The classical view of MS as a disease that exclusively affects the white matter has more recently been refuted. Pathological studies and modern MRI modalities have convincingly demonstrated diffuse pathology in both the normal appearing white matter (NAWM) of the brain and spinal cord, as well as cortical demyelination affecting the grey matter in MS patients. This diffuse pathology is seen even at very early stages of disease.

MS is believed to start with activation and proliferation of autoreactive CD4+ T helper lymphocytes in the periphery. These cells then migrate across the blood brain barrier (BBB), recognise auto-antigens, and initiate inflammation via the production of pro-inflammatory cytokines. This inflammatory cascade cumulates in damage to the myelin sheath, oligodendrocytes, and axons. It is an extremely complex process involving multiple cell types, cytokines, and co-stimulatory molecules. In the progressive stage of the disease less active inflammation is observed and disability is thought to occur due to degenerative changes. Nonetheless, oligodendrocyte progenitor cells (OPCs) capable of remyelination have been observed in the white matter plaques of chronic MS patients suggesting that remyelination may be possible even in the late stages of disease. This represents an encouraging therapeutic target for treatment of progressive MS.

MS is not inherited in a Mendelian fashion and is likely to be polygenic. There is however a familial recurrence rate of about 15 %. The age-adjusted risk is higher for siblings (3 %), parents (2 %), and children (2 %) than for second degree and third-degree relatives. Recurrence in monozygotic twins is around 35 %. Linkage studies in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) has the greatest individual effect on risk. A large genome wide association study (GWAS) has recently replicated this finding and has identified at least another 29 susceptibility loci. Immunologically relevant genes are significantly overrepresented among those mapping close to these loci confirming that MS is primarily an immune mediated disease.

Migration studies, geographical variation in disease rates, and high rates of discordancy in identical twins suggest that environmental agents must play a role in the pathogenesis of MS. The role of Vitamin D status in MS has gained importance in recent years as both epidemiological and experimental data increasingly suggest that Vitamin D deficiency plays an importance role in both MS pathogenesis and disease activity. A case control study involving seven million US military personnel with stored serum found that lower risk of MS was associated with higher levels of 25-hydroxyvitamin D. This effect was interestingly seen in white people but not in black or Hispanic people. A study that included 42,0000 people found that significantly fewer people with MS are born in November and significantly more are born in May, a fact that is putatively linked to the Vitamin D status of the mother during gestation. It has been shown that Vitamin D levels are significantly lower in relapsing remitting MS patients compared to controls and are also lower in patients experiencing disease activity compared to those in remission. A recent study demonstrated that a 50-nmol/L (20-ng/mL) increment in average serum 25-hydroxyvitamin D levels within the first 12 months of disease predicted a lower relapse rate, a lower rate of T2 lesion accumulation on MRI, and a lower rate of yearly brain atrophy from months 12–60. This suggests that vitamin D deficiency is a strong predictor of future relapse activity and disease progression.

With respect to lifestyle factors only smoking has emerged as a moderate risk factor for MS. More recently childhood obesity has been highlighted as a possible risk factor for later development of MS. Over the years several transmissible agents have been implicated as possible causes of MS though to date no infectious trigger has been definitively identified. In recent times the leading candidates include Epstein-Barr virus (EBV) and Human Immunodeficiency Virus (HIV). The epidemiological data associated EBV infection with MS remains strong. We know that almost all patients with MS (>99 %) have evidence of prior EBV infection when compared to only about 90 % of controls. People who have had symptomatic EBV infection (infectious mononucleosis) are at increased risk of developing MS for up to 30 years after the original infection. In this large Danish cohort the ratio of observed: expected MS cases was 2.27. High titres of EBV antibodies predict a higher risk of MS than low titres and Hodgkin’s lymphoma, another EBV associated condition, occurs more frequently in MS patients when compared to controls. None of these facts provide proof of causation but they do suggest a role for EBV in the pathogenesis of MS.

Though both MS and HIV are widely documented in the medical literature, only one case of co-existent MS and HIV infection has been documented. The individual in question was commenced on combination anti-retroviral therapy (cART) following which their MS remained quiescent for up to 12 years of follow up. It was postulated that the anti retroviral therapy may be coincidentally treating or preventing MS or that perhaps the HIV infection itself exerted some form of biological protection. This case report prompted further enquiry into this phenomenon. A large UK linkage study investigating the possible association between MS and HIV was recently reported. The relative risk of MS in people with HIV, relative to those without HIV, was 0.38. The magnitude of this effect (>60 %) is at the highest level of any prognostic risk factor reported to date. This finding may prompt future trials of anti-retroviral therapies in MS patients.

NMO (Devic’s disease) is an inflammatory demyelinating disease of the CNS that for many years was thought to be a variant of MS but is now known to be immunologically and pathologically distinct. Clinically it presents with optic neuritis and myelitis, often with a poor recovery and a relapsing course. MR imaging typically shows longitudinally extensive cord lesions, extending over three or more vertebral segments. Brain lesions can be clinically silent and are seen in about 60 % of patients often in the diencephalon and hypothalamus. Pathologically NMO is characterised by demyelination, neuronal loss, and often pronounced necrosis. The discovery of aquaporin-4 autoantibodies in 2004 (AQP4-Ab, also known as NMO-IgG) in the serum of patients with NMO represented a considerable advance in both the diagnosis and treatment of the disease and distinguished NMO from MS as an independent disease entity. The specificity of these antibodies is between 90 and 100 % in the correct clinical context. More recently, antibodies to myelin oligodendrocyte glycoprotein (MOG) have been reported in AQP4-Ab negative cases with a typical NMO phenotype. However, the exact diagnostic implications of this finding are still under investigation.

