Article Text
PDF
Abstract
Immune checkpoint inhibition unleashes the power of the immune system against tumour cells. Immune checkpoint inhibitors (ICIs) block the inhibitory effects of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed death protein 1 (PD-1), programmed death ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3) molecules on T-cells, and so enhance physiological cytotoxic effects. ICIs can significantly improve survival from cancers, including those previously associated with poor treatment response, such as metastatic melanoma. However, on-target off-tumour effects of ICIs result in immune-related adverse events. These toxicities are common and require new multidisciplinary expertise to manage. ICI neurotoxicity is relatively rare but ominous due to its severity, heterogenous manifestations and potential for long-term disability. Neurotoxic syndromes are novel and often present precipitously. Here, we describe ICI mechanisms of action, their impact on cancer outcomes and their frequency of immune-related adverse events. We focus particularly on neurotoxicity. We discuss the current appreciation of neurotoxic syndromes, management strategies and outcomes based on clinical expertise and consensus, multi-specialty guidance. The use of immunotherapy is expanding exponentially across multiple cancer types and so too will our approach to these cases.
- NEUROONCOLOGY
- NEUROTOXICOLOGY
Data availability statement
No data are available.
Statistics from Altmetric.com
Introduction
Immune system activation is an extremely effective anticancer therapy that has revolutionised oncological clinical practice over the last decade.1 The immune checkpoint inhibitors (ICIs) are a group of drugs that ‘take the brakes’ off the normal immune response and facilitate immunological, as opposed to traditional cytotoxic, anti-cancer effects. However, alongside the hugely improved survival rates across a broad range of cancers, there can be a plethora of immune-related toxicities affecting multiple body systems, including the nervous system2 (see table 1). Therefore, the mechanism of action of these drugs, their impact on cancer prognosis and their potential for triggering immune-related neurological complications are increasingly important and relevant to clinical neurology.
Range and frequency of multisystem ICI-toxicities
This immune activation causes toxicity in those exposed to ICI therapy through an overspill effect (on-target, off-tumour). Most patients in the early clinical trials developed some degree of immune-related adverse event.3 Dermatitis, colitis, hepatitis, pneumonitis and immune-related endocrinopathies are the most common organ systems affected.4 5 Oncologists have developed screening tools and clinical skills for recognising these complications early with support from relevant specialists. Recommendations for treating immune-related adverse events come from general consensus based on scientific literature, clinical experience and analogy to treatment of autoimmune diseases.6 There have been no prospective trials to test specifically whether one management strategy is better than another, but expertise has developed over the last decade. According to the 2022 European Society for Medical Oncology (ESMO), clinical practice guideline for toxicities of immunotherapy, the bedside approach comprises four sequential steps: (1) diagnosis and grading of immune-related adverse events, (2) ruling out differential diagnoses and pre-immunosuppression work-up, (3) selecting the appropriate immunosuppression strategy for grade 2+ events and (4) active evaluation at 72 hours to adapt treatment (table 2). The mainstay of medical management is to pause ICI therapy and treat with corticosteroids according to functionally assessed toxicity grade (Cancer Therapy Evaluation Programme, 2017) (table 3), but more nuanced therapeutic strategies are often required.
Oncology/neurology approach to ICI toxicity
Common Terminology Criteria for Adverse Events (CTCAE) grade definitions
With single agent regimens, most immune-related adverse events are mild, reversible and carry no significant short or long-term morbidity or mortality. Grades 3 or 4 toxicity occurs in 10%–20% and is more common with but not exclusive to anti-CTLA-4 (cytotoxic T-lymphocyte associated protein 4) agents.7 This incidence is proportionately similar to that of grade 3+ adverse events seen with many standard chemotherapy or targeted therapy regimens.8 9 However, ICI therapies are frequently used in combination, for example anti-CTLA-4 with PD-1 (programmed death protein 1) or PD-L1 (programmed death ligand 1) inhibitors or with LAG3 (lymphocyte activation gene 3) inhibitors. In this scenario, 50% of patients may experience grades 3–4 immune-related adverse events. Up to 20% can have irreversible endocrine complications requiring lifelong management and 15% of melanoma patients develop irreversible vitiligo. In the context of improved cancer survival, these long-term iatrogenic adverse effects can represent a significant burden for the patient. As soon as immune-related adverse event severity reaches grade 2+, it is strongly recommended to involve the appropriate specialist.
