REVIEW

CURRENT
OPINION Neurotoxicity associated with cancer
immunotherapy: immune checkpoint inhibitors and
chimeric antigen receptor T-cell therapy
Claire Perrinjaquet a,, Nicolas Desbaillets b,, and Andreas F. Hottinger a,b

Purpose of review
Immune checkpoint inhibitors (ICPI) and chimeric antigen receptor T cells (CAR-T) represent novel therapies
recently approved to treat a number of human cancers. As both approaches modulate the immune system,
they can generate a number of immune-related adverse events (irAEs), including a large spectrum of novel
neurological toxicities. These are of special interest given their potential severity and risk of compromising
further oncologic treatment. We aim to provide a comprehensive review of the literature and discuss their
optimal management.
Downloaded from http://journals.lww.com/co-neurology by BhDMf5ePHKbH4TTImqenVLIlg0cBmue4nzEvPxp1Oh6WQ25vpQlwmRfP13/9PVPC on 12/15/2019

Recent findings
In contrast to irAEs involving other organs, neurological complications of ICPI are uncommon, may present
throughout the course of treatment and involve the peripheral and central nervous system, including
polyneuropathy, myositis, myasthenia gravis, demyelinating polyradiculopathy, myelitis, encephalitis and
others. If started early, ICPI-related neurologic irAEs are usually responsive to steroids. In contrast, as many
as 40% of patients undergoing CAR-T therapy will develop neurologic complications in the form of a
cytokine-release-associated encephalopathy. It includes delirium, aphasia, tremor/myoclonus, seizure and
seizure-like activity.
Summary
irAEs associated with CAR-T and ICPI therapy constitute new entities. Early identification and treatment are
essential to optimize the functional outcome and further oncologic management of the patient.
Keywords
chimeric antigen receptor T-cell therapy, chimeric antigen receptor T-cell-related encephalopathy, immune
checkpoint inhibitor, neurologic complication

INTRODUCTION by the immune system [2]. Antibodies against CTLA-4

In the last decade, intensive research has focused on
the ability of cancer cells to evade the immune
system and how to harness this characteristic to
fight cancer. Stimulating the immune system rather
than destroying cancer cells directly has been so
efficient that immunotherapy is now considered
the fifth pillar of cancer care after radiotherapy,
surgery, medical oncology and interventional
oncology. To date, two main approaches have
shown efficacy in the fight against cancer.
IMMUNE CHECKPOINT INHIBITORS
Immune checkpoint inhibitors (ICPI) inhibit specific
membrane receptors expressed by T cells which
dampen their activation to maintain self-tolerance
and prevent autoimmunity [1]. Cancer cells may
highjack this inhibitory pathway to evade destruction
(cytotoxic T-lymphocyte-associated antigen-4) and
PD-1 or PD-L1 [programmed cell death-(ligand)-1]
have been the first approved ICPI given the impres-
sive results in a growing number of cancer indications
[3] (Table 1). The CTLA-4 antibodies mainly
a
Department of Oncology and bDepartment of Clinical Neurosciences,
Centre Hospitalier Universitaire Vaudois & Lausanne University, Lau-
sanne, Switzerland
Correspondence to Andreas F. Hottinger, Department of Oncology;
Department of Clinical Neurosciences, Centre Hospitalier Universitaire
Vaudois & Lausanne University, BH 08-634, 1011 Lausanne,
Switzerland. Tel: +41 21 314 1111; fax: +41 21 314 0737;
e-mail: Andreas.hottinger@gmail.com

Claire Perrinjaquet and Nicolas Desbaillets contributed equally to the
article.
Curr Opin Neurol 2019, 32:500–510
DOI:10.1097/WCO.0000000000000686

