Anticancer Drugs and The Nervous System.13

REVIEW ARTICLE

Anticancer Drugs and the
C O N T I N UU M AUDIO
I NT E R V I E W A V AI L A B L E
ONLINE
Nervous System
By Bianca D. Santomasso, MD, PhD
ABSTRACT
Downloaded from https://journals.lww.com/continuum by M2HW4GRx+0iGw3c+/Jl8t+LxKgj01xYlSYoW63gxa7PtwGT2KsmjGQsQgN9soLA49oNXtGzvY4KovayENoVYYW5yBlEvmBiuyoWx+qvNrspLCkqfy1kFrdlU/Nq/BCmh on 08/06/2020
PURPOSE OF REVIEW: This article reviews the clinical features, prognosis, and
treatment of neurotoxicity from anticancer drugs, including conventional
cytotoxic chemotherapy, biologics, and targeted therapies, with a focus
on the newer immunotherapies (immune checkpoint inhibitors and
chimeric antigen receptor T cells).
RECENT FINDINGS:Whereas neurologic complications from traditional

CITE AS: chemotherapy are widely recognized, newer cancer therapies, in
CONTINUUM (MINNEAP MINN)
2020;26(3, NEUROLOGY OF
particular immunotherapies, have unique and distinct patterns of
SYSTEMIC DISEASE):732 –764. neurologic adverse effects. Anticancer drugs may cause central or
peripheral nervous system complications. Neurologic complications of
Address correspondence to therapy are being seen with increasing frequency as patients with cancer
Dr Bianca D. Santomasso,
Memorial Sloan Kettering Cancer are living longer and receiving multiple courses of anticancer regimens,
Center, 1275 York Ave, New York, with novel agents, combinations, and longer duration. Neurologists must
NY 10065, Santomab@mskcc.org.
know how to recognize treatment-related neurologic toxicity since
RELATIONSHIP DISCLOSURE: discontinuation of the offending agent or dose adjustment may prevent
Dr Santomasso has served as a further or permanent neurologic injury. It is also imperative to differentiate
consultant for Janssen
Pharmaceuticals, Inc; Juno
neurologic complications of therapy from cancer progression into the
Therapeutics/Celgene nervous system and from comorbid neurologic disorders that do not
Corporation; and Kite Pharma/ require treatment dose reduction or discontinuation.
Gilead Sciences, Inc, and receives
research/grant support from ADC
Therapeutics SA; the American SUMMARY: Neurotoxicity from cancer therapy is common, with effects seen
Cancer Society, Inc; Comedy vs on both the central and peripheral nervous systems. Immune checkpoint
Cancer; the Melanoma Research
Alliance; the Parker Institute for inhibitor therapy and chimeric antigen receptor T-cell therapy are new
Cancer Immunotherapy; and the cancer treatments with distinct patterns of neurologic complications. Early
Society of Memorial Sloan
Kettering Cancer Center.
recognition and appropriate management are essential to help prevent
further neurologic injury and optimize oncologic management.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Santomasso discusses the
unlabeled/investigational use of
INTRODUCTION
A
anakinra for chimeric antigen s a result of remarkable advances in patient care and therapies,
receptor T-cell–associated patients with cancer are living longer. New cancer therapies have
cytokine release syndrome and
neurotoxicity and the unlabeled/ exploded over the past several years and include targeted therapies,
investigational use of IV biologic response modifiers, and immunotherapies that have
immunoglobulin and rituximab for
improved patient outcomes in oncology. However, along with the
certain severe neurologic
immune-related adverse events. improved outcomes associated with these exciting treatments, neurologic
complications of treatment are being encountered with increasing frequency,
© 2020 American Academy
and the spectrum of complications has expanded. In particular, although
of Neurology. immunotherapy has firmly cemented its place in the armamentarium of
732 JUNE 2020
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

contemporary cancer therapy,1 it is associated with new patterns of neurologic KEY POINTS
complications that are distinct from those associated with traditional
● Immunotherapy is
chemotherapy and affect both the central and peripheral nervous systems. Two associated with new
new approaches showing remarkable efficacy against cancer, immune patterns of neurotoxicity
checkpoint inhibitor therapy (US Food and Drug Administration [FDA] that are distinct from those
approved for multiple tumor types and indications) and chimeric antigen associated with traditional
chemotherapy and can
receptor (CAR) T-cell therapy (approved for B-cell malignancies), are associated
affect both the central and
with novel and potentially severe neurologic complications. peripheral nervous systems.
INTRODUCTION TO IMMUNE CHECKPOINT INHIBITOR THERAPY ● Neurologic immune-