There are some particular considerations for neurological immune-related adverse events. ICI neurotoxicities tend to be severe at presentation, predominantly Common Terminology Criteria for Adverse Event (CTCAE) grade 3+ (table 3). Inpatient mortality rate approached 30%–40% in early reports.10 11 Any acute inflammatory neurological insult has the potential for long-term disability if not optimally managed at presentation. Moreover, the clinical phenomenology of neurotoxicity is diverse and spans the whole of the central and peripheral nervous system. The myriad neurological presentations require specialist expertise for clinical phenotyping, directing and interpreting appropriate investigations, and monitoring/management of the recovery and rehabilitation phase. Also, given the relative rarity of ICI neurotoxicity, there is significant potential for other neurological disorders to occur in these patients. Careful consideration of the differential diagnosis has implications for access to appropriate treatment, potential re-institution of life-saving ICI-cancer therapy and the avoidance of immunosuppression and its associated adverse effects (table 2).
Here, we discuss the neurological manifestations associated with ICIs reported in the literature and seen by a range of specialist neurotoxicity services in the UK (NHNN and UCLH oncology, Cardiff Neurosciences Departments, Royal Marsden Hospital and Liverpool ICI toxicity service). We describe our experience with diagnosis, treatment and outcome. We include specialist oncology input on the use and expanding application of these drugs and consider how neurology can best contribute to the care of these patients. Checkpoint inhibitor use is expanding rapidly, and it is therefore highly likely that ICI neurotoxicity will be seen increasingly frequently.
Mechanism of action
The molecules targeted by ICIs include CTLA-4 and PD-1 receptors on CD4+ T cells, and LAG3 on CD8+ T cells. In addition, PD-L1 receptors are sometimes upregulated by the tumour and are normally expressed on the antigen presenting cell (figure 1a). These molecules are essential to normal immune homeostasis and can be considered as the ‘off switches’ for activated T cells.12 It is interesting that inherited deficiency of either PD-1 or CTLA-4 results in tissue specific autoimmune disorders13 and pathogenic mutations in CTLA-4 increase risk of lymphoproliferative diseases.14
T cell interaction with tumour or antigen presenting cell (APC). Immune checkpoint inhibitor sites of action are shown. (a) T cell activation: proliferation, maturation and recruitment of immune effector cells (neutrophils/macrophages) via pro-inflammatory cytokine/chemokine release. (b) Immune homeostasis: T cell inhibition/apoptosis of immune effector cells. (c) Sustained T cell activation via inhibition of regulatory molecules. CTLA-4, cytotoxic T-lymphocyte associated protein 4; MHC, major histocompatibility complex; LAG-3, lymphocyte activation gene 3; PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; TCR, T cell receptor.
Physiologically, T-cells are activated by presentation of an antigen by the major histocompatibility complex receptor on the APC to the T-cell receptor. Costimulation occurs through engagement of the T-cell expressed CD28 and APC-expressed CD80/86 ligand. Activation of CD4+ and CD8+ T cells results in T-cell proliferation, cytokine and chemokine release, cytokine-mediated T-cell maturation, and the recruitment of immune effector cells (neutrophils and macrophages) to the site of inflammatory response (figure 1a). To control and limit this response, CD28 stimulation induces almost immediate upregulation of CTLA-4 by the newly activated T-cell. CTLA-4 then competes for binding with CD80/86 leading to inhibition of the T-cell response. The other molecules discussed here are markers of T-cell exhaustion. PD-1 and LAG3 localise to the surface at the late stages of T cell activation when the T cell has been subjected to repeated stimulation. They provide additional pathways through which the exhausted T cell can be downregulated and ultimately inactivated.15 16 PD-1 interacts with its target molecule PD-L1 on the tumour cell or antigen presenting cell, inducing a negative effect on T cell activity on engagement (figure 1b). Histological staining shows marked upregulation of PD-L1 in a range of solid tumours, including triple negative breast cancer and glioblastoma.17 PD-L1 upregulation is a mechanism by which tumours may try to evade natural immune surveillance.