www.co-neurology.com Volume 32  Number 3  June 2019

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 Neurotoxicity associated with cancer immunotherapy Perrinjaquet et al.
KEY POINTS
 Patients treated with ICPI may develop a wide range of
immune-related neurologic adverse events involving the
central or peripheral nervous system, including myositis,
myasthenia gravis, demyelinating polyradiculopathy,
aseptic meningitis and encephalitis.
 Moderate-to-severe neurologic immune-related
neurologic adverse events occur in less than 1% of
patients treated with ICPI.
 The first line of treatment consists in discontinuation of
ICPI and administration of corticosteroids, even in
diseases in which corticosteroids are usually not
considered, such as Guillain–Barré syndrome. In cases
that remain nonresponsive, second-line treatment must
be tailored to the specific situation. Options include
plasmapheresis, intravenous immunoglobulins and other
immunosuppressive agents.
 CAR-T therapy induces durable oncologic responses,
but is associated with unique acute toxicities, which
can be severe or even fatal. The most common
toxicities are cytokine-release syndrome and CAR-T-
related encephalopathy.
 Prompt and aggressive management of cytokine-release
syndrome and CAR-T-related encephalopathy are
essential to minimize morbidity and mortality.
act during T-cell priming when antigen pre-
senting cells (APC) and the T cells interact in
the lymph node, whereas PD-1/PD-L1 anti-
bodies act directly at the tumor site when T
cells and tumor cells interact.
ADOPTIVE T-CELL THERAPIES
Adoptive T-cell therapies (ACT) consist in adminis-
trating a patient its own (autologous) or donor (allo-
genic) antitumor lymphocytes. The approach mimics
successful T-cell immunization with activation and
expansion of antigen-specific T cells. In ACT this
expansion is however performed ex vivo to maximize
the response. Practically, intratumoral T cells are
Table 1. Approved immune checkpoint inhibitors and indications
CTLA-4 Ipilimumab (Yervoy)
PD-L1 Pembrolizumab (Keytruda),
nivolumab (Optivo)
PD1 Atezolizumab (Tecentriq), durvalumab
(Imfinzi), avelumab (Bavencio)
CTLA-4 þ PD-L1 Ipilimumab þ nivolumab
CTLA-4, cytotoxic T-lymphocyte-associated antigen-4; dMMR, deficient mismatch repair; MSI-H, microsatellite instability high; NSCLC, nonsmall-cell lung cancer;
PD-L-1, programmed cell death-ligand 1; PMBCL, primary mediastinal large B cell lymphoma; RCC, renal-cell carcinoma.
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isolated, activated and expanded ex vivo and then
reinfused in patients after preparative lymphodeple-
tion. This allows attacking tumors with much more
favorable T-cell numbers. Moreover, preactivated
cells are less susceptible to immunosuppressive cues.
However, this approach is sometimes unsuccess-
ful, either because of a lack of intratumoral T cells or
because tumor cells don’t present immunogenic
epitopes. One workaround consists in enabling T-
cell activation and tumor cell killing in a T-cell
receptor (TCR) and costimulation independent
manner. Such engineered T cells are called chimeric
antigen receptor T cells (CAR-T) and express a chi-
meric transmembrane-receptor harboring an extra-
cellular scFv-fragment for tumor targeting linked via
a transmembrane domain to intracellular signaling
domains. The signaling domains consist of CD3j,
the TCR Immune-receptor-Tyrosine-based-Activa-
tion-Motif-containing domain and costimulatory
domains from CD28, 4-1BB or OX-40. This implies
that a single target-antigen recognition event trig-
gers full activation of the T cell without the need for
major histocompatibility complex-epitope presen-
tation nor APC co-stimulation [4]. To date, two CAR-
T therapies have been approved: Axicabtagene cil-
oleucel (Yescarta, Gilead, Foster City, CA, USA) to
treat diffuse large B-cell lymphoma (DLBCL) [5] and
Tisagenlecleucel (Kymriah, Novartis, Basel,
Switzerland) targeting CD19 against refractory B-cell
acute lymphoblastic leukemia and DLBCL [6,7].
Currently, over 340 CAR-T trials with over 10 phase
3 trials are ongoing [8]. Therefore, a growing number
of patients will be eligible, and clinicians should be
prepared to deal with their adverse events.
COMPLICATIONS OF IMMUNE
CHECKPOINT INHIBITORS
Systemic side effects of immune-related
adverse events
Immune-related adverse events (IrAE) occur when T-
cell activation exceeds its normal range and induces
Melanoma
NSCLC, small-cell lung cancer, head and neck carcinoma,
RCC, Hodgkin lymphoma, cervical carcinoma, PMBCL,
urothelial carcinoma, hepatocellular carcinoma, gastric cancer,
MSI-H or dMMR solid tumor
Urothelial cancer, NLCLC, Merckel cell carcinoma
Metastatic melanoma, RCC, colorectal cancer (MSI-H or dMMR)
www.co-neurology.com 501
Widening spectrum of CNS inflammatory disorders of the CNS
inflammation. They have been described in various
organs including colon, liver, kidney, lung, thyroid,
pituitary gland, skin, muscle, joint and eye. The
physiopathological pathway remains only partially
understood but immune checkpoints play an impor-
tant role in immune homeostasis, preventing auto-
&
immunity and promoting self-tolerance [9 ].
The overall reported incidence of irAEs varies
from 15 to 90% depending on study [10,11]. The rate
of severe irAEs requiring treatment discontinuation
is however much lower, depending on the agents
evaluated (0.5–13%) [12–18].
Overall, PD-1/PD-L1 inhibitors show a lower
incidence of irAEs compared with CTLA-4 inhibi-
tors. Combined double-axis inhibition (CTLA-4 and
PD-1/PD-L1) results in higher irAEs with 30–50% of
patients developing grades 3–4 side effects in con-
trast to 10–20% with either monotherapy
[11,12,17,19–30]. Significantly, whereas anti-PD-
1/PD-L1 irAEs appear to be dose independent, risks
of severe adverse event increase from 7 to 25% when
ipilimumab dosage increases from 3 to 10 mg/kg.
Overall, neurologic side effects linked to ICPI
remain rare. The most commonly affected organs
are, in order, the skin and gastrointestinal tract
&&
followed by the lung, and thyroid [31 ]. Moreover,
16–24% of patients report nonspecific symptoms
such as fatigue [32].
Neurologic side effects of immune
checkpoint inhibitors
The overall incidence of reported neurological
