Tag Archives: Tysabri

Cognition and mental health

Dissociative states and MS

This MS-related group of symptoms is probably neglected in routine MS neurological practice and may fall through the cracks.

Key points

  • Dissociative states in people with MS may arise for different reasons: organic (resulting from damage to the temporal and parietal lobes), psychogenic (following psychological trauma) or iatrogenic (induced by drug treatments).
  • Such states range from transient feelings of unreality to recurring episodes of depersonalisation and/or derealisation. Other presentations may also occur.
  • Depersonalisation feels like being detached from one’s own body or thoughts, feeling like an ‘outside observer’ of one’s life.
  • Derealisation feels like being detached from the external world, which may appear foggy, dreamlike, lifeless or two-dimensional.
  • In MS, dissociation often has a physical (organic) basis in the brain. This article explores the specific effects of damage to each of the four lobes of the human brain.
  • Managing dissociative states in MS requires a dual approach: biological (treating the underlying MS disease) and psychological.
  • To differentiate between physical and psychological causes, doctors must consider the possibility of an MS relapse, an infection or the effects of an MS-related treatment. Checks for balance, hearing and psychological screening are also needed.

Causes and range of dissociative states

People with MS have an elevated risk of experiencing dissociative phenomena that give rise to alterations of consciousness, self-perception and reality testing (being able to assess what is real versus what is imagined). These dissociative states − ranging from transient feelings of unreality to chronic depersonalisation−derealisation disorder (DPDR) and non-epileptic seizures − are often undiagnosed. They may arise for different reasons.

  • Organic dissociation results from damage(lesions)to the temporal and parietal lobes, which can disrupt neural networks responsible for ‘embodied self-awareness’ (the constant experience of oneself through physical sensations, emotions and bodily signals).
  • Psychogenic dissociative states can occur in people with MS following the psychological trauma of diagnosis and the high prevalence of comorbid post-traumatic stress disorder (PTSD).
  • Iatrogenic dissociative states can be induced by drug treatments, particularly high-dose corticosteroids and psychoactive symptomatic treatments.

Dissociation is typically characterised by disruption in the normal integration of consciousness, memory, identity, emotion, perception, body representation, motor control and behaviour.  The most frequently reported dissociative symptoms in the MS population fall under the spectrum of depersonalisation−derealisation.

Depersonalisation (the fragmentation of self)

Depersonalisation is characterised by a persistent or recurring feeling of being detached from one’s own body or thoughts. People with MS describe this as feeling like an ‘outside observer’ of their life, like watching oneself in a movie, or like a ‘robot’ with no control over their speech or actions. In MS, depersonalisation is associated with damage to the parietal lobe or the spinal cord – areas that help the brain detect body position and movement (proprioception). People with damage to these areas may feel as though a limb does not belong to them. This is not a delusion, because the person may see their limb move and intellectually know it is theirs. Rather, it is a sensory problem with the ‘body schema’ (the brain’s internal map of your body), that no longer matches your physical body.

Derealisation (the distortion of the world)

Derealisation involves a feeling of being detached from your surroundings. The external world may appear foggy, dreamlike, lifeless, colourless or artificially two-dimensional. Objects may appear distorted in size or shape; sounds may seem muted or distant. Derealisation is often worsened by sensory problems in people with MS (affecting sight, sound, touch, taste, smell or movement). Optic neuritis, a common early sign of MS, causes visual blurring, reduced colour intensity and visual field defects (gaps); see Colour vision and Driving at night. When the brain receives unclear visual input, it struggles to construct a vivid, real-feeling model of the environment, which can lead to a secondary sense of derealisation.

Problems with balance (vestibular dysfunction, leading to vertigo, dizziness and gait instability) are often associated with derealisation; conflicting signals from the eyes and inner ear can cause people with MS to feel disoriented. 

Non-epileptic seizures

Non-epileptic seizures, also referred to as dissociative seizures, resemble epileptic seizures − involving convulsive movements, apparent loss of consciousness and stiffening of the body. However, they are not caused by abnormal electrical activity in the brain (usually visible on an electroencephalogram) but are psychological, most likely a mechanism for managing distress or trauma. Care is needed to determine the correct cause in each individual because people with MS are actually at increased risk for epilepsy due to brain lesions. Studies of magnetic resonance imaging (MRI) scans suggest that damage in the right brain hemisphere or the frontal lobes may increase the risk of non-epileptic seizures.

Dissociative amnesia and brain fog

Dissociative amnesia is the inability to recall important personal information, far beyond ordinary forgetting. It is usually related to stress or trauma. In MS, this poses a diagnostic challenge because many patients already experience cognitive dysfunction that affects processing speed and working memory. A study differentiating organic (‘true’) memory loss from dissociative amnesia in MS found that people who reported memory problems often had high levels of dissociation and anxiety but did not show major problems on formal memory testing.1 This implies that the ‘memory loss’ experienced by many people with MS may be an attention problem due to a mild dissociative state or emotional overload, rather than a result of permanent damage to memory structures in the brain.

Dissociative identity disorder

While rare, cases of dissociative identity disorder (DID) have been reported in people with MS. DID is characterised by the presence of two or more distinct personality states. Affected individuals typically have experienced childhood trauma, which makes them more prone to develop dissociation. A diagnosis of MS acts as a further stressor that challenges their sense of identity. Other symptoms of DID may include physical weakness and sensory loss, which can mimic an MS relapse and lead to misdiagnosis. 

Underlying disease processes in MS

In the general psychiatric population, dissociative disorders are usually regarded as psychological in origin. In MS, however, dissociation often has a physical basis in the brain. MS damages myelin (the protective covering of nerve fibres), severs nerve connections and affects grey matter, all of which disrupts communication between different brain regions. When these connections are broken, the brain cannot integrate sensation, emotion and thought into a conscious experience.

