https://doi.org/10.

1590/0004-282X-ANP-2022-S116
NEURO-ONCOLOGY

Neurologic adverse events of cancer

immunotherapy
Eventos adversos neurológicos da imunoterapia contra o câncer
Marcelo Houat DE BRITO1,2

ABSTRACT
Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system and
have revolutionized oncological treatment in recent years, with approval for its use in more and more cancers. However, it is not without side
effects. Several neurological adverse events have been recognized associated with immune checkpoint inhibitors (ICI) and chimeric antigen
receptor (CAR) T-cell therapy, the two main classes of cancer immunotherapy. With the increase in the prevalence of oncological diseases
and this type of therapy, it is improbable that neurologists, oncologists, hematologists, and other healthcare professionals who deal with
cancer patients will not encounter this type of neurologic complication in their practice in the following years. This article aims to review the
epidemiology, clinical manifestations, diagnosis, and management of neurological complications associated with ICI and CAR T-cell therapy.
Keywords: Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Drug-Related Side Effects and Adverse Reactions; Neurologic
Manifestations; Neuromuscular Diseases.

RESUMO
A imunoterapia contra o câncer engloba uma gama de modalidades de tratamento que aumentam os efeitos antitumorais do próprio
sistema imunológico do paciente e revolucionaram o tratamento oncológico nos últimos anos, com aprovação para seu uso em cada vez mais
neoplasias. No entanto, não é sem efeitos colaterais. Vários eventos adversos neurológicos foram reconhecidos associados aos inibidores de
checkpoint imunológico (ICI) e à terapia de células T com receptor de antígeno quimérico (CAR-T), as duas principais classes de imunoterapia
contra o câncer. Com o aumento da prevalência de doenças oncológicas e desse tipo de terapia, é improvável que neurologistas, oncologistas,
hematologistas e demais profissionais de saúde que lidam com pacientes com câncer não encontrem esse tipo de complicação neurológica
em sua prática nos próximos anos. Este artigo tem como objetivo revisar a epidemiologia, as manifestações clínicas, o diagnóstico e o manejo
das complicações neurológicas associadas à terapia com ICI e células CAR-T
Palavras-chave: Inibidores de Checkpoint Imunológico; Imunoterapia Adotiva; Efeitos Colaterais e Reações Adversas Relacionados a
Medicamentos; Manifestações Neurológicas; Doenças Neuromusculares.

INTRODUCTION Cancer immunotherapy encompasses a wide range of treat-

ment modalities that harness the anti-tumor effects of the
In recent decades, we have seen a demographic and epi- immune system. Some immunotherapies broadly activate the
demiological transition globally, generating population aging immune system while others target precisely distinct tumor
and an increase in the incidence and prevalence of non-com- antigens2. This modality has revolutionized oncological treat-
municable chronic diseases, such as cancer. These result in a ment in recent years, with approval for its use in more and more
significant increase in years lived with disability due to onco- cancers, changing their prognosis. However, it is not without
logic pathologies, estimated at 40.6% between 2007 and 20171. side effects, some of them potentially serious. Several neurologi-
Another important factor that has led to the increase in the cal adverse events have been recognized associated with these
prevalence of oncological diseases has been the evolution of novel immunotherapeutic concepts3. With the increase in the
their treatment, with the emergence of new classes of thera- prevalence of oncological diseases and this type of therapy, it is
pies, such as cancer immunotherapy. improbable that neurologists, oncologists, hematologists, and

Universidade de São Paulo, Hospital das Clinicas, Departamento de Neurologia, São Paulo SP, Brazil.
1

Universidade de São Paulo Instituto do Câncer do Estado de São Paulo, Departamento de Neurologia, Sao Paulo SP, Brazil.
2

MHDB https://orcid.org/0000-0001-7521-1388
Correspondence: Marcelo Houat de Brito; Email: [email protected].
Conflict of interest: There is no conflict of interest to declare.
Received on March 15, 2022; Accepted on April 29, 2022.