adverse events (nAE) of any grade was 3.8% with
anti-CTLA-4, 6.1% for anti-PD-1/PD-L1 and 12%
with the combination of anti-PD-1 and anti-
CTLA-4 therapy. The most frequent side effects
described were aspecific symptoms (headache, dys-
geusia, dizziness, peripheral sensory neuropathy)
&
[33 ]. Severe (grades 3–4) nAE occurred in 1.9% of
patients under anti-CTLA-4 (ipilimumab) [34], and
0.2–0.4% under anti-PD-1 (nivolumab or pembro-
lizumab) [20,35] and 0.1–1% under anti-PD-L1 (ate-
zolizumab, avelumab or durvalumab) [28,36,37].
Diagnosis of neurological adverse events
When a patient under ICPI develops neurological
symptoms, one should keep in mind that nAE
remains a diagnosis of exclusion. Therefore, investi-
gating potential differential diagnoses, including vas-
cular, toxic, metabolic, epileptic, infectious causes or
the presence of progressive oncologic disease (brain
metastasis, leptomeningeal carcinomatosis or spinal
cord compression) should be prioritized.
Rapid diagnosis and treatment initiation are
crucial as sequelae or death can occur with all these
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different causes. A multidisciplinary team should be
involved in the management decision, as discontin-
uation of the oncologic treatment could decrease its
efficiency. A lumbar puncture should be realized
with symptoms emerging from the central nervous
system. An MRI may be helpful to exclude other
potential causes.
MANAGING NEUROLOGICAL
COMPLICATIONS OF IMMUNE
CHECKPOINT INHIBITORS
There are no prospective trials to help determine the
optimal management of nAEs. Early intervention is
the key to reduce both severity and duration [38]. As
nAEs are most likely caused by general immunologic
activation, temporary immunosuppression with cor-
ticosteroids is recommended as soon as symptoms are
severe enough or in certain-specific situations
&&
(encephalitis, myasthenia gravis) (Table 2) [31 ].
Plasmapheresis and immunosuppressants like myco-
fenolate, methotrexate, cyclophosphamide and rit-
uximab have been considered in refractory cases.
Alternative immunosuppressive strategies including
natalizumab, bortezomib, tacrolimus or IL-17 inhib-
itors have also been efficient [38,39]. Most nAEs
resolve with adequate management.
Toxicities of the peripheral nervous system
Inflammatory myopathies
Myopathy appears to be the most frequent nAE with
anti-PD-1/PD-L1 and occurs less commonly with
anti-CTLA-4. The most frequent types are necrotizing
autoimmune myositis, dermatomyositis and poly-
&
myositis [42 ,43–50]. Of note, rare cases of orbital
myositis and eosinophilic fasciitis have also been
&&
reported [50,51 ,52]. The usual symptoms include
muscle pain, proximal limb weakness, difficulties
speaking/swallowing, ptosis or oculomotor weak-
ness. Moreira et al. [53] described 19 cases of ICPI-
induced myositis, in which 32% presented associated
myocarditis and 5% had concomitant myasthenia
gravis, all of them receiving at least anti-PD-1 treat-
ment. Some patients developed respiratory distress
linked to diaphragm involvement. Laboratory
&&
workup often shows elevated creatine kinase [51 ].
Electrophysiological findings show a myopathic pat-
tern. Muscle biopsy may show necrotic myofibers
&&
and inflammatory changes [51 ]. Treatment with
high-dose corticosteroids and ICPI discontinuation
usually allows symptom improvement. Most patients
recover completely, although patients with sequelae
have been described.
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 Table 2. Differential diagnosis and work up of common immune checkpoint inhibitor-related neurological adverse events
Work up and management of common neurological complications of immune checkpoint inhibitors
Diagnosis Differential diagnosis
Peri pheral nervous system
Polyneuropathy
Metabolic
Toxic (previous chemotherapies,
vitamin deficits)
Exclude leptomeningeal spread in
case of cranial nerve involvement
Guillain–Barré syndrome (progressive symmetric ascending muscle weakness with decreased reflexes  facial, respiratory or oculomotor/bulbar muscle involvement  autonomic nerve
dysregulation)
Spinal cord compression, myelitis
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Infection (Lyme, HIV, HSV, HZV)
Metabolic (acute intermittent
porphyria, hypokalemia,
hyperkalemia)
Drug induced (amiodarone,
disulfiram, organophosphates)
Critical care polyneuropathy
CIDP, vasculitis
Myasthenia gravis (fluctuating muscle weakness, including cranial nerves with fatiguability, possible respiratory nerve involvement)
Metabolic myopathy
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Toxic-induced myasthenic syndrome
www.co-neurology.com
Polymyositis
503
Recommended work-up
ENMG (acute demyelinating
polyneuropathy)
CSF: normal WBC, elevated proteins
Pulmonary function test with measure
of vital capacity and max
inspiratory/expiratory pressures
Anti-GQ1b (positive in Miller Fisher
variant)
Serum: acetylcholinereceptor and anti
musk antibodies
Tensilon or ice pack test
Repetitive nerve stimulation and
single fiber EMG
Grade
Grade 1 (mild symptoms, without
interference in daily life
activities)
CAUTION: any cranial nerve
involvement must be considered
as grade 2
Grade 2 (moderate symptoms
with interference in activities of
daily life)
Grade 3 (severe limitation in
activities of daily life or life
threatening problems
(respiratory, other)
Management
Low threshold to withhold immune
checkpoint inhibitors. Close monitoring
for any progression
Withhold immune checkpoint inhibitor
treatment/close monitoring or steroids
(prednisolone/0.5–1 mg/kg).
Pregabalin or duloxetine for pain
Hospitalize patient/withhold ICPI, high-
dose steroids (prednisolone 2 mg/kg)
First line: high-dose corticosteroids.
CAUTION: possible initial
deterioration
In case of lack of improvement:
plasmapheresis or IVIG
Autonomic dysfunction or pulmonary
function deterioration determines
requirement for management in
intensive care
High-dose corticosteroids CAVE: risks of
deterioration
Pyridostigmine
If no improvement: plasmapheresis, IVIG,
azathioprine cyclosporine or
mycophenolate to be considered
Permanently discontinue ICPI
Neurotoxicity associated with cancer immunotherapy Perrinjaquet et al.
 504
Table 2 (Continued)