Structure of the brain

Structure of the brain, showing the left and right cerebral hemispheres (left) and the four lobes (frontal, parietal, temporal and occipital; right) in each cerebral hemisphere. Each individual lobe has particular key roles; however, they do not function in isolation but as part of a wider system of neural networks. From Gemini Pro.

Temporal lobe

The temporal lobes play a central role in processing memory and emotions as well as in combining auditory and visual information. MS-related damage in these areas is associated with psychiatric symptoms, including psychosis and dissociation. The temporal lobe also houses the limbic system, comprising the amygdala (which processes emotion) and the hippocampus (which supports memory). If there is damage to the white matter pathways between the limbic system and the frontal cortex (a region known as the uncinate fasciculus) or to sensory regions, the emotional content of experiences can be lost. For example, when a person with MS sees a familiar object or person, the visual cortex sends information to the limbic system, thus activating the appropriate emotional response (e.g. warmth, recognition). If MS disrupts this connection, the person may recognise the object but feel no emotional familiarity. This mismatch, i.e. recognition without feeling, is central to derealisation and to the jamais vu phenomenon (the strange feeling that something familiar is suddenly unfamiliar or new) that is often reported in temporal lobe disorders.

sagittal

A sagittal (longitudinal) view of the human brain showing the interconnected network of the limbic system, a key regulator of emotion, memory and spatial navigation. From Gemini Pro 3.0.

Temporal lobe epilepsy

MS lesions in the temporal lobe can sometimes trigger epileptic activity. Even in the absence of full-blown convulsions, abnormal electrical activity there can cause ‘dreamy states,’ profound déjà vu or feelings of unreality similar to the warning phase (aura) of temporal lobe epilepsy. Symptoms of depersonalisation disorder overlap with those experienced in temporal lobe epilepsy, particularly unusual body experiences and memory distortions.

Parietal lobe

The parietal lobe combines sensory information from different sources to form a single perception (cognition) and helps the brain build a map of the body and the world around us. The brain constantly updates this map, or ‘body schema’, using signals from the spinal cord. MS lesions in the parietal lobe or spinal cord can interrupt this information and deprive the brain of body map data.

When the brain ceases to receive reliable input from a limb, because of MS-related damage, it may ‘dissociate’ that body part from its self-image. This can manifest as:

  • asomatognosia (the inability to recognise a part of one’s own body)
  • somatoparaphrenia (the delusion that a limb belongs to someone else)
  • depersonalisation (see above).

Temporoparietal junction

The temporoparietal junction, where the temporal and parietal lobes meet, is a hub for integrating balance, visual and somatosensory signals to locate the ‘self’ in space. Electrical stimulation of this area can cause out-of-body experiences. In MS, lesions affecting the temporoparietal junction or the balance pathways in the brainstem can trigger dissociative events (for example, a feeling of floating above one’s body or viewing oneself from outside. These episodes are often linked to balance problems, suggesting that the brain is trying to make sense of conflicting signals.

Occipital lobe

The occipital lobe is the main visual processing centre of the brain. Damage in this region or in visual pathways can lead to complex visual distortions that trigger derealisation. ‘Alice in Wonderland Syndrome’ is a perceptual distortion in which objects appear much smaller (micropsia) or much larger (macropsia) than they really are. When damage from MS affects the visual association areas, vision may appear two-dimensional, with the world looking ‘flat’ or like a painted backdrop. This loss of depth perception contributes to the feeling of living in a movie or a simulation.

Clinico-radiological paradox

The clinico-radiological paradox refers to the discrepancy between the number and volume of MS lesions seen on MRI and a patient’s level of physical disability. Some people with MS have extensive brain lesions but relatively normal movement and minimal disability scores. While these patients may appear physically ‘fine’, lesions in high-level areas of the cortex (frontal, parietal and temporal lobes) can disrupt cognitive and emotional networks.  Such individuals may be at high risk for subjective dissociation − feeling fragmented or cognitively detached − while objective observers (and disability scales) fail to register any deficit. These hidden symptoms can worsen the patient’s sense of isolation and unreality.

Trauma-related causes

Receiving a diagnosis of MS

While localised MS lesions create the ‘hardware failure’ in the brain that enables dissociation, psychological factors often provide the ‘software trigger’. Receiving a diagnosis of MS may be considered a medical trauma, often involving invasive procedures (lumbar punctures), frightening MRI experiences (claustrophobia) and hospitalisations. These repeated exposures to threat and a feeling of helplessness and vulnerability can induce a state of chronic hyperarousal and subsequent dissociation, consistent with the dissociative subtype of PTSD. Many people with MS meet the diagnostic criteria for PTSD specifically related to their MS diagnosis and outlook (please see, How common is post-traumatic stress disorder in people with MS?). Developing an ongoing, incurable and potentially disabling neurological condition can shatter one’s expectations for the future. By detaching from the reality of their diagnosis, people with MS may attempt to shield themselves from overwhelming anxiety and grief. Dissociation serves as an adaptive defence mechanism – a ‘mental flight’ when physical flight is impossible. This sounds dramatic, but it may explain why some people with MS develop dissociative disorders. 

Childhood trauma

Research has demonstrated a potential relationship between childhood trauma, dissociation and the development of MS. Severe stress, neglect or abuse in childhood permanently dysregulates the hypothalamic−pituitary−adrenal axis (a system that is crucial for the body’s stress management). It consists of three organs that each release hormones to eventually raise cortisol levels in the body. This results in a chronic proinflammatory state and altered cortisol responses, which may increase biological susceptibility to developing MS later in life. Large-scale cohort studies indicate that women who experienced childhood abuse are significantly more likely to develop MS in the future.2

Treatment-related causes

The management of MS involves disease-modifying therapies (DMTs) and corticosteroids for acute relapse management. Many of these agents have significant neuropsychiatric side effects that can mimic, induce or exacerbate dissociative states.

