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Alsalem, A.N.; Scarffe, L.A.; Briemberg, H.R.; Aaroe, A.E.; Harrison, R.A. Neurologic Complications of Cancer Immunotherapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/46894 (accessed on 27 July 2024).
Alsalem AN, Scarffe LA, Briemberg HR, Aaroe AE, Harrison RA. Neurologic Complications of Cancer Immunotherapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/46894. Accessed July 27, 2024.
Alsalem, Aseel N., Leslie A. Scarffe, Hannah R. Briemberg, Ashley E. Aaroe, Rebecca A. Harrison. "Neurologic Complications of Cancer Immunotherapy" Encyclopedia, https://encyclopedia.pub/entry/46894 (accessed July 27, 2024).
Alsalem, A.N., Scarffe, L.A., Briemberg, H.R., Aaroe, A.E., & Harrison, R.A. (2023, July 17). Neurologic Complications of Cancer Immunotherapy. In Encyclopedia. https://encyclopedia.pub/entry/46894
Alsalem, Aseel N., et al. "Neurologic Complications of Cancer Immunotherapy." Encyclopedia. Web. 17 July, 2023.
Neurologic Complications of Cancer Immunotherapy
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This entry is adapted from the peer-reviewed paper 10.3390/curroncol30060440

Immunotherapy has revolutionized cancer treatment. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. Under physiological circumstances, immune checkpoints play a role in the maintenance of self-tolerance; the dysregulation of these pathways by cancers is thought to be an important mechanism of immune evasion. The most widely studied immune checkpoint inhibitors are cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitors and programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) inhibitors.

immunotherapy neurologic complications checkpoint inhibition

1. Introduction

The introduction of cancer immunotherapy has led to a paradigm shift in cancer treatment due to improved survival and more favorable safety profiles compared to traditional chemotherapy [1][2]. Since the first immune checkpoint inhibitor (ICI), ipilimumab, was approved in 2010, additional agents have been introduced into standard oncologic care. In recent years, other forms of immunotherapy, including adoptive cell therapies, have also entered the clinical arena.
Under physiological circumstances, immune checkpoints play a role in the maintenance of self-tolerance [3][4]; the dysregulation of these pathways by cancers is thought to be an important mechanism of immune evasion [5]. The most widely studied immune checkpoint inhibitors are cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitors and programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) inhibitors. Both of the former function to disinhibit T-cell activity at various stages, leading to enhanced T-cell activity in tissues and the tumor microenvironment at different stages [5]. CTLA-4 inhibitors are thought to exert their effect in the T-cell priming phase within lymphoid tissue, and PD-1/PD-L1 inhibitors act on T-cells in the tissues peripherally [6]. The disinhibition of the immune system leads to various adverse effects deemed immune-related adverse events (irAEs), but the exact mechanism of toxicity is not fully known. The biologic underpinnings of these adverse immune responses are likely complex—there is evidence for T-cell infiltration into target tissues, the generation of autoantibodies suggesting an additional B-cell mediated immune response, as well as increased levels of circulating inflammatory cytokines [6].
Adoptive T-cell therapies involve ex-vivo purification, modification, and expansion of autologous T-lymphocytes that are then transfused into the patient. Current approaches include T-cell receptor (TCR) therapy and chimeric antigen receptor (CAR) T-cell therapy. Of these, only CAR T-cell therapies have Food and Drug Administration (FDA)-approved indications to date, though other mechanisms of cell therapy are being explored in the clinical trial setting. CAR-T cells are autologous T-lymphocytes genetically manipulated to introduce an artificial receptor into the immune effector cell. These involve a modified T-cell receptor comprised of an antigen-binding fragment that recognizes a cell surface protein on the tumor cell. This fragment is conjugated to the T-cell receptor CD3 zeta intracellular signaling domain with the addition of a co-stimulatory domain, allowing these T cells to become activated and take upon a cytotoxic phenotype upon encountering their antigen [7].
Bispecific T cell Engager antibodies (BITEs) have overlapping toxicities with CAR T cells. They are comprised of fragments of two different antibodies, typically one that binds CD3 co-receptors on T cells and another that binds tumor cell antigen [8]. The best characterized BITE is blinatumomab, which targets CD19-positive B cells in B-cell lymphoma /leukemias and also binds CD3 on T cells. Thereby, CD3-positive T cells are redirected to CD19-positive tumor cells and engaged to lyse the latter [9][10]. Both CAR T cells and bispecific antibodies result in patient T cells directing a cytotoxic response to cells expressing the chosen antigen.

