Tag Archives: lesions

MS and bipolar disorder: understanding the link

22/02/2026 Gavin Giovannoni

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.

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.

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.

Diagnosis, Stages of MS

What should I expect during the diagnostic consultation?

16/05/2023 Gavin Giovannoni

The practice of neurology and medicine varies worldwide, so I will explain what to expect if you were to consult me.

Key points

The principles of diagnosing MS are to show the dissemination of lesions in space and time and to exclude alternative diagnoses that mimic MS.
Diagnosing MS takes time and should not be rushed; do not be afraid to ask questions.
Most patients diagnosed with MS have an emotional response similar to the five stages of grief – Denial, Anger, Bargaining, Depression and Acceptance (DABDA). Additionally, many patients experience Anxiety about the future (DABDA+A).
Newly diagnosed patients should avoid overloading themselves with information about MS; much of the online information can be misleading and anxiety-provoking. Guidance is provided below about reliable information sources.
Counselling, cognitive behavioural therapy and the support of an MS ‘buddy’ can help patients adjust to a diagnosis of MS, which is a serious condition and should be respected.
You should be aware that medical ‘gaslighting’ may happen and know how to deal with it.

Tests to exclude other diagnoses

MS is a clinical diagnosis and a diagnosis of exclusion. Therefore, I would take a detailed medical and neurological history and examine you for neurological signs. Finding signs of involvement in a particular neurological pathway is important for fulfilling the criteria for dissemination in space. MS must involve at least two neuronal pathways. To be confident that no alternative diagnosis could explain your presentation, a full work-up will likely include magnetic resonance imaging (MRI) of the brain and spinal cord, evoked potentials, a lumbar puncture and blood tests. In addition, I would need to show dissemination in time, involving two or more structures separated in time by at least 4 weeks.

The diagnosis of MS is not trivial and should not be rushed. If I doubted the diagnosis, I would wait. The old maxim ‘time is often the best diagnostician’ is as pertinent today as it was in the past. Despite this, the misdiagnosis rate remains stubbornly high. I recommend you read some of the posts that cover the diagnosis of MS in more detail, such as Am I sure that I have MS? and Do I have active MS?

Time to adjust to a diagnosis of MS

You should not expect too much from the initial consultation. The second consultation, once all the diagnostic tests are back, will be the difficult one. Before COVID-19, an MS diagnostic workup in the NHS would take about 6 ̶ 8 weeks. Due to COVID-19-related delays in getting MRI scans and evoked potentials, it currently takes up to 4 months. Occasionally, patients with possible MS are admitted to the hospital because of a disabling attack. This allows us to make a more rapid diagnosis.

Being diagnosed with MS or any other chronic and potentially disabling disease is distressing. In my experience, patients’ responses are highly variable, including relief about finally getting a diagnosis, surprise, shock, anger or blaming the messenger for the bad news. Some question my judgement and refuse to accept the diagnosis; they may accuse me of being wrong and seek a second, third or fourth opinion. Many are devastated and expect the worst: how long before I need a wheelchair? Rarely patients are uninformed, have little or no idea about MS and ask about the disease.

Examples of some responses to a diagnosis of MS

I always try and be reassuring and tell patients that MS is now a treatable disease. If we manage their MS actively, we can prevent or at least delay the development of disability for many decades.

Emotional response

I also warn patients about the emotional reaction they will likely have to being diagnosed with MS. The psychological impact of an MS diagnosis and the uncertainty associated with having a potentially disabling disease should never be underestimated. Elisabeth Kübler-Ross in 1969 described five common stages of grief, best known by the acronym DABDA:

Denial, Anger, Bargaining, Depression, Acceptance

We have added an extra A – for Anxiety about the future – to expand this to DABDA+A. People diagnosed with MS may go through these stages in order of the pneumonic, but some will jump around, and others go through some stages many times. Although the Kübler-Ross stages have been criticised in the psychological literature, they provide a valuable framework for discussing a patient’s emotional journey. Being diagnosed with MS is a marathon, not a sprint, and it will take time to come to terms with it.

It is important for healthcare professionals (HCPs) to be there for the journey and to make sure that newly diagnosed patients have access to their MS team and high-quality information about MS.