Corticosteroids. High doses of the intravenous corticosteroid methylprednisolone (e.g. 1000 mg daily for 3−5 days) are the standard of care for speeding up the recovery from acute MS relapses. It is known to cause acute psychiatric adverse effects in many patients (dependent on the corticosteroid dose).  Symptoms often begin with insomnia and euphoria but can progress to severe mood lability, anxiety and frank dissociation and delirium. Patients may experience a ‘steroid high’ followed by a crash into depression; some develop acute psychosis with hallucinations and confusion. Corticosteroids enhance dopamine activity. They may cause acute, reversible reductions in hippocampal volume. Their effect on the brain presumably decouples the patient from reality, leading to a temporary dissociative or psychotic state that resolves upon tapering the steroid dosage.

Interferon-beta has a longstanding association with depression and anxiety. Interferons are cytokines that induce a proinflammatory response similar to ‘sickness behaviour,’ which includes social withdrawal, fatigue and anhedonia (inability to feel pleasure in activities that are usually considered to be pleasurable). They may also decrease serotonin levels in the brain. While direct dissociation is less common, the severe anxiety and depression induced by interferons presumably lower the threshold for the onset of stress-induced depersonalisation.

Natalizumab is a highly effective monoclonal antibody, but it carries specific risks. The ‘wearing off’ effect in the week preceding the next infusion can be characterised by intensifying fatigue, cognitive fog and mood instability, which may manifest as a feeling of detachment or unreality.  The most severe risk associated with natalizumab is progressive multifocal leukoencephalopathy; this causes extensive, rapid demyelination that can lead to confusion, personality changes and cognitive decline. These symptoms can be misinterpreted as psychiatric dissociation or dementia in the early stages.

Fingolimod, an S1P modulator, has been associated with posterior reversible encephalopathy syndrome. This condition involves swelling in the posterior brain regions (parietal/occipital lobes) caused by leakage of fluid from capillaries. It presents with acute confusion, visual changes, headaches and altered consciousness − a constellation of symptoms that could mimic derealisation and dissociation.

Symptomatic treatments. Abrupt withdrawal of baclofen and tizanidine, which are used for spasticity, can cause severe delirium, hallucinations and dissociation. Similarly, gabapentin and pregabalin, which are often used in people with MS to manage neuropathic pain, can cause sedation and cognitive clouding (‘zombie-like’ feeling) that contribute to depersonalisation.

Diagnosis

When someone with MS develops dissociative symptoms, doctors must first rule out physical (organic) causes before assuming the problem is purely psychological. A diagnostic algorithm should do the following.

1. Rule out an MS relapse
Any new onset of psychiatric or dissociative symptoms warrants an MRI scan with gadolinium. New lesions in the temporal, parietal or frontal lobes can directly cause these symptoms.

2. Rule out infection
Urinary tract infections are extremely common in MS and are the leading cause of acute confusional states (delirium) that can mimic dissociation. A urinalysis and a workup for other infections are mandatory.

3. Review medication
Assess for recent steroid use, cumulative damage from anticholinergic drugs (e.g. for bladder dysfunction) or withdrawal from muscle relaxants (baclofen and tizanidine).

4. Check balance and hearing
‘Neuro-otological examination’ is a specialised assessment for dizziness, vertigo, hearing loss and balance disorders. Checking for nystagmus (uncontrollable eye movements) helps to diagnose balance disorders. Treating vertigo may resolve the derealisation.

5. Carry out psychological screening
Your health professional can use the Dissociative Experiences Scale (DES-II) or the Dissociative Disorders Interview Schedule to quantify symptom severity. People with MS generally score in the normal range on DES-II unless they have comorbid DID or PTSD.

Differentiating organic from psychiatric dissociation is difficult. It may require referral to a neuropsychiatrist. MS-related brain fog or cognitive impairment with an organic basis is characterised by slowed processing speed, word-finding difficulties and fatigue. Patients try to engage but fail. In comparison, psychiatric dissociation is characterised by a subjective sense of detachment (‘I am not here’). Patients may have preserved processing speed but feel emotionally disconnected. As noted above, MS cog-fog often contains a dissociative component driven by anxiety. Treating the anxiety usually clears the ‘cog-fog’ more effectively than cognitive rehabilitation alone.

Management

Managing dissociative states in MS requires a dual approach: biological (i.e. treating the underlying MS disease) and psychological. 

Drug treatments

The primary prevention of organic dissociation involves preventing new lesion formation. High-efficacy DMTs are the best way to preserve brain volume and connectivity. Psychotropics such as selective serotonin reuptake inhibitors (e.g. fluoxetine, sertraline) can help manage the anxiety and depression that underlie DPDR. They may also help with MS-related fatigue. Antipsychotics (e.g. quetiapine, olanzapine) may be rarely indicated for managing steroid-induced psychosis or organic paranoia related to temporal lobe lesions. Lamotrigine and other anticonvulsants (e.g. carbamazepine and oxcarbazepine) can be used to treat both seizures and depersonalisation; they are particularly beneficial in patients with temporal lobe pathology. 

Psychological interventions

Cognitive behavioural therapy is the gold standard for treating DPDR. It helps patients reframe the terrifying sensation of ‘going crazy’ or ‘disappearing’ as a harmless (albeit distressing) symptom of anxiety or the disease. This reduces the catastrophic thinking that perpetuates the dissociation. 