It is through the molecule-specific blockage of these self-regulatory receptors and the subsequent sustained T-cell activation, that ICIs impart their powerful, immune-mediated anti-cancer effects (figure 1c).1 18
Impact on cancer outcomes
Harnessing of T-cell power has radically altered the treatment paradigm across multiple cancers. For metastatic melanoma, the archetypal application for ICI therapy, combination therapy with ipilimumab and nivolumab has improved overall median survival to over 70 months, compared with less than 6 months with traditional chemotherapy, and 57% of patients are alive at 6.5 years.19 Following success with metastatic disease, checkpoint inhibitors are now also the standard of care in the adjuvant setting for earlier stage melanoma following surgical resection and are even moving to the neoadjuvant setting.20 21
The impact of ICIs has been felt across other solid tumours too. A study from the USA found that almost half of all patients with advanced cancer in the developed world would be eligible for checkpoint inhibitor therapy. There are now eight different ICIs approved across 17 different cancers (figure 2).22 Checkpoint inhibitors are also being used in combination with multiple other drugs, including targeted therapies such as tyrosine kinase inhibitors, other immunomodulatory drugs and chemotherapy. While there may be very good biological rationales for these combinations, it is becoming ever more complex to manage the associated toxicities.23
Immune checkpoint inhibitor approvals by individual cancer type since 2011. Adjuvant and neoadjuvant indications from 2021 not shown. BCC, basal cell carcinoma; CTLA-4, cytotoxic T-lymphocyte associated protein 4; cSCC, cutaneous squamous cell carcinoma; ESCC, oesophageal squamous cell cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; LAG-3, lymphocyte activation gene 3; LBCL, large B-cell lymphoma; MSI, microsatellite instability; MSI-CRC, microsatellite instability in colorectal cancer; NSCLC, non-small cell lung cancer; PD-1, programmed death protein 1; PD-L1, programmed death ligand 1; RCC, renal cell carcinoma; SCLC, small cell lung cancer.
Immune-related adverse events
Given their mechanism of action, it is not surprising that ICIs are associated with high rates of immune-mediated off-tumour effects. In the original Checkmate 067 trial in metastatic melanoma, which compared combined nivolumab and ipilimumab to each agent as monotherapy, 99% of those treated experienced an adverse event. Between 43% and 55% of adverse events were CTCAEs grade 3 or higher with monotherapy (either CTLA-4 or PD-1 inhibition) and 68% with dual therapy (combination CTLA-4 and PD-1 inhibition).24
In the context of all immune-related toxicities, neurological manifestations are relatively rare. Neurotoxicity occurs in 1%–4% of those on monotherapy25 26 and up to 14% on combination ICI treatment.27 28 Given the rarity of ICI neurotoxicity, many cases of neurological dysfunction in patients on ICI therapy may not relate to the ICI itself. Common neurological complaints such as migraine or mechanical radiculopathies can be easily identified by a neurologist and occur frequently in this cohort of patients who tend to be middle to late age and may have multiple comorbidities. Other cancer-related neurological pathologies are extremely important to identify and require a careful appreciation of clinical signs and investigative findings. Such diagnoses include infiltrative disease or neurotoxic effects of traditional chemotherapies. Correct classification and diagnosis of non-immune related neurology is important for access to appropriate treatment, can facilitate re-institution of potentially life-saving ICI cancer therapy, and can reduce adverse effects associated with inappropriate exposure to high-dose corticosteroids or other immunosuppressants. In our experience, prompt and careful clinical assessment of patients with possible ICI neurotoxicity referred to a specialist neurology service results in revision of the diagnosis in 50%–70% of cases.29 30
In addition to providing diagnostic security, neurologists can augment the management of patients with ICI neurotoxicity by:
Localising the lesion anatomically and recognising syndromes.
Identifying subacute progression supporting immune-related pathogenesis and differentiation from other aetiologies of neurological deficits.
Directing the selection of appropriate investigations and guiding their interpretation.
Appreciating and providing guidance on tempo and potential for neurological recovery.
Figure 3 provides a basic algorithm for managing ICI neurotoxicity. This is adapted from published guidelines created by international oncology organisations and published by experts in the field.6 7 31
An algorithmic approach to ICI-neurotoxicity. #Clinical assessment and directed investigation are key to diagnosis, there is no shortcut to informed neurological opinion.+Always consider the co-occurrence of another organ ICI-toxicity and manage with the input of the appropriate specialist. £Aim for the lowest cumulative dose of corticosteroids required to control symptoms. &Ensure appropriate prophylaxis: PPI cover and adequate bone protection as per local guidance. *MMF is the most common steroid-sparing medication recommended in this setting: start at 500 mg once a day, increasing by 500 mg every 2 weeks to a target dose of 1–1.5 mg two times a day with appropriate safety monitoring. **Consider IVIg or plasma exchange when evidence of humoral element to pathophysiology for example, AChR antibodies or MOG antibodies. ˆUnlicensed indications: consensus opinion required, likely to need individual funding request. ↑Focus points for national ICI-neurotox MDT input. ADL, activities of daily living, instrumental ADLs (cooking, cleaning); FcRN, neonatal Fc receptor inhibitor (eg, efgartigimod); ICIs, immune checkpoint inhibitors; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; MMF, mycophenolate mofetil.
