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Cognition and mental health

Management of mental health disorders in people with MS

Emotional problems in people with MS must be recognised, addressed and treated, rather than dismissed as an inevitable consequence of living with this chronic condition.

Key points

  • An MS diagnosis naturally triggers emotions similar to the stages of grief (denial, anger, bargaining, depression, acceptance); in addition, the unpredictability of MS causes anxiety in many patients.
  • Anxiety, often combined with depression, is linked to a poorer quality of life, cognitive dysfunction, increased risk of suicide, and significant occupational and social problems.
  • Emotional problems in MS are typically exacerbated by fatigue, pain and poor sleep – all of which interfere with therapy and lifestyle adjustments.
  • Emotional changes in MS require treatment, just as physical symptoms do. This should comprise routine screening, targeted drug treatment and structured psychological and behavioural therapies.
  • Motivational coping styles that involve direct problem-solving and active participation in treatment planning (i.e. self-management) help people with MS adjust to their diagnosis.
  • Avoidance coping strategies generally lead to poorer psychological outcomes.
  • The presence of social support is a critical protective factor.

Impact of emotional changes

Emotional disorders have an adverse effect in people with MS, potentially impairing their ability to cope with disability and reducing overall health-related quality of life. Living with MS can also adversely affect relationships, for complex reasons, including both emotional and physical problems associated with the disease. Therefore, such symptoms must be recognised, addressed and treated, rather than dismissed as an inevitable or acceptable consequence of living with a chronic condition such as MS.

Emotional disturbances in people with MS may be reactive, i.e. a natural, adaptive psychological response to being diagnosed with a long-term, unpredictable and potentially disabling disease. Common emotions include grief, sadness, worry, fear, irritability and moodiness. Elisabeth Kübler-Ross in 1969 described five common stages of grief, best known by the acronym DABDA. We have added an extra A, for Anxiety about the future, to include the emotional reaction to a diagnosis of MS. The expands the mnemonic to six stages: DABDAA.

Denial, Anger, Bargaining, Depression, Acceptance, Anxiety

These emotional stages are considered ‘normal’ and an understandable coping mechanism. As with grieving, if they are prolonged, dominant and impact your social and occupational functioning, they are considered abnormal and require intervention. Remaining angry, resentful and depressed for decades will negatively impact your functioning. 

Anxiety and depression in MS

Anxiety affects people with MS with a frequency often matching or exceeding that of depression. The highest prevalence of anxiety is observed in people with MS with low physical disability, defined by an Expanded Disability Status Scale (EDSS) score of less than 3.0. This finding suggests that anxiety is driven less by accumulated physical deficit than by the psychological factors of worry, fear and the inherent unpredictability of MS.

Maladaptive coping strategies are strongly associated with an increased risk of developing mood symptoms. A tendency to use avoidance coping – disengaging from problems rather than confronting them – is a significant predictor of poorer psychological outcomes. Similarly, psychological traits such as low optimism or a less positive attitude can heighten the risk of anxiety.

For a significant subset of patients, MS may first present not to a neurologist, but to a primary care physician, a therapist or a psychiatrist, with symptoms of anxiety or depression. Because the symptoms are psychiatric, the underlying neurological cause is not yet suspected.

Quality of life and daily functioning

Anxiety is a major contributor to the overall disease burden of MS, affecting nearly every aspect of life. Studies show that anxiety, often combined with depression, is linked to a poorer quality of life, cognitive dysfunction, increased risk of suicide, and significant occupational and social problems.

The impact of anxiety on many of the most challenging symptoms of MS – notably fatigue, pain and sleep problems – may be greater even than the effect of depression.  MS symptoms can trigger or worsen anxiety, and the resulting anxiety intensifies the perception and severity of those same symptoms, thus creating a negative feedback loop.

Damaging health behaviours linked to undiagnosed and untreated anxiety can further compromise a patient’s well-being. For example, alcohol and substance abuse, as well as smoking, not only have their own intrinsic health risks but can also interfere with MS management and adherence to treatment. 

Anxiety as a reaction to living with MS

The direct impact of the disease on the brain’s emotional circuits occurs in parallel with the profound psychological and existential challenges of living with MS. Even in the absence of any direct neurological damage to mood-regulating centres, the lived experience of MS itself provides rationale for the development of severe anxiety. 