Eye movement desensitisation and reprocessing (EMDR) can be effective for MS-related PTSD (medical trauma) or childhood trauma. However, standard EMDR can be overwhelming for patients with dissociation. Modified (e.g. ‘titrated’) EMDR protocols can prevent flooding the patient with traumatic memories before they have stabilisation skills. EMDR is available via some UK NHS psychiatric services. 

Grounding and mindfulness techniques (e.g. holding an ice cube, describing the environment) anchor the patient in the present moment and help them to manage acute episodes of derealisation. Mindfulness-based stress reduction has shown efficacy in improving the quality of life and reducing depressive symptoms in people with MS.

Vestibular rehabilitation therapy (VRT) is a specialised, exercise-based physical therapy designed to reduce vertigo, dizziness and imbalance. It should be offered to people with MS where derealisation is driven by vertigo. VRT helps the brain compensate for inner-ear deficits through personalised exercises that focus on gaze stabilisation, balance training and habituation. Physical therapy to improve balance and gaze stability can directly reduce the feeling of unreality. 

Conclusions

To self-manage dissociative states effectively, individuals with MS can proactively apply several key principles highlighted above. During acute episodes of derealisation or dissociation, employing practical grounding and mindfulness techniques – such as holding an ice cube or actively describing the immediate environment – can serve as vital tools to anchor oneself in the present moment. Furthermore, individuals can apply cognitive behavioural principles by ‘reframing’ their experiences. Recognising that terrifying feelings of ‘disappearing’ or ‘going crazy’ are often harmless symptoms of anxiety or the disease itself can help reduce the catastrophic thinking that perpetuates dissociation.

Effective self-management also involves staying vigilant about physical triggers (e.g. monitoring for signs of urinary tract infections or medication side effects) and pursuing targeted physical interventions, such as vestibular rehabilitation exercises, if feelings of unreality are driven by dizziness and balance issues. By combining these practical coping strategies with a clear understanding of the biological and psychological origins of their symptoms, individuals with MS can regain a sense of control and significantly reduce the impact of dissociative states on their daily lives.

References

  1. Bruce J, et al. Self-reported memory problems in multiple sclerosis: influence of psychiatric status and normative dissociative experiences. Arch Clin Neuropsychol 2010;25:39–48.
  2. Rehan ST, et al. Association of adverse childhood experiences with adulthood multiple sclerosis: A systematic review of observational studies. Brain Behav 2023;13:e3024.
DMTsDetail

Natalizumab

Summary

Natalizumab is a first-in-class selective adhesion molecule blocker that reduces the trafficking of lymphocytes into the central nervous system (CNS). It is a very high-efficacy DMT capable of achieving long-term NEIDA (no evident inflammatory disease activity) and limiting end-organ damage (brain volume loss) in most people with MS who receive it. Following rebaselining, average annual brain volume loss for patients treated with natalizumab is within the expected range for age-matched people without MS. Natalizumab has a rapid onset of action; when it is used early in the disease course, many people with MS report a reduction in symptoms of disability and fatigue.

One result of reduced lymphocyte trafficking in the brain is reduced immune surveillance. This puts patients receiving natalizumab at high risk of progressive multifocal leukoencephalopathy (PML) if infected with the JC virus that causes it. The risk of PML is variable and can be reduced by using extended interval dosing (EID), whereby natalizumab is given as a 6-weekly infusion and is very well tolerated. (Normally natalizumab is given every 4 weeks.) A small number of people with MS (<5%) may develop infusion reactions, which can be serious. Infusion reactions typically come on with the second, third or fourth natalizumab infusion and are associated with developing so-called neutralising antibodies (NAbs). 

Trade names

Tysabri.

Mode of action

Natalizumab is immunosuppressive, and it is associated with opportunistic infections, including PML, and possibly secondary malignancies of the CNS. Natalizumab is a monoclonal antibody that targets VLA-4 or α4β1 integrin on lymphocytes, preventing them from crossing the blood ̶̶ brain barrier. A lymphocyte must stick to the wall of a blood vessel before it can cross – like two surfaces of Velcro sticking together. Natalizumab blocks one of the surfaces so the lymphocytes cannot cross the blood vessel wall. People with MS on natalizumab treatment have more circulating white blood cells in their blood than normal. This is because the cells that normally adhere temporarily to blood vessel walls (marginating cells) are now found in the blood.

Efficacy

Very high, particularly in people with rapidly evolving severe MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but limited to the CNS.

Dosing

  • Tysabri 300 mg and Tyruko 300 mg are both administered by intravenous infusion once every 4 weeks. Tysabri is also available as a subcutaneous injection, given once every 4 weeks.
  • There is evidence that extended interval dosing (EID) of natalizumab – increasing the gap between infusions from 4 weeks to 5 or 6 weeks – may dramatically reduce the risk of PML.

Main adverse events of special interest

Infusion reactions

These tend to be mild and occur in about 20% of patients; they may be associated with headache, dizziness, nausea, urticaria and rigors.

Hypersensitivity reactions

These occur in approximately 5% of patients. In about a quarter of this 5% they can be anaphylactoid in nature and typically occur during the infusion or within an hour of completing the infusion. Hypersensitivity reactions are characterised by either a low or high blood pressure, chest pain, chest discomfort, shortness of breath, swelling of the throat, rash, urticaria, rigors, nausea, vomiting and flushing. Most hypersensitivity reactions occur on the second, third or fourth infusion and are associated with the development of anti-drug antibodies, i.e. your own body rejects natalizumab by making antibodies against it. Persistent anti-natalizumab antibodies develop in approximately 5 ̶ 6% of people with MS on natalizumab; they decrease the drug’s effectiveness and cause hypersensitivity reactions.