270
other healthcare professionals who deal with cancer patients melanoma than other cancers10,15. There seems to be no dif-
will not encounter this type of neurologic complication in their ference between sex and age when comparing patients who
practice in the years that follow. used ICI and had neurological complications with those who
This article will review the epidemiology, clinical manifes- did not15. Symptom onset is most frequent in the first three to
tations, diagnosis, and management of neurological complica- four months after ICI initiation, although it may occur at any
tions associated with immune checkpoint inhibitors (ICI) and time during the treatment3.
chimeric antigen receptor (CAR) T-cell therapy, two of the main Among the proposed pathophysiological mechanisms for
classes of cancer immunotherapy. the emergence of irAE is (1) a shift toward the pro-inflamma-
tory profile of T lymphocytes dominated by Th1/Th17 differ-
IMMUNE CHECKPOINT INHIBITORS (ICI) entiation that increases the production of pro-inflammatory
cytokines, (2) autoreactive antibody production, (3) activation
Immune checkpoint inhibitors are a class of antineoplastic of potentially pre-existing self-reactive T cells, and (4) cross-
drugs that enhance antitumor immune responses through the reactivity between normal tissue antigens and tumor neo-
upregulation of T-cell activity. They are specific monoclonal antigens16. There seem to be cases of both patients who start to
antibodies that block receptors that inhibit the T-cell response, develop autoimmune phenomena and cases of exacerbation of
the so-called inhibitory immune checkpoints. The main tar- already-present clinically manifested or latent autoimmunity,
gets of these medications are cytotoxic T lymphocyte antigen since the documentation of worsening of immune-mediated
4 (CTLA-4) receptor, programmed cell death 1 (PD-1) recep- neurological diseases after the use of ICI (e.g., multiple sclerosis
tor, and programmed cell death 1 ligand (PD-L1), which are relapse), as well as the presence of autoantibodies associated
molecules that ultimately break the T-cell immune-mediated with immune-mediated neurological diseases in several cases
response4. Their blockage has led to persistent and generalized of nirAE (e.g., presence of antibodies related to a paraneoplastic
activation of the humoral and cellular adaptative immune sys- neurological syndrome)3,10,12,16.
tem, enhancing antitumor immunity5. A recent systematic review gathered the cases of nirAE
There are currently seven ICIs approved for clinical use: present in publications, verifying the most frequent forms of
the anti-CTLA-4 ipilimumab; the anti-PD-1 pembrolizumab, presentation. Myositis (32%) was the most frequent neurologi-
nivolumab, and cemiplimab; and the anti-PD-L1 atezolizumab, cal complication, followed by peripheral neuropathies (22%),
avelumab, and durvalumab6. They have shown clinically effec- myasthenic syndrome (14%), encephalitis (13%), cranial neu-
tive antitumor response and improved survival for melanoma, ropathy (7%), central nervous system (CNS) demyelinating
non-small cell lung cancer (NSCLC), renal cell carcinoma, as disease/myelopathy ( 4%), and aseptic meningitis (3%)10. From
well as for an increasing number of other indications. However, now on, we will review the particularities of each of these clini-
because of their effect in activating the immune system, they cal presentations and cite other less frequent presentations
are associated with immune-related adverse events (irAE). The already reported. Table 1 summarizes the main forms of nirAEs’
most common irAEs are reactions involving the gastrointesti-
epidemiology, clinical manifestations and diagnostic workup.
nal tract, endocrine glands, skin, and liver7. Most of these are
mild and can be treated with symptomatic medications, but
some require interruption or discontinuation of the ICI and Myositis
the use of IV steroids or other immunosuppressive drugs (e.g., The most frequent form of nirAE can range from increases
infliximab for colitis)8. in creatine kinase (CK) with few symptoms to severe, life-
Although less frequent than other systems, neurologic threatening cases, such as respiratory muscle involvement or
irAEs (nirAE) may be severe and require prompt recognition necrotizing myopathy evolving with rhabdomyolysis3,17. The
and treatment9,10. A 2019 pharmacovigilance study from the most common presentation is a limb-girdle pattern of muscu-
Japanese Adverse Drug Event Report database found a 7.67% lar weakness associated with myalgia involving predominantly
incidence of any nirAE in patients who used ICI11. In a real-life proximal muscles. The involvement of ocular muscles, mainly
study, with data from over 1,800 patients undergoing ICI ther- ptosis, and bulbar muscles are also frequent. Facial and neck
apy, the frequency of severe (Common Terminology Criteria muscle involvement, respiratory dysfunction, and myocarditis
for Adverse Events grade 3–5) nirAE was 2.2% among patients are more common in ICI-associated myopathy than in other
treated with CTLA-4 inhibitors, 1.0% among patients receiv- inflammatory myopathies, such as polymyositis or dermato-
ing PD-1/PD-L1 inhibitors, and 2.8% among patients receiv- myositis10. Myocarditis can occur in up to 32% of cases of ICI-
ing combined treatment with drugs targeting the PD-1 and related myositis, and it is important to perform cardiologic
CTLA-4 pathways12. As seen in previous statistics, anti-CTLA4 evaluation in patients with this condition, including myocardial
was more associated with nirAE than other ICIs, with this risk enzymes, electrocardiogram, and echocardiogram17,18.
being greater the higher the dose, or if use is associated with In addition to increases in CK, the diagnostic workup may
anti-PD1, this also increases the chance of more severe symp- find a pattern of myopathy on electromyography (EMG) and
toms13,14. NirAE appears to be more frequent in patients with muscle edema and other findings compatible with myositis

De Brito MH. Neurologic adverse events of cancer immunotherapy. 271

 Table 1. Main forms of immune checkpoint inhibitor-associated neurologic adverse events.

Syndrome % of nirAE10 Clinical manifestations Diagnostic workup Mortality rate10

-Proximal muscular
-↑ serum CK and aldolase
weakness with myalgia
-EMG: myopathic pattern
-Ptosis, dysphagia
-Ab: SM, AChr (not frequent)
Myositis 32% -Facial and neck 17%
-Muscle biopsy: lymphocyte infiltration
weakness
-MNM, EKG, Echo: assess concomitant
-Respiratory dysfunction
myocarditis
-Myocarditis

-Ocular myasthenia
-NCS with repetitive nerve stimulation
-Generalized myasthenia
-EMG with single-fiber evaluation
Myasthenic syndromes 14% -Myositis / myocarditis 28%
-Ice pack test (when ptosis is present)
overlap
-Ab: AChr, VGCC
-LEMS