The unpredictability of the disease and the constant knowledge that a relapse could occur at any time, potentially worsening MS symptoms and existing function, create a state of chronic hypervigilance and worry. This pervasive sense of a loss of control over one’s own body and life is a catalyst for anxiety. Anxiety creates a vicious, self-perpetuating cycle where the physical and psychiatric symptoms mutually reinforce one another.

Anxiety cycle

Multiple stressors

Beyond this overarching uncertainty, living with MS entails a host of stressors.

  • Diagnosis. The diagnostic journey is a period of intense anxiety, often involving a prolonged period of uncertainty as symptoms are investigated. Once diagnosed, patients face a continuous process of adjusting and readjusting to changing abilities.
  • Hidden problems. The invisibility of some of the most burdensome symptoms, such as debilitating fatigue, cognitive fog, or sensory disturbances, can lead to a profound sense of feeling misunderstood, isolated and frustrated.
  • Visible symptoms. Conversely, the emergence of visible symptoms, like a limp or the need for a mobility aid, can bring its own anxieties related to stigma and self-image.
  • Daily life. Financial concerns related to healthcare costs, employment and the ability to continue working, as well as the impact of MS on relationships and potential parenting, may further increase anxiety. 

Existential threat

Profound existential and symbolic threats to a person’s sense of self can further exacerbate anxiety. The sense of loss triggered by a diagnosis of MS – loss of a healthy body, a previously held future and a former identity – is followed by changes in fundamental life roles. This can lead to feelings of inadequacy, guilt and a crisis of identity – perceived as a threat to one’s core self. The constant need to adapt to new limitations can feel like a continuous erosion of the self, and the fear of future disability becomes a fear of further loss of identity.

Addressing this existential dimension of anxiety is crucial for promoting long-term psychological adjustment and overall well-being. Treatment often involves helping individuals grieve their losses, redefine their sense of self and purpose within the context of their illness, and find new sources of meaning and value in their lives. 

Cognitive impairment

The impact of anxiety on cognitive function is well documented. Cognitive impairment, particularly slowed information processing speed, is a common and debilitating feature of MS. Anxiety has a detrimental effect on cognitive domains that are already compromised, such as attention and executive functions. It does this by increasing an individual’s awareness of task-irrelevant, often threat-related, stimuli, which interferes with the goal-oriented cognitive processing required for the task at hand. Thus, the underlying cognitive deficit from MS is compounded by the cognitive interference from anxiety, leading to a greater overall level of impairment than either condition would cause alone. Importantly, therefore, treating a patient’s anxiety can lead to measurable improvements in their cognitive functioning. 

Mood, fatigue, pain and sleep – a vicious cycle

Emotional problems rarely occur in isolation in MS; they are typically part of a clinical syndrome including fatigue, pain and poor sleep. This interconnected symptom cluster reduces health-related quality of life and establishes significant barriers to therapy and lifestyle modification.

Fatigue

Fatigue is one of the most common and disabling symptoms of MS, and it is strongly and consistently correlated with anxiety. This is not a simple correlation but a predictive relationship. Higher levels of anxiety at one point in time can predict the severity of fatigue at a later date. Conversely, higher levels of fatigue can predict the later development or worsening of anxiety.

The severity of depression in highly fatigued people with MS also makes the management of fatigue a high priority in reducing the overall psychiatric burden and allowing patients to engage in psychological interventions such as cognitive behavioural therapy (CBT).

Pain and emotional distress

A two-way relationship also exists between pain and anxiety, where anxiety is associated with higher reported pain intensity and greater interference of pain with daily activities.  The pain symptoms cause distress and anxiety, and the physical and mental state of anxiety (e.g. muscle tension, worry, poor sleep) in turn exacerbates the symptoms. Moderate or severe intensity pain that interferes with work, household activities or enjoyment of life affects about one-third of people with MS.

Sleep

Sleep is probably the most neglected MS-related problem in routine clinical practice; most people with MS have a sleep disorder. Depression, anxiety, pain and many other MS-related symptoms affect sleep quality. Therefore, it is challenging to manage MS-related emotional disorders without addressing sleep quality.

Lifestyle management and adherence

The cyclical nature of this grouping of mood disorder, fatigue, pain and poor sleep creates barriers to effective management. Emotional distress and physical symptoms can hamper efforts to start or maintain a healthy lifestyle. Since modifiable lifestyle factors (e.g. exercise) are associated with reduced pain burden, a vicious cycle is established: the disease causes emotional distress, the emotional distress prevents adherence to healthy behaviours, and the lack of healthy behaviours exacerbates physical symptoms.