Infections

In general, natalizumab is not associated with systemic infections. As an immunosuppressive therapy, natalizumab has been associated with opportunistic infections, particularly PML. Other opportunistic infections include cryptosporidium diarrhoea and cryptococcal meningitis. Herpes infections (varicella zoster virus, herpes simplex virus) have occurred more frequently in patients receiving natalizumab than in those receiving a placebo. Serious life-threatening encephalitis and meningitis caused by herpes simplex or varicella zoster can occur on natalizumab. The presentation of these infections is atypical because reduced trafficking of cells into the CNS reduces the intensity of the inflammation. Rarely, these viruses may infect the retinae and lead to acute retinal necrosis and loss of vision.

PML and granule cell neuronopathy

JCV is the commonest opportunistic infection in seropositive natalizumab-treated people with MS. JCV can cause PML and granule cell neuronopathy (GCN). PML is the commonest complication of JCV, and its management is described separately. GCN is characterised by lytic infection of the cerebellar granule cell layer and presents with a cerebellar ataxia and cerebellar atrophy and white matter changes in the cerebellum and brainstem on magnetic resonance imaging (MRI). Many cases of GCN also have white matter changes elsewhere, suggesting an overlap between GCN and PML. There is evidence that increasing the time interval between natalizumab doses – extended interval dosing  – may dramatically reduce the risk of PML.

Abnormal liver function

Autoimmune hepatitis, increased liver enzymes and hyperbilirubinaemia rarely occur with natalizumab.

Anaemia

Rare cases of anaemia and haemolytic anaemia have been reported in natalizumab-treated people with MS.

Malignancies

Several cases of CNS lymphoma have been reported in natalizumab-treated people with MS. The risk of CNS lymphoma is likely to be increased based on the mode of action of natalizumab, i.e. it blocks immune surveillance of the CNS and hence there will be an increased risk of CNS tumours.

Neutralising antibodies (NAbs)

Yes, in approximately 5% of natalizumab-treated patients.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, JC virus-serology and pregnancy test.

Follow-up

LFTs 3-monthly for one year, NAbs at 12 months and JCV–serology every 6 months. In people with MS at high risk of PML, 3 ̶ 4-monthly MRI; otherwise, annual MRI for disease activity monitoring.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or human papillomavirus testing every 3 years.

Rebaselining

I recommend a rebaseline MRI 3 ̶ 6 months after starting treatment with natalizumab and including gadolinium enhancement as part of this.

Pregnancy

Animal studies have shown no toxicity from natalizumab, and data from clinical trials and post-marketing studies in humans suggest natalizumab exposure has no adverse effect on pregnancy outcomes. Babies born to people with MS on natalizumab have a transient mild-to-moderate low platelet count and anaemia, which typically disappear within weeks. Most neurologists now allow their female patients to fall pregnant whilst on natalizumab and then offer to stop it after they have become pregnant. Some neurologists are letting patients continue natalizumab throughout pregnancy. The decision to do this is based on the emerging safety profile of natalizumab in pregnancy and the risk of rebound MS activity when natalizumab washes out.

Breastfeeding

The amount of natalizumab that crosses over into the breast milk is very small and is likely to be digested by the baby’s digestive enzymes; therefore, it is safe to breastfeed on natalizumab.

Male fertility

Safe.

Vaccination

Safe for component or inactivated vaccines. Live vaccines are contraindicated. Live viruses, particularly ones that can infect the CNS, are potentially dangerous.

Summary of Product Characteristics (SmPC)

Tysabri, Tyruko.

Extended interval dosing

Reducing the risk of PML

At present, several factors can help us assess the risk of PML:  JC virus testing (negative and positive), level of JCV antibodies (antibody index), previous exposure to immunosuppression, and treatment duration. We also have frequent MRI monitoring (3 ̶ 4-monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if a patient develops PML. Another option to reduce the risk of PML may be extended interval dosing (EID).

I have several patients who, despite being JCV-seropositive, insist on staying on natalizumab rather than trying an alternative treatment. A few patients, even after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab. The reason typically relates to the return of MS fatigue, or brain fog, after stopping natalizumab. After restarting natalizumab, patients come back and say, ‘I feel well, my fatigue has gone, and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is good.

Rationale for extended interval dosing

The theory behind EID is that some cells are less sensitive than others to the effects of natalizumab; if you delay the next natalizumab infusion by 1 or 2 weeks, the saturation of the surface receptors drops below a threshold and allows those cells to traffic into the CNS. If these cells with lower sensitivity to natalizumab are the antiviral T cells and/or the natural killer cells that fight viruses, this could allow immune surveillance of the CNS to occur and prevent PML from developing. By achieving the correct EID, the saturation of the immune cells that cause MS (possibly the memory B cells) is sufficient not to allow MS to reactivate. Clearly, not all cells are equal when it comes to the effect of natalizumab. Importantly, several other adhesion molecules impact the adhesion (stickiness) of immune cells to the blood vessels in the CNS. A delicate balance between the availability of different accessory adhesion molecules could also make the difference.

When these principles were adopted by several neurologists in the USA, the data emerging from their centres suggested they were correct in hypothesising that the risk of developing PML was reduced when JCV-seropositive people with MS received EID natalizumab.

Comparison of extended and standard interval dosing

Biogen, the manufacturer of Tysabri, sponsored some large studies to explore this theory.1,2 Using the so-called TOUCH program (Tysabri Outreach: Unified Commitment to Health), which is a mandatory database of all people with MS receiving Tysabri in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on Tysabri; they compared those on EID with those on standard interval dosing (SID) for PML risk.1 The TOUCH programme is real-life data, not a clinical trial database, so the periods of EID are variable. To deal with this, the statisticians defined three types of EID with increasing stringency. The remarkable finding was that EID was seen to reduce the risk of PML significantly compared with SID in two of the analyses; in the most stringently defined cohort of EID there were rare cases of PML.