Neurological immune-related toxicities
Immune-related neurotoxicity can affect any part of the nervous system with symptoms and signs correlating to the anatomical localisation of the inflammation (figure 4). A huge range of presentations have been described in the literature, usually in case reports or small, single-centre case series. However, there are some consistent patterns. In the larger, well-described case series and systematic reviews, the peripheral nervous system (myositis, myasthenia or neuritis) is much more commonly involved than the central nervous system (meningitis, myelitis and encephalitis). The ratio ranges from 4:1 to 6:1 and is consistent with our experience.30 Interestingly, multi-focal inflammation may involve the central and peripheral nervous system concurrently (neuritis and myelitis), or multi-system inflammatory manifestations may co-occur alongside a neurological syndrome (myasthenia with myocarditis, or neuritis with uveitis). It is important to be aware of the potential for overlap syndromes as involving the appropriate specialist can help to guide management and improve outcome. Sometimes the clinical syndrome is very recognisable, as in the typical fatiguable ptosis, diplopia, dysarthria, dysphagia and limb weakness of autoimmune myasthenia. Often, however, the clinical presentation, neurophysiology and histology may also be distinct and novel. For this reason, pre-existing nomenclature is often not appropriate for ICI neurotoxicity, despite common application, for example, Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) for ICI-neuritis.
Case examples of some of the different syndromes associated with immune checkpoint inhibitor. ADM, abductor digiti minimi; APB, abductor pollicis brevis; CK, creatine kinase; CSF, cerebrospinal fluid; EEG, electroencephalogram; FDIO, first dorsal interosseous; GAD, gadolinium contrast agent; IVIg, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; MOCA, Montreal cognitive assessment; MRC, Medical Research Council; MOG, myelin oligodendrocyte glycoprotein; NIV, non-invasive ventilation; OCBs, oligoclonal bands; PLEX, plasma exchange.
Figure 4 provides example cases seen in our practice over the last few years. These include ICI-encephalitis, ICI-induced acute disseminated encephalomyelitis with myelin oligodendrocyte glycoprotein antibody-associated disease, ICI-neuritis (polyradiculoneuritis and sensory ganglionopathy) and triple M syndrome (myasthenia, myocarditis and myositis). We provide information on timing and semiology of presentation, investigation findings, treatment and outcome. In the following section, we expand our description of some of the ICI-specific clinical syndromes that appear more frequently: triple M syndrome, ICI-neuritis and ICI-vestibulitis. We highlight some important differences between the ICI-induced manifestations of these diseases and their spontaneous, tissue-specific autoimmune counterparts.
Triple M syndrome
Triple M syndrome, also known as MMM overlap syndrome, is the co-occurrence of myasthenia, myocarditis and myositis. The actual frequency has not yet been reliably established but its incidence appears to be increasing, in line with increasing familiarity and recognition. Triple M syndrome most frequently occurs within weeks of treatment with PD-1 inhibitors (eg, pembrolizumab) and is more common in elderly males.32 A challenge in its diagnosis and management is that not all three components of the triad are always obvious, or even present. The finding of any one of the features of triple M syndrome soon after ICI exposure should prompt a dedicated search for the other two. This is especially important as the overall mortality rate of triple M syndrome is 37%. Coordinated multi-specialty management, incorporating neurology, cardiology, oncology and often intensive care can result in more positive outcomes. In a recent large case series, the likelihood of good long-term functional recovery in ICI myasthenia survivors was high with most people returning to a modified Rankin score of 1 at 6 months follow-up.33 This recovery is consistent with our experience, suggesting that assertive medical management in the acute phase can facilitate recovery. A national consensus guideline for managing triple M syndrome is being developed, with input from the Association of British Neurologists, British Cardio-Oncology Society and UK Systemic Anticancer Therapy Board.