Inappropriate laughing and crying

Inappropriate laughing and crying (pseudobulbar affect, PBA) are two neglected symptoms that often go undetected and untreated in people with MS. This doesn’t have to be the case. They are a further sign of significant damage to the brain and yet another reason to diagnose and treat MS early and effectively.

Case study 

When I first met her, she was in her early fifties. She had had MS for over 20 years. Her family now kept her at home, isolated from the wider world. Her behaviour would embarrass them. Why?

She suffered from pathological laughter and occasionally inappropriate crying; her husband and children could not deal with this in public. She was clearly very disabled when I met her; she was unsteady on her feet and had slurred speech and dancing eyes from cerebellar problems. She had gross cognitive impairment. When I introduced myself to her, she burst into tears. Within 2−3 months of starting sertraline, a selective serotonin reuptake inhibitor (SSRI), her husband informed me that her laughing and crying episodes had improved by over 50% and the family were now taking her out regularly. He was very grateful that I had been able to educate them about her symptoms and, more importantly, help her and them as a family deal with this problem.

PBA is diagnosed using standardised scales or questionnaires, which can be self-administered (Center for Neurologic Study-Lability Scale [CNS-LS]). These symptoms respond to tricyclic and SSRI antidepressants and to a combination pill (Nuedexta®; licensed in the USA) that includes dextromethorphan hydrobromide and quinidine sulfate. 

Management of emotional disorders                                                     

Routine screening, targeted drug treatment and structured psychological and behavioural therapies are core components of integrated care in MS. Emotional changes in MS require treatment, just as physical symptoms do.

Screening and education

Routine screening for both anxiety and depression should be part of standard MS care and should be conducted at all scheduled neurological visits. You may be asked to complete different screening questionnaires for depression, anxiety, fatigue and poor sleep. Ideally these should be done before your appointment so that the healthcare professional (HCP) can act on them during the consultation. 

HCPs should educate their patients and their families about potential emotional changes associated with MS, in particular, irritability, crying and mood swings. This education should help reduce the stigma and embarrassment associated with emotional outbursts and enable the patient’s support network to develop coping strategies.

Drug treatment

Drug treatment must be tailored to the specific diagnosis and emotional disorder.

  • Depression and anxiety: The standard use of selective serotonin reuptake inhibitors (SSRIs) and serotonin−norepinephrine reuptake inhibitors (SNRIs) is recommended for the management of clinical depression and anxiety disorders.
  • Irritability: Treatment options for irritability include SSRI antidepressants, which are often needed in addition to CBT. 
  • Pseudobulbar affect (PBA): Low-dose tricyclic or SSRI antidepressants can be effective in the treatment of PBA, but their use is off-label. In the USA, the combination of dextromethorphan hydrobromide and quinidine sulfate has been approved for PBA. In other countries, the combination of these two drugs can be effective in PBA, but again, the use of these two drugs separately is off-label and not recommended.
  • Apathy: Therapeutic strategies, such as cognitive rehabilitation, that enhance cognitive processing speed and executive function are more appropriate for apathy than antidepressants. However, such approaches are hard to access on the UK NHS and are not available in many healthcare systems. There are no licensed medications for apathy, but anecdotal evidence suggests that fampridine and some stimulants may help.
  • Further research: Properly randomised controlled trials are needed to determine the effectiveness of drugs that some patients obtain and use without a prescription. These include cannabis, psychedelics and ketamine, which are currently not licensed for managing anxiety in MS and are not advised.

Psychological and behavioural interventions

Evidence-based structured psychological interventions are as important as drug treatment for the management of anxiety and depression and should be considered a first-line approach in MS. CBT can address maladaptive thought patterns (e.g. catastrophic thinking about the future) and avoidant behaviours common in anxiety. Acceptance and commitment therapy (ACT) focuses on promoting psychological flexibility and acceptance, which is crucial for managing the reactive distress, grief and fear stemming from the unpredictable nature of the disease. Mindfulness, relaxation techniques and structured exercise programs have also been shown to manage anxiety and stress effectively. 

Interventions such as physical activity and social therapies enable some people with MS to process the grief and losses imposed by MS. Simple behavioural strategies, such as taking a break from a conversation when emotions escalate, can also be beneficial. 