Clinical implications

I have acted on this finding and have offered EID to my patients taking natalizumab who are at risk of PML. It is advisable to transition to 6-weekly EID over several months so as not to precipitate pre-infusion worsening of symptoms. I am now recommending three infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question to consider is whether EID will be associated with some loss of natalizumab effectiveness. A recent study showed no loss of efficacy with EID.2 In addition, the study was not clear on finding a personalised dose. Therefore, all patients on EID received it every 6 weeks.

I personally am thrilled by these results. Why? Because anything that derisks PML for people with MS on natalizumab is good, particularly for people with more advanced MS. This is important because natalizumab is effective in more advanced MS, particularly in slowing down or preventing worsening of hand and arm function.

Switching-2-natalizumab  

Natalizumab

Recent data have shown that increasing the dosing interval between natalizumab infusions (EID) will lower the risk of developing PML.

Restarting natalizumab

Before restarting natalizumab it is important to do routine blood tests, a baseline MRI and check for anti-natalizumab antibodies. The presence of anti-natalizumab antibodies increases the risk of developing infusion reactions and is a contraindication to restarting natalizumab. It is not uncommon for someone with MS to want to switch back to natalizumab after trying another DMT. Natalizumab is known to reduce MS-related fatigue and brain fog, and this often returns when it washes out. The ability to reduce PML risk with EID will increase the number of patients requesting to go back onto natalizumab to help manage such cognitive symptoms.

Other DMTs

In general, natalizumab can be used after any of the DMTs provided the baseline screening bloods are satisfactory and there are no contraindications to the specific DMT. Some important caveats are highlighted below.

Interferon-beta and glatiramer acetate

I have no concerns and would not recommend any specific washout period after stopping either IFN-beta or glatiramer acetate.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

If you wish to start natalizumab after alemtuzumab or HSCT because of recurrent disease activity, I suggest doing so as soon as possible. Alemtuzumab and HSCT are immunosuppressive therapies, however, so if you are JCV-seropositive they will greatly increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-alemtuzumab or HSCT, I would question the need for natalizumab because both these DMTs can induce long-term remission.

Cladribine and anti-CD20 therapies (selective cell depleting DMTs)

If you wish to start natalizumab after cladribine or an anti-CD20 therapy because of recurrent disease activity, then I would suggest doing so as soon as possible. Cladribine and anti-CD20s are immunosuppressive therapies, however, so if you are JCV-seropositive they will increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-cladribine or an anti-CD20, I would question the need for natalizumab because these DMTs can induce long-term remission.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

No washout period is required when switching from an S1P modulator to natalizumab. However, if you have an infectious complication, particularly a CNS infection, then you would be ill-advised to start natalizumab until the CNS infection has been cleared. Natalizumab will prevent lymphocyte trafficking into the CNS and hence will blunt the immune response to the infectious agent. 

Fumarates (dimethyl fumarate and diroximel fumarate)

No washout period is required when switching from a fumarate to natalizumab. The same warning about CNS infections applies to fumarates as to S1P modulators mentioned above.

Teriflunomide

No teriflunomide washout period is required when switching to natalizumab. However, if your reason for switching to natalizumab is to control MS disease or fall pregnant, then you will need to undergo rapid teriflunomide elimination because of its long half-life and potential for teratogenicity.

Mitoxantrone

Mitoxantrone is an immunosuppressive therapy. Therefore, if you are JCV-seropositive it will increase your risk of developing PML and will render the so-called anti-JCV index unreliable.

Special circumstances

The presence of specific comorbidities and adverse events may make it difficult to start natalizumab after certain DMTs. These are, however, uncommon in routine clinical practice.

What about switching from natalizumab to another DMT?

A switch is relatively straightforward if you are JC virus-seronegative and are switching because of lack of efficacy or for a lifestyle choice, for example:

  • you are tired of monthly infusions (please note, however, there is now a subcutaneous formulation that is given as two injections)
  • you want an immune reconstitution therapy (IRT) that offers the freedom to fall pregnant without worrying about rebound activity
  • you simply prefer the long-term potential of an IRT.

In this situation, switching from natalizumab without a washout period, to prevent rebound disease activity after natalizumab, makes sense and should be a relatively safe option.

The situation if you are JC virus-seropositive is much more problematic because of the risk of carry-over PML. With a maintenance agent, such as an S1P modulator, we simply exclude asymptomatic PML by doing an MRI and, if you want to be extra vigilant, a lumbar puncture to look for JCV DNA in the spinal fluid. If these tests are clear, we start the S1P modulator as soon as possible after the last natalizumab infusion, knowing that if PML should develop we can stop the S1P modulator and it will be cleared from the body within 4 ̶ 6 weeks or less (depending which S1P modulator you are taking). This early switching strategy also prevents rebound activity when natalizumab wears off after approximately 3 ̶ 4 months.

With an IRT, such as alemtuzumab, things are more complicated because we can’t reverse its action. Hence, we must be confident that there is no carry-over PML. Why am I so concerned? Simple: if you develop carry-over PML post-alemtuzumab, before reconstitution of your immune system, you are likely to succumb to PML – which is potentially fatal. We rely on a functioning immune system, in particular a population of cells called CD8+ cytotoxic T lymphocytes, to clear the JC virus from the brain. CD8+ lymphocytes take many months to reconstitute post-alemtuzumab and other IRTs, during which time the PML is unchecked.