-Acute
polyradiculoneuropathy
(GBS-like)
-CIDP
-NCS
-Sensory neuronopathy
-CSF: albuminocytologic dissociation or
-Miller-Fisher syndrome
pleocytosis with high protein
-Others: Phrenic
Peripheral neuropathy 22% -Ab: rarely positive, GM1 more common 11%
neuropathy, vasculitic
-MRI: contrast enhancement in nerve
neuropathy, small fiber
roots, plexus, and/or cranial nerves in
neuropathy, enteric
polyradiculoneuropathy
neuropathy, neuralgic
amyotrophy, motor
neuropathy, Mononeuritis
multiplex
-Facial nerve palsy
-Vestibulocochlear nerve
impairment -CSF: albuminocytologic dissociation or
-Trigeminal nerve pleocytosis with high protein
Cranial neuropathy 7% impairment -MRI: contrast enhancement in affected 0%
-Oculomotor nerve palsy. cranial nerves
-Multiple cranial -NCS (facial palsy)
neuropathy
simultaneously
-MRI: Mesial temporal lobes, basal ganglia,
-Altered mental status, cortico-subcortical, and/or brainstem areas of
cognitive impairment, increased signal in T2/FLAIR
Encephalitis 13% seizures, psychiatric -CSF: mild pleocytosis, elevated protein, OCB+ 21%
disturbances and/or -EEG: diffuse slow activity; epileptic or slow-
movement disorders wave activity involving focal cerebral regions
-Ab (CSF and serum): Ma2, Hu, others

-MS relapse -MRI: periventricular, juxtacortical,

-NMOSD infratentorial, spinal cord, and/or optic nerve
CNS demyelination /
3,5% -Isolated optic neuritis involvement characteristic of MS or NMOSD 12%
myelopathy
-Isolated myelitis -CSF: mild pleocytosis, elevated protein, OCB+
-Atypical demyelination -Ab: AQP4 (NMOSD)

- headache, neck stiffness, -MRI: meningeal contrast enhancement

Aseptic meningitis 3% 0%
fever and/or nausea -CSF: mild pleocytosis and elevated protein

nirAE: neurologic immune-related adverse events; CK: creatine kinase; EMG: electromyography; Ab: antibody; SM: striatal muscle; AChr: acetylcholine
receptor; MNM: myocardial necrosis markers; EKG: electrocardiogram; Echo: echocardiogram; LEMS: Lambert-Eaton myasthenic syndrome; NCS: nerve
conduction study; VGCC: voltage-gated calcium channel; GBS: Guillain-Barré syndrome; CIDP: chronic inflammatory demyelinating polyneuropathy; CSF:
cerebrospinal fluid; GM1: ganglioside-monosialic acid; MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery OCB: oligoclonal bands;
EEG: electroencephalogram; MS: multiple sclerosis; NMOSD: neuromyelitis optica spectrum disorder; AQP4: aquaporin 4.

on muscle magnetic resonance imaging (MRI)10,17. Histological Most patients received steroid treatment, which in some
analyses of muscle biopsy typically demonstrate infiltration of cases, especially in the refractory ones, had the addition of other
the muscle tissue with lymphocytes3. Antibodies (Ab) associ- immunomodulatory therapies, such as intravenous immuno-
ated with myositis are found in just over a third of cases, the globulin (IVIG), plasma exchange (PLEX), azathioprine, myco-
most common being anti-striated muscle (SM), followed by phenolate, tacrolimus, infliximab, and cyclosporine10,12,19. Partial
anti-acetylcholine receptor (AChr)10. or complete improvement is seen in the majority of the cases.

