclerosis is managed by dietary alteration and the use of bulk laxatives, avoiding agents that act directly on the bowel wall. Loperamide may be useful where the predominant complaint is rectal urge incontinence. Psychological factors contribute to impotence in males with multiple sclerosis, but in most cases the complaint is a direct consequence of spinal demyelination. Trends in management have shifted from the use of mechanical devices and cavernous injection of papaverine or prostaglandin E₁ applied through the urethra, to oral treatment with sildenafil (Viagra)—a phosphodiesterase inhibitor which acts by increasing local production of nitric oxide in response to sexual stimulation.

The mainstay of pharmacological treatment for tremor is β-blockers; alternatives include anticonvulsants, isoniazid, ondansetron, and hyoscine. Physical restraint is rarely successful. Stereotactic procedures involving stimulation of the ventrolateral nucleus produce results comparable to destructive procedures, but the dividend is small. Unsteadiness arising from altered vestibular input may improve with the use of a vestibular sedative.

Fatigue as a dominant symptom in multiple sclerosis is common and frequently disabling, although its pathophysiological basis is poorly understood. It is not easy to treat noting also that separating fatigue from depression and disability is difficult. Some evidence suggests improvement with amantadine or modafanil.

Baclofen, a GABA agonist acting on spinal cord reflexes, is still the most widely used effective antispastic agent. The principal adverse effect, like most conventional anti-spasticity agents is sedation and increased weakness. Benzodiazepines also reduce spasticity by increasing presynaptic spinal inhibition. Dantrolene sodium acts by uncoupling excitation–contraction mechanisms in individual muscle fibres. It is claimed that Tizanidine, an alpha-2 agonist that modulates activity of excitatory presynaptic interneurones, reduces spasticity without increasing weakness. Patients report that spasticity and pain improve with the use of cannabis and this is still formally being evaluated. Intrathecal baclofen carries the potential advantage of selectively reducing muscle tone in affected muscles whilst leaving others intact. It is mainly appropriate for patients with advanced disease and does not seem to have any additional adverse effects compared with systemic administration. Another approach targeted at focal spasticity is loal injection of botulinum toxin. There may be a role for surgical interruption of the reflex pathways or tenotomy and peripheral nerve block with phenol or alcohol.

The paroxysmal manifestations of multiple sclerosis usually stop abruptly with the use of carbamazepine or gabapentin; this and other anticonvulsants, especially gabapentin, may also relieve trigeminal neuralgia or the more refractory forms of pain arising from spinal demyelination. Nerve block and chemical or surgical destruction of nerve fibres are sometimes an acceptable method for reducing pain in multiple sclerosis. All these sensations are coped with less well in the context of impaired mood and can respond usefully to antidepressants.

For those who develop significant disabilities and impairments, comprehensive care includes access to physical and occupational therapists, social workers, and other health-care staff with expertise in the management of chronic neurological illness. Complications are best prevented by awareness and anticipation since they usually develop quickly yet take months to resolve. Minimizing handicap by attention to social, vocational, marital, sexual, and psychological aspects of the illness is more important for many patients than drug treatment. In situations where the natural history has already led to loss of mobility, the early use of mechanical aids and home adaptations should be encouraged despite the associated stigma.

Management of the acute episode

Corticosteroids are effective in abbreviating acute demyelinating episodes in multiple sclerosis and related disorders. Although many neurologists continue to prefer the well established intravenous route, convenience and no apparent increase in adverse effects or loss of efficacy have led to increased use of high-dose oral compared to the intravenous regimen. Empirical use of plasma exchange in the treatment of fulminant steroid-resistant disease has variable efficacy but–matching its role in neuromyelitis optica—recent evidence suggests that patients with disease characterized histologically by immunoglobulin deposition and complement activation also respond to plasma exchange. However, in the absence of reliable biomarkers of pathological substrate widespread selective use of plasma exchange is not indicated. There is no evidence for reduction in relapse frequency or long-term disability using either steroids or plasma exchange.