Work up and management of common neurological complications of immune checkpoint inhibitors

Diagnosis Differential diagnosis Recommended work-up Grade Management

Myositis (bilateral proximal limb weakness, possible muscle pain, fever, possible bulbar weakness, oculoparesis, bilateral ptosis)
Steroid myopathy Serum: elevated creatine kinase High-dose corticosteroids
Drugs (statins) ENMG: fibrillations Monitor patient closely if respiratory
muscle weakness
Consider muscle biopsy: necrotizing CAVE: possible concomitant myocarditis
myopathy with inflammatory infiltrate
Central nervous system

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Encephalitis (confusion or altered behavior, headaches, motor or sensory deficits, dysphasia, fever)
Infection Brain  spine MRI
Metabolic disturbances Serum: electrolytes, glucose, total
proteins, serum electrophoresis,
consider viral serologies
Brain metastasis CSF: WBC (usually <250/ml with
lymphocytic predominance),
Grade 1 (mild symptoms, no limits
on activities of daily life)
Grade 2
Hold ICPI/Initiate diagnostic work-up,
consider permanent discontinuation in
case of lack of improvement or if
worsening
Exclude viral and bacterial infection
(consider concurrent antiviral and
antibacterial treatment until infection
ruled out)
High-dose corticosteroids (0.5–1 mg/kg/
day) methylprednisolone once
Widening spectrum of CNS inflammatory disorders of the CNS

normal gram stain, protein, infection excluded

glucose, PCR for HSV and other
viruses, cytology
Leptomeningeal dissemination
Cerebrovascular infarct
Intracerebral hemorrhage
Meningitis (headache, photophobia, neck stiffness, possible fever, vomiting, normal cognition)
Infection Brain and spine MRI Exclude bacterial and viral infection
Metabolic disturbances CSF: WBC (typically <500 ml), PCR High-dose corticosteroids
for viral infection, cytology
Leptomeningeal dissemination
Metastasis
Transverse myelitis (acute or subacute, often bilateral motor or sensory symptoms  autonomic deficits, sensory level)

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Spinal metastasis Brain and spine MRI High-dose cortcosteroids
Spinal cord compression CSF: usually normal Plasmapheresis or IVIG if non responsive
to steroids
Infection Serum: B12, TSH, HIV, syphilis,
ANA, anti-RO and La antibodies,
anti aquaporin-4 IgGs