The bedside assessment of myasthenia is part of standard clinical practice for neurologists, and findings are specific to neuromuscular junction dysfunction. Patients present with fatiguable ptosis, diplopia, dysarthria, neck extensor and limb girdle weakness. There is demonstrable minute-to-minute fatiguability, as occurs in typical autoimmune myasthenia gravis. The confident elucidation of diagnostic signs can facilitate a definite diagnosis at the bedside without waiting for serological or neurophysiological tests. Although most (68%) ICI-myasthenia is AChR antibody positive, this test may initially be negative, becoming positive over time. The turnaround time for AChR antibodies can be up to a few weeks depending on hospital and laboratory, which poses a challenge in this rapidly progressing clinical scenario. Neurophysiology can be supportive, but it is important to remember that neither repetitive nerve stimulation nor single fibre electromyography (EMG) is perfectly sensitive or specific to neuromuscular junction dysfunction, though single-fibre EMG is superior.34 Therefore, the diagnostic tool of choice is assessment by a neurologist.
Positive clinical findings should trigger introduction of appropriate medical management and monitoring of neuromuscular respiratory status. Of the 70 individual cases of triple M syndrome reported in the literature, 41%–64% required intensive care unit admission for ventilatory support. Respiratory failure was the most common cause of death.32 Careful cardiac monitoring is also required when myocarditis is present, and decisions about the optimal location to manage patients with triple M syndrome can be challenging.
ICI-myocarditis can occur in isolation and our understanding of the consequences and management of this condition comes from the cardio-oncology experience. Cardiac muscle inflammation is marked by elevated troponin and dysrhythmia, particularly bradycardias or heart block. Troponin is a sensitive, specific and responsive biomarker with a rapid turnaround time and high availability across most healthcare systems. However, clinicians should note whether troponin I or troponin T is being tested, as numerical values differ between assays. Either is acceptable, but in ICI-myocarditis daily trajectory is important so consistency is critical.
Cardiac rhythm monitoring requires specialist equipment and experienced staff and is not commonly accessible on neurology wards. Patients with serum troponin >1000 ng/L should have 24-hour cardiac monitoring. Persistent or symptomatic bradycardia or block warrants discussion with a cardiologist or cardio-oncologist for consideration of temporary pacing. Clinicians should avoid using medications that might exacerbate bradycardia, including pyridostigmine and neostigmine, which might be considered in early symptom management of the myasthenia.
The third component of triple M syndrome, ICI-myositis, may also occur in isolation. ICI-myositis typically presents with limb girdle pain, weakness and elevated serum creatine kinase (CK) in the range of 600–60 000 IU/L. The presence of myopathy can confuse the clinical assessment of triple M syndrome by masking myasthenic fatiguability and also complicate the interpretation of neurophysiology tests. Awareness of the co-occurrence of multi-tissue inflammation is helpful in guiding clinical interpretation and monitoring.
Although the understanding of the optimal management of triple M is evolving, it is generally accepted that isolated ocular myasthenia can be managed with pyridostigmine alone with or without withdrawal of ICI. The first line treatment of triple M syndrome is high-dose corticosteroids as per 2022 ESMO guidelines.6 Intravenous methylprednisolone followed by prednisolone at 1 mg/kg is often effective and a meaningful reduction in troponin and CK with resolution of myalgia usually occurs within days. Early introduction of either intravenous immunoglobulin (IVIg, 1 g/kg over 2–5 days) or plasma exchange can help the myasthenia outcome. The pathophysiological basis for IVIg or plasma exchange is their impact on humoral elements (AChR antibodies). In steroid-refractory cases (persistently elevated troponin >1000 ng/L, and/or ongoing myasthenia signs and/or CK >500 IU/L despite treatment), then second-line treatment with mycophenolate mofetil may be adequate. Abatacept has shown promise in steroid-resistant ICI myositis and triple M syndrome, where PD-1 inhibition is the common driver, due to its high affinity for CD28. Abatacept blocks the activating CD28-CD80-CD86 interaction between the T-cell and APC. In this way, abatacept enhances the inhibitory effect of CTLA-4 engagement to counteract PD-1 mediated T-cell over-activation.35 In cases where troponin remains elevated despite first-line therapy, an echocardiogram to monitor for cardiac decompensation is sensible, with ongoing cardiac rhythm monitoring and access to pacing if required. There is some evidence for the benefit of JAK inhibitors (tofacitinib and ruxolitinib) in refractory ICI myositis.36
Because troponin is a highly available and sensitive bedside test, myocarditis is often diagnosed early, especially if under care by a specialist cardiology unit, with the other elements of triple M syndrome becoming apparent only later. In the cardio-oncology setting, proactive screening for elevated CK is recommended but awareness of the clinical signs of myasthenia can be challenging. The concept of the ‘steroid dip’ in myasthenia is not universally accepted but the potential worsening of myasthenic weakness around day 10 of steroids is acknowledged and does influence our current approach to MG crisis management. There are reports in the ICI literature of myasthenic decompensation in triple M syndrome patients after starting high-dose corticosteroids when the treatment driver may have been biomarkers of cardiac dysfunction. One case series showed a definitive improvement in triple M outcome after the early introduction of IVIg into the treatment algorithm.37 When myasthenic symptoms are refractory there is some justification for using rituximab, complement inhibitors (zulicoplan or eculizumab) or neonatal Fc receptor blockers (FcRn, efgartigimod) given the evidence for efficacy of these agents in autoimmune MG.7 However, in the UK not all these drugs are licenced, either for autoimmune MG or ICI-related myasthenia, and so access to these drugs probably requires individual funding requests.
