Introduction

Multiple sclerosis (MS) is one of the most dreaded diagnoses in neurology. Patients visualise a fit and healthy person, such as the Olympic athlete Betty Cuthbert, reduced to a wheelchair existence. Patients told the diagnosis of MS are often reduced to tears in much the same way as the diagnosis of cancer causes patients to jettison hope. This should no longer be the case in the light of recent advances in the treatment of MS. In the past, the neurologist’s waiting room was crowded with the wheelchairs of patients with MS but, thankfully, this has now become the exception rather than the rule.

Even the understanding of the basic pathophysiology of MS has changed enormously over the last decade. It used to be thought that MS was purely a white T-cell autoimmune demyelinating central nervous system (CNS) disease. More recently, the immunological role of B-lymphocytes in the evolution of MS has been appreciated, as has the major contribution of the associated axonal degeneration that causes shrinkage of the brain volume. To better understand the concept of demyelination contrasted with axonal degeneration, the reader is referred to Chapter 11 on peripheral neuropathy in which the issues are discussed in depth. The basic concepts remain the same although the location is the central rather than the peripheral nervous system.

One reason MS is feared is that it is an unpredictable disease with exacerbations and remissions. It is a disease in which lesions occur within the CNS that are ‘separated in time and place’. The diagnostic criteria for MS have also been modified with the international acceptance of the ‘McDonald criteria’ (see Table 10.1).

These criteria acknowledge the role of magnetic resonance imaging (MRI) in the diagnosis of MS. The criteria, formulated by a panel of experts chaired by McDonald, recognised that MS may be identified by clinical symptoms and signs, MRI detected lesions (that may occur without associated clinical features) and the presence of oligoclonal bands in the cerebral spinal fluid (CSF) that herald CSF immunological insult.¹

The easier access to MRI has produced a practical recognition that for every clinically identified ‘attack’ of MS, there may be as many as six to ten sub-clinical ‘attacks’ that would remain silent were it not for the MRI trademark of the MS plaque.

While the treatment of MS remains largely the precinct of the consultant neurologist, there should exist an effective partnership between the neurologist and the general practitioner to maximise patient wellbeing. The role of the general practitioner within this partnership should not be underrated, and is mandatory for an optimal outcome. This chapter maps out the clinical features of MS so that the diagnosis is appropriately made, without which this partnership cannot operate to the patient’s advantage.

There is a variety of types of MS, and it is accepted that not all types respond equally to accepted MS treatment. Use of disease modifying agents, such as the interferons or glatiramer acetate, requires a diagnosis of MS confirmed by MRI² (the date of that MRI being part of the prescription approval process), but these agents are not available to patients with advanced disability (unable to walk more than 100 metres without assistance). This is equivalent to the disability rating of 6.0 on the Expanded Disability Status Scale (EDSS)³ (see Table 10.2).

TABLE 10.2 Expanded disability status scale

EDSS score	Description	Summary
0.0	Normal neurological functioning	Able to partake in regular activities
1.0	Minimal impairment in one functional system but essentially normal
1.5	Minimal impairment in more than one functional system but essentially normal
2.0	One functional system with minimal disability
2.5	Two functional systems with minimal disability
3.0	One functional system with moderate disability or minimal disability in three or four
3.5	No problems walking but with moderate disability in one functional system plus mild disability in two or more functional systems	Moderate impairment in daily functions
4.0	No problems walking without aid for 500 m but severe impairment in one functional system or combinations of mild to moderate impairments in multiple functional systems
4.5	No problems walking without aid for 300 m but severe impairment in one functional system or combinations of mild to moderate impairments in multiple functional systems
5.0	Cannot walk more than 200 m without aid and unable to complete a full day of activities without impairment	Unable to complete all daily activities
5.5	Cannot walk more than 100 m without aid and unable to complete a full day of activities without impairment
6.0	Requires unilateral assistance to walk 100 m	Needs ambulatory assistance
6.5	Requires bilateral assistance to walk 100 m
7.0	Unable to walk 5 m even with bilateral assistance, restricted to a wheelchair	Mostly restricted to a wheelchair
7.5	Unable to take two steps even with bilateral assistance, restricted to a wheelchair
8.0	Arms still effective, confined to wheelchair or bed
8.5	Arms have some functioning, confined to bed	Bedridden
9.0	Arms not functional, can communicate and eat
9.5	Cannot communicate or eat effectively
10.0	Death due to MS	Death

These agents are likewise denied to patients with MS who do not have relapsing remitting MS (RRMS). Patients with progressive disease are at a distinct disadvantage and, in many instances, symptomatic relief as provided by the general practitioner is the only therapeutic option available on the Pharmaceutical Benefits Scheme (PBS).