272 Arq Neuropsiquiatr 2022;80(5 Suppl. 1):270-280

However, a mortality rate of 17% has been reported, mainly Cerebrospinal fluid (CSF) analysis has abnormal findings in
due to respiratory failure and sudden cardiac arrest associ- most cases, demonstrating albuminocytologic dissociation
ated with myocarditis10. in almost half and an increase of both protein and cell count
in about a third10. Autoantibody positivity was verified in just
under a quarter of the peripheral neuropathy patients in whom
Myasthenic syndrome
they were measured, with GM1 being the only one verified in
A characteristic of the myasthenic syndromes associated
two different cases described in a nirAE systematic review10.
with ICI is the tendency to severity. The most common clini-
In complex cases, in which the remainder of the diagnostic
cal presentation is generalized myasthenia, with respiratory
workup was doubtful, an MRI could help by demonstrating
failure and bulbar muscle involvement in most cases. The iso-
contrast enhancement in nerve roots, plexus, and/or cranial
lated ocular form was identified in less than 20% of patients10.
nerves in polyradiculoneuropathy as a nirAE3,10.
It is commonly associated with myositis, and myocarditis may
Unlike classical GBS, in which corticosteroids have no evi-
also be present, adding morbidity to the condition10,17,18. In con-
dence of benefit26, the treatment of peripheral neuropathies asso-
trast to conventional myasthenia gravis (MG), where around
ciated with ICI seems to have a great response to this therapy,
85% of anti-AChr Ab positivity and 90% of any Ab positivity
even in cases of acute polyradiculoneuritis3,10,27. IVIG or PLEX
exists20, only approximately 60% of ICI-related myasthenia
are often used in severe or refractory cases3,27. Treatment with
patients described had Ab positivity, with anti-AChr represent-
tacrolimus, rituximab, infliximab, and mycophenolate has also
ing its totality3. There is also a case report of Lambert-Eaton
been reported10. The vast majority of patients with this con-
Myasthenic Syndrome (LEMS) associated with nivolumab in
dition had good responses to treatment. However, there is a
a patient with pulmonary squamous cell carcinoma and posi-
reported mortality of 11% and described relapses following ICI
tive anti-P/Q-type voltage-gated calcium channel (VGCC) Ab21.
rechallenge or after the end of neurologic therapy10.
Similar to non-ICI-related myasthenic syndromes, Nerve
conduction study (NCS), including repetitive nerve stimulation,
and single-fiber electromyography could be used to document Cranial neuropathy
neuromuscular junction compromise. EMG is also helpful in Isolated cranial neuropathies are less frequent than other
evaluating the presence of concomitant myositis, as are the forms of peripheral neuropathies. However, they still repre-
CK serum levels12,18. The ice pack test in cases with ptosis also sent a considerable portion of the nirAE and are important in
seems to be very useful for diagnosis in myasthenic syndromes the differential diagnosis of myasthenic syndromes with facial
associated with ICI, as well as in classic MG18,22,23. involvement. In order of frequency, the most affected nerves
Most reported patients were treated with pyridostigmine are facial, optic, vestibulocochlear, trigeminal, and oculomo-
and steroids associated with another immunomodulatory tor. Although less common, the presentation could be bilateral
treatment, including IVIG, PLEX, rituximab, and/or mycophe- and with multiple cranial nerves simultaneously10.
nolate3,10,17. Although most patients showed a favorable response CSF examination is usually altered in most cases, and there
to treatment and relapses were uncommon, the mortality rate may be an overlap with asseptic meningitis and hypophysitis.
was 28% in ICI-induced myasthenia cases described, being the MRI may demonstrate contrast enhancement in the affected
highest mortality rate of a nirAE10. Respiratory failure was the nerve. The treatment usually follows the same principles
most frequently reported cause of death10. described in peripheral neuropathies, with most cases having
an excellent response to corticosteroid therapy, despite some
Peripheral neuropathy reports of recurrence during weaning10,12,28.
Several forms of peripheral neuropathy have been reported
associated with ICI10,17–19. The most frequent condition was acute Encephalitis
or subacute demyelination polyradiculoneuropathy, with sen- Encephalitis is the main form of nirAE in the CNS, being
sory and/or motor deficits primarily affecting the extremities, potentially very serious, with a mortality rate of 21% among the
typically symmetrical, areflexia, and cranial nerve impairment described cases. Altered mental status, cognitive impairment,
in some cases, similar to Guillain-Barré syndrome (GBS)3,10. seizures, psychiatric disturbances and movement disorders
Other presentations described were sensory neuropathy/neu- are the primary presentation signs in order of frequency10. The
ronopathy, chronic inflammatory demyelinating polyradiculo- condition seems to be directly triggered by ICI or an acceler-
neuropathy, plexopathy, Miller-Fisher syndrome, phrenic neu- ated form of a paraneoplastic syndrome typically associated
ropathy, vasculitic neuropathy, small fiber neuropathy, isolated with the treated tumor (as in small-cell lung cancer)5,29. The
enteric neuropathy, neuralgic amyotrophy, motor neuropathy, latter is reinforced by about half of the reported cases having
and mononeuritis multiplex10. Severe dysautonomia may also autoantibody positivity, with Ma2 and Hu Abs being the most
occur in cases of ICI-related peripheral neuropathy10,24,25. frequent10. There are reports of two cases in which Ma2 Abs
NCS could confirm peripheral nerve impairment and demon- were positive even before treatment with ICI and then devel-
strate the pattern of injury, whether axonal or demyelinating3,18. oped clinical encephalitis30,31.