ICI-neuritis
Much of the early ICI neurotoxicity literature describes GBS- or CIDP-like neuropathy presentations. There are some similarities between these clinical syndromes and the most common pattern of neuropathy seen with ICIs, which is better labelled ICI-neuritis.38 ICI-neuritis presents with a subacute onset over weeks but with progression beyond the 4 weeks from onset to nadir that would define GBS. The pattern is often a symmetrical, non-length-dependent neuropathy with positive sensory phenomena but more neuropathic discomfort than is typical for CIDP. There is a proximal and distal pattern of weakness and areflexia. Neurophysiological testing shows an axonal pattern with attenuated sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs) with relatively spared conduction velocities but absent F waves, reflecting the polyradicular pattern of inflammation. However, features of demyelination can also develop.39 Cerebrospinal fluid (CSF) can be inflammatory, with white cells >10 cells/µL, but cytology should show a mixed inflammatory infiltrate without malignant cells. The presence of malignant cells could suggest an infiltrative pachymeningeal process, which may be in the differential diagnosis depending on the primary cancer. CSF protein is usually elevated and, if tested, CSF neurofilament light is often high, reflecting neuronal damage. Anti-ganglioside antibodies and anti-paranodal antibodies do not help, although if the clinical syndrome strongly suggests a paranodal antibody-mediated syndrome then this should be considered as with any other neurological differential diagnosis. Sural nerve biopsy shows a very different but characteristic pattern with axonal depletion and marked inflammatory cell infiltration throughout the epineurium, perineurium and endoneurium. The histological features described in CIDP and GBS—macrophage mediated myelin digestion and decreased intranodal interval on teased fibre examination—do not occur.
Another important difference between ICI-neuritis and GBS or CIDP is the lack of improvement with intravenous immunoglobulin treatment but definitive and prompt response to high-dose corticosteroids, coupled with stopping the ICI. This response reflects the role of T cell activation as the primary pathophysiology in ICI-neuritis. In patients with impaired mobility or significant loss of independence, we give high-dose oral prednisolone at 1 mg/kg/day to a maximum of 60 mg/day for 4–6 weeks followed by a slow taper (reducing by 5 mg every 2–4 weeks). In patients who have lost independent mobility we often precede this with intravenous methylprednisolone 1 g/day for 3 days followed by a slow oral corticosteroid taper; however, lower doses may be adequate in milder cases with less functional impact (less than grade 3). Careful pre-steroid screening, consent and appropriate safety monitoring are important.40 Neurology and oncology should discuss decisions about which team takes primary responsibility for steroid treatment. Efficacy monitoring is probably more effectively performed by neurology. ICI-neuritis is usually a monophasic, steroid-responsive illness with good potential for recovery if diagnosed and treated promptly. However, weaning of steroids may occasionally be associated with relapse or worsening. In this scenario, clinicians may consider using steroid-sparing agents such as mycophenolate mofetil or, if tolerated, brief re-escalation of the steroid dose. The addition of any immunosuppressant therapy should be made in conjunction with the treating oncologist as these drugs increase the risk of recurrence of some cancers due to interference with immune surveillance. Cancer outcomes related to pausing ICI treatment and discussions around potential ICI re-challenge are complex and discussed in more detail later.