You might argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression, on the other hand, can be derisked to some extent and its consequences – in particular, opportunistic infections – can be treated. For more information, please read the sections on each DMT.

We now know that people with MS who are JCV-seropositive either need to come off natalizumab or switch to EID, because of the risk of PML. For high-risk subjects who decide to stay on natalizumab we offer 3-monthly MRI studies to detect asymptomatic PML, which has a better prognosis than symptomatic PML.

References

  1. Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
  2. Foley JF, et al. NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608 ̶ 19.
DMTsSafety

Natalizumab PML

What is PML?

PML stands for progressive multifocal leukoencephalopathy and is a relatively rare, potentially fatal disease of the brain caused by a viral infection. PML is characterised by progressive damage to the brain’s white matter, typically in multiple different areas – hence the descriptor ‘multifocal’. It is triggered by the JC virus (JCV), which causes a persistent infection that is normally kept under control by your immune system. (JC refers to John Cunningham, the patient in whom PML was first described; the tradition of naming viruses after patients has now stopped.) The JC virus is harmless and only causes problems in people who are immunocompromised or have a weakened immune system.

You can get infected with the JC virus at any time. Infections start in childhood and increase gradually; by adulthood, about 50 ̶ 60% of the general population are infected with the virus. JCV causes an asymptomatic primary, or initial, infection; in other words, you have no known ill effects. The virus then resides in the kidney and possibly the bone marrow and lymphoid tissue. Infected people intermittently shed the virus in their urine and saliva, spreading the infection to others; we estimate that about 0.5% of the population gets infected every year.

Your immune system responds to the virus by making antibodies, i.e. you become JCV– seropositive. We detect these antibodies with a simple blood test. We assume that all JCV-seropositive people are still infected with the virus.

How does the JC virus cause PML?

If you are immunocompetent, your immune system keeps the virus in check. If your immune system is compromised, however, JCV replicates and mutates. Some of the mutants acquire the ability to infect glial cells in the brain. Once the mutant JCV infects the glial cells, it hijacks the cells’ machinery and reproduces itself, causing the cells to burst and release thousands of new viruses to infect adjacent cells. When a critical number of glial cells are infected and destroyed, focal neurological symptoms develop. The type of symptoms associated with PML depends on the areas of the brain infected with the virus. PML symptoms are non-specific and can mimic an MS relapse, leading to misdiagnosis initially. Some common PML presenting symptoms include a change in cognition, personality and performance of complex motor tasks (apraxia), accompanied by seizures.

How do you diagnose PML?

PML is diagnosed clinically with the aid of a magnetic resonance imaging (MRI) scan and cerebrospinal fluid to detect the virus using a lab test called JCV-DNA PCR. Occasionally a brain biopsy is required to make the diagnosis, but this is rare nowadays.

How common is PML in people with MS?

PML is quite rare in people with MS and was not reported until the era of immunosuppressive DMTs. (This lack of earlier reporting may be because of misdiagnosis.)

PML is particularly a problem with natalizumab. Natalizumab blocks the trafficking of lymphocytes into the central nervous system (CNS) and thereby prevents the immune system surveying the brain and spinal cord for viruses. PML also occurs with other immunosuppressive therapies, unrelated to previous natalizumab treatment, including fingolimod and dimethyl fumarate.

Carry-over PML

Some people with MS have developed PML while on alemtuzumab, teriflunomide, fingolimod, rituximab or ocrelizumab as a carry-over effect from previous natalizumab therapy. We assume here that the PML was asymptomatic when they stopped natalizumab and only presented after they had switched to another DMT. PML is classified as ‘carry-over’ if it occurs within 12 months of stopping natalizumab. However, I don’t believe the risk from natalizumab ever goes away because PML is a complex disease and takes time to develop. The mutant strain that evolves to potentially cause PML may persist in the body long term and hence increase your risk, or at least lower your threshold, for developing PML in the future if you remain on immunosuppression.

How do I know if I’m at risk of PML?

JCV-seropositive test result

Everyone with MS on natalizumab is at risk of PML. If you are JCV-seronegative your risk of PML is very low, unless you become infected with the virus; each year, about 0.5 ̶ 2% of people with MS who are JCV-seronegative become seropositive. If you are JCV-seropositive your risk increases with duration of natalizumab treatment; it is particularly low if you have been on natalizumab less than 12 ̶ 24 months.

Raised JCV antibodies

The level of antibody against JCV also predicts risk. In people with a raised JCV antibody index, the high or rising level of antibodies indicates ongoing active infection, which boosts the antibody response. This means the virus is active, possibly mutating, so there is a higher risk of developing PML. People with MS who were previously on an immunosuppressive therapy such as mitoxantrone or azathioprine are also at high risk of developing PML. Immunosuppressive therapies presumably allow the virus to escape immune surveillance, to acquire the necessary PML-associated mutations and thus to put you at higher risk.

Not everyone with MS who is JCV-seropositive sheds virus; a subset of individuals may have cleared the virus from the body and hence be at low risk of PML. This may explain why a persistently low index of antibodies to JCV indicates a low risk of PML, i.e. it suggests past infection and no active infection at present.

Immunosuppressive therapy

Immunosuppressive therapies also blunt the immune response to the virus and affect the JCV antibody index. People with MS previously exposed to immunosuppression are still at high risk of developing PML even if they have a low JCV antibody index. This makes the index unreliable in people with MS previously exposed to an immunosuppressive therapy. The following table and graph summarise these risk factors.

Barts-MS PML Risk Guide table simplified_27 06 23

Key risk factors for developing PML; risk increases with increasing time on Tysabri. Based on manufacturer’s February 2023 data and modified from Barts-MS PML Risk Guide. Extrapolated extended interval dosing values show ~94% risk reduction compared with standard dosing.
IS, immunosuppressive therapy; JCV, JC virus; PML, progressive multifocal leukoencephalopathy.