De Brito MH. Neurologic adverse events of cancer immunotherapy. 273

 As with non-ICI-related autoimmune encephalitis, MRI may widely in ICI-related refractory colitis with good outcomes40,
be normal or demonstrate different patterns of brain involve- suggesting that decreasing the pro-inflammatory state associ-
ment3,10,29,32. Mesial temporal lobes, basal ganglia, cortico-sub- ated with TNF-α helps treat irAE. The two patients who used
cortical, and brainstem areas of increased signal in T2/FLAIR infliximab had isolated myelitis refractory to steroids and
MRI have been described10,33. In most reported cases, CSF PLEX or IVIG, with improved neurological symptoms with
analysis demonstrated pleocytosis (mean 17 leukocytes/μL) the anti-TNF-α16. The reported patients diagnosed with MS
and increased protein (mean 85mg/dL)10. Oligoclonal bands (demyelinating pathology defined) and ICI-associated relapse
(OCB) were encountered in almost a quarter of the patients10. used corticosteroids in the acute phase and interferon or glat-
It is essential to discard infectious differential diagnoses in the iramer as a disease-modifying drug16. None of them used inf-
CSF, such as HSV encephalitis29,32. Another important comple- liximab; therefore the effects in this specific group could not
mentary test is the electroencephalogram (EEG), which may be better evaluated.
demonstrate epileptic or slow-wave activity involving focal
cerebral regions. The mesial temporal lobe involvement on
Aseptic meningitis
EEG is present in the proposed diagnostic criteria for auto-
Its most common clinical manifestations are headache, neck
immune limbic encephalitis, the most common form of ICI-
stiffness, fever and nausea3. Patients with melanoma and treated
related encephalitis5,10,32.
with ipilimumab are more likely to develop aseptic meningitis
Most cases were treated with corticosteroids in associa-
than carriers of other neoplasms that have used another ICI10.
tion with another method, including IVIG, PLEX, rituximab,
The key diagnostic findings are sterile CSF with lymphocytosis
cyclophosphamide, and natalizumab10. Symptomatic treat-
and brain MRI demonstrating meningeal contrast enhance-
ment of epileptic seizures, movement disorders, dysautono-
ment3. The prognosis is usually excellent, probably the nirAE
mia, sleep, and behavioral symptoms may be required together
having the best percentage of response to therapy, which is
with immunomodulatory treatment and still more in the case
performed mainly with corticosteroids alone10,12.
of sequelae34. Despite the high reported mortality rate, most
patients still have a complete or partial response to treatment10.
Other CNS syndromes
There are descriptions of six cases of subacute cerebellar
CNS demyelination and myelopathy degeneration related to ICI10, a syndrome with a known para-
A 2020 systematic review specifically evaluated central ner- neoplastic association41. Despite this, antibodies were negative
vous system demyelination associated with ICI16. Five patients in the cases tested. Half of the patients had MRI abnormalities,
with multiple sclerosis (MS) were described, with two distinct including cerebellar edema, T2/FLAIR hyperintensity lesions,
patterns: three patients already diagnosed with the disease who and contrast enhancement. CSF usually demonstrates mild
had a relapse during ICI use, and two patients with radiologi- pleocytosis and increased protein10.
cally isolated syndrome (i.e., with demyelinating lesions highly Other CNS reported syndromes associated with ICI were
suggestive of MS but without clinical symptoms of the disease)35 posterior reversible encephalopathy syndrome (PRES, n=5),
who developed symptoms after the use of ICI and then fulfilled neurosarcoidosis (n = 2), CNS vasculitis (n = 2), opsoclonus
criteria for the diagnosis of MS36. One reported patient met the myoclonus, leptomeningitis with cranial nerves involvement,
criteria for neuromyelitis optica spectrum disease (NMOSD) steroid-responsive encephalopathy associated with autoim-
by developing longitudinally extensive transverse myelitis mune thyroiditis, mild encephalitis with reversible splenial
(LETM) after exposure to nivolumab, with documentation lesion, neuro-Sjögren syndrome, non-defined CNS granuloma-
of the presence of anti-AQP4 Ab37. Another similar case was tosis, Tolosa-Hunt syndrome, orbital inflammatory syndrome,
described after this systematic review, with pembrolizumab- bilateral internuclear ophthalmoplegia, and isolated akathisia10.
induced LETM and positive anti-AQP438. Seven cases of myelitis, Although best characterized as an endocrinologic adverse
four cases of isolated optic neuritis, and six cases of what was event, hypophysitis is often reported as a nirAE3,11. This probably
called atypical demyelination were also reported in the 2020 occurs because of the anatomical proximity, symptoms simi-
systematic review; none of these met the criteria for the two lar to those manifested in some neurological syndromes, and
earlier-mentioned diseases. the likelihood of simultaneous neurological involvement (e.g.,
In the diagnostic workup, brain, spine, and optic nerves aseptic meningitis). Hypophysitis or isolated hypopituitarism
MRI may demonstrate typical findings for MS or NMOSD. CSF were found in 2.45% of patients undergoing treatment with ICI
could show modest pleocytosis, increased protein content, present in the Japanese Adverse Drug Event Report database,
and presence of OCB10,16. Most patients were treated with cor- which was more frequent than the other groups of neurological
ticosteroids. PLEX, IVIG, cyclophosphamide, mycophenolate, syndromes reported11. This AE is typically grade 1/2 in severity
and infliximab were also used16. The last of these is interesting and often presents non-specific symptoms, including fatigue,
since the potential of TNF-α blockers in triggering or aggravat- muscular weakness, and headaches, making it challenging to
ing demyelination is known39. Infliximab is already used more diagnose42. Diagnostic workup includes serum hormonal levels

