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Cognition and mental health

MS and bipolar disorder: understanding the link

The association between multiple sclerosis (MS) and depression is well-established. Are people with MS also at risk of developing bipolar disorder?

Key points

  • Bipolar disorder is significantly more common in people with MS than in the general population.
  • This is not merely a byproduct of the stress of chronic illness; it also has to do with changes in the brain, caused by MS, that affect mood as well as physical function.
  • Mood symptoms may be caused by MS lesions, disease-related inflammation, or medications (steroids in particular).
  • Differentiating ‘primary’ (organic) mania from ‘secondary’ (MS-related) mania is crucial to ensure the correct diagnosis and treatment.
  • Key features that distinguish MS-related mania from organic mania include:
    • Late onset, often after age 35–40 years, or onset associated with MS disease progression
    • Weak or absent family history of bipolar disorder
    • Lack of response to standard treatments for bipolar disorder
  • Treatment for people with MS who experience bipolar disorder is available and effective. With coordinated care, they can successfully manage their symptoms.

MS affects movement, sensation and other bodily functions, but it also impacts the brain systems involved in thinking, emotions and behaviour. Here, I discuss the relationship between MS and bipolar disorder, a mental health condition that causes episodes of unusually high mood (mania or hypomania) and low mood (depression). Bipolar disorder has received less attention than depression in people with MS, despite its substantial effect on quality of life, treatment adherence and prognosis.

For some people with MS, symptoms of bipolar disorder appear for the first time as their disease develops. In others, existing mood symptoms may be made worse by inflammation, brain lesions or medications used to treat MS. This article explains why bipolar symptoms occur in MS, how they may present, how they can be recognised early and how they can be effectively managed.

How common is bipolar disorder in MS?

Research consistently shows that bipolar disorder is more common in people with MS than in the general population. In the general population, bipolar disorder affects roughly 1–2.4% of people. In MS, studies report current and lifetime prevalence rates of about 3% and 8%, respectively. This means people with MS have approximately double or even treble the usual risk.

Importantly, this increased risk is not simply because people with MS interact with healthcare systems more frequently than the general population, which increases the likelihood of mental health conditions being detected (we call this the ‘admission rate’ bias). Nor is it merely a byproduct of the stress of chronic illness (which might explain depression). Large studies that compare people with MS to similar individuals without MS still show a higher rate of bipolar disorder in the MS group. This suggests the association is real and probably related to changes in the brain caused by MS.

What factors cause MS-related mania?

Researchers believe there are three main mechanisms that drive cognitive and behavioural changes in MS; they can occur alone or together.

  • MS lesions that affect mood-regulating circuits
  • inflammation and immune changes
  • treatment-related factors.

Understanding these mechanisms allows clinicians to distinguish MS-related mania from ‘primary’ (organic) psychiatric illness and to deliver appropriate management.

MS lesions that affect mood-regulating circuits

This mechanism disrupts the ‘hardware’ that controls mood. MS causes inflammation and lesions (scarring) in the brain. Areas that are especially important for controlling emotions and behaviour include:

  • the right orbitofrontal cortex (OFC) – involved in regulating social behaviour, judgement and impulse control
  • the temporal lobes – important for memory and emotional processing
  • the white-matter pathways that connect these regions with deeper emotional and reward centres such as the amygdala and thalamus.

If MS lesions interfere with these circuits, the balance between emotional impulses and rational control can be disrupted. This may lead to behaviours that are characteristic of mania, including disinhibition (reduced ‘internal brakes’), uncontrolled emotions, euphoria (unusually elevated mood) and impulsivity. This pattern is sometimes called secondary mania (mania caused directly by a brain condition such as MS).

There is evidence that right-sided frontal or temporal injury leads to mania-like behaviours in other conditions (e.g. stroke, traumatic brain injury, tumours).

Understanding right- and left-sided brain functions

Consistent with literature on secondary mania from stroke or tumours, MS-associated mania is most often associated with right-sided brain lesions. The right hemisphere is dominant for processing negative emotions and withdrawal behaviours, while the left hemisphere processes positive emotions and approach behaviours. A lesion in the right hemisphere may impair the processing of negative emotions, leading to an unopposed ‘positive’ or euphoric affect (‘highs’) driven by the intact left hemisphere.

Inflammation and immune changes

During MS relapses or periods of immune activation, inflammatory molecules disrupt how brain cells communicate (think of it as a disruption to the brain’s ‘software’). One important system involved is the kynurenine pathway, which controls how the body uses tryptophan (an amino acid essential for the creation of compounds such as serotonin and melatonin).

Inflammation increases the activity of an enzyme called indoleamine 2,3-dioxygenase. This shifts tryptophan away from serotonin production towards production of quinolinic acid, a substance that overly stimulates nerve cells through NMDA receptors (N-methyl-D-aspartate receptors). This ‘excitatory overload’ can lead to symptoms like those seen in primary mania, such as agitation, mood instability, sleep disturbance and racing thoughts.

Kynurenic pathway - MS-Selfie gg1

The kynurenine pathway in inflammation-induced pathology of the central nervous system. Activation of IDO in peripheral immune cells (e.g. macrophages) or in the brain leads to production of kynurenine. This is converted to kynurenic acid in astrocytes and to quinolinic acid in microglia. Kynurenic acid can block the release of glutamate and dopamine, contributing to cognitive dysfunction. Quinolinic acid, by contrast, can increase glutamate release, which contributes to neurodegeneration. Figure modified from Haroon et al.

3-HAO, 3-hydroxy-anthranilic acid oxygenase; IDO, indoleamine-2,3-dioxygenase; KAT II, kynurenine aminotransferase II; KMO, kynurenine-3-monooxygenase; NMDA, N-methyl-D-aspartate.

This pathway is one of the clearest biochemical links between MS inflammation and bipolar-type symptoms.

Treatment-related factors

Some medications used in MS influence mood and may contribute to manic symptoms.

Steroids

High-dose intravenous methylprednisolone, typically 1000 mg/day for 3–5 days, is the most common cause of drug-induced mania in MS. Up to 12% of people treated with corticosteroids experience symptoms of mania, and nearly 65% of those with psychiatric side effects present with a mix of mania and psychosis.

A history of prior steroid-induced mood changes, female sex, older age and higher steroid doses increase risk. Steroid-induced mania typically appears 3 − 4 days after starting treatment (median 11 days in some studies) and may involve:

  • severe insomnia
  • pressured speech
  • irritability or agitation
  • grandiosity
  • psychosis in severe cases.

Symptoms usually resolve when the dose is tapered (within roughly 3 weeks), but they can persist longer in individuals with underlying bipolar disorder. I therefore try to avoid treating MS relapses with steroids. However, this is not always possible.

Other agents that may cause mania

  • Amantadine, used for fatigue, can trigger mania in susceptible individuals.
  • Modafinil and methylphenidate, also used for fatigue, have been linked to sudden switching between manic and depressive symptoms.
  • Cannabinoids may destabilise mood or cognition.
  • Interferons more commonly cause depression than mania, but irritability, aggression and mania have been reported. The risk of new psychiatric symptoms is low, and patients with stable mood disorders can usually tolerate interferons with careful monitoring.
  • Fingolimod is linked to mood changes; severe rebound inflammatory activity after discontinuation could theoretically trigger mania.

Diagnosis of MS-related mania

Distinguishing between primary bipolar disorder, secondary MS-related mania and steroid-induced mania can be difficult. Accurate diagnosis is essential for effective management, as treatment for one form may exacerbate another. Below are some of the ‘atypical’ features of MS-related mania that deviate from classic bipolar disorder.

Late onset of symptoms

Primary bipolar disorder usually begins in adolescence or early adulthood. In contrast, secondary mania associated with MS can appear later, often after age 35–40 or during disease progression. A manic or psychotic episode may sometimes be the first manifestation of MS, occurring months or years before a neurological diagnosis.

Mania coinciding with an MS relapse

A sudden change in mood, sleep or behaviour that coincides with new neurological symptoms (e.g. numbness, vision changes, weakness) may indicate that inflammation or new lesions are affecting mood circuits. There may also be evidence of disease progression from MRI scans.

Weak family history

Primary bipolar disorder often runs in families; the absence of a family history suggests a secondary cause (i.e. MS-related pathology).

Disproportionate cognitive decline

Impulse control and executive functions, such as planning, organising and paying attention, are impaired – possibly reflecting frontal lobe involvement.

Mania as an MS relapse

A minority of patients present with isolated psychiatric symptoms (mania, psychosis, delirium) as the only manifestation of a relapse. MRI often reveals new frontal or temporal lesions, even when motor or sensory signs are absent.

Lack of response to standard treatments

Failure to respond to standard mood stabilisers, or paradoxical worsening with antidepressants, warrants a re-evaluation for organic causes.

