The demonstration that a serum autoantibody present in neuromyelitis optic (Lennon et al., 2004), subsequently shown to be an IgG antibody binding to the aquaporin-4 water channel (Lennon et al., 2005), allows a clear distinction to be made between most people with MS and the majority of those whose clinical pattern involves the optic nerves and spinal cord. It is possible that better understanding of the pathology and immunology of the demyelinating diseases will result in the recognition and identification of other clinical sub-types of the disease.

Demyelination of nerve fibres

In the CNS, myelin is produced by oligodendrocytes (Shepherd, 1994). Each oligodendrocyte gives off a number of processes to ensheath surrounding axons. These processes, which envelope the axon, form a specialized membranous organelle – the myelin segment. A myelinated nerve fibre has many such myelin segments, all ofa similar size, arranged along its length. Between the myelinated segments there is an area of exposed axon known as the node of Ranvier. The myelin segment is termed the ‘internode’ (Figure 5.1). When an action potential is conducted along the axon, ionic transfer predominantly occurs across the axonal membrane at the node of Ranvier. The lipid-rich myelin of the internode insulates the axon and inhibits ionic transfer at the internode. This arrangement of segmental myelination allows rapid and efficient axonal conduction by the process of saltatory conduction where the signal spreads rapidly from one node of Ranvier to the next.

Figure 5.1 Myelinated nerve fibres in the central nervous system.

When myelin is lost the insulation fails and the action potential cannot be conducted normally and at speed along the nerve, the function of which thereby effectively ceases, even though the axon remains intact.

Distribution of plaques

Pathological examination of the brain and spinal cord reveals characteristic plaques of MS which are predominantly, though not exclusively, in the white matter where most myelin is deposited around the axons of the fibretracts.The lesions are random throughout the cerebral hemispheres, the brainstem, the cerebellum and the spinal cord, but there is a proponderance of lesions in the periventricular white matter, particularly at the anterior and posterior horns of the lateral ventricles, within the optic nerves and chiasm and in the long tracts of the spinal cord.

The microscopic appearance of a plaque depends upon its age. An acute lesion consists of a marked inflammatory reaction with perivenous infiltration of mononuclear cells and lymphocytes (Lucchinetti et al., 1996). There is destruction of myelin and degeneration of oligodendrocytes with relative sparing of the nerve cell body (neurone) and the axon. Axonal integrity may be disrupted early in the inflammatory process and may be the most important determinant of residual damage and disability (Trapp et al., 1998). In older lesions there is infiltration with macrophages (microglial phagocytes), proliferation of astrocytes and laying down of fibrous tissue. Ultimately this results in the production of an acellular scar of fibrosis which has no potential for remyelination or recovery.

It is suggested by some pathologists that the variation seen in the appearance of individual plaques indicates hetrogeneity in the underlying pathology and differing immunological causes of MS (Lucchinetti et al., 2000).Others, however, feel that the variability in lesions may represent only a temporal progression of the pathology and that varying lesions are within the same individual (Prineas et al., 2001). It is evident that the pathology in people with primary progressive MS (PPMS) differs from that seen in relapsing remitting disease (RRMS) (Bruck et al., 2003).

Remyelination

Remyelination can occur following an acute inflammatory demyelinating episode. There are, within the brain, oligodendroglial precursors which can mature into oligodendrocytes, infiltrate the demyelinated area and provide partial remyelination of axons (Prineas & Connell, 1978). This can be demonstrated in postmortem tissue and, though remyelination always appears thinner than the original myelin, it may allow functional recovery.

Axonal damage

It is now recognized that during the acute inflammatory phase of the disease axonal transection and damage occurs in the demyelinating plaque (Trapp et al., 1998).In the later stages of the disease, and in addition to the scarring which develops at the site of the inflammatory plaques, there is increasing damage to the axons which can be seen both at the site of the original inflammation and distant from the areas involved in the original inflammation. It is likely that this axonal damage is an important part of the pathology of MS and, though less well recognized and researched than demyelination, is probably responsible for the more progressive and chronic forms of the illness. This axonal loss can be demonstrated on magnetic resonance imaging (MRI) scans as atrophy of the brain white matter, ventricular dilatation, ‘black holes’ and degeneration of the long ascending and descending tracts of the brainstem and spinal cord. Brain atrophy is also the main morphological counterpart of psychological deficits and dementia occurring in people with MS (Loseff et al., 1996).