Protective factors

Several protective factors can bolster resilience and lower the risk of anxiety. Motivational coping styles that involve direct problem-solving and active participation in treatment planning (i.e. self-management) are associated with better adjustment. One of the most critical protective factors is the presence of social support. Robust practical and emotional help from friends and family, and the knowledge that help is available if needed, significantly reduces the risk of mood symptoms. Finding ways to continue participating in previously enjoyed activities, albeit with new limitations, are key to coping. Interventions aimed at strengthening coping skills, fostering optimism and building social support networks can play a crucial role in preventing and treating anxiety in this population.

The therapeutic challenge

There is substantial symptom overlap between anxiety and depression (e.g. sleep disturbance, fatigue, difficulty concentrating) and between these mood disorders and the primary symptoms of MS. This can make it challenging for HCPs to discern whether a specific symptom, e.g. fatigue, is primarily a neurological symptom of MS, a physical symptom of depression, a consequence of the hyperarousal and poor sleep of anxiety, or a combination of all three. Use of appropriate screening tools can help to ensure that both anxiety and depression are accurately identified and appropriately treated.

Conclusion

MS profoundly affects emotional health across a broad and complex spectrum, manifesting as major depressive disorders, high levels of anxiety, the neurological syndrome of pseudobulbar affect, the cognitive−behavioural syndrome of apathy and, rarely, mania. These emotional changes are driven by primary damage to cortical-subcortical and brainstem circuits, coupled with reactive psychological distress resulting from living with a chronic, unpredictable illness. The current standard of care mandates routine screening, targeted drug treatments and psychological support utilising CBT and ACT. 

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.
Bladder and bowel, Intimate issues

Intimate issues: bladder dysfunction

Bladder dysfunction in people with MS is a sign of early damage, particularly to the spinal cord, and an early indication of a poor prognosis. Why do people with MS who develop bladder dysfunction do worse than those with no bladder symptoms? Here, I explain why I take bladder problems seriously and their implications for MS management.

Key points

  • Urinary hesitancy, urgency, frequency and incontinence, including at night, are bladder problems that affect many people with MS and cause significant frustration and anxiety.
  • A range of drug-based treatments, behavioural techniques and specialist physical interventions can help people with MS to manage bladder dysfunction and achieve adequate control.
  • However, the bladder pathways will probably continue to be affected in the long term due to the development of new lesions or the expansion of old lesions.
  • Frequent and severe urinary tract infections (UTIs) increase the likelihood that MS will progress.
  • I recommend regular dipstick testing at home, as part of your MS self-management, to increase the chances of early detection and treatment of a UTI.
  • Lifestyle approaches, such as avoiding smoking and reducing alcohol and caffeine consumption, should help to reduce bladder symptoms. Pelvic floor exercises are also important.
  • Dehydration is not a good way to control your bladder symptoms. Chronic dehydration can have a significant impact on your overall health and well-being and can exacerbate many of your MS symptoms.

Causes and significance of bladder dysfunction

Bladder dysfunction is the most common symptomatic problem I encounter in an MS clinic, affecting more than 50% of people with MS. It is one of the signs of early damage, particularly spinal cord damage, and an early indication of a poor prognosis. It therefore has important implications for treatment: if you have early bladder symptoms, you may want to take a more effective therapy early on rather than starting on a less effective DMT and waiting to see how you respond. It is best to maximise your chances of responding to treatment by opting for a highly efficacious therapy first-line. I call this ‘flipping the pyramid’.

Infections, both viral and bacterial, are a known trigger of relapse in MS. Frequent and severe urinary tract infections (UTIs) increase the likelihood that your MS will progress. This is why it is important to improve the management of bladder problems in people with MS to prevent or reduce UTIs. You can read more about managing  UTIs here.

Why do people with MS who develop bladder dysfunction do worse than those with no bladder symptoms? The bladder is a complicated organ with several neurological components that need to be coordinated. The descending nerve fibres that travel from the brain to the lower segments of the spinal cord are very long and have the greatest chance of being damaged by MS lesions in their path down to the bladder centre in the sacral area of the lower spinal cord. Therefore, any progressive or worsening MS damage is likely to manifest with bladder dysfunction early on.

The detrusor (or balloon) muscles and the sphincter (or valve) need to coordinate their action to enable normal bladder function. When the bladder is filling, the detrusor muscle relaxes to allow the bladder to expand and the sphincter contracts to keep the urine in the bladder. The opposite occurs when you pass urine; the sphincter opens and the detrusor contracts to empty the bladder.