Diagnosing MS

A repeated mantra in this book is that ‘without heightened index of suspicion the diagnosis will often be missed’. This is equally true and important when diagnosing MS.

MS occurs more commonly in females than males (ratio 2 : 1), usually between the ages of 20 and 40 years, although childhood and geriatric onset are now becoming more widely diagnosed because of MRI. The diagnosis of MS is becoming more common, but it is suspected that this reflects better diagnostic tools and heightened index of suspicion rather than an increased prevalence.

If the place of birth is further from the equator, migration after the age of 15 years means one brings the prevalence of MS of the place of origin to the destination rather than assuming the prevalence appropriate to the destination. Within the Australian context, the incidence of MS is sixfold greater in Tasmania than in northern Queensland. Some argue that this relates to an increased exposure to sunlight and vitamin D, which occurs closer to the equator, but the absolute answer remains unclear. If one parent has MS there is a 1–2% chance of the child having MS and, if a monozygotic twin has MS, then the chance of the sibling twin developing MS is of the order of 35%. There is a suspicion of an association between MS and previous infection with the Epstein-Barr (EB) virus. It follows that there is a variety of red flags that should alert the general practitioner to the possibility of MS.⁴

Because the presentation of MS can be so varied, it is most important, especially when assessing young women, not to dismiss symptoms that are difficult to understand. If it is possible for the symptoms to emanate from the CNS, then the diagnosis of MS should be entertained. As a rule of thumb, the diagnosis of MS is beyond the scope of the average general practitioner. It requires lumbar puncture, looking for oligoclonal bands; evoked potential studies (including visual, somatosensory and possibly brainstem) looking for lesions that are separated in place (located within the CNS); as well as the MRI. Despite general practitioners now having greater access to MRI, in reality, to diagnose MS most general practitioners will refer the patient to a consultant before ordering an MRI. Another reason for early referral is that there is good evidence to suggest that the earlier treatment is instigated, the better is the outcome.² A number of companies are now offering special compassionate access to disease modifying drugs for patients with Clinically Isolated Syndrome (CIS)—for patients having experienced a single attack without meeting the criteria for a definitive diagnosis of MS—to ensure the earliest possible availability of treatment. This further recognises the merit of early intervention on long-term prognosis.

As stated in other chapters, it is far more intellectually rewarding for the general practitioner to refer the patient to the consultant with a confirmed and correct provisional diagnosis, so the family doctor needs to be aware of the symptoms of MS to take an appropriate history (see Table 10.3).

TABLE 10.3 Symptoms of MS

	Symptoms	Signs
Optic neuritis	Unilateral loss of central vision Pain on moving the eye Blurred vision

Swelling of single nerve head (papillitis) Motor involvement Sensory involvement Sensory changes on testing Spinal cord involvement Bending neck causes electric shock sensation down spine Psychological factors  

Types of MS

Of the variety of types of MS, the most common is relapsing remitting MS (RRMS) that occurs in approximately 85% of MS at the onset of the disease and about 60% of the total MS population.⁴ Patients with RRMS may have subclinical episodes preceding and following a clinical ‘attack’ (see Fig 10.1).

The first clinically identified attack is termed CIS, because at this stage there is no history of repeated episodes. While the disease may remain subclinical, at the time of CIS it does not prevent the accumulation of the burden of disease with possible decreased volume of the brain.

Once the relapses combined with the burden of disease surpass the threshold for clinical disease expression on a more permanent basis, the RRMS enters the secondary progressive phase, known as secondary progressive MS (SPMS). The patient never returns to a subclinical status (see Fig 10.2). This accounts for approximately 20% of all people with MS.

About 5% of all MS patients are said to have progressive relapsing MS (PRMS) in which they never really return to a subclinical status below the threshold of a disease expression, and the disease continues relentlessly. They do have bouts of increased disease expression, which constitute relapses, from which they do improve, but the burden of disease increases and is cumulative (see Fig 10.3).

In one form of primary progressive MS (PPMS) there appears to be a linear progression of disease from the outset, without apparent relapses and remissions, without the patient returning to a subclinical state, with constant expression of disease (above the threshold of disease expression). PPMS more commonly includes spinal involvement and appears to affect a somewhat older population at onset (30s and 40s at onset). This is also said to occur in approximately 5% of all MS patients and 10% at the onset of disease.

Some 10–30% of MS is said to be benign as the diagnostic criteria are met yet there is minimal or no disability after 15 years and the attacks, if they are recognised as such, may be very minor, infrequent and with excellent recovery. Conversely, there is also a malignant and severe form of MS with rapid progression that may result in death or marked disability within two years.