Volume 32  Number 3  June 2019

CIDP, chronic inflammatory demyelinating polyneuropathy; CSF, cerebrospinal fluid; ENMG, electroneuromyography; HSV, herpes simplex virus; HZV, herpes zoster virus; ICPI, immune checkpoint inhibitor; IVIG,
&&
intravenous immunoglobulins; TSH, thyroid stimulating hormone; WBC, white blood cells. Adapted from [31 ,40,41].
 Neurotoxicity associated with cancer immunotherapy Perrinjaquet et al.
Myasthenia gravis
Makarious et al. [54] reported 23 cases of ICPI-asso-
ciated myasthenia gravis with 70% of de novo cases
(13 receiving anti-PD-1, four anti-CTLA-4 and three
a combination). The incidence was 0.12% in a large
set of patients treated with nivolumab [55]. Clinical
manifestations included ptosis, diplopia, muscle
weakness, dyspnea and dysphagia. Acetylcholine
receptor antibodies were positive in only 59% of
patients. Concomitant myositis was present in nine
cases. Symptoms began 7–11 weeks after treatment
initiation. One-third of patients passed away despite
aggressive treatments including pyridostigmine, ste-
roids, intravenous immunoglobulins (IVIG), plas-
mapheresis or plasma exchange.
Guillain–Barré syndrome and other
peripheral neuropathies
Guillain–Barré syndrom (GBS) is a rare side effect.
Supakornnumporn et al. described five patients. All
but one developed symptoms around the third treat-
ment-cycle, with sensory loss, paresis, areflexia,
weakness, paresthesia, numbness, dysphagia as
main symptoms. Diagnosis is established by the
cerebrospinal fluid (CSF) showing an albuminocy-
tologic dissociation and a demyelinating polyneur-
opathy on electroneuromyography (ENMG). The
treatment consisted in immunoglobulins alone or
with added corticoids for two patients. One was
treated with corticosteroids alone. The last patient
received tacrolimus, corticoids followed by plasma
exchanges. Regarding outcome, two patients died,
two improved and one remained debilitated [56].
ICPI-induced neuropathies occur in less than 1%
of patients and show great variability in severity. ICPI
may affect small sensory-type fibers or show more
typical presentations of immune-mediated phenom-
ena such as chronic inflammatory demyelinating pol-
&
yneuropathy [33 ,45,57–60]. For instance, Gu et al.
reported 14 cases of acute neuropathy, mainly elicit-
ing sensorimotor neuropathy and hyporeflexia. Half
of the patients showed lymphocytosis in the CSF and
an axonal pattern on ENMG allowing the distinction
with GBS [61].
Polyradiculopathies and meningoradiculoneur-
itis with facial diplegia, muscle weakness and con-
trast enhancement of the caudal nerve fibers have
been described [46,57,58], as have cases of isolated
cranial mononeuropathies [62,63]. Steroids and
IVIG are typically used.
Toxicities of the central nervous system
Hypophysitis
Clinical manifestations of a hypophysitis can evoke
neurological symptoms, in particular headache,
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fatigue and weakness. Up to 10% of patients under
ipilimimab develop hypophysitis. Anti-PD-1/PD-L1
is rarely implicated. Typically, hypophysitis appears
2–3 months after treatment initiation [64]. The
diagnostic workup includes blood tests to analyze
all endocrine axes (adrenocorticotrophic hormone,
cortisol, thyroid stimulating hormone, f-T4, lutei-
nizing hormone, follicle stimulating hormone, tes-
tosterone/estrogen, electrolytes). MRI may show an
enlargement of the gland and exclude other differ-
ential diagnoses (metastasis) in the presence of
endocrine modification.
High-dose steroids are not prescribed anymore
(unless in a clearly symptomatic patient), as this
treatment doesn’t improve the outcome. Most of
the time, the pituitary gland is definitely destroyed,
requiring long-term substitution [65]. Once the
patient is substituted, ICPI can be resumed.
Encephalitis
Autoimmune encephalitis occurs in 0.1–0.25% of
ICPI-treated patients, especially when combined
[66–69]. Larkin et al. reported six patients who devel-
oped encephalitis under nivolumab or nivolumab/
ipilimumab combination for melanoma 18–297 days
after treatment introduction. Clinical presentation
was varied and included altered mental status with
confusion, aphasia, agitation, memory problems,
seizures, fever, fatigue, weakness, headache, stiff neck
[62]. Some patients may present with positive para-
neoplastic antibodies including anti-Hu and anti-N-
methyl-D-aspartate (NMDA) [70]. One case of cere-
bellitis developing after three cycles of nivolumab has
been described [71]. The differential diagnosis
includes brain metastasis, leptomeningeal dissemi-
nation, metabolic encephalopathy and infectious
origin, requiring a large diagnostic workup including
lumbar puncture (with viral, bacterial, paraneoplastic
panel, cytology analyses), MRI, EEG, pituitary hor-
monal axes, toxic screening, complete blood tests.
Rapid management of encephalitis with treatment
discontinuation and high-dose corticosteroids seem
to be crucial for better outcome. Half of patients also
received IVIG. Empirically antiviral and broad-spec-
trum antibiotics should be started until an infectious
cause is excluded.
Vasculitis
Cases of giant cell arteritis and polymyalgia rheu-
matica have been described in patients treated with
ipilimumab [45,46,72].
Aseptic meningitis
Aseptic meningitis is a rare side-effect, described