Disease modifying treatment in multiple sclerosis

Multiple sclerosis has two distinct clinical phases, each reflecting a dominant role for inter-related pathological processes: inflammation drives activity during the relapsing – remitting (RR) stage; and neurodegeneration represents the principal substrate of progressive disability. Disease modifying agents target the inflammatory component. Efficacy has been demonstrated in the treatment of relapsing-remitting and rapidly worsening multiple sclerosis. There are no proven therapies for progressive disease independent of relapses. Development of disease modifying drugs has evolved from non-specific immunosuppressive drugs to more selective agents including humanized monoclonal antibodies targeting distinct stages in the initiation and evolution of tissue injury. Established and emerging anti-inflammatory or immune-modulatory drugs can be broadly grouped into drugs that act systemically or limit entry of inflammatory cells into the brain, and those that are thought to modify the immune environment within the brain.

β-interferons (Rebif, Avonex and Betaseron) and glatiramer acetate (Copaxone) were the first approved therapies for relapsing-remitting multiple sclerosis. The therapeutic rationale for use of the β-interferons initially was based on anti-viral properties but now rests on the catch-all hypothesis that IFN-β limits inflammation by inhibiting antigen presentation, promoting the Th-2 immune phenotype and restricting migration of cells across the blood-brain barrier. β-interferons administered subcutaneously or intramuscularly are generally well tolerated and reduce relapse frequency by around 30%. But up to 40% of patients receiving β-interferons develop neutralizing antibodies that are immunologically and biologically cross-reactive. Because of the reduction, albeit modest, in relapse frequency, initiation of treatment after a first demyelinating event will inevitably delay conversion to clinically definite multiple sclerosis. A series of trials has confirmed this prediction although it is important to understand that these results do not show that these drugs prevent the development of multiple sclerosis. The effect of β-interferon on progression is less persuasive with no convincing evidence for efficacy in the absence of on-going relapses. The focus around β-interferons has moved to timing of treatment with a plausible case being made for early initiation. The absence of reliable measures to predict disease course and separate those with benign multiple sclerosis provide counter arguments to early treatment. Glatiramer acetate has been used in multiple sclerosis on the basis that disease activity can be suppressed by mimicking the antigenic challenge initiating brain inflammation. Initial enthusiasm for the use of glatiramer acetate is conditioned by a recent Cochrane review concluding that there is little evidence for effect on relapse or progression.

In view of the modest effects of disease modifying drugs, there has been a willingness to consider more potent drugs or bone marrow transplantation in individual patients, refractory to other treatments or with above average clinical activity, using approaches that may be more effective but at the cost of increased adverse effects. Mitoxantrone, a cytotoxic agent, achieves a higher rate of conversion to disease inactivity (clinical and enhanced magnetic resonance imaging) in patients with active disease receiving monthly injections of methyl prednisolone—at least in the short term—but treatment is limited by the cumulative potential for cardiotoxicity and some cases of acute leukaemia. Accumulated experience from over 300 patients has shown that autologous haematopoietic stem cell transplantation can be effective in suppressing disease activity with evidence for stabilizing disease progression if administered at the inflammatory stage of disease. However, given the associated morbidity and mortality, treatment tends to be reserved to aggressive disease refractory to conventional treatments. A phase III study is ongoing comparing immunoablation (using combination of immune suppressant drugs) and autologous haematopoietic stem cell transplantation with Mitoxantrone in patients with severe multiple sclerosis.

