Multiple sclerosis (MS) is defined as a chronic, autoimmune disorder in which inflammatory lesions in the central nervous system (CNS) strip myelin sheaths from nerve axons (demyelination). MS is characterised by demyelinated lesions (plaques) which are ‘separated in space’ ie, in multiple different locations in the CNS; and ‘separated in time’ ie, different plaques appear at different times over many years. 

MS is broadly divided in to relapsing remitting (RRMS, 85%) and primary progressive (PPMS, 15%) forms.¹ This article will concentrate on the former. Relapsing remitting MS may be suspected at the time of a first clinical relapse. Patients will usually make a complete or near complete recovery from first relapse, over two to six weeks. They may then experience future relapses on average once per year, if untreated. 

The course is highly variable, with some individuals having so-called ‘benign MS’ with just one or two attacks in their lifetime; while others have highly active relapsing MS (HARMS) with several clinical relapses per year. Eventually, and typically at 15-20 years from first diagnosis, many RRMS patients will enter secondary progressive MS with accumulating fixed disability. 

The chances of a patient with newly-diagnosed RRMS needing a cane or wheelchair within 15 years is one in four – so we can reassure our patients that three-quarters will not. The best predictors of late, long-term disability in early RRMS are frequent relapses in the first year² and activity on MRI scan.³ These observations have driven the trend towards earlier, stronger treatments in that subgroup.  

When to suspect MS in general practice

MS should be suspected in patients whose presentation is suggestive of a first relapse⁴ or where MS is demonstrated on MRI.⁵ In day-to-day practice, it can be very challenging to refine this index of suspicion. The diagnosis of MS should be confirmed by a consultant neurologist. Patients with a clinically disabling relapse should be seen urgently for IV steroids; those without disabling symptoms should be seen on an urgent outpatient basis. 

Interpreting clinical and MRI features in general practice

Presentations suggestive of an MS relapse

The key point is that it is not the symptoms, but rather their timing and behaviour, that suggest an MS relapse. The symptoms themselves – numbness, pins and needles, limb weakness, monocular visual loss, vertigo, pain – could be due to any neurological process and might be very benign.

A typical MS relapse will evolve slowly over 24 to 72 hours. This can be thought of just like a bruise coming up on your arm, except it is in the CNS. For example, optic neuritis will evolve, such that a patient has slight blurring on a Monday but significant visual loss by Wednesday. 

Spinal cord involvement will also emerge slowly, with a numb right foot on Monday, a weak right leg by Tuesday and bilateral leg involvement by the Wednesday. Symptoms are then continual and sustained over days or weeks (not coming and going in short attacks or changing with posture). MS relapses will usually then slowly recover, over two to six weeks. 

Optic neuritis presents with monocular visual loss, often a central scotoma. There is usually pain on eye movement. A relative afferent papillary defect (Marcus-Gunn sign) on the swinging flashlight test is invariably present, and as such is a very useful sign. 

Spinal cord plaques are the other common presentation. These relapses can be motor or sensory. Sensory attacks are a particular challenge, given the common occurrence of sensory symptoms due to compressive neuropathies and migraine. Clues to a relapse include sustained continual sensory symptoms, which do not alter with posture; bilateral lower limb involvement; sensory symptoms on the trunk or tummy; and motor signs. Associated bladder dysfunction is also suggestive. 

Presentations not suggestive of an MS relapse

The key difference is the timing, with symptoms appearing suddenly and lasting for short periods.

• Hand numbness/paraesthesia that is situational and intermittent, lasting just minutes per time, especially where this wakes the patient at night: consider carpal tunnel syndrome or ulnar neuropathy at the elbow

• Pain or sensory symptoms in a leg which are situational eg: when driving; in certain postures; or associated with low back pain: consider compressive lumbosacral radiculopathy due to a disc prolapse or degenerative spondylosis

• Monocular visual loss lasting just seconds or a few minutes, or intermittently re-occuring: consider TIA or migraine aura.

Symptoms in established MS not suggestive of relapse

These situations would rarely lead to a fresh MS diagnosis, but are encountered as established patients are followed over time:

• Uhthoff’s phenomenon is transient worsening of an existing MS symptom when the patient heats up. For example, a patient recovered from optic neuritis in the past now notices blurred vision in the same eye whenever exercising at the gym

• Paroxysmal symptoms are brief, electrical short circuits within old plaques, eg. short sensory attacks lasting five to 60 seconds. They are rare. They are reminiscent of more common or garden compressive neuropathies and as such would never form the basis of suspicion for new MS

• Pseudo-relapse is the most important for general practice. This is, again, the unmasking of an old plaque’s symptoms but due to systemic illness. For example, a patient with a previous spinal relapse could re-develop leg weakness in the face of a fever. The same principle can lead to a dramatic, but reversible, decline in cognition and mobility in progressive MS patients who develop urinary infections or sepsis. 

MRI scans highly suggestive, and not so highly suggestive, of MS

The majority of patients with MS have multiple T2 hyperintensities on a standard, unenhanced MRI brain scan at first presentation. As such, standard MRI brain is highly sensitive; a normal MRI brain is pretty reassuring against the diagnosis. Unfortunately, specificity is far more variable depending on pattern and interpretation. The difficulty is that smaller T2 hyperintensities are very common in the general population. The vast majority are tiny white dots and are benign. Furthermore, bigger white matter lesions accumulate with age and hypertension. 

MRI scans reported as ‘highly suggestive of demyelination’ usually correspond to true MS after assessment. However, we are all familiar with the more common MRI report which states ‘scattered T2 hyperintensities, which can represent migraine, demyelination, vascular, infectious and inflammatory aetiologies’. In this situation, at a guess the chances of MS are well below 20%, but specialist opinion should be sought. Neurologists will want to see the MR images for themselves and correlate with the clinical picture. The vast majority with ‘scattered hyperintensities’ can then be reassured against MS; some may need a lumbar puncture to clarify.    