Genetic considerations

Is the risk solely environmental (inflammation/lesions), or do MS and bipolar disorder share a genetic root? The Major Histocompatibility Complex (MHC) on chromosome 6 is the primary genetic risk factor for MS (specifically the HLA-DRB1*15:01 allele). Interestingly, Genome-Wide Association Studies have suggested that the MHC region is also involved in bipolar disorder and schizophrenia.
There is some evidence that, in certain familial clusters, a gene located near the HLA locus (possibly involving the HLA-DR2 antigen) could confer susceptibility to both autoimmune demyelination and bipolar disorder. Other studies have indicated the opposite: that specific MS risk alleles in the HLA region are associated with decreased schizophrenia risk. The results are therefore mixed; some haplotypes may increase the risk of severe mental illness, while others appear protective against it. It is likely that environmental factors (inflammation, lesion burden) play a greater role than genetics in most cases.

Is the risk solely environmental (inflammation/lesions), or do MS and bipolar disorder share a genetic root? The Major Histocompatibility Complex (MHC) on chromosome 6 is the primary genetic risk factor for MS (specifically the HLA-DRB1*15:01 allele). Interestingly, Genome-Wide Association Studies have suggested that the MHC region is also involved in bipolar disorder and schizophrenia.

There is some evidence that, in certain familial clusters, a gene located near the HLA locus (possibly involving the HLA-DR2 antigen) could confer susceptibility to both autoimmune demyelination and bipolar disorder. Other studies have indicated the opposite: that specific MS risk alleles in the HLA region are associated with decreased schizophrenia risk. The results are therefore mixed; some haplotypes may increase the risk of severe mental illness, while others appear protective against it. It is likely that environmental factors (inflammation, lesion burden) play a greater role than genetics in most cases.

Management

Treatment of MS-related mania depends on the cause.

Steroid-induced mania

If steroids triggered the symptoms, the steroids should be tapered or discontinued if safe.
Short-term antipsychotic medications, such as quetiapine, olanzapine or risperidone, can help stabilise mania symptoms. Quetiapine has the added benefit of aiding sleep, which is commonly disrupted in people with MS. Use of low-dose benzodiazepines during the steroid course can help to reduce the insomnia that often precedes or triggers mania.

Mania caused by MS inflammation

If mania is part of an organic, MS relapse, treating the inflammation is important. High-dose steroids may then be necessary, even though they can in other circumstances cause mania.
This crucial distinction underscores the need for close coordination between neurology and psychiatry.

Mood swings

Lithium is still the gold standard mood stabiliser and is generally safe for psychiatric management in MS. The anticonvulsants valproate, lamotrigine and carbamazepine are useful alternatives in people with MS; they treat both the mania and other MS-related comorbidities, such as neuropathic pain and trigeminal neuralgia.

Managing future steroid treatment

People with a known history of bipolar disorder or steroid-induced instability may benefit from:

  • starting a low-dose mood stabiliser (e.g. lithium) before the steroid course
  • adding an antipsychotic temporarily (e.g. olanzapine)
  • using sleep support (e.g. low-dose benzodiazepines) to prevent insomnia (a common trigger for mania).

Long-term management

Any MS patient presenting with new-onset mania requires a comprehensive workup, including MRI (to check for new frontal/temporal lesions) and a review of recent medication changes, rather than a direct referral to psychiatry. Ongoing coordination between neurologists and psychiatrists is, however, essential. A neurologist might misinterpret mania as ‘euphoria’ related to frontal lobe damage (pseudobulbar affect), while a psychiatrist might miss the neurological signs of an MS relapse that is driving the mood change. Screening tools (e.g. Mood Disorder Questionnaire) may help identify individuals at higher risk but should not replace clinical judgement.

Recognising the distinguishing features of MS-related mania allows clinicians to intervene promptly, reduce misdiagnosis and optimise care. With integrated neurological and psychiatric management, most people with MS experiencing bipolar symptoms can achieve stable, effective control of their mood and maintain a high quality of life.

Reference

Haroon, E et al. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology Rev; 2011:1–26.

Cognition and mental health

Mental ill-health in MS: prevalence and causes

It is now well established that the burden of MS extends far beyond the purely neurological problems to include mental health.

Key points

  • Many patients with MS experience both anxiety and depression.
  • Other emotional and behavioural changes associated with MS include cognitive changes, apathy, inappropriate laughing and crying, euphoria, mania and bipolar disorder.
  • Physical symptoms like fatigue, sleep disturbances, concentration difficulties, numbness, tingling and dizziness may occur both in MS and in anxiety states, complicating diagnosis.
  • Unless severe anxiety symptoms are formally diagnosed as an anxiety disorder, individuals miss out on targeted treatments.
  • There is growing evidence that MS-related emotional changes are not necessarily a psychological consequence of living with a disability.
    • They may have a biological origin related to structural damage in the brain, caused by the MS disease process.
    • Brain imaging techniques that measure activity reveal how these brain networks function in real time.
  • Emotional changes sometimes occur as a side effect of medications used in the management of MS, including steroids used to treat MS relapses..

Background and introduction

Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease of the central nervous system (CNS) that is typically defined by its physical manifestations, such as motor weakness, sensory disturbances and fatigue. However, the burden of MS extends far beyond the purely neurological problems to include cognitive changes and mental health disorders such as anxiety, depression, apathy, mania and uncontrolled laughter and crying.

Anxiety and depression in people with MS

Among the most prevalent mental health problems in MS is anxiety, a condition that for many years was overshadowed by the clinical and research focus on depression. Anxiety is not a secondary issue but a core component of the disease experience for many people with MS. Anxiety and depression in MS are closely related, with many patients experiencing both simultaneously. Indeed, the presence of depression in people with MS is a strong predictor of the future development of anxiety, and vice versa. Both conditions share common underlying psychological risk factors such as avoidant coping styles and low optimism as well as unhealthy behaviours like smoking or lack of exercise.

Many large-scale studies have shown that anxiety is more prevalent in the MS population than in the general population. Two meta-analyses published in 2017 and 2023 assessed more than 50 published studies; based on pooled results, they estimated that 22% and 36%, respectively, of people with MS experienced anxiety.1,2 The prevalence rates for depressive disorders in people with MS are about 20−30%. Further research, utilising the UK MS Register, suggests that more than half (54%) of the 4000 patients recorded in the database have experienced clinically significant anxiety and 47% have experienced depression.3

MH anxiety

The proportions of people with different levels of anxiety (normal, mild, moderate or severe) and who have a depression score of 8 or above (N = 1961). Data from UK MS Register.3

MH depression

The proportions of people with different levels of depression (normal, mild, moderate or severe) and who have an anxiety score of 8 or above (N = 2268).  Data from UK MS Register.3

By contrast, the lifetime prevalence of any anxiety disorder in the general population in the USA is around 29% (though the prevalence at a specific point in time is lower). Anxiety is also significantly more prevalent in MS than in many other chronic neurological conditions, suggesting a relationship that may be specific to the pathophysiology or lived experience of MS.

Psychiatric symptoms versus psychiatric disorders

A critical nuance in understanding the epidemiology of anxiety in MS lies in the distinction between clinically significant anxiety symptoms and formally diagnosed anxiety disorders. The two are related but not interchangeable, and the disparity between their prevalence rates reveals a crucial aspect of the clinical challenge. The 2017 meta-analysis that found a 22% prevalence for anxiety disorders also found a substantially higher (34%) prevalence of clinically significant anxiety symptoms. This discrepancy indicates that for every ten patients who meet the formal diagnostic criteria for a specific anxiety disorder, such as generalised anxiety disorder (GAD) or panic disorder, there are approximately 15 patients who experience a level of anxiety that is severe enough to cause distress and impair functioning but is not formally identified and diagnosed in a clinical setting. The result is that these individuals miss out on targeted interventions such as specific psychotherapies or drug treatment that they might otherwise receive.

This large population of symptomatic but undiagnosed individuals may exist for several reasons. First, there is considerable symptom overlap between anxiety and MS itself. Physical symptoms like fatigue, sleep disturbances, concentration difficulties, numbness, tingling and dizziness can be manifestations of either MS or an anxiety state, creating a diagnostic challenge for clinicians and confusion for people with MS. Second, both patients and clinicians may view anxiety as an ’understandable’ or ’normal’ psychological reaction to living with a chronic, unpredictable illness, rather than as a distinct, treatable clinical entity. Finally, the historical research emphasis on depression may have led to less routine screening for anxiety in clinical practice. As an MSologist, it is also essential to differentiate formal depressive disorders from clinically significant depressive symptoms, which are much commoner than disorders.

Among those who do meet the criteria for a formal disorder, GAD appears to be the most prevalent, followed by panic disorder and obsessive-compulsive disorder. Recognising the full spectrum of anxiety, from subclinical symptoms to formal disorders, is essential for developing effective screening protocols and ensuring that all people with MS experiencing anxiety receive appropriate care (see article on management of mental ill-health in MS).