274 Arq Neuropsiquiatr 2022;80(5 Suppl. 1):270-280

and MRI to evaluate the function and integrity of the pituitary or provide data-driven recommendations for ICI rechallenge
gland and exclude differential diagnoses such as tumor metas- after severe nirAE. A 2020 case series reported ten patients who
tasis or pituitary apoplexy3. The condition is treated with the had a severe nirAE and were re-treated with ICI, demonstrat-
replacement of deficient hormones only, as systemic high-dose ing a 60% recurrence rate12. Half of those patients either did
corticosteroids do not appear to be beneficial43. not receive immunosuppressive therapy to manage the initial
event or received a short course of oral prednisone (less than
two weeks). Therefore, it is likely that the recurrence rate among
Management of nirAE
ICI re-treated patients could be reduced by treating all severe
There is a European Society for Medical Oncology (ESMO)
nirAE with immunosuppressive therapies12.
guideline for managing immunotherapy toxicities that tries
to provide guidance based on the best available evidence for
the treatment of nirAE8. Unfortunately, the evidence for neu- CAR T-CELL THERAPY
rological syndromes is low, considered level V, based on stud-
Chimeric antigen receptors (CAR) are engineered recep-
ies without a control group, case reports, or expert opinions.
tors that graft a defined specificity onto an immune effector
This guideline recommends checkpoint inhibitor therapy be
cell, typically a T cell, and augment T-cell function. One of
withheld until the nature of the AE is defined, except for mild
the main problems with the body’s immune response against
(grade 1) neurological symptoms. Also, except for mild cases,
cancer is that tumor antigens are often shared with healthy
corticosteroids are recommended; prednisolone 0.5mg/kg/day
tissues. Mechanisms to avoid autoimmunity end up mitigat-
orally for moderate cases (grade 2) and prednisolone 1-2mg/
ing the antitumor response, making it often transient or inef-
kg/day orally or equivalent intravenously for more severe cases
fective. The rationale of CAR T-cell therapy is to overcome
(grades 3 and 4). The possible necessity for use of IVIG and
this immune tolerance45. It is done by collecting the patient’s
PLEX is specifically mentioned in GBS and myasthenic syn-
own T cells, modifying them with a CAR transgene targeting
drome cases. It is important to point out that other therapies
tumor antigens, expanding the cells, and reinfusing them into
have already been described in publications and previously
the patient after preconditioning chemotherapy (usually with
mentioned in this article (i.e., cyclophosphamide, rituximab,
fludarabine and cyclophosphamide)46. After infusion, CAR T
infliximab). They could be used in cases refractory to the
cells leave the blood and travel to sites of the tumor, where
guideline-recommended therapies. The oral corticosteroids
they identify and kill tumor cells. This can trigger extensive
could be tapered down within four to eight weeks depending
proliferation of CAR T cells and the release of tumor antigens,
on symptom severity23. Table 2 summarizes nirAE treatment
which activates the immune system to recruit non–CAR T
recommendations.
cells, thus eliciting further antitumor responses in a process
An adequate diagnostic investigation should be delivered
known as cross priming45.
in every suspected case of nirAE. This could avoid potentially
The first CAR T-cell therapy approved by the United States
serious differential diagnoses being left untreated (i.e., herpetic
Food and Drug Administration (FDA) was tisagenlecleucel,
encephalitis, meningeal carcinomatosis) and unnecessary ICI
targeting CD19 antigen47. It was first indicated against B-cell
discontinuation. It is also essential to keep in mind that the
acute lymphoblastic leukemia (ALL) in children and young
treatment not only involves the immunomodulatory part.
adults and was later accepted for B-cell non-Hodgkin lymphoma
Treatment of specific symptoms of each syndrome could be
(NHL). As of March 2022, the FDA approved another five CAR
needed, such as using pyridostigmine in myasthenic syndromes,
T-cell therapies. Three are directed against CD19 to treat lym-
antiepileptic drugs when seizures occur, or ventilatory support
phomas and/or B-cell ALL in adults: axicabtagene ciloleucel,
in neuromuscular syndromes with respiratory failure. Therefore,
brexucabtagene autoleucel, and lysocabtagene maraleucel.
for better differential diagnosis of neurological symptoms and
The other two target B-cell maturation antigen (BCMA) for the
specific symptomatic treatment, the ESMO guideline advises a
treatment of multiple myeloma (MM): idecabtagene vileucel
neurologist’s early evaluation of nirAE-suspected cases8.
and ciltacabtagene autoleucel48. While this treatment is more
and more frequently used against hematological malignancies
ICI rechallenge
in clinical routine, it needs to be seen if this approach will also
As a general rule, guidelines on the subject do not recom-
work against solid tumors3. This therapy has shown excellent
mend ICI rechallenge after cases of severe nirAE8,44. However,
results, with impressive, long-lasting remission rates in patients
there are cases where there is no other effective alternative
with relapsed/refractory hematologic cancers. Although the
for cancer treatment or where ICI treatment had a fantastic
clinical responses of these agents in these malignancies have
response previously, and the disease recurred with its discon-
been very encouraging, they have also produced substantial
tinuation. In this context, many oncologists, neurologists,
morbidity and occasionally mortality resulting from toxicity49.
and patients accept the risks of nirAE relapse and opt for
The most common form of CAR T-cell toxicity is the cytokine
cautious retreatment with ICI therapy to manage advanced
release syndrome (CRS), a supra-physiologic response following
malignancy. There are few data in the literature to inform risk
immune therapy that results in activation or engagement of