A form of possible MS known as Devic’s disease, also known as neuro myelitis optica (NMO), appears to affect a somewhat different population, being more common among Occidental people. It is less responsive to currently available remedies. There remains an argument as to whether NMO is actually part of the MS spectrum or is a completely different disease entity with specific involvement of the spinal cord and optic pathway.⁵ For the purpose of this discussion such debate is irrelevant and remains the precinct of specialists, as the patient will have been referred for a consultative opinion prior to diagnosis of NMO. What is worth noting is that there is an NMO antibody, also called aquaporin³, that is measurable in NMO patients.

The reason for delineating the various patterns of MS is to help the general practitioner better understand how MS expresses itself. It empowers the general practitioner to better understand the disease, and therefore assists in trying to support patients with MS. Patient reassurance, support, rehabilitation and symptomatic relief often rely more heavily on the family doctor with whom the patient generally has a closer relationship.

Symptoms and Signs of MS

As MS is a disease of relapses and remissions, it is important to appreciate that a relapse is classically defined as the onset of new symptoms or the exacerbation of existing symptoms that last for at least 48 hours, and are often called ‘attacks’. Such exacerbations represent an episode of demyelination: what occurs within the relapse is defined by the site, be it in the cerebral hemispheres (affecting cognition, emotions, motor activity or sensation); brainstem (possibly affecting cranial nerves or their interconnections); or the cerebellum (affecting coordination). It is accepted that MS can also cause demyelination within the spinal cord and, again, its expression is determined by the site within the cord and the pathways affected (see Tables 10.2 and 10.3). As touched upon above, in the condition known as NMO demyelination is restricted to the optic pathways and the spinal cord. One of the hallmark features of NMO is that the spinal cord involvement is much longer, covering a number of vertebral segments, than is usually encountered in other forms of MS. As indicated above, aquaporin³, also called NMO-antibody, can be measured in the blood and/or CSF of the patient with NMO.⁶

Often the first presentation of MS is optic neuritis, with demyelination and inflammation of the optic nerve. This causes obscuration of vision, usually restricted to one eye, with pain that is often exacerbated by eye movement. Ophthalmoscopic examination of the optic fundus should provide the diagnosis of optic neuritis (also called retrobulbar neuritis or papillitis) with the appearance of what looks like papilloedema that is usually restricted to one eye, while papilloedema is usually bilateral.

A lesion in the brainstem may cause internuclear ophthalmoplegia (INO) with involvement of the medial longitudinal bundle that connects the midbrain with the pons, and hence coordinates the movements of the eye muscles. An INO lesion in the midbrain may result in failure to adduct the affected eye due to poor communication between the third cranial nerve and sixth cranial nerve, when looking laterally, with nystagmus in the abducted eye (see Fig 10.4). The converse may be the case with a lesion in the pons (see Fig 10.4).

Discussion so far has focused upon the major symptoms and signs that attach to MS, but there remains a host of MS-related symptoms and signs for which the general practitioner plays the principal role in treatment. These include help with rehabilitation in the advanced case, and assistance with bowel and bladder problems, such as urgency, urinary retention or constipation. Counselling, particularly in the area of potential sexual dysfunction, with possible erectile impotence, or the consequences of emotional problems, are often best addressed by the family doctor with whom the patient usually has a more intimate relationship.

Fatigue is often a major concern for people with MS. A recent pilot study showed the potential for sleep disorders, such as periodic leg or limb movement in sleep with arousal (PLMS with PLMA) and possibly even obstructive sleep apnoea to be contributing factors to this symptom.⁷ It follows that referral to a sleep physician and polysomnography may provide additional insight into the associated fatigue with the potential for intervention, such as continuous positive air pressure (CPAP).

Emotional factors may play a significant role within the evolution of MS, both for the affected patient and their relatives and loved ones. Anxiety and depression are often associated with MS. The general practitioner is ideally placed to identify the needs, provide counselling and, when necessary, medication to alleviate these symptoms.

Treatment of MS

The treatment of MS is divided into the treatment of relapses and the provision of more long-term disease modifying therapies, together with symptom relief and counselling.

Conclusion

MS is a disease that carries with it a great amount of fear and negative connotations. The diagnosis often produces similar patient responses as a diagnosis of cancer, but it is an exciting time for those treating patients with MS.

The condition is easier to diagnose with the benefit of MR, and there are treatments available even before the diagnosis of clinically definite MS has been established. In addition to the traditional disease modifying injectable agents, such as the interferons and glatiramer acetate, treatment of MS is at the dawn of new age oral treatments with medications such as fingolimod and cladribine currently undergoing international regulatory review, and other agents being trialled or just completing clinical trialling.

These remedies are complemented by Tysabri® or Mitoxantrone®, and brave new world use of stem cells is on the horizon. All of these treatments remain the precinct of the consultant specialist but the true hands-on, direct patient care, day-to-day management of intrusive symptoms and psychosocial issues, and relief of fear and assistance with rehabilitation or even habilitation, remain the domain of the primary care general practitioner.