2. Neurotoxicities Associated with Immune Checkpoint Inhibitors

2.1. Central Nervous System Complications

2.1.1. Encephalitis

The estimated proportion of encephalitis among patients treated with an ICI was 0.86% in one pharmacovigilance study [11]. The clinical phenotype of ICI-related encephalitis is often non-specific. Clinically, the majority of patients present with altered mental status, and around 30% have seizures [12][13][14][15]. Two distinct clinical phenotypes can occur: a diffuse meningoencephalitic picture characterized by fever, headache, and altered level of conscious, or a focal encephalitic picture presenting with neuropsychiatric changes, extrapyramidal signs, cranial nerve abnormalities, brainstem, or cerebellum involvement [13][15]. The differential diagnosis includes infectious, inflammatory, autoimmune, or paraneoplastic encephalitides.
Neuroimaging findings are variable, with 51% having a normal MRI [12]. Compared to patients with HSV-encephalitis, patients with ICI-related encephalitis more frequently had a normal MRI [15]. Abnormal MRI findings were more common in patients with focal encephalitis [13] and included T2 hyperintense lesions in the medial temporal lobes, basal ganglia, diencephalon, or subcortical white matter [12][13]. Pachy- or leptomeningeal enhancement has also been reported [14][16].
CSF analysis is abnormal in more than 90% of patients [12][13], typically with a lymphocytic pleocytosis and elevated protein. The exclusion of infectious and neoplastic causes is prudent as these CSF findings are nonspecific. Autoantibodies were detected in approximately 50% of cases as reported by Stuby et al. [17] and Marini et al. [12], and 30% of patients in the series by Velasco et al. [13], most commonly intracellular onconeural antibodies such as anti-Hu or anti-Ma. Other autoantibodies reported in association with ICI-related encephalitis include anti-Ri, anti-GAD, anti-NMDAR, anti-CASPR2, anti-CRMP5, and anti-SOX1 [12][13][16][17]. Interestingly, Velasco et al. [13] also found that patients with positive onconeural autoantibodies more frequently had a more aggressive focal encephalitic presentation. This raises the question of whether ICIs play a role in unmasking paraneoplastic syndromes.
Prognosis is generally favorable [12][13], though patient subgroups with ICI-related encephalitis associated with a positive intracellular autoantibody had worse outcomes [13], which may explain the findings of Vogrig et al. [16], who found that 5/8 patients in their case series died from neurologic complications, and 7/8 of their cohort had positive anti-Ma antibodies. Other poor prognostic factors include the presence of a focal syndrome or an abnormal MRI [13]. No data exist on long term cognitive outcomes in this group of patients.

2.1.2. Meningitis

Meningitis can occur with associated encephalitis, described above, or in isolation. In the latter, patients will often lack the pronounced mental status changes or focal neurologic signs that suggest parenchymal CNS involvement, except if there is associated intracranial hypertension. It is estimated to occur in 0.38% of patients treated with ICIs [11]; however, given the frequency of headache in patients treated with ICIs, the possibility of more frequent low-grade aseptic meningitis should be considered [18]. Clinically, symptoms are similar to those of other causes of infectious and noninfectious meningitis, with fever, headache, neck pain, and nausea, or vomiting dominating the clinical picture [12][19][20]. Symptoms develop after a median of 2 cycles but may occur up to 14 cycles later [20]. Lumbar puncture shows a nonspecific lymphocytic pleocytosis and mild–moderately elevated protein (median 0.87 g/L) [20]. MRI is similarly nonspecific, with about half of cases showing meningeal enhancement [19][20]. Meningitis typically has a more favorable prognosis than encephalitis, with 11 of 13 patients in one systemic review recovering completely [12].