Extended interval dosing

Reducing the risk of PML

At present, several factors can help us assess the risk of PML:  JC virus testing (negative and positive), level of JCV antibodies (antibody index), previous exposure to immunosuppression, and treatment duration. We also have frequent MRI monitoring (3 ̶ 4-monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if a patient develops PML. Another option to reduce the risk of PML may be extended interval dosing (EID).

I have several patients who, despite being JCV-seropositive, insist on staying on natalizumab rather than trying an alternative treatment. A few patients, even after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab. The reason typically relates to the return of MS fatigue, or brain fog, after stopping natalizumab. After restarting natalizumab, patients come back and say, ‘I feel well, my fatigue has gone, and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is good.

Rationale for extended interval dosing

The theory behind EID is that some cells are less sensitive than others to the effects of natalizumab; if you delay the next natalizumab infusion by 1 or 2 weeks, the saturation of the surface receptors drops below a threshold and allows those cells to traffic into the CNS. If these cells with lower sensitivity to natalizumab are the antiviral T cells and/or the natural killer cells that fight viruses, this could allow immune surveillance of the CNS to occur and prevent PML from developing. By achieving the correct EID, the saturation of the immune cells that cause MS (possibly the memory B cells) is sufficient not to allow MS to reactivate. Clearly, not all cells are equal when it comes to the effect of natalizumab. Importantly, several other adhesion molecules impact the adhesion (stickiness) of immune cells to the blood vessels in the CNS. A delicate balance between the availability of different accessory adhesion molecules could also make the difference.

When these principles were adopted by several neurologists in the USA, the data emerging from their centres suggested they were correct in hypothesising that the risk of developing PML was reduced when JCV-seropositive people with MS received EID natalizumab.

Comparison of extended and standard interval dosing

Biogen, the manufacturer of Tysabri, sponsored some large studies to explore this theory.1,2 Using the so-called TOUCH program (Tysabri Outreach: Unified Commitment to Health), which is a mandatory database of all people with MS receiving Tysabri in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on Tysabri; they compared those on EID with those on standard interval dosing (SID) for PML risk.1 The TOUCH programme is real-life data, not a clinical trial database, so the periods of EID are variable. To deal with this, the statisticians defined three types of EID with increasing stringency. The remarkable finding was that EID was seen to reduce the risk of PML significantly compared with SID in two of the analyses; in the most stringently defined cohort of EID there were rare cases of PML.

Clinical implications

I have acted on this finding and have offered EID to my patients taking natalizumab who are at risk of PML. It is advisable to transition to 6-weekly EID over several months so as not to precipitate pre-infusion worsening of symptoms. I am now recommending three infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question to consider is whether EID will be associated with some loss of natalizumab effectiveness. A recent study showed no loss of efficacy with EID.2 In addition, the study was not clear on finding a personalised dose. Therefore, all patients on EID received it every 6 weeks.

I personally am thrilled by these results. Why? Because anything that derisks PML for people with MS on natalizumab is good, particularly for people with more advanced MS. This is important because natalizumab is effective in more advanced MS, particularly in slowing down or preventing worsening of hand and arm function.

Can you treat PML?

The short answer is no. Some potential treatments for PML have been proposed, but none has been shown to work. In the MS context, you need immune reconstitution to clear the virus from the brain, and herein lies the problem. When you remove natalizumab with either plasma exchange or by waiting for it to wash out spontaneously, your immune cells start re-trafficking into the brain and you develop encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome) and it can be potentially very dangerous. Therefore, in patients with a large PML burden or PML in strategic brain areas such as the brainstem, we try to reduce the damage associated with IRIS by giving steroids. Anecdotal experience suggests steroids work.

Is there another strategy that we can try? The anti-HIV drug, maviroc, blocks a particular chemokine receptor (CCR5) on lymphocytes and may help prevent or dampen down IRIS. T cells, including cytotoxic CD8+ T cells, use the CCR5 receptor to cross the blood ̶ brain barrier. Blocking CCR5 seems to dampen down IRIS, and in two reported cases it appeared to prevent IRIS-related damage. Clearly, maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. To determine whether maraviroc does this more effectively than steroids will require a clinical trial.

The mainstay of treating natalizumab-associated PML is reversal of the natalizumab effect. Plasma exchange can speed this up, i.e. removal of the plasma and hence the circulating natalizumab. When natalizumab levels in the peripheral blood fall sufficiently low, the receptors become active again and immune system re-trafficking occurs, allowing your own T cells to fight the infection. However, recent data suggest that benefits of plasma exchange are marginal and for this reason most centres don’t perform plasma exchange to treat PML.  A problem arises when we can’t reconstitute CNS immunosurveillance. This can happen after immune reconstitution therapy, particularly with alemtuzumab or possibly cladribine, or in people with persistent lymphopaenia. One strategy here is an immune transplant, i.e. giving donor anti-JCV lymphocytes to someone with PML, matched to their own HLA (human leukocyte antigens), to fight the JCV infection. This strategy has helped several people recover from PML who might otherwise have died.

I hope that cases of natalizumab-associated PML become increasingly rare. Now that we have derisking strategies and other safer, highly effective DMTs, should we continue to put people with MS at such a high risk of PML? However, until we get a drug that clears JCV from the body we will never remove the PML risk completely. It is a complication of immunosuppression and therefore it will remain a rare complication of our MS treatments. Further information about natalizumab can be found under DMT: Details

References

  1. Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
  2. Foley JF, et al. NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608 ̶ 19.