The advent of humanized monoclonal antibodies allows selective treatments targeting discrete stages in the immune-pathogenesis of multiple sclerosis. Three are currently considered; natalizumab, alemtuzamab and rituximab. Natalizumab is a recombinant antibody delivered by monthly infusion that prevents activated T cells entering the brain by binding to leucocyte α4 integrin thus blocking adhesion of T cells to endothelial cells. Natalizumab offers a significant advance in efficacy over current therapies – 68% reduction in annual relapse rate and 83% reduction in gadolinium enhancing MR lesions - but six cases of progressive multifocal leucoencephalopathy (PML), two of whom had concomitant β-interferon treatment and multiple sclerosis, have qualified the indications for its use as monotherapy under a restricted prescribing programme to patients with relapsing disease who are non-responders or cannot tolerate other treatments. The relationship between natalizumab and PML may indicate impaired immune surveillance leading to reactivation or bone marrow mobilization of persistent JC virus infection. To date, no head-to-head comparisons of natalizumab against β-interferon or glatiramer acetate have been undertaken and its role in progressive disease has not been evaluated in clinical trials. Despite the salutary lesson of PML, natalizumab represents a step-change in the level of efficacy that can be achieved in relapsing-remitting multiple sclerosis. Alemtuzumab, another humanized monoclonal that targets the CD52 antigen resulting in sustained depletion of lymphocytes and monocytes, shows promising reduction in sustained accumulation of disability and annualized relapse rate in early active relapsing-remitting disease in a phase II trial against β-interferon. But, as with all other new disease modifying therapies, there are adverse effects–mild transient infusion related events and more significant secondary auto-immune disease. The experience of using alemtuzumab in secondary progressive–where despite suppression of clinical and radiological inflammatory activity disease activity continues–and relapsing-remitting multiple sclerosis provides strong evidence for the hypothesis that the contribution of inflammation wanes and becomes uncoupled from neurodegeneration as the disease matures. Rituximab, an anti-CD20 monoclonal that depletes B cells, has recently been shown in a phase II study to reduce clinical and radiological activity over 24 weeks. Its rapidity of action in suppressing radiological measures of acute activity suggests mechanisms additional to loss of pathological auto-antibodies.

Of the many other drugs undergoing clinical evaluation FTY720 (fingolimod) and cladribine are worth noting. Fingolimod is a fungal derivative that upon phosphorylation acts as a sphingosine receptor agonist and non-specifically limits lymphocyte egress from lymphoid organs. Cladribine inhibits adenosine deaminase and results in immunomodulation through selective depletion of lymphoctyte subsets. Unusually both drugs are administered orally and recent clinical trials have demonstrated tolerability and efficacy against standard clinical and radiological measures of relapse and activity. Other emerging and promising oral agents include laquinimod and fumarate.

Stepping back from individual drug analyses, it is clear that a growing range of immunological therapies is becoming available: these act at different points of disease evolution and will most likely best prevent progression of disability if given early in the course before neurodegeneration is irretrievably established. This raises the dilemma of exposing individuals who may never develop disabilities from multiple sclerosis to the unpredictable hazards of prolonged immunosuppression. Apart from aiming for an ideal balance between high efficacy and low toxicity, and taking into account the preferred use of oral rather than parenteral medications and daily versus infrequent exposure, the main goal of future therapies in multiple sclerosis is to meet the unmet need of how to limit disease progression.

Neuroprotection and repair strategies

A body of evidence supports the hypothesis that chronically demyelinated axons - devoid of myelin-derived support – are vulnerable to degeneration. Spontaneously remyelinated plaques show no significant axonal injury compared to inactive demyelinated lesions. Together with the recognition that spontaneous remyelination contributes to restoration of structure and function and that neurodegeneration underlies progressive disability, this supports the idea that myelin repair will prove neuroprotective. One approach under consideration is the use of human stem cells to supplement and promote endogenous remyelination by mechanisms dependent and independent of directed differentiation.

A parallel strategy under clinical trial is the testing of putative neuroprotective agents that seek to act directly on neurons. These are hampered by incomplete understanding of the mechanisms underlying neurodegeneration, although experimental work identifies some rational candidates such as sodium channel blockade. Lamotrigine and cannabinoids are currently under randomized trial for secondary progression. Other agents that are believed to be beneficial through pleiotropic mechanisms, including statins, are also under clinical trial in the progressive phase of disease.