Aetiology and epidemiology

Geographical prevalence

Epidemiological research into MS has been bedevilled by problems with ascertainment, identification of the baseline population to estimate prevalence, and the difficulty in interpreting minor changes in the small numbers of patients identified. Nonetheless, there appears to be a reproducible finding that the prevalence of MS varies with latitude (see Langton Hewer, 1993, for a review). In equatorial regions the disease is rare, with a prevalence of less than 1 per 100 000, whereas in the temperate climates of northern Europe and North America this figure increases to about 120 per 100 000 and in some areas as high as 200 per 100 000. In the UK it has a prevalence of about 80 000, affecting approximately 120 in every 100 000 of the population (O’Brien, 1987).

Genetic influences

A familial tendency towards MS is now well established but no clear pattern of Mendelian inheritance has been found. Between 10 and 15% of people with MS have an affected relative, which is higher than expected from population prevalence. The highest concordance rate is for identical twins – about 30%; non-identical twins and siblings are affected in 3–5% of cases. Children of people with MS are affected in about 0.5% of cases (Ebers et al., 1986).

A genetic factor is supported by the excess of certain major histocompatibility (MHC) antigens in people with MS. Human leukocyte antigen (HLA) A₃ and B₇ are overrepresented in people with MS and the HLA complex on chromosome 6 has been considered as the possible site of an MS ‘susceptibility gene’. Systematic genome screening to attempt to define the number and location of susceptibility genes has been undertaken (Sawcer & Compston, 2003) and the most obvious candidates are DR(2)15 and DQ6, the former genotype is now defined as DRB1⁎1501, DRB5⁎0101 and the latter DQA1⁎0102, DQB2⁎0602. More recently assocation has been suggested with genes encoding the cytokines IL2 (Matesanz et al., 2004) and IL7 (Lundmark et al., 2007); almost all genes so far identified affect the immune system. Recently an axonal gene, KIF1B, has been identified to carry a susceptibility risk (Aulchenko et al., 2008). The probability is that, as in the case of diabetes mellitus, any genetic factor in MS is likely to involve several different genes and be complex (Compston, 2000).

Viral ‘epidemic’ theory

One other intriguing aspect of epidemiology of MS is the so-called ‘epidemics’ of MS occurring in the Faroes, the Orkney and Shetland Islands, and Iceland in the decades following the Second World War (Kurtzke & Hyllested, 1986). It was suggested that the occupation troops may have introduced an infective agent which, with an assumed incubation period of 2–20 years, resulted in the postwar ‘epidemic’. It should be emphasized that despite extensive research no such infective agent has ever been isolated. Several factors influence the accuracy of such research and one or two errors in the numerator, when defining the base population, would make huge differences in the interpretation of the data.

Migration studies have lent support to the possibility of incomers adopting the risk and prevalence of MS closer to their host population. Studies have suggested that when migration occurs in childhood, the child assumes the risk of the country of destination, but these studies rely upon relatively small numbers of defined cases and interpretation is difficult (Dean & Kurtzke, 1971).

Summary

It is highly likely that MS is the product of both environmental and genetic factors. Exposure to some external agent, possibly viral, during childhood in those who are genetically susceptible results in the development of an autoimmune response against native myelin. When the blood–brain barrier is subsequently injured, often in the context of an infective illness, the autoimmunity can manifest, the myelin is attacked and the symptoms develop. Many autoimmune diseases are more common in women than men but whereas some commonly coexist, there is no evidence that other autoimmune diseases are more prevalent in people with MS than in the general population.