Although ICI-neuritis is the most common peripheral nerve manifestation of ICI neurotoxicity, it is not the only one. The summary statistics of neurophysiological findings from a cohort of patients with ICI neurotoxicity admitted sequentially to an intensive care unit in a single centre show a broad range of CMAP and SNAP amplitudes, including normal values. Conduction velocities show the same breadth of findings.39 Together, these findings reflect the fact that peripheral nerve inflammation is highly variable from case to case. In a very detailed, early case series of ICI neurotoxicity from the Mayo Clinic, 10 of 14 cases developed peripheral neuropathy. Most cases were consistent with ICI-neuritis as described above, but other cases of mononeuritis multiplex with vasculitis histology also occurred.26 Subacute onset dorsal root ganglionopathies, with sudden and severe proprioceptive loss and significant impairment in function can also develop. These rarer presentations tend to respond less well to corticosteroid treatment. Dorsal root ganglionopathy following ICI treatment may be associated with positive anti-Hu antibodies and might be considered an ICI-precipitated paraneoplastic syndrome. The relationship between ICIs and neurological paraneoplastic syndromes has not been fully characterised. Despite several case reports and case series in the literature,41 there does not appear to have been a real-world increase in the incidence of such syndromes since the introduction of ICI treatments. This lack of association may be because the cancers in which ICIs are most used, such as melanoma, are not strongly associated with paraneoplastic neurological syndromes. The picture may change as ICIs use extends more widely to lung and breast cancer.
ICI-vestibulitis
Subacute, bilateral vestibular failure may be a manifestation of ICI neurotoxicity, but is exceedingly rare outside of this setting. In ICI-vestibulitis, patients report extreme unsteadiness and oscillopsia (the perception of jumpy vision on walking or sitting in a moving car). They are usually extremely disabled. Gait failure occurs in the presence of a normal peripheral nervous system examination, without cerebellar signs but with bilaterally abnormal vestibulo-ocular reflexes.42 Imaging is normal. CSF may be normal or show some evidence of inflammation. Although corticosteroids and stopping ICI is indicated, this rarely gives any improvement. Vestibular rehabilitation physiotherapy may give some functional recovery.
Immunosuppression safety and monitoring
Immunosuppression is essential for treating ICI neurotoxicity, controlling symptoms and preventing long-term neurological damage and disability. However, corticosteroids and other immunosuppressives are associated with adverse effects, which must be considered and managed appropriately. Patients should be consented for the common and rare but serious adverse effects of any medication being used. Patient information booklets are helpful. Prescreening to assist in risk stratification is recommended. There is a range of established guidelines available for using immunosuppression, which are often disease or system specific. A recent publication in Practical Neurology on immunosuppression in neuromuscular disease may be particularly relevant given the predilection of ICI neurotoxicity for the peripheral nervous system.40 This article provides guidance on consent, prescreening, anti-microbial prophylaxis and vaccination, and safety and efficacy monitoring for corticosteroids as well as common oral steroid sparing agents applicable to neurological diseases. Other recent papers provide similar advice on IVIg and plasma exchange.43 44 The clinician taking responsibility for safety monitoring should be clearly delineated in each case, especially if oncology and neurology care might be delivered through different sites. We suggest efficacy monitoring is best performed by neurology when possible.
ICI-rechallenge after neurotoxicity
The decision of whether or not to re-introduce ICI treatment after management of a neurotoxic syndrome is exceptionally nuanced. This will be guided by the severity of neurotoxicity, and the responsiveness and recovery following treatment. There should be reasonable concern that re-exposure will simply result in recurrence of the original syndrome, which may be of a higher grade and less straightforward to manage the second time. This concern is particularly true where there is residual functional deficit or where the syndrome has been steroid resistant and required using a second agent.
Where patients have already had a good anti-cancer response to ICI treatment, in some cases this response may be sustained even without re-introduction of ICI. This is particularly true for diseases such as metastatic melanoma. Where ICI is combined with another non-ICI agent, it may well be more appropriate to continue with the non-ICI treatment in isolation, rather than to risk further avoidable issues. This strategy is especially true in neoadjuvant settings where it is important to maintain dose density and schedule of the chemotherapy components wherever possible.
Ultimately, neurotoxicity often prompts the permanently stopping ICI treatment, given the risk of persisting functional issues for the patient. Any re-challenge needs to be clearly discussed with the patient, detailing the attendant risks and potential benefits. Patients should be formally consented for re-challenge. Any re-challenge requires close collaboration between the treating neurologist and oncologist to pick up any toxicity recurrence promptly.
Why should neurologists and oncologists work together?