De Brito MH. Neurologic adverse events of cancer immunotherapy. 275

 Table 2. Management of immune checkpoint inhibitor-associated neurologic adverse events.
Grade of neurologic toxicity (CTCAE) Management
-Continue ICI
I – Mild symptoms
-Neurologic vigilance
-Delay ICI
II – Moderate symptoms, limiting instrumental ADL
-Low dose steroidsa (prednisolone 0,5mg/kg/d)
-Discontinue ICI
-High dose steroidsa (prednisolone 1-2mg/kg/d or IV equivalent)
III or IV – Severe symptoms, limiting self-care ADL (III), life
-Consider IVIG or PLEX
threatening (IV)
-Refractory cases: consider other immunomodulatory therapiesb
(i.e., rituximab, cyclophosphamide, infliximab)

a: oral corticosteroids could be tapered down within 4-8 weeks depending on symptom severity; b: limited evidence, based on individual case reports of each
specific neurologic syndrome; CTCAE: common terminology criteria for adverse events; ICI: immune checkpoint inhibitor; ADL: activities of daily living; IVIG:
intravenous immunoglobulin; PLEX: plasma exchange.

endogenous or infused T cells50. Its incidence varies depending presence of ICANS and the severity of CRS53,56,57. As there are
on the neoplasm and the therapy used; it may reach up to 100% described cases of ICANS without CRS, it cannot be said that
with mild symptoms and up to 46% in the cases with grade 3 the pathophysiology of one is necessarily related to the other.
or greater symptoms51. CRS usually begins with fever, myalgia, Reports have suggested a role for IL-1 in pathophysiology of
rigors, and fatigue within the first one to 14 days following CAR both CRS and ICANS; IL-6 does not seem to be directly related
T-cell infusion and can include hypotension, vascular leak, to ICANS since its blockade, one of the hallmarks of CRS treat-
hypoxia, and/or end organ dysfunction. These manifestations ment, does not decrease the incidence of neurotoxicity and may
may be progressive and can last two to three weeks, although be linked to a slightly higher severe ICANS rate46,58. The main
this is often resolved sooner with optimal management46,52. proposed mechanisms that lead to CAR T-cell neurotoxicity
CRS treatment is made with corticosteroids and tocilizumab, are endothelial activation and disruption of the blood-brain
a monoclonal antibody that blocks the IL-6 receptor, one of barrier integrity3,56. Myeloid cell activation in the CNS and high
the significantly elevated cytokines in patients with this syn- CSF levels of excitatory glutamate and quinolinic acid have
drome. Siltuximab, which also acts on the IL-6 pathway, is already been documented in ICANS; the latter can be impli-
another option that can be used51. Although it is not a directly cated in epileptogenesis46,57.
neurological adverse event, it is important to know about CRS ICANS usually occurs within the first 28 days after the CAR
because there may be an overlap of part of its pathophysiol- T-cell infusion, often occurring during CRS or more commonly
ogy with that of the neurotoxicity associated with CAR T-cell, shortly after it ends46. Symptoms appear on average three days
which will be better addressed from now on. after the infusion and last for about two weeks3. Its typical pre-
sentation is similar to another toxic-metabolic encephalopathy,
with lack of attention, confusion, myoclonus, and word-finding
Immune effector cell-associated neurotoxicity difficulty. Initially, symptoms may be mild, waxing and wan-
syndrome (ICANS) ing. However, they may progress in hours to a few days to more
Neurotoxicity associated with CAR T-cell therapy is known severe forms, such as global aphasia, seizures, motor weakness,
as immune effector cell-associated neurotoxicity syndrome diffuse cerebral edema, and coma3,46. Aphasia, ranging from mild
(ICANS) and occurs with high frequency3,46,49,52. The incidence fluency alteration to global aphasia with mutism, is perhaps
in studies with CD19-targeted CAR T-cell therapies ranges from the most specific symptom of this syndrome, which helps to
23%–67% for patients with lymphoma and 40%–62% for those differentiate it from other types of toxic-metabolic encepha-
with leukemia. About half of these cases are severe, grade 3 or lopathy46,57. It is important to mention that high-grade ICANS
more49. ICANS appears to be much less frequent in BCMA- was associated with bleeding and coagulation abnormalities,
targeted treatment of multiple myeloma and no toxic death including prolonged prothrombin time, decreased fibrinogen,
due to ICANS has been reported in trials in patients with MM, and increased d-dimer; it was also related to thrombosis, mainly
but there are some reports of severe cases53. Similar neurotox- deep vein thrombosis, but strokes have also been reported59.
icity, usually grade 1 or 2, has also been reported using another Diagnostic workup is made through neurological exami-
type of cancer immunotherapy, the CD19/CD3-bispecific T-cell nation including fundoscopy to exclude papilledema, EEG,
receptor-engaging antibody blinatumomab, used for relapsed/ neuroimaging, and lumbar puncture in some cases, in the
refractory ALL; this therapy is also related to CRS3,46,54. absence of contraindications53,60. Although most EEG findings
CRS is more common than ICANS, and most of the patients are nonspecific, such as diffuse slow activity, this test is impor-
with ICANS also present a CRS55. This leads us to think that tant to rule out nonconvulsive status or subclinical seizures46.
the two conditions have a pathophysiological overlap, includ- Neuroimaging, preferably MRI, is helpful in ruling out other acute
ing previous studies demonstrating a relationship between the neurologic abnormalities, such as ischemic or hemorrhagic