mostly with ipilimumab, which typically develops
between weeks 1 and 7 after initiation of ICPI. Main
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Widening spectrum of CNS inflammatory disorders of the CNS
symptoms include neck stiffness (but not always),
fever and headache [57]. CSF shows sterile liquid
with lymphocytic predominance. Meningeal
enhancement is usually present on MRI. Steroid
treatment is generally effective [38,62].
Multiple sclerosis
De novo or relapsed multiple sclerosis, including
optic neuritis, transverse myelitis and acute tumefac-
tive demyelinating lesions have been described under
ipilimumab treatment [73–76]. Significantly, even in
the absence of ICPI therapy, expression of CTLA-4,
PD-1 and T cell immunoglobulin and mucin domain
3 is downregulated in multiple sclerosis patient when
compared with controls, strengthening the crucial
role of inhibitory receptors in the maintenance of
immune homeostasis [77].
Neurosarcoidosis
A 68-year-old patient treated with combined ICPI
(nivolumab/ipilimumab) developed several systemic
irAEs including colitis, rash and transaminitis fol-
lowed by pulmonary sarcoidosis 4 months after dis-
continuation of ICPI treatment that further evolved
to neurosarcoidosis with hemianopsia, agnosia, acal-
culia, disorientation and alexia. MRI revealed subtle
leptomeningeal enhancement and T2-weighted sig-
nal abnormalities. The patient initially improved
with dexamethasone but relapsed during dose taper-
ing. Methotrexate allowed an almost complete recov-
ery and stable oncological status [78].
TOXICITY OF CHIMERIC ANTIGEN
RECEPTOR T-CELL THERAPY
In contrast to ICPI adverse events, CAR-T compli-
cations are typically linked to acute complications
during T-cell reinfusion, that is, cytokine-release
syndrome (CRS). It must however, be recognized
that nAEs may arise both in the frame of the CRS
and with distinct timing.
Cytokine-release syndrome
The most common complication faced by patients
receiving CAR-T is a CRS. Clinically, it resembles
sepsis, with high fever, hypotension, tachycardia,
respiratory insufficiency, myalgias, vascular leak,
coagulopathy (DIC) and oliguria leading to multiple
organ failure in severe cases. CRS can affect any
organ, including the nervous system. Symptoms
usually start within the 1st days following T-cell
infusion and peak between 1 and 2 weeks postin-
fusion. All CAR-T cell therapies elicit some degree of
CRS; 27% present severe CRS requiring intensive
care support [79]. Even when well managed, CRS
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is a frequent cause of death in CAR-T-treated
patients [80].
CRS is triggered by the activation of CAR-T when
they encounter their target cells. This leads to a
massive release of cytokines such as IL-2, sIL-2Ra,
IFNg, IL-6, s-IL-6R and granulocyte colony stimulat-
ing factor by the T cells and neighboring immune
cells, producing what is sometimes called a cytokine
storm. Serum IL-6 levels correlate with CRS severity,
and thus, IL-6R blockade with tocilizumab has been
approved as standard of care to treat CRS following
&&
tisagenlecleucel infusion [81 ]. Similarly, blocking
IL-6 directly with siltuximab is also used. Cortico-
steroids can be used, but as they inhibit T-cell func-
tion and induce T-cell apoptosis, thereby reducing
the efficacy of the oncologic treatment, they should
be avoided whenever possible.
Chimeric antigen receptor T-cell-related
encephalopathy
CAR-T-related encephalopathy (CRES) is a central
nervous system toxicity mediated by CAR-T which
represents a significant cause of morbidity and mor-
tality potentially hindering the expansion of CAR-T
treatments. Such nAEs are not rare, with up to 40%
of patients developing severe and sometimes even
fatal neurologic symptoms, [79,80,82,83]. Adverse
events have been observed in all CD19 CAR studies
and seem to occur with both CD28 and 4-1BB cos-
timulatory domains although their incidence may
&&
be different [81 ]. The mechanisms underlying
these toxicities are only starting to emerge but dis-
&&
ruption of the brain–blood barrier [81 ,82,83] and
cerebellar edema [5] via cytokine release by CAR-T
&&
are key features of CRES [81 ]. This leakage results in
cerebral edema, hemorrhage, infarction and necro-
sis due to intravascular coagulation [83]. The later
can be measured in the patients’ blood with severe
neurotoxicity as they have significantly elevated
&&
DIC markers [81 ].
Although CRES can occur without a CRS, patients
usually present both (91%) simultaneously. The
severity of CRES is proportional to the CRS, thus
being tightly linked to in-vivo T-cell expansion with
CRES occurring when CAR-T reach high levels
&&
[81 ,83]. Neurotoxic symptoms usually follow a ste-
reotypical progression beginning with somnolence,
disorientation, confusion, diminished attention,
mild aphasia, progressing to delirium, hallucina-
tions, global aphasia, myoclonus or tremor. Finally,
severe cases evolve to generalized seizures and
encephalopathy potentially leading to coma and
&&
death [81 ]. EEG findings are nonspecific with dif-
fuse generalized slowing  triphasic waves. These
patients are at risk of developing posterior reversible
Volume 32  Number 3  June 2019
 Neurotoxicity associated with cancer immunotherapy Perrinjaquet et al.