More women than men have NMO (ratio 9:1) and the median age of onset is more than 10 years older than in MS. Moderate pleocytosis in the CSF of NMO patients is seen more commonly than in MS and OCBs are only seen in about 30 % of cases. In NMO the CSF OCB status can change over time, which is uncommon in MS. More recently high concentrations of IL-6 have been found in the CSF of NMO patients which may help in differentiating it from other demyelinating diseases. Therapy should be initiated early in NMO and the therapeutic pathway is different from that of MS. Azathioprine and Rituximab are recommended as first line agents. Other immunosuppressant agents such as methotrexate, mycophenylate mofetil, and mitoxantrone are recommended as second line agents. Promising new therapies such as anti- AQP4-Ab and anti-IL-6 receptor biologicals are emerging.

AQP4-Ab have also been demonstrated in patients with clinical syndromes atypical of NMO such as brainstem syndromes including intractable vomiting, narcolepsy, neuroendocrine disturbances, and olfactory dysfunction. The term “NMO spectrum disorders” is often used as an umbrella term for these varied presentations.

ADEM is an inflammatory demyelinating disorder that can often be considered in the differential diagnosis of an initial demyelinating event or clinically isolated syndrome (CIS). It can present with a number of clinical symptoms but usually includes encephalopathy as well as multifocal symptoms suggestive of an inflammatory disorder. ADEM differs from MS and NMO in that it is a monophasic illness that does not relapse and therefore does not require disease modifying therapy (DMT). A recent review has proposed a number of clinical, imaging, and laboratory features that are helpful in distinguishing ADEM from a first presentation of other inflammatory disorders. ADEM is seen much more commonly in the paediatric population but can also occur in adults. Unlike MS, it is often preceded by an infection or vaccination. It should be considered when there is a multifocal polysymptomatic presentation, encephalopathy, seizures, fever, headache, and bilateral optic neuritis. On CSF examination a lymphocytic pleocytosis is more commonly seen in ADEM than in MS and CSF OCBs are seen less frequently than in MS and often resolve when present in ADEM. MRI will often demonstrate large (1–2 cm) multifocal areas of T2 abnormality in the CNS white matter often with diffuse enhancement and grey matter involvement in addition. Periventricular involvement is less prominent than in MS. A brain biopsy is sometimes warranted when the diagnosis remains uncertain and the pathological hallmark of ADEM is perivenular inflammation with “sleeves of demyelination”. Intravenous methylprednisolone is the most common treatment used in practice when an infectious aetiology has been excluded, IVIG may be an effective alternative.

Diagnostic criteria for MS emphasize that that an alternative explanation for the presentation must be considered and excluded before a diagnosis of MS can be made. International consensus based guidelines have been published to guide the clinical, laboratory, and imaging assessments of patients with possible MS in order to best exclude alternative diagnoses. The differential diagnosis of MS is wide and includes diseases that can mimic both relapsing and progressive neurological disturbances. These are outlined in Table 15.2 although such lists are always selective and incomplete.

In the long-term management of MS, a number of disease modifying therapies (DMTs) are used to reduce the relapse rate and therefore reduce the amount of relapse- associated disability accumulated during the relapsing remitting phase of the illness. Several new DMTs have been developed in recent years many of which are more targeted and efficacious than their predecessors. Each of these agents have undesirable side effects and the risk benefit ratio of each therapy has to be considered for each individual patient. There is currently no DMT licensed for use in progressive MS and this remains a critical area of unmet need in MS therapeutics. In RRMS it is now recognised that there is a therapeutic “window of opportunity” during the first 5 years of the disease during which aggressive control of the inflammatory phase of the illness is of most benefit in the long term. It remains unclear to date whether early suppression of relapses and neuro-inflammation with any drug will ultimately prevent the onset of progressive disease.

The first DMTs to be licensed for use in RRMS were self administered injections given either subcutaneously or intramuscularly at a variable frequency depending on the specific agent used. The type 1 beta-interferons were the first immunomodulatory agents to be licensed for use in MS in 1993, and while they are used routinely in RRMS patients, their precise mechanism of action remains to be elucidated. There are currently five commercially available beta-interferon preparations in clinical use (see Table 15.3). Glatiramer acetate (GA, Copaxone) is a synthetic peptide composed of four amino acids designed specifically to mimic the structure of myelin basic protein (MBP). MBP is the principle component of CNS myelin and is therefore a putative autoantigen in MS. Glatiramer acetate received US Food and Drug Administration (FDA) approval for use in MS patents in 1987. All these drugs have comparable efficacy, reducing the relapse rate by about a third, reducing the number of new brain lesions in RRMS patients, and slowing but not preventing the onset of disease progression. They have all established long-term safety but are limited by injection-related skin reactions, and flu-like side effects seen with the interferon-beta preparations. A PEGylated form of interferon-beta 1a plegridy with a longer half-life and a reduced dosing frequency (once every 2 weeks) has recently received a license in RRMS.

Three oral agents have been approved for use in relapsing MS: fingolimod, teriflunomide and dimethyl-fumarate (BG-12). Efficacy data from pivotal randomised controlled trials of these agents are summarized in Table 15.4