Management of a relapse

• Exclude mimics and sepsis/infection causing pseudo-relapse

• Call your local MS or neurology clinical nurse specialist 

• Refer those with disabling relapse urgently

• Best treatment is IV methylprednisolone 1g daily for three days. There is evidence for benefit of 500mg oral methylprednisolone for three days, but this is extremely difficult to obtain at short notice in the community. Standard oral prednisolone is not effective.

Diagnosis

A neurologist makes the diagnosis of MS based on revised versions of the McDonald criteria.⁶ Revisions to the guidelines allow for RRMS to be diagnosed following the first attack, using MRI features to prove dissemination in time or space. 

Breaking the news of MS to a patient is life-changing. The diagnosis should be firm before broaching the subject, and the patient should be accompanied by a friend or relative. It is often advisable to have two meetings, one to break the news and a second to discuss the details of disease-modifying therapy (DMT). The neurology or MS clinical nurse specialist will provide initial support. 

The burgeoning choice of treatments, and emphasis on earlier treatment, can prove bewildering for the newly-diagnosed patient. It is essential to emphasise that the overall prognosis for MS is better than one might fear. 

The chances of a patient with newly diagnosed RRMS remaining ambulant without a stick after 20 years are over 70%. However, building hope must be carefully balanced against the need for the patient to understand the benefits of DMTs, and attendant side-effects, particularly in those with early active disease. Striking the right balance is important. 

DMTs for relapsing forms of multiple sclerosis

DMTs are recommended for the majority of patients with RRMS. They are broadly divided into first-line or ‘platform’ DMTs which may be either (a) ‘the injections’ or (b) the newer ‘orals’. Second-line DMTs are usually hospital-administered infusions, such as natalizumab and alemtuzumab. 

DMTs are certain to reduce the frequency of MS relapses, but their effect on long-term progression has been less clear. Twenty years from their introduction, there is now finally epidemiological and phase IV evidence of reduced long-term disability also.

The modern MS narrative emphasises that elimination of relapses in the early years will reduce risk for secondary progression later. The acute MS plaque in a neural pathway is akin to a tree that has fallen on a railway track. After a few weeks, the relapse will settle and the trains can run again. However, the event has caused microfractures in the rails, and routes that were to last another 60 years are now set to degenerate after 20.

Therapeutic goals have shifted to ‘treating to target’, aiming for ‘no evident disease activity’⁷ (NEDA), defined as:

• No clinical relapses

• No progression of fixed impairments on clinical exam

• No new MRI T2 lesions 

• No MRI gadolinium-enhancing lesions.

No available DMT can actually achieve NEDA in all cases, but it is a useful construct to prompt escalation where needed.

The injections

‘The injections’ refers to interferons and glatiramer acetate, indicated for RRMS first-line. There is a range of options available, self-administered between daily and every two weeks, and ranging between subcutaneous and intramuscular. The injections are broadly equivalent in terms of efficacy, leading to approximately 30% reduction in annualised relapse rate (ARR), ie. preventing one in three relapses. 

Most products are accompanied by ergonomically designed injection pens, specific support nurses and clever reminder apps. Injections have a long safety record, good tolerance, lack of significant teratogenicity and lack of opportunistic infections. The most common side-effect for interferons is flu-like symptoms in the hours following injection; this can usually be ameliorated by taking paracetamol or an NSAID before the dose.

The orals

Three oral DMTs for MS are now in use: fingolimod, dimethyl fumarate (DMF) and teriflunomide. Broadly speaking, these are oral alternatives to the injections, again indicated first-line and with broadly similar efficacy. Fingolimod has perhaps higher efficacy (~50% reduction ARR) and is labelled for early active disease and as second-line. 

Oral medicines offer greater convenience. GI tolerability and facial flushing are common side-effects with DMF and teriflunomide. Sometimes a snack, eg. a banana, with the tablet can help. 

Patients on oral DMTs should avoid pregnancy. Teriflunomide is labelled as potentially teratogenic and must be washed out urgently in the setting of unexpected pregnancy. To date, the oral DMTs are associated with lower rates of opportunistic infection when compared to infusions, although PML has occurred with fingolimod and DMF at a rate below 1:10,000.

The infusions

The infusions achieve a 60% to 80% reduction in relapses, but carry more significant risks. The infusions are thus reserved for highly active cases, either ab initio or after failure to achieve NEDA. Here, the severe consequences of debilitating MS outstrip the hazards. Natalizumab and alemtuzumab are in use in Ireland, while it is expected that beta cell depleting infusions such as ocrelizumab will gain regulatory approval in the near future. There is excellent day-to-day tolerability. 

Again, patients should take precautions not to become pregnant while taking infusions, although therapy can be paused for planned pregnancies. Close monitoring is mandatory for these agents.

Special mention should be made of natalizumab, which is administered IV once per month. The main long-term risk is for PML (progressive multifocal leukoencephalopathy), a devastating brain infection due to the JC virus in the immunodeficient, and associated with blindness, dementia and 20% mortality. 

About half of the general population is JC-seropositive. MS patients who are JC-seronegative have < 1/10,000 risk for PML when treated with natalizumab, whereas JC seropositive individuals have a risk for PML as high as one in 100 after four years of therapy. 

Alemtuzumab is administered IV on five consecutive days in year one and three consecutive days in year two. It is remission-inducing in 80% of those treated, sustained out to five years. It carries risks for autoimmune thyroid disease in one-third and a 1% rate of idiopathic thrombocytopaenic purpura. Close vigilance is mandatory for five years. 

References on request