Table 3. Diagnosis and management of cytokine release syndrome and chimeric antigen receptor T-cell-related
encephalopathy syndrome
Grading and management of CRS and CRES
1. Grading of CRS
CRS grade 1 CRS grade 2 CRS grade 3 CRS grade 4

Symptoms or signs of CRS

(A) Temperature >38 8C
(B) SBP < 90 mmHg
(C) AND/OR hypoxia
Yes Yes Yes Yes
No Yes, responds to IV fluids/does Requires vasopressor with or Requires multiple vasopressors (excluding
not require vasopressors without vasopressin vasopressin)
No Requiring low-flow nasal Requiring high-flow cannula Requies positive pressure (CPAP, BiPAP,
canula (6 l/min) or blow- (>6 l/min), facemask, non intubation and mechanical ventilation)
by rebreather mask or Venturi
mask

2. Grading of CRES
CRES grade 1 CRES grade 2 CRES grade 3 CRES grade 4

Neurological assessment score (by ICE 7–9 (Mild 3–6 (Moderate 0–2 (Severe impairment) 0 Patient in critical condition and/
score) impairment) impairment) or unable to perform assessment
Depressed level of consciousness (not Spontaneous Awakens to voice Awakens only to tactical Patient is unarousable or need for
attributable to other factors (sedation, awakening stimulus vigourous/repetitive tactical
. . .) stimulus. Stupor or coma
Raised intracranial pressure NA NA Focal/local edema on Diffuse cerebral edema on
neuroimaging neuroimaging; decerebrate or
decorticate posturing or cranial
nerve VI palsy; or papilledema
or Cushing’s triad
Seizure NA NA Any clinical seizure that Life-threatening generalized seizure
resolves rapidly or non (>5 min) or repetitive clinical or
convulsive seizure on electrical seizures without return
EEG that resolves with to baseline in between
intervention
Motor findings NA NA NA Deep focal motor weakness such
as hemi or paraparesis

3. Management recommendations for CRS

Grade 1
Fever or organ toxicity Acetaminophen and hypothermia blanket to treat fever/tocilizuma 8 mg/kg IV or siltuximab 11 mg/kg
IV for fever lasting >3 days Ibuprofen as 2nd line option/assess for infection/hydration with
IV fluids
Grade 2
Hypotension 500–1000 ml normal saline IV bolus (may be repeated)/tocilizumab or siltuximab if refractory to fluid
boluses/if refractory: start vasopressors, transfer to ICU/consider starting corticosteroids
Hypoxia O2 substitution (high flow  noninvasive positive pressure ventilation)/tocilizumab or siltuximab and
high-dose corticosteroids
Organ toxicity Symptomatic management/Tocilizumab or siltuximab and high-dose corticosteroids
Grade 3
Hypotension 500–1000 ml normal saline IV bolus (may be repeated)/tocilizumab or siltuximab if refractory to fluid
boluses/vasopressors as needed/transfer to ICU, echocardiogram and hemodynamic monitoring/
corticosteroids (dexamethasone 10 mg IV q6h, if refractory increase to 20 mg)
Hypoxia O2 substitution (high flow  non invasive positive pressure ventilation)/tocilizumab or siltuximab and
high-dose corticosteroids
Organ toxicity Symptomatic management/tocilizumab or siltuximab and high-dose corticosteroids
Grade 4
Hypotension ICU management: IV fluids, tocilizumab or siltuximab and methylprednisolone 1 g/day IV, vasopressors
and hemodynamic monitoring
Hypoxia Mechanical ventilation/tocilizumab or siltuximab and high-dose corticosteroids and supportive care as
described for grade 3 CRS
Organ toxicity Symptomatic management of organ toxicity/tocilizumab or siltuximab and high-dose corticosteroids and
supportive care as described for grade 3 CRS