Other emotional and behavioural changes

MS impairs neuropsychiatric function (the interplay between neurological and psychological functioning) in a similar manner to its effects on other neurological functions. Living with MS can result in personality changes and subsequent relationship problems.

Cognitive changes

Cognitive impairment (i.e. dysfunction), particularly slowed information processing speed, is a common, well-documented and debilitating feature of MS. Anxiety has a demonstrably detrimental effect on cognitive domains that are often already compromised in MS, such as attention and executive functions.

Apathy

Apathy, characterised by profound loss of interest, blunted affect and reduced motivation, is also common in MS, particularly advanced MS. It is often misdiagnosed as depression. Apathy is not merely a component of low mood but is linked to executive dysfunction. Predictors identified include depressive symptoms, poor global quality of life, and poor attention and information processing speeds, probably due to MS lesions in the frontal lobe.

Inappropriate laughing and crying

Pathological laughing and crying, also known as pseudobulbar affect (PBA), are common but under-recognised and undertreated symptoms of MS that can be highly distressing and embarrassing for the patient and their relatives. The sudden, involuntary and explosive expressions of laughter or crying characteristic of PBA are often disproportionate or unrelated to the individual’s underlying emotional state.PBA is also associated with cognitive and mood problems, though the sudden and disproportionate emotional reactivity differentiates it from depression. The clinical presentation is due to frontal lobe or brainstem damage resulting from MS, which disrupts motor control pathways for emotional expression.  

Rare affective changes

Euphoria and mania are relatively uncommon in people with MS but are often triggered by high-dose steroids used to treat MS relapses.

Bipolar disorder is significantly more common in people with MS than in the general population; please see the separate post/chapter on this. The diagnosis must be made and treated by psychiatrists and involves lifelong therapy. 

The biological basis of mental illness in MS

MS-related emotional and mood changes are not necessarily a consequence of disability; they are often intrinsic to the MS disease process. This was recognised by the French neurologist Charcot, who, in 1877, noted pathological laughing, weeping, euphoria and depression in his patients who had MS.

Anxiety as a manifestation of MS pathology

While the psychological stress of living with a chronic illness contributes to anxiety in MS, there is growing evidence that anxiety is not solely a reactive or psychological phenomenon. The same autoimmune attack that damages myelin and axons, leading to physical disability, also targets and disrupts the complex neural circuits responsible for mood regulation, threat perception and emotional processing. 

Neuroinflammation and demyelination (damage to nerve insulation) are directly implicated in the development of anxiety and other psychiatric disorders. MS lesions are not confined to areas of the brain responsible for motor and sensory function but also occur within the networks that govern emotion and mood.

Structural and functional brain changes

Research has shown that people with MS can develop gradual grey matter loss in brain regions involved in emotion and motivation, particularly the limbic system and the basal ganglia. The limbic system includes the hippocampus, amygdala and cingulate cortex, and it plays a central role in processing emotions. Changes in the shape of the hippocampus have also been observed.

MH limbic system

Primary components of the limbic system. Modified from Encyclopaedia Britannica Inc.

These structural changes are thought to contribute to the development of mood and anxiety problems in MS. When MS-related inflammation, demyelination (damage to nerve insulation) or atrophy affects these areas, the brain’s ability to regulate fear and emotional responses can be disrupted. This creates a biological vulnerability to anxiety. From a structural perspective, therefore, anxiety in MS can be viewed as a direct consequence of neurological damage, in the same way that damage to the optic nerve causes visual impairment, or damage to the spinal cord leads to motor weakness.

In people with MS, depressive symptoms are consistently correlated with the volume of lesions in the brain and the degree of damage to connections between the cortex and subcortex. Neuroimaging studies show an association between depression and damage in the frontal and temporal areas of the cortex. In contrast, PBA is associated with lesions in the brainstem.

Brain imaging techniques that measure activity, such as functional MRI (fMRI), help to explain how these structural changes translate into anxiety symptoms. Rather than only showing where structural damage exists, fMRI studies reveal how brain networks function in real time. One key process identified in anxious people with MS is ‘fear overgeneralisation’. This occurs when the brain reacts to safe or neutral situations as if they were dangerous. For example, an individual learns to associate a specific signal (e.g. a picture of a circle) with a negative outcome (e.g. a mild electric shock). Anxious individuals tend to ’overgeneralise’ this fear, responding with fear to a similar but harmless signal (e.g. an oval), thus expanding their perception of danger in everyday life.

fMRI studies show that this process mainly involves the hippocampus (which is responsible for comparing incoming new experiences with ‘learned’ memories of danger) and the anterior insula (which plays a key role in generating the physical and emotional feeling of fear). In MS patients with anxiety, the physical pathways connecting these two regions are often disrupted, so that accurate information from the hippocampus is less effectively communicated to the anterior insula. As a result, the anterior insula may generate strong fear responses even when a situation is only mildly threatening or even safe.

fMRI studies have also revealed that many MS patients exhibit greater brain responses or increased recruitment of key emotional regions (e.g. prefrontal cortex and amygdala) compared to healthy controls. This likely reflects compensatory mechanisms the brain deploys to limit the clinical expression of emotional symptoms. The damaged MS brain tries to cope.

Neurological versus psychological causes

MS can trigger primary psychopathology as a result of demyelination and damage to specific functional circuits within the brain, as described above. It can be challenging to differentiate primary organic issues from reactive psychological problems, which is why people with MS may be referred for psychiatric assessments. 

I have, however, also seen patients in whom the initial symptoms were psychiatric, e.g. depression or (rarely) mania, but who were later found to have MS. The link between MS-related CNS damage and emotional symptoms is based on lesion location and lesion burden. For example, MS patients with lesions affecting the functional parts of the brain (rather than the connecting structures) exhibit a higher burden of emotional symptoms than those with lesions confined to the spinal cord. Our emotions are part of brain function in a similar way to motor function. Therefore, it is not surprising that MS impacts emotions. 

Lesion location and emotional symptoms

The evidence for a direct correlation between lesion location and anxiety is inconsistent. Some researchers suggest that, unlike depression, anxiety in MS may be driven more by psychosocial pressures and the psychological reaction to the illness rather than by focal brain damage. This discrepancy does not necessarily invalidate the biological basis of anxiety in MS. It may be that anxiety is related to more diffuse or subtle pathological changes, such as microstructural damage in white matter tracts or widespread neuroinflammation, that are not easily captured by conventional MRI lesion analysis. It is also possible that the broad distribution of the brain’s anxiety circuits means that damage to any number of different locations could produce a similar clinical outcome, making it difficult to pinpoint a single ’anxiety-causing’ lesion location. 

Other contributing factors

Emotional changes may occur as a side effect of medications used in the management of MS, including certain disease-modifying therapies. People with MS are also susceptible to the effects of the menopause, seasonal affective disorder and comorbidities associated with depression and anxiety, such as alcohol and other substance misuse disorders. It is advisable, therefore, to have a complete assessment before having a mood disorder labelled as being due to MS. 

Anxiety in MS may also be caused by high-dose corticosteroids, which are the standard treatment for MS relapses. Steroids have significant neuropsychiatric side effects, including anxiety, mania, insomnia and psychosis. For someone with MS already dealing with the stress of a relapse, the addition of steroid-induced anxiety can be particularly distressing.

‘Prodromal’ MS and psychiatric symptoms

Psychiatric comorbidities, such as anxiety and depression, have historically been viewed as consequences that follow the diagnosis of MS. Recent research, however, points to the existence of an ‘MS prodrome’, during which anxiety and depression occur years before the first classical neurological event.4 Increased rates of anxiety are a significant feature of this prodromal phase, suggesting that anxiety and/or depression may be early signs of MS, not merely a consequence. This body of recent research supports the idea that psychiatric symptoms in MS have a biological origin. This is most likely driven by the same low-level, diffuse neuroinflammatory and neurodegenerative processes that are smouldering away in the CNS long before the first eloquent MS lesion.

References

  1. Boeschoten, RE et al. Prevalence of depression and anxiety in multiple sclerosis: A systematic review and meta-analysis. J Neurol Sci 2017;372:331−341.
  2. Zhang X et al. The prevalence and risk factors of anxiety in multiple sclerosis: A systematic review and meta-analysis. Front Neurosci 2023;17:1120541.
  3. Jones KH, et al. A large-scale study of anxiety and depression in people with multiple sclerosis: a survey via the web portal of the UK MS Register. PLoS ONE 2012;7:e41910.
  4. Ruiz-Algueró, M et al. Health care use before multiple sclerosis symptom onset. JAMA Netw Open 2025;8:e2524635.
Causes and prevention of MS

What is multiple sclerosis?

This is the first of a series of basic lessons to help you understand multiple sclerosis (MS).