Common MS-related bladder problems

Hesitancy

Urinary hesitancy occurs when the function of the detrusor and sphincter muscles is not coordinated: you try to pass urine, but the bladder sphincter won’t open. Hesitancy may be intermittent; if you try again later, the bladder will open, allowing you to pass urine. Conversely, the sphincter may close as you pass urine, which breaks up the urine stream or prevents complete bladder emptying; this can cause dribbling. The medical term for incoordination of the bladder muscles is dyssynergia or, more correctly, detrusor-sphincter-dyssynergia (DSD). People with MS find urinary hesitancy and its unpredictability very frustrating.

The drug treatment for DSD includes alpha-blockers (prazosin, indoramin, tamsulosin, alfuzosin, doxazosin and terazosin). Other strategies include small bladder stimulators or vibrators that are placed over the pubic area and work by blocking signals that inhibit the sphincters. The vibrators work in some people with MS and may help relax the sphincter.

Trying to relax when passing urine can help to improve hesitancy. The sound of running water, for example from a tap, may trigger the relaxation of the sphincter. Simulating this in public toilets may not be possible. Some people with MS find pressing on the lower abdomen helps. If all else fails, intermittent self-catheterisation (ISC) may be the only option to manage urinary hesitancy (see below).

Frequency and urgency

In MS the commonest bladder problem is spasticity, or irritability, of the detrusor muscle. The detrusor can’t relax, which prevents the bladder from filling to its maximum capacity. Frequent spasms of the detrusor muscle tell the brain that the bladder is full and you need to pass urine. This causes frequency, i.e. the need to use the toilet many times during the day and night. Frequency often accompanies the symptom of urgency, the need to get to the toilet as quickly as possible to prevent incontinence. 

When urgency is a problem, distraction techniques such as breathing exercises and mental tricks (e.g. counting) may be helpful. If urinary frequency is your main problem, you might try to retrain your bladder by holding on for as long as you can each time before passing urine. The aim is to train the detrusor muscle to expand more to hold on for longer when you need the toilet. These behavioural techniques rarely work for long; MS is a relapsing and/or progressive disease, and the bladder pathways will likely continue to be affected due to the development of new lesions or the expansion of old lesions.

Incontinence

Incontinence occurs when you lose the ability to suppress or ignore the signals from the detrusor muscle with the result that the sphincter relaxes or opens as part of a spinal cord reflex. We typically treat this problem with anticholinergic drugs, e.g. oxybutynin, solifenacin or tolterodine. The older generation anticholinergics such as oxybutynin cross the blood ̶ brain barrier and enter the brain, where they can exacerbate cognitive problems in people with MS. The commonest side effect of anticholinergics is dryness of the mouth; they can also worsen constipation. People with MS must be warned about the risk that anticholinergics will relax the bladder too much and precipitate urinary retention; the solution to urinary retention is ISC. 

The good news is that we now have a relatively new muscle relaxant, mirabegron (Betmiga), which activates the β3 adrenergic receptor in the detrusor muscle. I am increasingly using mirabegron to avoid the side effects (particularly cognitive issues) associated with anticholinergics. The main side effect of mirabegron is that it tends to increase your blood pressure.

Nocturia

Nocturia means you need to get up frequently at night to pass urine. If nocturia is your main bladder problem, using agents to concentrate the urine at night might help. A hormone called DDAVP works on the kidneys to reduce urine production; it is available as a nasal spray or tablets (Desmotabs or Desmospray). DDAVP should only be taken once a day, to avoid continuous water retention by the kidneys; this presents as swelling of the feet and reduces the salt or sodium levels in your blood, which can be dangerous. You therefore need to have your sodium levels checked about 4 ̶ 6 weeks after starting DDAVP therapy. 

Second-line treatments for bladder problems

If you fail to respond to anticholinergics, mirabegron and/or behavioural techniques, you need a bladder scan to see if you have a raised residual volume (the amount of urine left after you have emptied your bladder). If the residual volume is greater than 80 ̶ 100mL you may need to consider intermittent self-catheterisation (ISC). Some continence advisors act at the 80 mL threshold, and others at the 100 mL threshold, when recommending ISC.

Intermittent self-catheterisation

ISC serves two purposes. It increases your functional residual bladder volume, allowing more storage space for urine, which reduces frequency and urgency. This can help if you need to travel some distance or to join in a social activity without having to pass urine. It also helps to reduce nocturia, which in turn improves sleep and possibly MS-related daytime fatigue.