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Widening spectrum of CNS inflammatory disorders of the CNS

4. Management recommendations for CRES

Grade 1
IV hydration, vigilant supportive care, aspiration precautions
Withhold oral intake of food, fluids and medicines, assess swallowing
Avoid all medications that may cause CNS depression
Agitated patients may be controlled with low-dose lorazepam (0.25–0.5 mg IV q8h) or haldoperidol (0.5 mg IV q6h)
Search for and follow a possible papilledema
Brain MRI
Lumbar puncture with measurement of opening pressure
MRI of spine if focal peripheral neurological deficits
Daily 30 min EEG until toxicity symptoms resolve, in absence of seizure prophylactic levetiracetam q12h
Consider tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV if concomitant CRS
Grade 2
Consider transferring patient to ICU if CRES associated with grade 2 CRES
Supportive care and neurological work-up as indicated for grade 1 CRES
Toxilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV if concurrent CRS
Dexamethasone 10 mg IV q6h if refractory to anti-IL-6 or for CRES without CRS
Grade 3
Transfer to ICU
Supportive care and neurological work-up as indicated for grade 1 CRES
Anti IL-6 therapy if associated with concurrent CRS
Dexamethasone 10 mg IV q6h if CRES symptoms worsen despite anti IL-6 therapy or for CRES without CRS. Taper once CRES is resolved to grade 1
Follow papilledema
Consider repeat MRI every 2–3 days if persistent CRES grade 3
Grade 4
ICU monitoring, consider mechanical ventilation for airway protection
Supportive care and neurological work-up as indicated for grade 1 CRES
Anti IL-6 therapy and repeat neuroimaging as described for grades 2 and 3 CRES
High-dose corticosteroids continued until improvement to CRES grade 1 (methylprednisolone IV 1 g/day, followed by rapid taper at 250 mg q12h for 2 days,
125 mg q12h for 2 days, 60 mg q12h for 2 days)
Stage 3 papilledema with CSF opening pressure 20 mmHg: high-dose corticosteroids (methylprednisolone IV 1 g/day)/elevate head end of patient’s bed to
308/hyperventilation to achieve a partial pressure of arterial carbon dioxide (PaCO2) of 28–30 mmHg, but maintained for no longer than 24 h/
hyperosmolar therapy with mannitol or hypertonic saline/consider neurosurgery consultation for Ommaya reservoir/drain/consider anesthetics for burst-
suppression pattern on EEG/metabolic profiling and daily imaging of brain to prevent rebound cerebral edema, renal failure, electrolyte abnormalities,
hypovolemia and hypotension

Comments: ICE score: 1 point for each of the following points: orientation to year, month, city, hospital (4 pts), name 3 objects (3 pts), ability to follow simple
command (show me 2 fingers: 1 pt), write a standard sentence (1 pt), count backwards from 100 in tens (1 pt). BiPAP, Bilevel Positive Airway Pressure; CNS,
central nervous system; CPAP, continuous positive airway pressure; CSF, cerebrospinal fluid; CRES, chimeric antigen receptor-T-related encephalopathy; CRS,
cytokine-release syndrome; EEG, electroencephalogram; ICE score, immune effector cell-associated encephalopathy score; IV, intravenous. Adapted from
&& &&
[80,81 ,85 ].

encephalopathy syndrome and acute necrotizing CONCLUSION

encephalopathy [83].
On the contrary, CRES remains unresponsive to
IL-6R blockade (tocilizumab) which is used to treat
CRS. Dexamethasone intravenous and anticonvul-
sive drugs (levetiracetam) are the only available
&&
treatments [80,81 ]. Plasmapheresis has been pro-
posed, as it works for thrombotic thrombocytopenic
purpura, which shares similar endothelial cell acti-
vation mechanisms but this approach still requires
validation [84]. Consensus guidelines have been
published by the American Society of Bone Marrow
&&
Transplant (Table 3) [85 ].
Immunotoxicity and autoimmunity are important
issues to consider in patients treated with ICPI or
CAR-T therapies. Following ICPI therapy, neurolog-
ical irAEs are rare but may become severe or even
life-threatening if not managed adequately. More-
over, they may occur at any time during or even
after ICPI treatment. In contrast, neurologic toxic-
ity of CAR-T therapy is often associated closely
(within days or weeks) of the treatment infusion.
Preventing or reducing the severity and duration of
neurologic symptoms remains a key challenge. Cur-
rent consensus guidelines remain however based

508 www.co-neurology.com Volume 32  Number 3  June 2019

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 Neurotoxicity associated with cancer immunotherapy Perrinjaquet et al.
on empirical data. Prospective clinical trials remain
a key priority.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 32  Number 3  June 2019