Central pontine myelinolysis

Central pontine myelinolysis is associated with metabolic disturbances induced by alcohol with and without Wernicke’s encephalopathy, nonalcoholic cirrhosis, Wilson’s disease, following hepatic transplantation, as a complication of uraemia and haemodialysis, after prolonged vomiting, and in the context of diuretic therapy. In each of these situations, affected individuals have usually been hyponatraemic before the onset of neurological symptoms. Central pontine myelinolysis seems to result from overzealous correction of a low (and occasionally also a high) serum sodium. Demyelination correlates both with the degree of hyponatraemia and rate at which this is corrected, with starting levels of less than 110 mmol/litre or rates of correction of more than 2 mmol/litre per hour substantially increasing the risk. Rapid changes in sodium are better tolerated in acute than chronic hyponatraemia. See Chapter 21.2.1 for further discussion.

The illness affects central pontine pathways and spreads centrifugally. The fully evolved clinical picture is of flaccid paralysis with facial and bulbar weakness, disordered eye movements, loss of balance, and altered consciousness. Features of severe hyponatraemia, such as epilepsy, are not usually present since pontine demyelination follows correction of the serum sodium. Extrapontine manifestations including movement disorders and other features of extrapyramidal disease may be seen. The clinical features are distinctive and present no diagnostic difficulties unless the reduction in serum sodium has been overlooked; the acute changes of central pontine myelinolysis can be imaged by MRI, with abnormalities persisting after clinical recovery. Prognosis depends on the underlying metabolic disorder. With stabilization of the serum sodium and management of bulbar failure, neurological recovery is usually complete and the condition does not recur spontaneously.

Leucodystrophies

The leucodystrophies are a heterogeneous group of conditions characterized by noninflammatory demyelination. Increasingly, these are being shown to result from mutations affecting genes which determine the synthesis, maintenance, and structure of myelin. Although rare even in paediatric practice, these need to be considered in young adults with atypical syndromes combining physical and intellectual deficits, sometimes with peripheral nerve involvement, in whom imaging shows confluent lesions confined to white matter.

Childhood-onset leucodystrophies

Diffuse sclerosis (Schilder’s disease)

The term diffuse cerebral sclerosis was originally used to identify a heterogeneous group of diseases affecting cerebral white matter. Of the diseases previously classified under this heading, familial sudanophilic diffuse sclerosis, Pelizaeus–Merzbacher disease, Krabbe’s diffuse sclerosis (globoid cell leucodystrophy), Canavan’s diffuse sclerosis (spongy degeneration of the white matter), Alexander’s disease, and metachromatic leucodystrophy are dysmyelinating leucodystrophies. Conversely, Binswager’s subcortical encephalopathy is now considered a consequence of diffuse cerebral arteriosclerosis—although some cases may have been examples of CADASIL; and Balo’s concentric sclerosis is now considered within the spectrum of multiple sclerosis. Many male patients previously classified as having diffuse sclerosis were probably suffering from adrenoleucodystrophy. Some of the relapsing disorders may have been examples of Leigh’s disease associated with mutations of mitochondrial DNA. But even after separating these newly recognized conditions, the nosological status of diffuse sclerosis remains uncertain and some consider that, between them, acute childhood multiple sclerosis and adrenoleucodystrophy account for all the unclassified cases.

Krabbe’s disease

Globoid cell leucodystrophy, an autosomal recessive condition, usually presents as an early infantile disorder. Late-onset globoid cell leucodystrophy is uncommon, almost all patients becoming symptomatic before the age of 5 years, so it is almost never confused with childhood multiple sclerosis. The clinical picture is dominated by behavioural changes with startle, progressive intellectual and motor deterioration, epilepsy, visual failure, and peripheral neuropathy leading to severe disabilities; pyrexia and other autonomic features usher in the onset of a vegetative state. Visual evoked potentials are delayed and the spinal fluid has a raised protein level but does not contain oligoclonal bands. MRI shows periventricular lesions subsequently extending into extensive white matter changes. The deficiency of α-galactocerebrosidase, best demonstrated in peripheral blood leucocytes or skin fibroblasts, leads to the accumulation of galactocerebroside in oligodendrocytes and Schwann cells, the neurotoxic molecule psychosine, and characteristic myelin-laden macrophages or globoid cells.