Key points

  • MS is an autoimmune disease in which the immune system attacks the central nervous system.
  • Its exact cause is unknown; some contributory environmental factors are outlined.
  • Common manifestations of MS include lesions, relapses and intermittent symptoms, which often worsen with fatigue.
  • Early treatment is important to help prevent the damage that occurs with MS.

Multiple sclerosis (MS) is an organ-specific autoimmune disease. Autoimmune simply means that the immune system, whose primary role is to fight infections and cancers, goes awry and attacks itself. Organ-specific means that a disease is limited to one organ. So, in the case of MS, the immune system attacks the central nervous system (CNS), which consists of the brain, spinal cord and optic nerves.

Every organ in the body has its specific autoimmune disease. For example:

  • joints: rheumatoid arthritis
  • skin: psoriasis 
  • insulin-producing cells of the pancreas: type 1 diabetes
  • intestines: inflammatory bowel disease
  • kidneys: autoimmune nephritis (interstitial or glomerulonephritis).

The cause of MS

At present, the exact cause of MS is unproven. MS is a complex disease that occurs due to the environment’s interaction with inherited or genetic factors.1 Some of the main environmental factors are:

  • low vitamin D levels or a lack of sunshine
  • smoking 
  • Epstein–Barr virus (EBV), the virus that causes infectious mononucleosis (glandular fever) 
  • obesity, particularly in adolescence.

What we don’t know is how these genetic and environmental factors interact to cause MS. There are many genetic variants that predispose someone to get MS, but only a minority of people who have these variants will get the disease. Similarly, only a minority of people exposed to environmental risk factors get the disease.

Mechanisms that underlie the common manifestations of MS

Lesions

MS is characterised by inflammatory lesions – areas of damage or scarring (sclerosis) in the CNS – that come and go. The clinical manifestations of MS depend on where these inflammatory lesions occur. If, for example, a lesion involves the optic nerve, it will cause impaired vision; if it involves the brain stem, it causes double vision, vertigo or unsteadiness of gait; a spinal cord lesion leads to loss of feeling, limb weakness or bladder and bowel problems.  

Relapses

A new MS lesion in a site that is eloquent will cause symptoms and neurological signs; if these last for at least a day, they are called an attack or a relapse. If a lesion occurs in a site not associated with overt symptoms, this is often referred to as a subclinical or asymptomatic relapse. Subclinical relapses can be detected using magnetic resonance imaging (MRI). It is said that for every clinical attack there are 10 or more sub-clinical attacks (new MRI lesions).2 

Damage frequently occurs at the site of MS lesions. The inflammation strips the myelin covering the nerve processes and may cut through axons. Axons are the nerve processes that transmit electrical impulses or signals. When the axons are stripped of their myelin sheath, and/or are cut, they can’t transmit electrical signals. This causes loss of function, which manifests with specific symptoms.

Demyelination: loss of the myelin sheath that insulates nerves, leading to disruption of electrical signals. Image courtesy of Timonina/shutterstock.com. 

Intermittent symptoms

Surviving axons that pass through the lesion are able to recover function, by synthesising and distributing so-called ion channels across the demyelinated segment or by being remyelinated. Both these processes are not perfect. For example, the new sodium channels may not function normally, so they sometimes fire spontaneously. The spontaneous firing of axons may cause positive symptoms, for example, pins and needles, pain or spasms. The new myelin is typically thinner and shorter than normal and is temperature, fatigue and stretch sensitive. 

Stretch sensitivity

If someone with MS has a lesion in their spinal cord, electric shock-like sensations may occur when they stretch the spinal cord by bending or flexing their neck; this is known as Lhermitte’s sign.  

Temperature sensitivity

Recurrent symptoms may occur when body temperature rises, for example following fever, exercise or a hot bath. The MS symptoms (which may vary among individuals) disappear when the fever resolves or the body cools down. The temperature sensitivity is often referred to as Uhtoff’s phenomenon. 

Fatigue

Symptoms tend to worsen with physical and/or mental fatigue; for example, someone with MS may begin dragging a leg or dropping their foot after 20–30 minutes of walking. This is because the transmission in the functioning nerves, which have been previously damaged, begins to fail. This failure may be related to a lack of energy and/or to temperature changes that occur with exercise. 

Worsening MS (also called progressive MS)

If the axons, or nerve processes, above and below an MS lesion die off, the surviving axons may sprout to take over the function of the axons below the lesion. This puts an unnecessary strain on the surviving axons, which makes them vulnerable to die off in the future. A reduction in the number of nerves in a neuronal system reduces the neurological reserve of that system, making it more vulnerable to future attacks. In other words, the ability to recover from future attacks is reduced, and the neuronal pathway is susceptible to delayed degeneration and premature ageing. Clearly, if no treatment is given and focal inflammatory lesions continue to come and go, this will cause worsening of the disease. If enough damage is allowed to accrue, even switching off new inflammatory lesions may not prevent the so-called delayed neurodegeneration. This is why one of the primary principles of managing MS is early treatment to prevent damage from occurring in the first place. We have also discovered that the neuronal systems with the longest nerve fibres, in particular the bladder and legs, are much more susceptible to damage. We think this is simply because the longest pathways provide the greatest scope to be hit by multiple MS lesions.

Ageing and MS

As we get older our nervous systems degenerate. If we live long enough, we will all develop age-related neurological problems, such as unsteadiness of gait, loss of memory, reduced vision, loss of hearing, and poor coordination. 

What protects people with MS from becoming disabled and developing age-related neurodegeneration are brain reserve and cognitive reserve. Brain reserve is simply the size of your brain or the number of nerve cells you have. Cognitive reserve, in comparison, relates to how well these nerves function; it is associated with your level of education and how well you enrich your life by using your brain. From about 35 years of age, our brains start to shrink. In MS, this brain shrinkage is in general much greater than normal, and the resulting reduction in brain and cognitive reserve almost certainly primes the nervous system to age earlier. This is one of the reasons why people with MS continue to develop worsening disability later in the course of their disease. This insight is one of the main reasons why we promote early effective treatment of MS to protect and maintain brain and cognitive reserves.  

References

  1. Olsson T, et al. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 2017;13:25–36.
  2. Gafson A, et al. The diagnostic criteria for multiple sclerosis: From Charcot to McDonald. Mult Scler Relat Disord 2012;1:9–14

Diagnosis

Am I sure that I have MS?

The multiple sclerosis misdiagnosis rate is around 5% and this has major implications for individuals and the treatment of MS.

Key points

  • A wrong diagnosis of MS may have financial, social and psychological consequences for the individuals concerned, affecting major life decisions.
  • Some MS treatments have life-threatening complications and should only be prescribed for people with a clear diagnosis of MS.
  • Some of the diseases that mimic MS can be made worse by disease-modifying treatments for MS.
  • Diagnostic criteria for MS have evolved and now take account of clinical, electrical, laboratory and magnetic resonance imaging findings.

A case study

She had been diagnosed with multiple sclerosis 8 years ago and had been taking interferon-beta since her diagnosis. I told her that I didn’t think she had MS and that her diagnosis was almost certainly complicated migraine with aura. The lesions on her magnetic resonance imaging (MRI) scan were non-specific white matter lesions and not inflammatory. Her neurological examination, spinal fluid analysis and evoked potentials (EPs) were normal. What clinched the non-MS diagnosis for me was the history of neurological events, which were too short-lived and migratory to be MS attacks. The final piece of the jigsaw was that a special MRI sequence showed none of her white matter lesions had a central vein, which told me that none of her white matter lesions was an MS lesion.  Her anger was palpable. She was angry because she had decided not to start a family and had changed her career because of the fear of becoming disabled in the future and not being able to work or look after a child.  This case illustrates why I always try to review the diagnosis of patients referred to me with MS and why it is important to answer this question before starting a disease-modifying therapy (DMT).   

Making a diagnosis of MS

Unfortunately, there is no single test to diagnose MS. Rather, MS is diagnosed by combining a set of clinical and MRI findings, electrical or neurophysiological investigations and laboratory tests. If these tests fulfil a set of so-called MS diagnostic criteria, the healthcare professional (HCP) or neurologist makes a diagnosis of MS. 

The underlying principles of diagnosing MS are to show the dissemination of lesions in space and time and exclude possible mimics of MS. The diagnostic criteria have evolved over time from 1) being based purely on clinical attacks,1 to 2) include electrical and spinal fluid tests as well as clinical attacks,2 and 3) to add on the use of MRI to help confirm dissemination in time and space.3–6  

Dissemination in time 

This means that two attacks or MS lesions must occur at least 30 days apart or that oligoclonal bands (OCBs) of immunoglobulins can be detected in the spinal fluid.

Dissemination in space 

This requires MS lesions to occur in different locations, for example, the optic nerve and the spinal cord. 