Step-wise approach to understanding MS

In the modern era, most patients I diagnose as having MS are aware of the disease and suspect they have MS before I tell them so. I say this because Dr Google, Dr ChatGPT and Dr Bing are only keystrokes away, and their answers are very credible.

Because of their anxiety, most newly diagnosed patients only take away one thing from the consultation: they have MS. Almost everything else they hear is forgotten. I encourage patients to record the consultation or bring a partner, friend or family member who can be their backup memory.

I try to avoid overloading patients with information early on. Instead, I provide links to online resources about having MS. We arrange a follow-up session with the MS nurse specialist in the next 10 ̶ 14 days so that they can ask questions.

Guidance about what information to trust

I counsel patients to stay away from Dr Google, Dr ChatGPT and Dr Bing until they have come to terms with having MS. Much of the MS-related content available on the web is misinformation and disinformation; until you understand the disease, it is difficult to know what information is valid, reliable and helpful and what is quackery. Many patients ignore this advice and overwhelm themselves with information, which can worsen anxiety.

I don’t introduce recently diagnosed patients to MS-Selfie initially. MS-Selfie is written at too high a level for the average person who is newly diagnosed. If patients want more information, I direct them to the MS Trust, the MS Society and ‘MS Brain Health: time matters’ (for more detail, see Resources and hot topics).

Counselling, support and respect

Depending on a patient’s response to the diagnosis, we may refer them for counselling, cognitive behavioural therapy and/or mindfulness therapy to help them come to terms with having MS and to help manage their anxiety. Most patients are receptive to these psychological therapies.

Many people with MS are traumatised by their diagnostic consultation and may experience symptoms of post-traumatic stress disorder from the event. This should not happen in the modern era. In my experience, gestures such as having tissues on hand for a distressed patient or holding their hand are ways that HCPs can demonstrate their empathy.

On rare occasions, particularly for patients who are alone and socially isolated, we may buddy them up with another carefully chosen patient to ask questions and learn about MS. These MS buddies need to be optimistic, able to communicate well and not overwhelm the recently diagnosed patient with information. I work closely with the charity Shift.ms, which does a similar thing.

In the diagnostic consultation, I avoid too much detail about treating MS and the specific DMTs. These are best discussed at the next visit. With some patients, however, the discussion gets to treatments very quickly. In such cases, I tailor the consultation to the individual’s needs.

During the diagnostic consultation, I also show patients their MRI scans. Seeing your brain, spinal cord and MS lesions provides an objective way of helping you to visualise the disease.

Recently diagnosed patients must be given time to ask questions and even to sit in silence. MS is a serious disease, and informing someone about the diagnosis must be done carefully. After more than 30 years as a neurologist, I still find telling my patients they have MS challenging. The patient being diagnosed with MS, as well as the disease, must be respected.

What if a doctor belittles my concerns?

The term ‘medical gaslighting’ describes a scenario where health professionals dismiss or downplay a patient’s real symptoms, leading to an incorrect diagnosis. Now that we have recognised medical gaslighting as a significant problem in MS, please don’t allow a neurologist to gaslight you. There are things you can do to prevent this.

Keep detailed notes and records. Patient-held notes transform consultations and allow you to become a partner in your healthcare.
Ask to record the consultation. Many HCPs don’t like this; just tell them you must listen to the conversation again to ensure you don’t forget things or miss important information. You will be surprised how this changes the HCP’s behaviour.
Ask questions. Then ask some more. And don’t be fobbed off; if you are dissatisfied with the answer, ask the question again.
Take someone with you for support. Having a witness during the consultation has a similar effect to recording the conversation or documenting it with notes.
Focus on your most pressing issues to make the best use of your consultation time. If your HCP is pressed for time, say you understand, but you would like to prioritise the following issues today. This helps you to frame the limits of the consultation and promote a two-way discussion. Also, don’t expect the HCP to have all the answers at their fingertips, but do expect them to come back to you later with the answers.
Try and pin down the next steps for your problem; ask what the action points are. For example, if the MRI shows this, how will that change my management? Do I need further investigations? How soon should I switch treatments?

If you still feel that you are being ignored, here are some of your options.

Some courses of action open to you if you experience medical gaslighting.

Abuse, manipulation, gaslighting and delaying a diagnosis are potentially reportable events which HCPs need to know about. Therefore, make your healthcare system aware of the problem rather than suffer in silence.