ISC also removes urine from the bladder. The residual urine acts as a culture medium for bacteria; by clearing your bladder you can prevent bladder infections. Conversely, if you don’t do the ISC technique correctly you can introduce bacteria into the bladder that then cause infections.

Botox

Botox injection into the detrusor muscle is increasingly used as a treatment for bladder dysfunction, in conjunction with ISC. Botox paralyses the muscle, turning it into a flaccid bag for urine storage. The surgical techniques that were previously used to remove the nerve supply to the bladder (which had the same effect as Botox) are now rarely used.

Percutaneous tibial nerve stimulation 

Percutaneous (or posterior) tibial nerve stimulation is a form of neuromodulation that can help with impaired bladder function and may improve urinary urgency, urinary frequency and urge incontinence. It is offered as a treatment in specialist neuro-urology units.

Permanent catheterisation

If all else fails, some people with MS may need to be permanently catheterised. This can be done via the urethra or the lower abdominal wall; the latter is called a suprapubic catheter. Being permanently catheterised sounds drastic, but this significantly improves the quality of life in some people with MS. Allowing bladder dysfunction to control your life can result in social isolation and constant anxiety about being incontinent in public. With the above-mentioned strategies, adequate bladder control should be the norm in MS.

In my experience, the biggest hurdle to achieving adequate bladder control is when people with MS assume their bladder symptoms are part of the disease and resign themselves to living with them. Such patients may start using continence pads as if this is normal or inevitable for someone living with MS. This is not normal; incontinence can lead to skin rashes and pressure sores. Please don’t accept this as the norm or something you must live with. If you have problems, tell your MS nurse or neurologist; they can help you.

Anatomy of the human urinary bladder; reproduced from Wikipedia, created by U.S. National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program.

Lifestyle factors that impact your bladder

Smoking, alcohol and caffeine

Nicotine irritates the bladder. If you are a smoker, then stopping smoking may significantly improve your bladder symptoms. Similarly, reducing alcohol and caffeine consumption may help; these agents are diuretics and cause the kidneys to make more urine.

Pelvic floor exercises

One of the treatments recommended to all patients with bladder problems is pelvic floor exercises. These are also important for managing bowel and/or sexual problems. For detailed guidance on incorporating these into your daily life, please see pelvic floor training post.

Avoiding dehydration

Try to anticipate times when urinary frequency and urgency will be most inconvenient; reducing the amount you drink beforehand may help. For example, don’t drink too much for 2 ̶ 3 hours before you go out. After you have finished passing urine, go back to the toilet again after a few minutes to try to pass some more urine. This is called the double micturition technique, which aims to ensure the bladder is emptied completely. However, do not reduce your total fluid intake to less than 1.5 litres each day.

Dehydration is not a good way to control your bladder symptoms. The issue of people with MS dehydrating themselves to manage their bladder problems was highlighted as early as the 1960s by Professor Bryan Matthews, a neurologist in Oxford, in his textbook on MS.

When researching the topic in the 1990s, it became clear to me that people with MS with severe disability were most likely to have bladder dysfunction and were chronically dehydrating themselves to manage urinary frequency, urgency and nocturia. Studies showed that a high urinary concentration of creatinine, a waste product that the kidneys filter out of the blood through the urine, correlated with increased disability levels. Urine containing myelin basic protein-like material (MBPLM), an indicator of myelin damage in MS, was also shown to correlate with disability. It is dehydration that causes higher levels of MBPLM and creatinine in the urine, indicating that dehydration is associated with disability.1 

A more recent paper from researchers in the Southampton group described the same findings, that urinary tract symptoms are very common in people with progressive MS and are associated with inadequate hydration.2

Despite highlighting the issue of chronic dehydration in MS over the years, it remains a persistent problem. My message is clear: don’t use dehydration to manage your bladder symptoms. Chronic dehydration can have a significant impact on your overall health and well-being and can exacerbate many of your MS symptoms. Some potential effects of chronic dehydration are listed in the box below.