2.1.3. Hypophysitis

The categorization of hypophysitis varies, and hypophysitis is often classified as an endocrine irAE as opposed to a neurologic irAE. Its signs and symptoms are important for neurologists to be aware of however, as its clinical presentation overlaps with that of other neurologic irAEs. Hypophysitis is estimated to occur in 1.79% of patients treated with ICIs, with an almost 300 times higher risk compared to patients not treated with an ICI [11] and occurring a median of 2.3 months after initiation of the drug [21]. This risk is mostly driven by the use of CTLA-4 inhibitors as opposed to PD-1 inhibitors [11][21].
Clinical diagnosis is often challenging, as patients may present with signs of raised intracranial pressure, such as headache, nausea, and vomiting, or visual field deficits, or with symptoms of hormonal deficiency, such as hypothyroidism, diabetes insipidus, or adrenal insufficiency [22][23]. Subtle symptoms such as sinus pressure or fatigue are possible, and hypophysitis may also be identified incidentally on laboratory testing or neuroimaging. Of the endocrinopathies, adrenal insufficiency is by far the most common manifestation of ICI-related hypophysitis [21]. A high index of suspicion should be maintained for patients on an ICI with new onset headache, particularly if the aforementioned symptoms accompany this, and endocrinology consultation is recommended. If hypophysitis is suspected, laboratory testing includes thyroid function tests, adrenocorticotropic-releasing hormone, and follicle-stimulating and -luteinizing hormones. Hypophysitis may also be found in association with other immune-related adverse events [24]. New unexplained hyponatremia, particularly in association with the symptoms noted above or other neurological issues, may also raise suspicion for an immunotherapy-related toxicity. Treatment consists of steroids and the replacement of deficient hormones.

2.1.4. CNS Demyelination

Demyelinating disorders are relatively uncommon complications of ICI therapy, with no significant signal detected in a pharmacovigilance database analysis [11]. This was corroborated in a study by Kelly et al. [25], who found a low prevalence of iatrogenic CNS inflammation, with seven cases of ICI-related demyelinating events among 422 patients, with a prevalence of 0.016%. The majority of the iatrogenic events reported were monophasic. They also found that patients taking an ICI were less likely to present with a relapsing demyelinating disorder compared to patients who experienced immune-related adverse events following TNF-a inhibitor use or vaccination [25]. A systematic review by Oliveira et al. [26] described 23 patients with CNS demyelinating disorders associated with ICI use, including eight cases of myelitis (including one with seropositive NMOSD), four cases of optic neuritis, three with a relapse of known multiple sclerosis (MS), two cases of radiologically isolated syndrome (RIS), and six atypical demyelinating lesions.
ICI therapy has been associated with both new onset demyelinating disease, such as RIS, MS, or acute disseminated encephalomyelitis (ADEM), and relapses of known multiple sclerosis [27][28][29][30]. The clinical presentation is heterogenous, and no neuroimaging finding is specific [11][31]. CSF is typically inflammatory, with oligoclonal banding positivity in approximately 60% of cases [11]. ICI-related demyelinating events are typically monophasic, with the majority of patients achieving partial or complete symptom resolution with therapy [11][26][28]. However, tumefactive lesions with poor response to corticosteroid therapy may occur [29]. Interestingly, patients with a known history of MS may have a more aggressive course, with 4/9 patients experiencing a poor outcome (disability or death) in one analysis [31].
ICI-related transverse myelitis may be short-segment [32] or longitudinally extensive [33][34][35][36]. CSF analysis is typically inflammatory, with lymphocytic pleocytosis and elevated protein. Positive oligoclonal banding and an elevated IgG synthesis rate have been reported [11][26]. The majority of cases are seronegative, but cases of aquaporin-4 positive NMOSD [37][38] and paraneoplastic autoantibodies, including CRMP5 [33] and other novel autoantibodies [36][39], have been reported. Approximately 70% patients attain a partial or complete response to variable combinations of steroids, IVIG, or plasma exchange [12][26]. In those who do not, treatments such as rituximab, tacrolimus, and infliximab have been used [40]. These clinical presentations beget the question of whether the ICIs are unmasking a latent predisposition to inflammatory demyelination in some patients.
Optic neuritis can occur in isolation or in conjunction with other sites of CNS demyelination [26]. It is typically bilateral, painless (as opposed to classical ON in adults), and frequently associated with disc edema. Visual recovery is usually favorable, with partial or complete recovery after the administration of systemic steroids [26][41][42]. MRI may be normal or may show T2 enhancing lesions of the optic nerve. Most cases of optic neuritis are seronegative; however, there is one case of optic neuritis secondary to antibody-positive NMOSD 3 months following ipilimumab and nivolumab adjuvant therapy [43].