Clinical manifestations

There are different types of MS, which are classified in Table 5.1. The disease can run a benign course with many people able to lead a near-normal life with either mild or moderate disability.

Table 5.1 Classification of multiple sclerosis

Classification	Definition
Benign MS	One or two relapses, separated by some considerable time, allowing full recovery and not resulting in any disability
Relapsing remitting MS	Characterized by a course of recurrent discrete relapses, interspersed by periods of remission when recovery is either complete or partial
Secondary progressive MS	Having begun with relapses and remissions, the disease enters a phase of progressive deterioration, with or without identifiable relapses, where disability increases even when no relapse is apparent
Primary progressive MS	Typified by progressive and cumulative neurological deficit without remission or evident exacerbation

MS, multiple sclerosis.

The fundamental clinical characteristic of MS is that episodes of acute neurological disturbance, affecting non-contiguous parts of the CNS, are separated by periods of remission; attacks are disseminated in time and place. The disease can be progressive in nature and initially, resolution following a relapse is usually complete. Some attacks, however, do not recover completely, there remains some continuing disability and further attacks can leave the individual with increasing and permanent neurological disability.

The disease can enter a phase of secondary progression, in which deterioration occurs without evident exacerbations.

Rarely, particularly with the presentation of paraparesis in older males, the disease may be steadily progressive from the outset. This is termed ‘primary progressive’ multiple sclerosis.

MS can also be classified according to the certainty of diagnosis (Table 5.2). It should always be remembered that the diagnosis is one of exclusion; haematological and biochemical investigations are essential to rule out other confounding diseases and, during the course of the disease, the physician must always be willing to reconsider the possibility of differential diagnosis. The classification of disease by the certainty of the diagnosis is of predominant importance for the inclusion of patients into drug trials and for epidemiological studies (McDonald et al., 2001; Poser et al., 1983). Recently an updated classification of diagnostic criteria has been produced (Polman et al., 2005) and this is currently being assessed.

Table 5.2 Classification of multiple sclerosis according to certainty of diagnosis

Clinically definite MS	Two attacks and clinical evidence of two separate lesions Two attacks; clinical evidence of one lesion and paraclinical evidence of another separate lesion
Laboratory-supported definite MS	Two attacks; either clinical or paraclinical evidence of one lesion and CSF oligoclonal bands One attack; clinical evidence of two separate lesions and CSF oligoclonal bands One attack; clinical evidence of one lesion and paraclinical evidence of another, separate lesion and CSF oligoclonal bands
Clinically probable MS	Two attacks and clinical evidence of one lesion One attack and clinical evidence of two separate lesions One attack; clinical evidence of one lesion and paraclinical evidence of another, separate lesion
Laboratory-supported probable MS	Two attacks and CSF oligoclonal bands

Paraclinical evidence is derived from magnetic resonance imaging, computed tomographic scanning or evoked potentials measurement. CSF, cerebrospinal fluid; MS, multiple sclerosis.

Early signs and symptoms

It is a common misconception that the first attack of MS strikes as a ‘bolt out of the blue’, in a young adult previously in good health. In fact, a careful history will often reveal vague feelings of ill health over the preceding months or years, often taking the form of sensory disturbances, aches, pains and lethargy. Not uncommonly there is a history which clearly suggests a previous episode of demyelination, such as the symptom of double vision, blurring of vision or blindness, rotational vertigo or weakness. Such episodes have often been dismissed as trivial by the patient and, as such, are poorly remembered and may not have caused the person to seek advice from the general practitioner. Demyelination can occur anywhere throughout the white matter of the CNS and, therefore, the initial presentation of MS is extremely variable.

Visual symptoms

• Visual loss

• Double vision.