Adrenoleucodystrophy

This important group of disorders is characterized by deposition of saturated fatty acids in the brain and other lipid-containing tissues as a result of defective very-long-chain fatty acyl-CoA synthetase activity in peroxisomes. Mutations are present in the ABC transporter gene. The molecular defect may result from failure of the adrenoleucodystrophy gene product to anchor very-long-chain fatty acids (VLCFA) into the peroxisomal membrane or translocate these into peroxisomes. Diagnosis can be made by serum analysis of very long chain fatty acids and nerve biopsy. Evidence of adrenal insufficiency is a valuable discriminator from multiple sclerosis.

Four related syndromes share this biochemical abnormality: childhood adrenoleucodystrophy and adult-onset adrenomyeloneuropathy are X linked; neonatal adrenoleucodystrophy and Zellweger’s syndrome are autosomal recessive disorders.

X-linked childhood adrenoleucodystrophy presents with behavioural disturbance, dementia, and epilepsy followed by involvement of special senses and motor systems. Although a significant proportion of children later develop adrenal insufficiency, Addison’s disease may precede the neurological manifestations by several years. Treatment has been proposed with a dietary supplement containing a 4:1 mixture of glyceryl trioleate and trieructate, popularly known as Lorenzo’s oil. This lowers the plasma levels of VLCFA, but does not appear to influence the phenotype in individuals with established neurological disease, although there may be a prophylactic role. Bone marrow transplantation is successful in early symptomatic cases and, in view of the inflammatory reaction, immunosuppression has also been used.

Adrenomyeloneuropathy presents in young adult men with spastic paraparesis and sensory loss in the legs; attention is drawn to an unusual cause for this otherwise common neurological problem by the associated peripheral neuropathy, but the diagnosis is frequently overlooked if adrenal insufficiency is not obvious at presentation. It may be associated with dementia later in disease course. Identification of the peroxisomal defect in easily sampled body tissues has led to the description of cases with obscure clinical manifestations; these include focal cerebral lesions, Kluver–Bucy syndrome, dementia, and spinocerebellar degeneration. Mild spastic paraparesis with sphincter involvement and peripheral neuropathy may occur in obligate heterozygote female carriers with elevated VLCFA. Carriers tend not to have adrenal insufficiency, although abnormal brain MRI and delayed evoked potentials may be present.

Autosomal recessive adrenoleucodystrophy presents in infancy with seizures, hypotonia, retardation, retinal degeneration, and hepatic involvement; females are more commonly affected than males. Although the clinical manifestations and mode of inheritance are similar in neonatal adrenoleucodystrophy and Zellweger’s syndrome, these are thought to be separate disorders.

The sensitivity and specificity of routine assays for VLCFA show that the level of hexacosanoic acid and its ratios to tetracosanoic and docosanoic acids are fully discriminating in homozygote males, irrespective of the clinical phenotype, from the day of birth if dietary supplements have not been given, providing an opportunity for mass screening; there is a false-negative rate of 15% for heterozygotes.

Metachromatic leucodystrophy

Metachromatic leucodystrophy is an autosomal recessive lysosomal storage disorder due to arylsulphatase A deficiency leading to increased urinary sulphatide excretion with a deficiency of arylsulphatase A in urine, peripheral blood leucocytes, and skin fibroblasts, or showing metachromatic material in peripheral nerve biopsies having segmental demyelination and remyelination. There is diffuse white matter involvement due to noninflammatory demyelination with loss of oligodendrocytes, axon preservation, and reactive astrocytes which, together with macrophages, contain the metachromatic material, especially in the most extensively demyelinated areas.