Electrical tests

The electrical or neurophysiological tests are called evoked potential (EPs) and test electrical conduction in a particular pathway. They can show lesions in nerve pathways that are not evident on the neurological examination or seen on MRI. The EPs can also show slow electrical conduction, which is one of the hallmarks of diseases that affect myelin, the insulation around nerves that is responsible for speeding up the electrical conduction of nerve impulses.

Laboratory tests

The laboratory tests are typically done to exclude other diseases that can mimic MS. Examining the spinal fluid for the presence of OCBs is useful in helping to make an MS diagnosis. OCBs are the fingerprint of a specific type of immune activation within the central nervous system (CNS). The OCB fingerprint is relatively specific for the diagnosis of MS in the correct clinical context. (OCBs are also found in CNS infections and other autoimmune diseases, but these are relatively easy to differentiate from MS.)

Please be aware that you may have MS according to the latest diagnostic criteria when you could not be diagnosed with MS using past criteria.

Why is a correct diagnosis important?

Neurologists get the diagnosis wrong in approximately 5% of people with MS. In other words, one in 20 people who have a diagnosis of MS in life does not have MS when their brain is studied post mortem. This data is based on a large study in a region of Denmark.7 More recently, a study from a specialist MS centre in the United States reported a misdiagnosis rate of approximately 15% in patients with presumed MS referred to their centre for treatment.8 

Why is getting the diagnosis of MS correct so important? Firstly, some MS treatments have life-threatening complications; you don’t want to expose people without MS to these complications. More concerning is that some of the diseases that mimic MS can be made worse by MS DMTs. Finally, a diagnosis of MS has many psychological, social, financial and economic implications. Even if you turn out to have ‘benign disease’, just having a diagnosis of MS, has implications for your life choices and may impact your ability to get insurance cover, to name obvious examples. I, therefore, advise you to make sure you have MS and not an MS mimic.

Common MS mimics

References

  1. Schumacher GA, et al. Problems of experimental trials of therapy in multiple sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci 1965;122:552–68.
  2. Poser CM, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227–31.
  3. McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
  4. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6.
  5. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.
  6. Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 2018;17:162–73.
  7. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand 1988;78:39–44.
  8. Kaisey M, et al. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 2019;30:51–6.
DMTs, Treatment strategy

Am I eligible for an MS disease-modifying therapy?

Key points

Do you know the eligibility criteria for MS disease-modifying therapies? And who decides what drugs can be prescribed for your MS?

  • Disease-modifying treatments (DMTs) change the long-term trajectory of MS and protect the central nervous system from further damage.
  • Regulators such as the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) decide in which group(s) of patients a particular drug can be used, based on the results of clinical trials.
  • Once a drug has been licensed in your region, local payers decide whether to make it available within your country, based on cost-effective assessments.
  • If you have active MS, your level of disease activity, its severity and speed of development will determine which DMTs you can be offered.
  • In some countries, ocrelizumab has been approved for the treatment of active primary progressive MS (PPMS) and siponimod has been approved for the treatment of active secondary progressive MS.
  • Protecting upper limb function has been a neglected area; studies are now ongoing, however, with a view to finding DMTs that limit the progression of upper limb disability.

What do disease-modifying drugs do?

Disease-modifying therapies (DMTs) are treatments that change the natural history – that is, the long-term trajectory – of the disease. They reduce the rate of disability worsening and so protect the end-organ (in the case of MS, this is the central nervous system). To simplify, let’s say that a person with MS on no treatment may manage for an average of 18-20 years before needing to use a walking stick (corresponding to Expanded Disability Status Scale [EDSS] 6.0), while someone on treatment might manage without aid for 24 years, i.e. a 4-6-year delay, then the treatment can be called disease-modifying. (Please note, the treatment effect or 4-6-year delay in reaching EDSS 6.0 is an average and some people with MS will do better than others. Conversely, some will do worse than average.) 

Is interferon a DMT?

In the early days of interferon therapy, there was debate about whether simply reducing the relapse rate by 30% relative to placebo treatment, without slowing down the worsening of the disease over 2 years, was disease-modification. However, subsequent trials and follow-up of people with MS treated with interferon-beta showed a slowing down of disease worsening, delays in developing secondary progressive MS and a favourable impact on survival.1 

Do symptomatic treatments modify the disease?

Symptomatic treatments improve the symptoms associated with MS without affecting the natural history. Treatments are classified as symptomatic in relation to their mode of action; but some classes of treatment may yet prove to be disease-modifying. For example, we often use sodium channel blocking agents, such as phenytoin, carbamazepine, oxcarbazepine and lamotrigine, for MS-related neuralgia and other pain syndromes. However, there is evidence that this class of therapy may be neuroprotective and hence disease-modifying. 

Who decides on eligibility for a licensed DMT?

Regulators decide in which group of people with MS the DMT can be used, and they grant a licence for its use. Regulators include the EMA, the FDA and the Medicines and Healthcare products Regulatory Agency (MHRA in the UK).

Payers hold the purse strings and decide which licensed drugs to make available. They makecost-effectiveness assessments to try and optimise the use of the drug in clinical practice. Payers include medical insurance companies and the NHS in the UK. 

Guidelines are formulated to help healthcare professionals use DMTs in the most appropriate way within a particular healthcare system. Guidelines often go much further than the regulators and payers, in that they try to address potential ambiguities in the prescribing of DMTs. National, regional or local guidelines that provide expert clinical guidance include the UK NICE (National Institute for Health and Care Excellence) MS management guidelines and the Association of British Neurologists guidelines. 

In the NHS in England, we must abide by NHS England’s algorithm that is predominantly based on NICE technology appraisals, NICE standards of care and the Association of British Neurologists guidelines. To navigate the specifics of the eligibility criteria is quite complex. However, a simpler way of looking at this is to start by defining how active your MS is. 

How does disease activity affect my treatment options?

To be eligible for DMTs, you must have active MS. A summary of the four categories of disease activity is given below. Further details can be found in the section entitled Do I have active MS?

  1. Inactive MS – you are not currently eligible for DMTs.
  2. Active MS – you should be eligible for a so-called platform therapy (interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate or ponesimod) and ocrelizumab or ofatumumab.
  3. Highly active MS – you are eligible for all therapies except natalizumab. Please note in England fingolimod can only be used as a second-line therapy (after another DMT has failed).
  4. Rapidly evolving severe MS – you should be eligible for all DMTs.

Advanced or progressive MS

Ocrelizumab and siponimod are now approved in several countries for the treatment of active PPMS and active SPMS, respectively. A classification of active PPMS requires recent MRI evidence of disease activity, that is, the formation of new T2 lesions and/or the presence of gadolinium-enhancing lesions in the last 3 years. Active SPMS is confirmed by the occurrence of superimposed relapses and/or the presence of new T2 lesions and/or gadolinium-enhancing lesions in the last 2 years. Based on these very narrow definitions, most patients with PPMS and SPMS will not be eligible for ocrelizumab or siponimod, respectively. The differences between the MRI criteria for active PPMS and active SPMS reflect the reality that people with PPMS are less likely to be having regular monitoring MRI scans.

Stages of MS currently not eligible for treatment

In the UK, people with MS who are wheelchair users are not eligible for DMTs. The reason for this is that patients with more advanced MS have generally been excluded from phase 3 clinical trials; hence there are no data to show whether licensed DMTs are effective in this group.

There is a long-held view that inflammation is reduced or absent in advanced MS. However, clinical, imaging and pathological data show that inflammation still plays a large, and possibly a major, role in advanced MS. Therefore, not targeting more advanced MS with an anti-inflammatory is counterintuitive.

The importance of upper limb function

In 2016, the #ThinkHand campaign was launched to raise awareness of the importance of hand and arm function in people with MS and the need for clinical trials in this population. Studies currently ongoing that focus on limiting upper limb disability progression include ChariotMS (oral cladribine)2 in people with advanced MS (UK only) and the global, multicentre O’HAND trial  (ocrelizumab)3 in participants with PPMS. 

Once someone with MS becomes a wheelchair user, they still have neuronal systems that are potentially modifiable – for example, upper limb, bulbar (speech and swallowing), cognition and visual function. There is an extensive evidence base showing that several licensed DMTs can slow the worsening of upper limb function despite subjects having advanced MS. Now that ocrelizumab and siponimod have been licensed for active primary and secondary progressive MS, respectively, these DMTs may form the platform for future add-on trials. 

References

  1. Goodin DS, et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012;78:1315 ̶ 22.
  2. National Institute for Health and Care Research (NIHR). MS clinical trial to focus on people who can’t walk. November 2020. Available at https://www.nihr.ac.uk/news/ms-clinical-trial-to-focus-on-people-who-cant-walk/26227 (accessed June 2022).
  3. US National Library of Medicine. A Study to Evaluate the Efficacy and Safety of Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis (O’HAND). First posted July 2019. Available at https://clinicaltrials.gov/ct2/show/NCT04035005 (accessed June 2022).
Brain health and holistic management of MS, Treatment strategy

What are the consequences of not treating MS?