The most common single symptom in presentation is of acute or subacute visual loss in one, or rarely both, eyes. Twenty-five per cent of patients will present in this way, often with pain or discomfort in the eye and the classical symptom of a lesion in an optic nerve (optic neuritis or retrobulbar neuritis) is of loss of colour vision of the eye followed by blurring and ultimately by a central scotoma (blind spot) and visual loss. Improvement usually begins spontaneously within days to weeks; in about 30% of cases recovery will be complete but the remainder will be aware of some reduction in visual acuity or of the brightness of their vision. Following an episode of optic neuritis, the optic disc becomes pale and atrophic (optic atrophy). More than one-half of those presenting with optic neuritis will go on to develop other signs of MS. Those who do not may have had a single episode of inflammatory demyelination or they may have some other disease entity.

Double vision (diplopia) is a particularly common presenting complaint and may be due to weakness of muscles innervated by the third, fourth or sixth cranial nerves, or the connections between their nuclei in the brainstem. A very characteristic abnormality is an internuclear ophthalmoplegia due to a lesion of the medial longitudinal fasciculus, in which there is failure of adduction of the adducting eye on lateral gaze with nystagmus in the abducting eye. When a bilateral internuclear ophthalmoplegia is seen in the young adult this is virtually diagnostic of MS.

Neurological deficit

The second most common presenting symptom is a clearly defined episode of neurological deficit, that may occur alone or with others, such as:

• weakness

• numbness

• unsteadiness, imbalance, clumsiness

• slurred speech

• nystagmus

• intention tremor

• trigeminal neuralgia.

Weakness, numbness or tingling can affect one or more limbs. Symptoms may develop acutely over minutes or chronically over weeks to months, but more typically they evolve over hours or days. Such a presentation, with or without sphincter involvement, usually indicates an area of spinal demyelination. Lhermitte’s phenomenon, which is the sensation of shooting, electric-shock-like sensations radiating down the back and into the legs when the neck is flexed, is a symptom of cervical cord irritation and is commonly described when there is demyelination within the cervical spinal cord.

Not infrequently the disease may begin with the signs and symptoms of cerebellar dysfunction causing unsteadiness, imbalance, clumsiness and dysarthria (slurring of speech). Examination may reveal the patient to have nystagmus (a jerky movement of the eyes), an intention tremor (see Ch. 4) and a cerebellar dysarthria, the combination of which is termed Charcot’s triad and is one of the classical features of MS. These symptoms are due to demyelination occurring within the brainstem and there are a wide variety of brainstem syndromes causing cranial nerve disturbances and long tract signs. Other clues are the development of trigeminal neuralgia, or tic douloureux (sharp facial pains), in young adults suggesting the presence of a lesion within the brainstem.

Possible signs and symptoms in the course of multiple sclerosis

A number of symptoms and signs can become established and can be severe, although many can occur at any stage of the disease. These include:

• fatigue

• optic atrophy – with associated visual symptoms

• ophthalmoplegia – with facial sensory and motor symptoms

• cerebellar disease causing nystagmus, ataxia and tremor

• muscle hypertonia

• muscle weakness

• brisk reflexes

• impaired walking ability

• sphincter disturbances

• sexual dysfunction

• psychiatric and psychological disturbances

• symptoms being exacerbated by heat and cold.

General weakness and fatigue are almost invariable symptoms, and fatigue may indeed be the presenting symptom in people with MS. There is often optic atrophy with associated decreased visual acuity, a central scotoma or large blind spot and pupillary abnormalities. There may be bilateral internuclear ophthalmoplegia with facial sensory disturbance, or weakness, and a brisk jaw jerk, with slurring speech. There is usually evidence of cerebellar disease with nystagmus, ataxia and tremor which, in its most severe form (dentatorubral) can be incapacitating such that any attempt to move the limbs precipitates violent uncontrollable movements and prevents mobility and feeding. In the limbs there is usually increased tone and weakness in a pyramidal distribution. The reflexes are pathologically brisk; the plantar responses are extensor. Walking is usually affected due to progressive weakness, spasticity and ataxia, and the combination of spasticity and ataxia is suggestive of inflammatory demyelination. Many people will rely on walking aids and a significant proportion will need a wheelchair.