2.1.5. Vasculitis

In a pharmacovigilance study [11], 100 cases of vasculitis were detected amongst 3619 patients with neurologic adverse effects of ICI, with a crude reporting odd’s ratio of 1.50. They did not specify whether these cases represented central or peripheral nervous system vasculitis. A review of 20 patients with ICI-related vasculitis found that large and medium vessel vasculitis, including giant cell arteritis (GCA), was the most common manifestation followed by central nervous system vasculitis, including four cases of primary angiitis of the CNS (PACNS) [44]. Clinical presentation of patients with ICI-related GCA is similar to idiopathic GCA with transient visual loss, diplopia, headache, scalp tenderness, or jaw claudication [42]. The clinical presentation of PACNS can be nonspecific, with subacute headache, encephalopathy, or progressive focal neurologic deficits [45][46][47]. CSF analysis in PACNS may be normal [45] or show pleocytosis and elevated protein [46]. Vascular imaging, including CT, MRI, or catheter angiography, may show vasospasm [48]. Brain biopsy remains the diagnostic gold standard [48]. A study examining the incidence of MRI changes among 135 patients with NSCLC receiving ICI therapy found 11 patients with lesions suggestive of ischemic stroke and 4 with lesions suggestive of CNS vasculitis or encephalitis, though other clinical and paraclinical parameters were not reported [49].

2.2. Peripheral Nervous System Complications

2.2.1. Radiculopathies and Neuropathies

A study including 920 patients treated with ICI estimates the overall incidence of peripheral neuropathy to be 1.2% [50]. Variable phenotypes have been reported, including isolated polyradiculopathy, inflammatory polyradiculoneuropathy (AIDP, CIDP), cranial neuropathies, small-fiber neuropathy, length-dependent polyneuropathy, mononeuritis multiplex, and neuralgic amyotrophy [51][52]. Of these, the most common manifestation is acute polyradiculoneuropathy [12][50]. Clinical presentation is similar to that of idiopathic forms, though a preceding infectious prodrome is uncommon; however, diarrhea secondary to gastrointestinal irAEs has been reported [53]. Cases of Miller–Fisher and anti-Gq1B syndrome have also been reported [12][35]. The median time to nadir from symptom onset was 3.5 weeks in one series [50], though cases of CIDP have been reported [54]. Symptoms may consist of either symmetric or asymmetric sensory and/or motor abnormalities, and autonomic dysfunction may also be observed. Pain in the low back or thighs may be a heralding symptom.
CSF shows elevated protein in most patients, with or without white blood cell elevation [12][50]. Ganglioside and onconeural autoantibodies are usually negative [12][35]. Electrodiagnostic studies typically show changes of an acquired demyelinating polyradiculoneuropathy, with or without secondary axonal loss [51][55]; a minority of patients have subclinical evidence of concurrent myopathy [12][51]. Contrary to idiopathic AIDP, corticosteroids are recommended as part of standard treatment [56]. IVIG and plasma exchange may also be considered.
Cranial neuropathies most commonly involve the facial nerve and are typically associated with abnormal gadolinium enhancement on MRI. Oculomotor, abducens, trigeminal, vestibulocochlear, and glossopharyngeal nerve involvement have also been reported [51][57]. Most patients achieve full clinical recovery with corticosteroid treatment and cessation of the immune checkpoint inhibitor [12][50][51].