Are there valid reasons not to treat MS with a disease-modifying therapy? What are the consequences of not treating MS? Is watchful waiting justified?

Key points

  • Untreated MS will, given time, result in physical disability, impaired quality of life and ‘hidden’ problems such as cognitive impairment, anxiety and depression.
  • Brain atrophy, or shrinkage, occurs at a faster rate in people with MS than in healthy individuals.
  • Optic neuritis, inflammation or destruction of nerve fibres in the brain and spinal cord, and extensive damage to the cerebral cortex (grey matter) are some consequences of MS lesion development.
  • Quality of life impacts may include reduced mobility, relationship difficulties, increased likelihood of unemployment and memory impairment.
  • Without treatment, the life expectancy of people with MS is reduced by about 6 ̶ 8 years.
  • There are, however, several valid reasons why some people with MS prefer not to receive disease-modifying treatments.

Risks from no disease-modifying treatment

Many patients ask me what will happen to their MS if they don’t take a disease-modifying treatment (DMT) and how effective DMTs are at preventing negative outcomes. Here I try and address questions you need to ask yourself before starting a DMT.

If you are an individual with MS, predicting your disease course is difficult. However, many studies monitoring groups of people with MS show patterns in relation to the progression of the disease and its outcome, with various data sets being consistent.

Given sufficient time, most people with MS who are not treated will become disabled. Most people focus on physical disability, but MS causes many hidden problems, such as cognitive impairment, anxiety and depression.

How untreated MS can progress – headline results

The slides below summarise some of the outcomes of untreated MS; these include brain changes (atrophy), further MS lesion development, reduced health-related quality of life, long-term impact on physical and mental health and shorter life expectancy. (To enlarge an individual slide, click on the arrow at the top right.)

Brain changes
MS lesion development
Quality of life impact
Long-term outlook

DMTs have changed the landscape

It is important to note that these outcomes are from the pre-DMT era and don’t apply to populations of people with MS treated with DMTs. New real-life data indicate that DMTs, particularly high-efficacy DMTs, are preventing many of these problems. By not being on a DMT, if you have active MS, you are at risk of acquiring damage from focal inflammatory lesions. Early in the disease course, you may not be aware of this damage because of the remarkable capacity of the nervous system to compensate for damage (neurological reserve). However, once the compensatory mechanisms have been exhausted, further damage results in overt disability. It is important to regard DMTs as preventive treatments, i.e. their aim is to delay, and hopefully prevent, future disability.

Possible reasons for not receiving a DMT

Many people with MS will not be on a DMT, for a variety of reasons. The list below is probably not extensive; if you know of other reasons why someone who qualifies is not taking a DMT, please let me know.

Inactive MS

Someone with inactive MS will not be eligible for a DMT. There is no standard definition of active MS. To me, active MS is recent evidence of focal inflammatory disease activity, defined as:

  • clinical relapse(s) in the last 2 years
  • OR magnetic resonance imaging (MRI) activity in the last 12 ̶ 36 months (new or enlarging T2 lesions or T1 Gd-enhancing lesions)
  • OR a raised cerebrospinal fluid (CSF) neurofilament light chain level in the last 12 months.

Worsening disability in MS without focal inflammatory disease activity is not active disease. It can be due to damage caused by past inflammation, smouldering MS or the effects of premature ageing; anti-inflammatory DMTs can’t address this problem. We need different types of DMTs to address these mechanisms – for example, neuroprotective and/or remyelination therapies and anti-ageing therapies.

Watchful waiting

In many situations, some neurologists think someone with MS will end up having benign disease, so they are not prepared to start treatment until the patient develops some overt disability. I abhor this practice and it is one of the reasons I spend so much of my time disseminating knowledge and getting involved with health politics. Watchful waiting, in terms of treating MS, is not supported by data. The earlier and more effectively you treat MS, the better the outcome. The only situation I could condone watchful waiting in someone with active MS is when the diagnosis of MS is in question. Sometimes in neurology, time is the best diagnostician. If the person has MS, it will declare itself with further disease activity, and this would be the trigger to start a DMT.

Family planning

Trying to fall pregnant, pregnancy or breastfeeding are common reasons to interrupt or stop DMTs. Please note that most neurologists now have options to treat MS during pregnancy and while breastfeeding, so this is becoming a less common reason for not taking a DMT.

Risk aversion

Some people with MS are not prepared to take the potential risks associated with DMTs.

Personal reasons

Some people with MS don’t believe in having their MS treated, preferring to try alternative medicines and turn down traditional DMTs. If you are one of these people, I would recommend you continue to interact with your MS team and have regular monitoring of your MS (clinical, MRI, patient-related outcome measures [PROMS] and possibly CSF analyses). Then, if these alternative strategies don’t work, you will keep open the option of treatment with a ‘traditional DMT‘. Most alternative treatment strategies for MS are compatible with DMTs and hence should be viewed as complementary. Understanding the difference between complementary and alternative treatments is important. Complementary treatment strategies are part of the holistic management of MS.

Financial constraints

In some parts of the world, MS treatment is not covered by a national health service or medical insurance scheme and some people with MS simply can’t afford DMTs. Even in rich countries, people with MS who are disenfranchised don’t have access to treatment; these may include illegal immigrants, refugees and asylum seekers waiting for their applications to be processed.

Progressive or more advanced MS

In most countries, neurologists don’t initiate treatment in patients with more advanced MS. This approach is based on a lack of evidence of the effectiveness of DMTs in this population. However, we are increasingly offering ocrelizumab (for active primary progressive MS), siponimod (for active secondary progressive MS) or off-label therapies on a compassionate basis to people with more advanced MS. In addition, there is also the potential to participate in clinical trials of new treatments for more advanced MS.

Ageism

Some healthcare systems and some neurologists are reluctant to start DMTs in people with MS who are over a certain age. This is based on a lack of evidence of the effectiveness of DMTs in this population, and it is why we need to do clinical trials in older people with MS.

Comorbidities

Many people have other medical problems for which the treatment takes priority over the treatment of MS. For example, a patient of mine was diagnosed with stage four bowel cancer. After her surgery, she started an intensive period of chemotherapy during which we stopped her DMT.

References

  1. Fisher E, et al. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255–65.
  2. Barkhof F, et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256–66.
  3. Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Mult Scler 2006;12:679–87.
  4. Ziemssen T, et al. Optimizing treatment success in multiple sclerosis. J Neurol 2016;263:1053–65.
  5. Hickman SJ, et al. Detection of optic nerve atrophy following a single episode of unilateral optic neuritis by MRI using a fat-saturated short-echo fast FLAIR sequence. Neuroradiology 2001;43:123–8.
  6. Trapp BD, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278–85.
  7. Peterson JW, et al. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389–400.
  8. Orme M, et al. The effect of disease, functional status, and relapses on the utility of people with multiple sclerosis in the UK. Value Health 2007;10:54–60.
  9. Pfleger CC, et al. Social consequences of multiple sclerosis (1): early pension and temporary unemployment – a historical prospective cohort study. Mult Scler 2010;16:121–6.
  10. Kobelt G, et al. Costs and quality of life of patients with multiple sclerosis in Europe. J Neurol Neurosurg Psychiatry 2006;77:918–26.
  11. Feuillet L, et al. Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2007;13:124–7. 
  12. Confavreux C and Compston A. Chapter 4. The natural history of multiple sclerosis. In: McAlpine’s Multiple Sclerosis, Fourth Edition, 2006; 183 ̶ 272. Churchill Livingstone.
  13. Weinshenker BG et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112:133 ̶ 46.
  14. Torkildsen GN, et al. Survival and cause of death in multiple sclerosis: results from a 50-year follow-up in Western Norway. Mult Scler 2008;14:1191–8.
  15. Kingwell E, et al. Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry 2012;83:61–6.
  16. Sadovnick AD, et al. Cause of death in patients attending multiple sclerosis clinics. Neurology 1991;41:1193–6.
  17. Brenner P, et al. Multiple sclerosis and risk of attempted and completed suicide – a cohort study. Eur J Neurol 2016;23:1329–36. 

Diagnosis, Stages of MS

Do I have active MS?

Before deciding to start a disease-modifying therapy you need to know if you have active MS.

Key points

  • To qualify for a disease-modifying treatment for MS you must have active disease.
  • Active MS is characterised by relapses (new symptomatic or asymptomatic lesions); the clinical diagnosis of relapse may be supported by MRI or CSF evidence of activity.
  • Different levels of disease activity qualify for different types of DMT.
  • Diagnostic criteria for MS have evolved considerably over the past two decades; this has helped to make treatment decisions earlier and easier, both for MS neurologists and for people with MS.