When there is disease affecting the spinal cord, symptoms of sphincter disturbances are common. These range from mild urgency and frequency of micturition to acute retention of urine, constipation and incontinence. Sexual dysfunction is common with erectile and ejaculatory difficulties in men and loss of libido in women. Modern prospective studies of the effect of pregnancy in MS are reassuring and there is no reason to suggest that families should be limited. During pregnancy, the patient has a statistically lower likelihood of relapse, though this may be counterbalanced by a slight increase early in the puerperium.

Psychiatric and psychological disturbances are common (see Ch. 17). Depression is the most common affective disturbance in MS and may compound the underlying physical problems, exaggerating symptoms of lethargy and reduced mobility. With diffuse disease some people develop frank dementia, a few become psychotic and epileptic seizures are seen in 2–3% of cases, an increase of four to five times over that of the normal population. Patients can show evidence of emotional instability or affective disturbance. Euphoria, or inappropriate cheerfulness, was said to be a classical feature of the disease but this is now considered a myth. It is, in practice, quite rare and probably occurs when lesions affect the subcortical white matter of the frontal lobes, resulting in an effective leucotomy.

Patients will frequently record an increase in their symptoms with exercise and with a rise in body temperature. The physiology behind these symptoms is probably the same, due to the fact that the propagation of an action potential along a neurone is greatly affected by temperature. Nerve conduction in an area of demyelination can be critical and paradoxically an increase in temperature, which normally improves conduction, may, in the demyelinated axon, result in a complete conduction block. This phenomenon of worsening of symptoms with exercise and increased temperature is Uhthoff’s phenomenon and is most dramatically manifest when patients describe how they are able to get into a hot bath but not able to extricate themselves. Patients should be warned to avoid extremes of temperature and overexertion to avoid this increase in symptoms (Costello et al., 1996).

Diagnosis

To make a clinical definitive diagnosis of MS there has to be a history of two attacks and evidence, clinically, of two separate lesions (Poser et al., 1983). It is also important to remember that other diagnoses should be excluded and, since at presentation all these criteria may not be fulfilled, corroborative paraclinical, laboratory and radiological evidence is usually sought (see O’Connor, 2002, for a review).

Magnetic resonance imaging

MRI of the head and spinal cord is extremely useful in demonstrating the lesions of MS (see Figure 2.2 in Ch. 2). Typically, high signal lesions on T2-weighted sequences are seen throughout the white matter. Gadolinium enhancement demonstrates areas of active inflammation with breakdown in the blood–brain barrier, which are associated with an acute relapse (Paty et al., 1988). In particular circumstances, as with acute optic neuritis or cervical myelopathy, the demonstration on an MRI scan of disseminated asymptomatic lesions is particularly helpful in confirming the diagnosis and there are rigid criteria for interpreting the MRI scan changes. Newer techniques, such as fluid-attentuated inversion recovery (FLAIR) and magnetization transfer imaging (MTI), improve the sensitivity and selectivity of MRI in MS (Filippi et al., 1998).

Lumbar puncture

Analysis of the cerebrospinal fluid (CSF) in a patient suspected of having MS is valuable diagnostically. There is production of immunoglobulin (mainly IgG) within the CNS and these antibodies are detected by biochemical analysis of the CSF. Electrophoresis of the CSF allows the immunoglobulin fraction to separate into a few discrete bands (oligoclonal bands) and simultaneous analysis of the immunoglobulin from the blood can demonstrate that these antibodies are confined to the CNS and, therefore, provide confirmatory evidence of inflammatory CNS disease (Tourtellotte & Booe, 1978).

The antigens that provoke this antibody response have not been identified, nor is it known whether the response is integral to the underlying pathogenic process or a ‘bystander reaction’. The CSF normally contains very few cells but during an acute exacerbation of MS there may be an increase in the lymphocytes in the CSF. The level of protein in the CSF is slightly raised but the level of sugar is normal. CSF examination is important in helping to differentiate other diseases from MS and is one of the prerequisites to making a diagnosis of primary progressive MS.