The clinical phenotype varies with the amount of surviving arylsulphatase A depending on heterozygosity of the mutant allele; pseudodeficiency refers to those individuals with low levels of arylsulphatase A that are sufficiently high not to display a clinical phenotype. Some affected individuals have a genetic defect of the arylsulphatase A activator and this is associated with a more complex pattern of sphingomyelin storage, biochemically and in terms of the tissue distribution.

The most common form of metachromatic leucodystrophy develops in late infancy with delayed walking due to the neuropathy, which may be painful. There are also features of brainstem involvement and the emergence of diffuse upper motor neuron signs with reduced intellectual development, optic atrophy, and death within about 5 years from presentation. In later-onset childhood cases, after several years of normal development, there are behavioural changes with poor school performance, anticipating cerebellar and upper motor neuron disability which then follows much the same course as in younger patients, although with less evidence for neuropathy. The early adult form of metachromatic leucodystrophy is rare, or perhaps seldom diagnosed, and tends to present with intellectual or emotional abnormalities. Onset with dementia and behavioural disorders is usual with ataxia, paralysis, and optic atrophy only developing at late stages; the presentation is occasionally with paraparesis or cerebellar ataxia and the condition can then more easily be mistaken for multiple sclerosis. Clinical evidence for peripheral neuropathy may be revealed by slowed nerve conduction. Treatments have included dietary manipulation with reduced vitamin A and sulphur-containing substances, and bone marrow transplantation, but the successes are limited.

Multiple sulphatase deficiency combines the features of metachromatic leucodystrophy with mucopolysaccharidosis. It also has neonatal, early childhood, and juvenile forms. The pattern of combined motor and mental regression or lack of development reflecting widespread dysmyelination with peripheral neuropathy is associated with dysmorphic features and organomegaly. The more severe phenotype also reflects extensive neuronal loss due to the combination of stored sulphatide, sulphated steroids, and mucopolysaccharides. The enzyme defects are complex involving many sulphatases including arylsulphatase A.

Pelizaeus–Merzbacher disease

The three phenotypes of X-linked Pelizaeus–Merzbacher disease usually present in childhood. The clinical features which may distinguish the otherwise ubiquitous motor and developmental delay with epilepsy are abnormal eye movements, dystonia and choreoathetosis, and laryngeal paralysis. Affected individuals often stabilize with severe disabilities and live into early adult life. Some cases do not manifest until early adult life, but here the blur with specifically different disorders becomes more apparent. MRI either fails to show myelin or depicts myelin which is immature with an atrophic brain.

The molecular defect is most frequently due to duplication of a variable length of genome containing the proteolipid protein gene. Recent evidence implicates defects in replication mechanism that leads to the complex rearrangements seen in Pelizaeus–Merzbacher disease. Proteolipid protein is normally involved in stabilizing the lamellar structure of central myelin. Gene dosage abnormalities results in oligodendrocyte loss and failure of myelination.

Adult-onset dominant leucodystrophies

Forms of dominantly inherited leucodystrophy also occur exclusively in adults and may closely resemble chronic progressive multiple sclerosis. MRI shows diffuse, nondiscrete, white-matter disease and there are no oligoclonal bands in the spinal fluid. It remains uncertain whether all the adult-onset dominant leucodystrophies are one and the same disorder, and many are difficult to distinguish from the heterogeneous group of hereditary spastic paraplegias. The various phenotypes are gradually being classified as their biochemical and genetic defects are characterized. A family with spastic paraparesis, ataxia, and mild dementia presenting in adulthood, but with onset in childhood, has been described; diffuse white matter abnormalities were present on cerebral MRI, whereas pathognomic features of the other leucodystrophies were absent. Similarly familial cases of a behavioural presentation evolving to dementia and a recent report of two unrelated families with an autosomal dominant pedigree of ataxic paraparesis associated with autonomic dysfunction hint at the range of presentations within this grouping. The relationship to a recently reported series of sporadic adult onset leucodystrophy is uncertain. Five cases with progressive cognitive and motor decline, abnormal brain MRI, and absent oligoclonal bands were described with histological features of leukodystrophy and neuroaxonal spheroids.

Further reading