  1. Physical performance: Dehydration can decrease physical endurance, cause muscle cramps and exacerbate or cause fatigue. This can affect overall physical performance and make everyday tasks more challenging.
  2. Cognitive function: Dehydration has been linked to cognitive impairment, including issues with concentration, alertness and short-term memory. Prolonged dehydration may even contribute to long-term cognitive decline.
  3. Mood and mental health: Studies have shown that dehydration can affect mood and contribute to increased feelings of anxiety and irritability. In severe cases, it can even lead to symptoms resembling depression.
  4. Kidney function: Chronic dehydration can put a strain on the kidneys, potentially leading to the formation of kidney stones and urinary tract infections. It can impair the kidneys’ ability to effectively filter waste from the blood. It also makes you more susceptible to the side effects of non-steroidal anti-inflammatory medications.
  5. Digestive problems: Dehydration can lead to constipation and other digestive issues. It may also contribute to an increased risk of developing peptic ulcers and acid reflux.
  6. Skin health: Inadequate hydration can lead to dry, flaky skin and exacerbate conditions such as eczema and psoriasis. Proper hydration is essential for maintaining overall skin health and elasticity.
  7. Heat-related illnesses: Dehydration reduces your body’s ability to regulate temperature, increasing the risk of heat exhaustion and heat stroke, particularly in hot and humid conditions. Please remember that people with MS, particularly those with more advanced MS, may already have a problem with thermoregulation.

In conclusion

I advise using a holistic approach to managing urinary symptoms, in addition to medication or other aids where recommended. Please review the questions below to check whether you are optimising your self-management.

  • Have you deconditioned your bladder because you are not training yourself to resist emptying it whenever you get the urge to pass urine? The bladder is a muscle that needs to be trained.
  • Have you tried peripherally acting anticholinergics or mirabegron?
  • Have you had a post-micturition bladder scan to see if you are emptying your bladder?
  • Do you need to use intermittent self-catheterisation to increase your functional bladder volume?
  • Do you have a chronic low-grade urinary tract infection? Are you performing regular urine dipstick testing (see post on UTIs and dipstick testing)?
  • Do you have bladder stones?
  • Have you tried DDAVP (Desmotabs or Desmospray) to help concentrate your urine without dehydrating yourself?
  • Are you avoiding bladder irritants or stimulants such as caffeine and nicotine?
  • Are you doing your pelvic floor exercises? If you are a post-menopausal woman, have you tried HRT (hormone replacement therapy)? Pelvic floor tone and bladder function often improve on HRT. 

References

  1. Giovannoni G, et al. Urinary myelin basic protein-like material as a correlate of the progression of multiple sclerosis. Ann Neurol 1996;40:128 ̶ 9.
  2. Kaninia S, et al. Dehydration associates with lower urinary tract symptoms in progressive multiple sclerosis. Eur J Neurol 2024;31: e16175.
Pregnancy and childbirth, Women's health

Concerns about parenting

Being disabled or unemployed because of MS does not mean you cannot be a good parent. Here I cover some of these practical considerations as well as the steps you can take to reduce the potential risk of your child developing MS.

Can I be a good parent if I become disabled from my MS?

This is difficult to answer and depends on how disabled you are, the nature of your disabilities and whether you have support. For example, some patients who are wheelchair users, or close to being wheelchair users, when they give birth manage to nurse and look after their children. On the other hand, some patients with cerebellar problems find it very difficult to bathe, change and feed their babies due to poor coordination and tremor. If you have advanced MS, the decision to start or extend your family needs to be discussed with your partner. If necessary, ask an occupational therapist to assess you and discuss all the issues relevant to you becoming a parent. Disability per se is not a reason not to have children, but it does raise important issues that need careful consideration. The decision to have children needs to be taken by you and not by your HCP.

If I become disabled or unemployed because of MS, will I be able to support my children?

This is another difficult question, and the answer depends on your circumstances. In the modern era having children and supporting them is expensive, but most high-income countries have social safety nets to protect you and your family in times of adversity. We now have effective DMTs that prevent or delay disability, so deciding to have children is easier than it was in the pre-DMT era.

What is the risk of my children getting MS?

MS is not a genetic disease in the Mendelian sense that you pass on to your children with a well-defined inheritance pattern. However, there are genetic factors that increase your risk of getting MS. In high-prevalence countries such as the UK, the lifetime chances of a woman developing MS is about 1 in 375 ̶ 400; for a man, it is close to 1 in 750 ̶ 800. However, for a daughter whose mother has MS, the risk is close to 1 in 40, and for a son, it is lower than 1 in 80. In some studies, the latter risk is no higher than the background rate. If the father has MS, the risk of his daughter developing MS is about half the risk of mother ̶ daughter pairing, i.e. 1 in 70. For a son of a father with MS, the risk is likely lower than this, but the results across studies are inconsistent.  

Can I prevent my children from getting MS?