Evoked potentials

A typical history, the signs of more than one lesion affecting the CNS, together with disseminated white-matter lesions shown on MRI and the presence of unmatched oligoclonal bands in the CSF, puts the diagnosis beyond reasonable doubt. However, when one or more of these findings are inconclusive further support for the diagnosis may be obtained by evoked potential (EP) testing (Misulis, 1993) (Figure 5.2). These tests, which include visual, brainstem auditory and somatosensory evoked potentials (VEP, BAEP, SSEP) may provide evidence of a subclinical lesion, which has previously been undetected (Halliday & McDonald, 1977). For example, the finding of abnormal SSEPs from both legs, in a patient presenting with blindness in an eye, strongly suggests a lesion in the spinal cord and raises the possibility of MS. The demonstration of more than one lesion is essential in making a secure diagnosis of MS.

Figure 5.2 Evoked potentials (EP). A visual EP: study showing the typical prolonged latency and poor waveform in a lesion of the right optic nerve, such as potic neuritis, in a patient with multiple sclerosis.

The management of multiple sclerosis

Not all MS patients require active intervention but even those with mild symptoms should be given support and advice from appropriate professionals, relevant to the patient’s condition and circumstances. Interventions available for those with moderate to severe disabilities mainly involve drug therapy and physiotherapy. For a recent review of the management of MS, see O’Connor (2002).

There is no proven benefit from any dietary restrictions, though there is suggestive evidence that diets low in animal fat and high in vegetable oil and fish-body oil have potential benefits (Klaus, 1997; Payne, 2001).

Breaking the news

The neurology outpatient clinic is full of people with a history of episodic neurological symptoms, particularly sensory disturbances. The decision to investigate depends upon the individual presentation, consideration of the evidence for relapses, the clinical and objective evidence for multiple sites of disease, and the suspicion of the physician. Anxious, polysymptomatic patients with normal neurological examination would not usually be investigated for the possibility of MS and, although the symptom of fatigue is common in MS, it may also be a physiological symptom which is heightened by the presence of depression.

At present many neurologists, jointly with their patients, prefer not to investigate a single resolved attack, especially when there are no objective signs. However, if early treatment with disease-modifying therapies can reduce long-term disability, then the threshold for investigating such patients will be lowered.

The diagnosis of MS is in part the exclusion of other diagnoses, but when the clinical conditions and the laboratory and imaging tests support the diagnosis, then such should be discussed with the patient with the aim of reducing the initial shock and giving an optimistic picture of the prognosis. Once the diagnosis of MS has been intimated, it is important that individuals have time to ask questions and be given the necessary information, often in the form of literature or videos, to enable them to formulate their questions. It is here that the role of an MS specialist nurse is so vital; he or she can visit the patient at home, provide more time than is possible for the physician and hopefully answer many of the relevant questions.

Drug therapy

Many patients with MS do not require drug therapy but when they do, there are three treatment options (see Ch. 28):

1. Drug management of an acute exacerbation, e.g. steroids

2. Symptomatic drug therapy to alleviate individual problems, e.g. antispasticity drugs

3. Use of disease-modifying therapies to reduce the underlying pathological process, e.g. interferons.

Since MS is an incurable condition, drug treatments aim primarily to manage acute episodes and specific symptoms. The disease-modifying therapies are, at best, only partially effective to date.

Tremor

The treatment of tremor in MS, as in most other situations, is difficult (see Ch. 14). Minor action tremors may be helped by the use of beta-blockers, such as propranolol, or low-dose barbiturates such as primidone. The more disabling intention tremor of cerebellar disease and the most disabling dentatorubral thalamic tremor, which prevents any form of movement or activity, is refractory to treatment. There have been reports of agents such as clonazepam, carbamazepine and choline chloride helping individuals, and by serendipity, the antituberculous agent isoniazid has been shown to be effective but should be given with a vitamin B₆ supplement. None of these treatments are particularly effective and the possibility of deep brain stimulation is now being increasingly considered. Surgical treatments are most effective for unilateral tremor; bilateral treatment is associated with significant morbidity and mortality.