To be eligible for disease-modifying therapy (DMT) you must have ‘active MS’. This term is increasingly used to refer to current or recent evidence of focal inflammatory activity, i.e. new lesions on magnetic resonance imaging (MRI) or a relapse. Inflammation damages axons, or nerve processes. When a lesion develops, the effects of inflammatory mediators can cut (transect) axons, demyelinate them or stop them from working.

By contrast, the gradual worsening of disability that occurs in people with more advanced MS (which may, or may not, occur in the presence of focal inflammatory activity) has many potential causes, only one of which is focal inflammation.

Signs of active MS

Relapses

When a new MS lesion occurs in an eloquent part of the central nervous system it causes new symptoms or exacerbates old ones – this is usually interpreted as a relapse. Relapses, by definition, last at least 24 hours in the absence of infection or fever.

Criteria for ‘active’ MS accepted by many MS health professionals. CSF, cerebrospinal fluid; NFL, neurofilament light.
*Some neurologists accept 24 months, 36 months or even more when assessing MRI activity. There is no international consensus on the gap between the baseline and new MRI scan to define active disease.

Asymptomatic lesions

Most focal MS disease activity does not cause any overt symptoms because the brain has a way of compensating for damage. For every clinical relapse, there are at least 10 or more lesions on MRI. Therefore, what we see clinically in terms of relapses is the tip of the iceberg. Even standard MRI is relatively insensitive in detecting and monitoring MS disease activity; it misses new lesions that are smaller than 3 ̶ 4 mm in size and does not detect most lesions that occur in the grey matter of the brain (cortex and deep grey matter nuclei, e.g. thalamus and basal ganglia). Therefore, MRI scans also reveal just the tip of the iceberg. This is one of the reasons we also use cerebrospinal fluid (CSF) neurofilament levels as a marker of this microscopic activity.

Disease activity levels

Inactive MS

Many people with MS experience frequent intermittent symptoms or ‘pseudorelapses’ that come on when they are tired, after exercise or have a raised body temperature from a fever, exercise, hot bath or a warm environment. These intermittent symptoms are usually quite stereotyped and last minutes to hours. They are indicative of a previously damaged pathway but do not represent a relapse or disease activity.

Active MS

Most neurologists require evidence of disease activity in the last 12 months, with some of us accepting a 24-month or 36-month window if there is no serial or regular MRI support. However, if you have had no relapses or MRI evidence of new lesions in the last 24 months, then your MS is defined as inactive. (This does not mean your MS is necessarily stable; you could have worsening disability as part of the progressive or smouldering phase of the disease.) Inactive MS needs to be monitored in case it reactivates, in which case you could become eligible for treatment.

Inactive MS - format updated 180625 SS

Schematic showing different levels of MS disease activity.
*Some neurologists accept MRI activity in the last 24 months, 36 months or even longer as a criterion for active MS.

Highly active MS and rapidly evolving severe MS

Active MS has been divided into an additional two categories that have implications for DMT prescribing (depending on where you live).

  • Highly active MS describes MS with unchanged or increased relapse rates, or ongoing severe relapses compared with the previous year, despite treatment with beta-interferon or another so-called first-line therapy. In England, patients in this subgroup are eligible for natalizumab, alemtuzumab, fingolimod and cladribine.
  • Rapidly evolving severe MS (RES) is defined as two disabling relapses and MRI evidence of activity within a 12-month period. In England, patients in this subgroup are eligible for natalizumab, alemtuzumab and cladribine.

Evolution of diagnostic criteria

In the early 2000s, disease activity was defined using clinical criteria only; you needed at least two documented relapses in the last 2 years to be eligible for DMT.1 This meant that a neurologist had to examine you to confirm abnormalities compatible with a relapse. However, many people with MS without rapid access to a neurologist would recover before being assessed, meaning that their relapses often could not be documented. This was very frustrating for someone wanting to start a DMT. If patients had MRI evidence to support recent disease activity, how could we deny them access to a DMT because they were not seen in a timely way to have their relapse documented in the clinical notes?

In 2009, the criteria for diagnosing MS incorporated MRI into the definition to allow us to treat so-called high-risk patients with CIS (clinically isolated syndromes compatible with demyelination). These criteria required patients with CIS to have nine or more T2 lesions on MRI or at least one gadolinium-enhancing lesion. These MRI criteria were based on the McDonald diagnostic criteria at the time.2 These eligibility criteria evolved further in 2014, once alemtuzumab was licensed, to include clinical or MRI activity.

References

  1. McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–7.
  2. Polman CH, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292–302.
Brain health and holistic management of MS, Causes and prevention of MS

What prognostic group do I fall into?

Having some idea of how bad your MS is, or not, will allow you to discuss important issues with your neurologist so that you can make an informed decision about your MS treatment.

Key points

  • It is hard to predict the disease course of MS accurately for an individual.
  • Population data allow us to define three broad prognostic MS categories: good, indeterminate or poor.
  • Given sufficient time, most people with MS will do badly without treatment.
  • Factors linked to poor prognosis in untreated people with MS are listed.
  • The wide use of disease-modifying therapies is changing the natural history of MS for the better.
  • Adopting a healthy lifestyle, in parallel with appropriate treatment, can help to improve outcomes.  

Predicting MS outcomes: an imperfect science

We can’t predict the prognosis of an individual person with MS very accurately. So don’t let your neurologist mislead you if he or she says you are likely to have benign MS. ‘Benign MS’ is a relative term and can only be used retrospectively once you have had MS for many years or decades. In the era before disease-modifying treatments (DMTs), most people with MS would eventually become disabled, which is why I prefer not to use the term benign MS to predict outcomes. I now use it as a treatment aim, because we want all people with MS to have benign disease.

Three broad prognostic categories

Applying population data to place an individual into a broad prognostic group is often helpful. It allows you to frame your disease in terms of potential outcomes and may help you balance the risks of some treatments against the potential impact of MS later in your life. Predicting outcomes in MS is comparable to an actuary working in the insurance industry; we try to give you an average prognosis with a wide range of possibilities or errors. For this reason, I try to keep it simple and classify people with MS into three prognostic categories: poor, indeterminate, or good. Poor in this context means that if you leave MS to its own devices and let it run its natural course, the average person in this category will do badly.

Most people with a predicted poor prognosis will do badly without treatment for their MS.

Given sufficient time, most people with MS will deteriorate without treatment. This is why I actively promote treatment based on the scientific rationale that preventing damage now will protect your brain reserve and cognitive reserve and improve your long-term outcome. This is the philosophy behind the MS Brain Health initiative and the report Brain health: time matters in multiple sclerosis,1 which everyone with MS should take time to read. 

Factors linked to poor prognosis

Below is a list of factors that have been linked to poor prognosis in people who have not received a DMT. If you have fewer than five of these factors, you are likely to have a good outcome. In comparison, people with ten or more of these factors fall into the poor prognostic group. Most people with MS fall into the intermediate (indeterminate) prognostic group, with 5–10 of these factors. Some of these baseline factors are modifiable,2,3 so you can make the effort to help improve your own prognosis. 

Please note that the factors listed here only apply to people with MS who are untreated.  It is clear that DMTs are changing the outcome of MS.

  1. Older age of onset (greater than 40 years).
  2. Male sex.
  3. Multifocal onset – more than one site in the nervous system involved with the initial attack.
  4. Efferent or effector system is affected early – that is, the motor (power), cerebellar (balance and coordination) or bladder and bowel functions.  
  5. Partial or no recovery from initial relapses – do you have residual deficits from your initial attacks?
  6. A high relapse rate in the first 2 years – that is, more than two relapses. 
  7. Early disability – an Expanded Disability Status Scale (EDSS) score > 3.0 within 5 years of symptom onset indicates a poor prognosis. You can calculate your EDSS using an online calculator (web-EDSS calculator).
  8. Abnormal magnetic resonance imaging (MRI) scan with large lesion load – more than nine T2 lesions (white blobs) on the baseline MRI.
  9. Active or enhancing lesions on your baseline (initial) MRI – enhancing lesions imply that the lesions are new and actively inflamed.
  10. Posterior fossa lesions on the MRI – these refer to lesions in the back of the brain that involve the brainstem and cerebellum.
  11. Lesions in the spinal cord on MRI.
  12. Obvious early brain atrophy on MRI – brain atrophy refers to premature shrinkage of the brain over and above what you would expect for your age. This information is unlikely to be available to you because neuroradiologists often do not measure or comment on it. 
  13. Retinal thinning on optic coherence tomography (OCT) – people with MS who have lost a lot of retinal nerve fibres do worse than people with a normal retina. Yes, the eye is truly a window into what is happening in the brain of someone with MS. 
  14. Abnormal cerebrospinal fluid – positive immunoglobulin (Ig) bands (known as oligoclonal bands, OCBs) in the spinal fluid.
  15. Raised neurofilament levels in your spinal fluid – this test may not be part of routine care at your neurology centre. Neurofilaments are proteins that are released from damaged nerve fibres, and high neurofilament levels indicate greater damage and poorer outcome than low levels.
  16. Low vitamin D levels – this is controversial, but several studies have shown that people with MS with low vitamin D levels do worse than those with higher levels. These observations do not necessarily imply that by taking vitamin D you will do better. Low vitamin D levels may be related to reverse causation, in that the MS-associated inflammation uses up vitamin D; more inflammation indicates worse MS and is therefore linked with greater depletion of vitamin D levels.
  17. Smoking – smokers with MS do worse than non-smokers. This is modifiable and it is one of many reasons why you should try and give up smoking. 
  18. Comorbidities – people with MS who are obese, have diabetes, prediabetes, hypertension or raised cholesterol do worse than people with MS without these comorbidities.4
  19. Cognitive impairment – people with MS with poor cognitive function do worse than people with MS with good cognition. You can’t really assess your own cognition at present; you need to have it tested by a neuropsychologist.