276 Arq Neuropsiquiatr 2022;80(5 Suppl. 1):270-280

stroke, and monitoring for signs of cerebral edema or the pres- on a multidisciplinary assessment since measures may be nec-
ence of underlying mass lesions. Most of the neuroimaging tests essary to control behavior in a confused state (pharmacologi-
requested do not show anatomical alterations. However, MRI cal and non-pharmacological), treatment of epileptic seizures
hyperintense signal abnormalities were already described on and intracranial hypertension, as well as compensation for any
FLAIR and T2-weighted images secondary to vasogenic edema other associated organic dysfunction.
that may involve thalami, brainstem, basal ganglia, cingulate In order to perform the grading of this condition similarly
gyrus, hippocampus, and/or splenium of the corpus callosum; between services, helping to standardize clinical management,
leptomeningeal enhancement and multifocal microhemor- the American Society for Transplantation and Cellular Therapy
rhages have also been observed61. CSF analysis may be useful (ASTCT) published an objective consensus grading system for
when there is a suspicion of neuroinfection or leptomeningeal ICANS50. An interesting instrument that is part of this gradua-
disease progression, as well as measuring intracranial pressure tion is the Immune Effector Cell-associated Encephalopathy
(ICP). Ferritin and C-reactive protein, markers of inflammatory (ICE) assessment tool (Table 3), which is somewhat similar to
activity, can also be useful in the evaluation of these patients. the mini-mental state exam (MMSE) but shorter and focused
ICANS is usually self-limiting and completely reversible on the areas most affected by the disease. For children under 12
in most patients, although it is still uncertain whether it can years of age, another tool, the Cornell Assessment of Pediatric
cause long-term subclinical neurological sequelae. It is primar- Delirium (CAPD), was suggested46,50. Table 4 provides an adap-
ily managed with supportive care for low-grade toxicities and tation of the ASTCT grading scale in conjunction with ICANS
corticosteroids for more severe cases46. Care should be based management guidelines50,53,60,62.

Table 3. Immune Effector Cell-Associated Encephalopathy (ICE) score to neurological toxicity assess50.
Test Points
Orientation: orientation to year, month, city and hospital 4
Naming: name three objects (i.e., point to pen, clock and table) 3
Following commands: ability to follow simples commands (i.e.,
1
“smile”, “show me two fingers”
Writing: ability to write a standard sentence 1
Attention: ability to count backwards from 100 by 10 1

Table 4. The American Society for Transplantation and Cellular Therapy (ASTCT) grading system49 with respective management
strategy for Immune effector cell-associated neurotoxicity syndrome (ICANS) – [adapted from Zhou, et al.52].
Grade 1 Grade 2 Grade 3 Grade 4
ICE score 7-9 3-6 0-2 Unable to perform
Depressed Unarousable or requires vigorous or
Awakens Awakens Awakens only to tactile
level of repetitive tactile stimuli to arouse. Stupor
spontaneously to voice stimulus
consciousness or coma
Any clinical seizure that
Life-threatening prolonged seizure (>5 min)
resolves rapidly or non-
Seizure No No or repetitive clinical or electrical seizures
convulsive seizures on EEG
without return to baseline in between
that resolve with intervention
Deep focal motor weakness such as
Motor findings No No No
hemiparesis or paraparesis
Diffuse cerebral edema on neuroimaging;
Elevated ICP/ Focal/local edema decerebrate or decorticate posturing; or
No No
cerebral edema on neuroimaging cranial nerve VI palsy; or papilledema; or
Cushing’s triada
ICU Alert ICU Transfer to ICU Transfer to ICU Transfer to ICU
Alert neurologist, elevate the head of the patient’s bed to 30°, management of CRS if concurrent
Dexamethasone Dexamethasone IV 20 Management of seizure as per grade 3. If
IV 10mg every 6 mg every 6 h. If seizure, papilledema, start acetazolamide IV (or
h, and consider clonazepam IV 1mg or enteral if IV form not available) 1,000 mg
levetiracetam other benzodiazepines to followed by 250–1,000 mg bid. If elevated
Close
Management 750 mg bid as terminate it, then loading ICP/cerebral edema, consider hyperosmolar
monitoring
prophylaxis for with levetiracetam (or other therapy with mannitol and hyperventilation.
seizures available IV AED) Methylprednisolone IV 1,000 mg/d.
Evaluation of other experimental salvage
options

a: Irregular, decreased respirations, Bradycardia, Systolic hypertension; CRS: cytokine release syndrome; ICE: immune effector cell associated encephalopathy;
ICP: intracranial pressure; ICU: intensive care unit; IV: intravenous; MRI: magnetic resonance imaging; AED: antiepileptic drug.

De Brito MH. Neurologic adverse events of cancer immunotherapy. 277

 In conclusion, cancer immunotherapy has revolutionized due to varied nonspecific symptoms and a broad differential
oncological treatments, changing paradigms of neoplasms diagnosis. Neurologists, oncologists, hematologists, and other
previously considered intractable due to refractoriness or poor healthcare professionals who deal with cancer patients should
prognosis. The trend is for new therapies to emerge involving be aware and up-to-date regarding the neurological adverse
immunotherapeutic concepts and expanding the indications events of immune checkpoint inhibitors and CAR T-cell ther-
of treatments already available for other neoplasms. However, apy. They occur with considerable frequency, can be potentially
it is crucial to keep in mind their adverse effects, especially the serious, and should increasingly be seen in the coming years
neurological ones, which are sometimes challenging to diagnose with a greater availability of these therapies.

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