Based on the known and modifiable risk factors for MS, you should try and keep your children vitamin D replete. To do this, you will likely need to supplement your children’s vitamin D intake as follows:

  • for children less than 2 years of age, 600 IU per day
  • for children 2 ̶ 10 years of age 2,000 IU per day
  • for children above 10 years of age, 4,000 IU vitamin D3 per day (the same dose we recommend for adults).

Other modifiable risk factors are childhood and adolescent obesity and smoking. We estimate that about 15 ̶ 20% of new or incident new cases could potentially be prevented by eliminating obesity and smoking in the general population. I must stress that these suggested interventions are based on studies that show associations between the risk factors and MS but may not necessarily be cause and effect. I should also point out that most people with all the risk factors for MS will not get the disease. This implies that the development of MS involves other random factors, or bad luck, that can’t necessarily be modified.

The issues raised above show you how complex the management of MS has become, which is why there is a push for people with MS to be managed in specialist MS units.

References

Krysko KM et al. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol 2021;23:11.

Other articles in this series on Pregnancy and childbirth
Planning for pregnancy
Managing MS during pregnancy
Preparing to give birth
Breastfeeding if you are on a DMT

DMTs, Treatment strategy

How immunosuppressed am I?

Do you understand the difference between short-term intermittent and long-term continuous immunosuppression? Here we address another of the key questions to consider before deciding on a specific disease-modifying therapy (DMT).

Key points

  • Immunosuppressive disease-modifying therapies (DMTs) reduce the immune system’s effectiveness.
  • It is important to weigh up the benefits and risks of short-term versus continuous immunosuppression.
  • Non-selective DMTs suppress the adaptive and innate immune systems; selective DMTs do not affect the innate immune system and are thus associated with a low risk of bacterial infections.
  • The implications of immunosuppression need to be considered within the context of other health and lifestyle factors.

Which DMTs cause immunosuppression?

A useful way of thinking about DMTs is based on whether they are immunosuppressive. Broadly speaking, an immunosuppressive is any DMT that reduces the immune system’s activation or effectiveness. 

From a regulatory perspective, for a drug to be classified as immunosuppressive, it should: 

  • cause significant lymphopaenia or leukopenia (reduced white cell counts)
  • be associated with opportunistic infections (infections that don’t occur in people with a normal, healthy immune system)
  • reduce antibody and/or T-cell responses to vaccines 
  • increase the risk of secondary malignancies. 

Based on the above criteria, the interferon-beta preparations and glatiramer acetate are immunomodulatory rather than immunosuppressive. Teriflunomide is also an immunomodulatory therapy with the potential, albeit small, to cause immunosuppression. In real life, however, very few people with MS treated with teriflunomide develop significant lymphopaenia or leukopenia; if they do, we tend to stop the drug. The other licensed DMTs are immunosuppressive to a greater or lesser degree. 

Short-term versus continuous immunosuppression

The duration and intensity of immunosuppression further determine the risks. Short-term or intermittent immunosuppression associated with an immune reconstitution therapy (IRT) front-loads the risks, which decrease substantially once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies.

Live vaccines are, in general, contraindicated in patients on continuous immunosuppressive therapies. However, someone with MS on an IRT who has reconstituted their immune system can tolerate and respond to live vaccines. The benefits of administering live vaccines always need to be balanced against the risks of the vaccine.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Selective versus non-selective immunosuppression

Immunosuppression that accompanies DMTs may be selective or non-selective. Non-selective therapies deplete and/or suppress both the adaptive immune system (T cells and B cells) and the innate immune system (monocytes, neutrophils and natural killer [NK] cells). Alemtuzumab, AHSCT (autologous haematopoietic stem cell transplantation) and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as listeriosis, nocardiosis and cytomegalovirus reactivation. In comparison, anti-CD20 agents (ocrelizumab and ofatumumab) and cladribine are selective, do not affect the innate immune system and are therefore associated with a low risk of acute bacterial infections. 

How immunosuppressed are you_MET vs IRT_2 Dec 2024

Classification of disease-modifying therapies for relapsing forms of MS. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation.

Other considerations

Please note that the implications of immunosuppression are not black and white but interact with other factors such as:

These factors have been highlighted during the COVID-19 pandemic, particularly in relation to the risk of severe COVID-19 and the variations in vaccine responses among people with MS (including waning of the immune response).

It is important to realise that we can derisk (reduce the risk of) some complications associated with long-term immunosuppression and the use of DMTs. Please see the post entitled How can I reduce my chances of adverse events on specific DMTs?

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
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.