2.2.2. Myasthenia Gravis

ICI-related myasthenia gravis (MG) frequently overlaps with myositis (further discussed below). It usually presents in patients with no prior history of MG, but cases of MG exacerbation triggered by ICI therapy have been reported as well [50][58]. The median latency from ICI administration to symptom onset was 6.6 weeks in one study [50] and ranged from 6–106 days in another series [59]. The clinical presentation is more fulminant than idiopathic MG, with more than 50% of patients having bulbar or respiratory muscle weakness [12][50]. The presence of thymoma was not found to be correlated with the development of ICI-related MG [59][60]. However, a recent study in patients with thymoma found that patients with thymoma and MG had fewer CTLA-4 positive cells within the tumor compared to thymoma patients without MG, suggesting a possible association between CTLA-4 downregulation and idiopathic MG [61]. Most patients present with the MG-myositis overlap syndrome, and around 80% of patients have concomitant non-neurologic irAEs, particularly myocarditis [50]. Ptosis can arise from either MG or the involvement of the extraocular muscles by myositis and cannot be reliably used to distinguish one entity from another.
Electrodiagnostic parameters are similar to idiopathic MG and frequently show concomitant myopathy. Acetylcholine receptor (AChR) seropositivity occurs in approximately 60% of patients [12]. Anti-MuSK antibodies are rare [60]. It is thought that patients with pre-existing MG or AChR seropositivity are at higher risk of developing an MG flare when exposed to ICIs [28][59]. A retrospective analysis of 137 patients with non-small cell lung cancer receiving ICIs found that patients with pre-existing non-neurologic autoantibodies were at a higher risk of immune-related adverse events [62], supporting the findings of Suzuki et al. [59] that ICIs could precipitate autoimmunity in patients with an underlying predisposition. However, there is one report of a patient with anti-AChR antibodies who tolerated ICI treatment well without the development of MG [63] and another case of mild MG relapse not requiring any specific therapy [64]. Thus, further study is needed to determine the safety of ICI in asymptomatic patients with anti-AChR antibodies and patients with pre-existing MG. Routine AChR antibody screening, prompting closer neurologic monitoring of seropositive patients during ICI treatment, has been recommended [50], though the relative cost–benefit of this approach is not clear. At this time, we recommend vigilant screening and the evaluation of patients who have symptoms suggestive of neuromuscular junction disorder, as well as a low threshold for closer monitoring or hospital admission in this population.
The majority improve with treatment, though the mortality rate remains high [12][50][60]. Respiratory failure is more common than that in idiopathic MG, and the presence of concomitant MG and myositis is associated with increased risk compared to MG alone [50], consistent with previous evidence that patients with concurrent MG, myositis, and myocarditis have a higher mortality rate compared to those with MG alone [50][58][60].

2.2.3. Myositis

Myositis was the most common neurologic irAE in one systematic review, representing 32% of all cases [12][65]. It usually develops at a median of 5–6 weeks after ICI administration [50][65]. The clinical spectrum is variable, ranging from minimally symptomatic hyperCKemia to severe weakness and rhabdomyolysis [12][65]. The pattern of weakness is typically limb girdle, with frequent neck, bulbar, or respiratory muscle involvement either due to primary myositis or concurrent MG [12][66]. In one series, head drop was a common presenting symptom of ICI-related myositis [50]. Cutaneous manifestations suggestive of dermatomyositis can be seen in around 18% of patients [66]. Orbital myositis causing diplopia and restrictive orbitopathy has been reported, sometimes mimicking MG [42][67]. Most cases had clinical or paraclinical evidence of systemic myopathy [64].
Myositis-associated antibodies are usually negative [68][69], though in one review, anti-striational antibodies were present in approximately 50% of patients. MRI typically shows evidence of myositis. Electrodiagnostic studies show changes consistent with an irritable myopathy in approximately 80% of patients [12]. Skeletal muscle biopsy shows necrotizing myopathy in the majority of cases [12][68]. Assessment for concurrent MG with repetitive nerve stimulation is recommended. Electrodiagnostic studies may be used to target specific muscles most amenable to biopsy. In addition, all patients should undergo serum troponin measurement, electrocardiogram, and echocardiography to screen for myocarditis. Cardiac MRI is more sensitive than echocardiography in this situation and should be pursued if the echocardiogram is negative.
Approximately 70% of patients improve with treatment, though there is a 17% mortality rate [12]. Patients with concurrent MG and myocarditis had a 13.75 higher odds of death compared to those with isolated myositis, consistent with other studies describing a high mortality rate with the so-called “triple M syndrome” [50][60][66]. First line treatment is typically with corticosteroids (e.g., prednisolone 0.5–1 mg/kg/day); a suggested approach is continuing steroids for 4–8 weeks followed by a taper over several months (depending on initial symptom severity) [70]. However, data on optimal duration and tapering schedules are scarce.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Aseel N. Alsalem
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Leslie A. Scarffe
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Hannah R. Briemberg
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Ashley E. Aaroe
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Rebecca A. Harrison
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