Developing a working relationship between neurologists and oncologists is increasingly important given the rapid expansion in the use, complexity and diversity of oncological therapeutics and their associated toxicities. Currently, recognition and management of toxicities is usually undertaken by oncologists and acute oncology services in conjunction with acute medical teams. This arrangement has resulted in oncologists becoming increasingly familiar with ICI neurotoxicity, including some of the idiosyncrasies observed in this patient group. However, neurotoxicology is not an area of expertise for these teams. A particular challenge, as discussed above, is that many ICI neurotoxic syndromes mimic, but are distinct from, more common and better-recognised neurological conditions. An understanding of the similarities and differences is essential to effectively manage patients. Partnerships between specialties are the best way to achieve this. Early, rapid access to neurological advice and review coupled with an increasing body of expertise within neurology and oncology for this subgroup of patients will enhance the knowledge and experience of both parties.
National ICI neurotoxicity MDT
In this paper, we have discussed the importance of identifying the clinical syndrome, considering alternative, non-immune, differential diagnoses and approaches to management of ICI neurotoxicity. Episodes are often monophasic and with prompt recognition and effective immunosuppression outcomes can be good.33 Developing appropriate service models for the management of ICI neurotoxicity is challenging at a regional level. These challenges predominantly relate to the rarity and sporadic nature of ICI neurotoxicity. It is not usually appropriate to refer to outpatient general neurology or neuro-oncology given outpatient waiting times and the acuity of ICI neurotoxicity. Over time, with expanding anti-cancer immunotherapy, the incidence of ICI neurotoxicity is expected to increase, and it will become more viable to create business cases to provide dedicated neurological care. For now, it has been suggested that existing neurology clinical services providing acute or subacute clinical input might be best suited to these patients. Examples include rapid access MS relapse clinics or myasthenia or inflammatory peripheral nerve services designed to manage crises or relapses.
In response to increasing queries on challenging cases from clinicians around the UK to each of our individual specialist services, we have recently established a national ICI neurotoxicity multidisciplinary advice service. The focus will be on providing expertise and consensus support in cases where (1) diagnosis of ICI neurotoxicity is uncertain, or (2) symptoms are refractory to first and second-line therapy and guidance on treatment escalation is required (figure 3). This service runs through UCLH-NHNN and is delivered by a team of consultants with appropriate expertise including neurology, oncology, neuroradiology, cardio-oncology and rheumatology with clinical nurse specialist support. Referrals are submitted by email (UCLH.IO-NEUROTOX@nhs.net) via a standardised proforma and discussed fortnightly on the Microsoft Teams platform. Urgent advice is available when required by telephone or email. We hope that this service will provide support, guidance and the opportunity for us all to learn through shared experience about how best to manage ICI neurotoxicity in conjunction with our colleagues in oncology.
Key points
Immune checkpoint inhibitors (ICIs) can have toxic effects on almost any part of the central or peripheral nervous system.
Diagnosis and management of ICI-neurotoxicity requires a cross-disciplinary approach, and close collaboration between oncologists, neurologists and other healthcare professionals.
The mainstay of medical management is to pause ICI therapy and to treat with corticosteroids according to toxicity grade; however, more nuanced therapeutic strategies are often required.
It is important to consider alternative diagnoses to prevent unnecessary cessation of highly effective cancer treatments.
Further reading
Haanen, J., Obeid, M., Spain, L., Carbonnel, F., Wang, Y., Robert, C., Lyon, A. R., Wick, W., Kostine, M., Peters, S., Jordan, K., & Larkin, J. (2022). Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 33(12), 1217–1238. https://doi.org/10.1016/j.annonc.2022.10.001
O’Hare, M., & Guidon, A. C. (2024). Peripheral nervous system immune-related adverse events due to checkpoint inhibition. Nature reviews. Neurology, 20(9), 509–525. https://doi.org/10.1038/s41582-024-01001-6
Spain, L., Walls, G., Julve, M., O'Meara, K., Schmid, T., Kalaitzaki, E., Turajlic, S., Gore, M., Rees, J., & Larkin, J. (2017). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol, 28(2), 377–385. https://doi.org/10.1093/annonc/mdw558
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
Images created using Biorender, www.biorender.com
References
Footnotes
Contributors ASC, KY, HS and AO-B prepared the first draft of the manuscript. ASC, FWV and MW contributed to manuscript revisions. FWV, ASC and SK made the figures. All authors read and approved the submitted version. ASC is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests ASC is supported by clinical research funding from the NIHR BRC. FWV is supported by a Guarantors of Brain postdoctoral clinical fellowship.
Provenance and peer review Commissioned. Externally peer reviewed by Saiju Jacob, Birmingham, UK.