‘It won’t happen to me’

Humans have interesting psychology in that they tend to consider themselves to be the exception to the rule. Gamblers don’t enter a casino to lose; they always believe they will win. A person with lung cancer who starts chemotherapy believes they will be one of the 10% who is cured. When someone is diagnosed with MS, they believe they will be one of the 30% with benign disease. (The current view among MS neurologists is that 30% of untreated people with MS will have benign disease.) 

This definition of ‘benign MS’ is based on having no or little disability at 15 years since onset, i.e., an EDSS score of 3.0 or less (no visible disability). However, when you interrogate people with so-called benign MS you find that more than 50% of them have hidden symptoms of depression, anxiety or cognitive impairment. Can we really justify this definition of benign MS? What is more, when you follow people with benign MS past 15 years, only 15% remain benign at 25 years and 5% at 30 years. If you get to 40 years of follow-up, half of these with benign MS will become disabled over the next 10 years.

Moving towards a more favourable outcome

Many will state that these figures are now out of date and there are newer and better figures, which show MS is a more benign disease. You are right, and there are several very good reasons for this. In population-based studies, the proportion of subjects with benign MS is greater than in hospital- or clinic-based studies; for example, in the Olmsted Mayo Clinic MS population, about 45% have benign disease at 15 years. The reason for this is that people with MS with benign disease often drop out of hospital follow-up, but still show up in population-based studies. 

The earlier diagnosis of MS, that is, identification of those who would not have been diagnosed in the past, is changing the definition of MS. For example, most people with a clinically isolated syndrome (CIS) are now being diagnosed as having MS. The wide use of DMTs is beginning to change the natural history of MS for the better; making sure that people with MS adopt a healthy lifestyle is another strategy that can be done in parallel. 

With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.
With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely number of people with MS in each prognostic category.

With currently available high-efficacy DMTs and the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase. The blue areas illustrate the likely proportion of people with MS in each prognostic category.

The above figures illustrate what we aim to do with currently available high-efficacy DMTs (compared with older, lower efficacy treatments). We are simply trying to move you to the right, into a more favourable prognostic group. In other words, we want to make sure your MS is benign and that you reach old age with as healthy a brain as possible. Your brain reserve and cognitive reserve protect you from developing age-related cognitive impairment and dementia. MS reduces both of these reserves, which is why it is so important to protect them. With the prospect of effective combination treatments in the future, the proportion of people with MS who experience normal ageing is set to increase.

References

  1. Giovannoni G, et al. Brain health: time matters in multiple sclerosis. 2015, Oxford Health Policy Forum CIC.
  2. Miller DH, et al. Clinically isolated syndromes. Lancet Neurol 2012: 11:157–69.
  3. Weld-Blundell IV, et al. Lifestyle and complementary therapies in multiple sclerosis guidelines: Systematic review. Acta Neurol Scand 2022;145:379–92.
  4. Kappus N, et al. Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 2016;87:181–7.
Stages of MS

What type of MS do I have?

MS has historically been classified into different subtypes, and this subdivision dictates what treatments you are eligible for. These MS disease subtypes are not supported biologically, however, and many MS neurologists are of the opinion that MS is one disease.1

Key points

  • The difference between relapsing MS and non-relapsing progressive MS is explained.
  • The stages of MS have different labels, for historical development and reimbursement reasons, but biologically MS is one disease.
  • From a treatment perspective, the key thing is to know if your MS is active or inactive.
  • Active MS can be differentiated from inactive MS by relapses, MRI evidence of disease activity and raised neurofilament levels in the cerebrospinal fluid.

Type of MS

You should be able to classify yourself as having either relapsing MS or non-relapsing progressive MS. Knowing what type of MS has been diagnosed and whether your MS is active or inactive will allow you to ask your MS neurologist questions about the MS treatments available to you. 

Around 85–90% of people with MS start with so-called relapse-onset MS, i.e. they have a definite attack of symptoms that is usually followed by a period of complete or incomplete recovery. A single attack may be labelled as a clinically isolated syndrome (CIS): it does not fulfil the current diagnostic criteria for full-blown MS, but it means someone is at risk of further attacks and hence of developing MS in the future.

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

Once you have more attacks, either clinically in the form of relapse or subclinically with new lesions on magnetic resonance imaging (MRI), then you are usually diagnosed as having MS. The diagram below illustrates the typical course of repeated relapses and remissions, with worsening disability over time, that characterises so-called relapsing–remitting MS (RRMS).

After a variable period, people with relapse-onset MS may notice worsening neurological function without improvement. This is called secondary progressive MS (SPMS) and it can occur with superimposed relapses (so-called relapsing SPMS [RSPMS]) or without relapses.

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

A small number of people with MS (10–15%) will present with worsening neurological function without a prior history of relapses; this is called primary progressive MS (PPMS).

Interestingly, some people with PPMS go on to have relapses, and this is referred to as progressive relapsing MS (PRMS).

EDSS, Expanded Disability Status Scale score
EDSS, Expanded Disability Status Scale score

Rarely, someone may present with worsening neurological function, similar to PPMS, but have a prior history of just one relapse. This is referred to as single-attack progressive MS (SAP), but most MS specialists classify these patients as having SPMS. 

In summary …

  • Relapsing MS captures all people with MS who are still having relapses, i.e. within the last 2 years, and includes RRMS, RSPMS and PRMS.
  • Non-relapsing progressive MS refers to SPMS and PPMS: these latter two groups should have no history of recent relapses, i.e. in the last 2 years.

To further confuse things, non-relapsing progressive MS used to be referred to as chronic progressive MS (see below). 

Why is this important?

Different DMTs are licensed for different types of MS, and many treatment guidelines specifically state the type of MS for which a particular drug can be used.

Is MS one or more diseases?

In the past, MS was regarded as one disease: either you had MS, or you did not. The stages were referred to as early relapsing MS or chronic progressive MS, but MS was still one disease. 

When disease-modifying therapies (DMTs) were developed, MS was split into multiple sub-types. This categorisation was driven by commercial considerations, and it allowed interferon-beta to be licensed in the US under the Orphan Drug Act. The classification of orphan disease in the US requires there to be fewer than 200,000 people with that diagnosis. Dividing MS into RRMS, SPMS, PPMS and later CIS ensured that each category met this criterion. 

Since then, PRMS and radiologically isolated syndrome (RIS) have been added as potential subtypes. These classifications tend to be arbitrary and overlap, but there is no biological basis to support MS being more than one disease. 

Is your MS active or inactive?

From a treatment perspective, it is important to know if your disease is active or inactive. In active MS, there is evidence of ongoing inflammation in the brain and spinal cord. If you are having relapses, are developing new lesions on MRI or have raised neurofilament (NFL) levels in your cerebrospinal fluid (CSF) or blood, your MS is active. 

Active MS responds to anti-inflammatory treatments; inactive MS is less responsive to currently licensed DMTs. 

Criteria for ‘active’ MS accepted by many MS health professionals. CSF, cerebrospinal fluid; NFL, neurofilament light.
*Some neurologists accept 24 months, 36 months or even longer when assessing MRI activity. There is no international consensus on the gap between the baseline and new MRI scan to define active disease.

The term progressive MS refers to the stage of MS when your disability gets worse – independent of relapses, and possibly of focal inflammatory lesions. I say ‘possibly’, because our current MRI scans don’t show new or enlarging microscopic lesions but only those that are larger than ~3–4 mm. NFL measurements in either the CSF or blood have the advantage of being additive and integrating inflammatory activity. In my experience, about one in ten patients classified as ‘inactive’ based on clinical and MRI activity is found to have active MS when CSF NFL levels are analysed. Unfortunately, however, many MS neurologists, regulators and payers do not accept this latest definition of MS disease activity because tests for NFL levels are currently not widely available. 

In conclusion, knowing the type of MS you have and whether your disease is active or inactive will allow you to discuss with your MS specialist the kinds of treatment available to you. 

References

Giovannoni G, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord 2022;15:17562864211066751.