Immune checkpoint inhibitor therapy has revolutionized cancer treatment by related adverse events have
been reported throughout
generating durable responses in a subset of patients; it is FDA approved for the course of treatment and
multiple tumor types, with indications continuing to expand.2,3 The therapy even after treatment
consists of monoclonal antibodies directed against cytotoxic T-lymphocyte discontinuation; however,
associated protein 4 (CTLA4, ipilimumab), programmed cell death 1 (PD1, serious events tend to
occur days to weeks after
nivolumab and pembrolizumab), or programmed death ligand 1 (PD-L1, treatment initiation.
atezolizumab and avelumab),4 molecules that are present on activated immune
cells (most notably on T cells but also on other immune cells) that usually maintain ● Neurologic immune-
self-tolerance and prevent autoimmunity. Immune checkpoint inhibitor therapy related adverse events are
frequently associated with
works by disrupting inhibitory signals that normally keep immune responses
immune-related adverse
within a physiologic range and protect the body from autoimmunity. These events affecting other
therapies deliver clinical responses by unleashing a highly activated T-cell organ systems; this can
response, but they can also release a cascade of unpredictable and unintended be a clue alerting to the
possibility of a given
autoimmune toxicities known as immune-related adverse events. Immune-related
neurologic symptom being
adverse events can manifest in any organ system, most commonly the skin, the related to the therapy.
gastrointestinal tract, the endocrine organs, and the lungs.5 Combined PD1 plus
CTLA4 blockade is associated with the highest rates of immune-related adverse
events, with 30% to 50% of patients developing severe grade 3 to grade 4 adverse
events compared to 10% to 20% with either monotherapy (TABLE 10-16).2,7
Neurologic immune-related adverse events are rare, with the incidence of
severe cases estimated to be around 1% to 3%.8,9 They can negatively impact
patients’ quality of life and are potentially fatal,10 underscoring the critical need
for appropriate and early diagnosis and management. Agents targeting both
PD1/PD-L1 and CTLA4 pathways have been implicated, but neurologic
immune-related adverse events are most commonly seen after combination
checkpoint blockade.9 Neurologic immune-related adverse events have been
reported throughout the course of treatment and even after treatment
discontinuation11; however, serious events tend to occur days to weeks after
treatment initiation.10 Events may affect any part of the nervous system
(FIGURE 10-112) and are described in detail in later sections of this article. Most
patients experience a single neurologic immune-related adverse event, although
some may develop two or more simultaneous neurologic syndromes. Neurologic
immune-related adverse events are frequently associated with immune-related
adverse events affecting other organ systems; this can be a clue alerting the
clinician to the possibility of a given neurologic symptom being related to the
therapy. With expanding use of immune checkpoint inhibitors as neoadjuvant,
adjuvant, or maintenance therapy, neurologic immune-related adverse events
are expected to become more prevalent.
Since neurologic immune-related adverse events are caused by generalized
immune system activation, management involves first holding the immune
CONTINUUMJOURNAL.COM 733

ANTICANCER DRUGS
checkpoint inhibitor while other potential causes are eliminated. Once a

neurologic immune-related adverse event seems the most likely diagnosis and
as soon as symptoms are severe enough, corticosteroids are considered the
first line of immunosuppression. Certain neurologic immune-related adverse
events readily resolve with low-dose corticosteroids or with holding the
immune checkpoint inhibitor alone, whereas other types of events and severe
toxicity may require high-dose or even pulse-dose corticosteroids, IV
immunoglobulin (IVIg), plasma exchange, or other immunosuppressants.
Early recognition and intervention are the key to reducing both the severity
and duration of the neurologic complications. Management guidelines exist
for immune-related adverse events, including those affecting the nervous
system5,13,14; however, they are based on expert consensus and largely empiric,
based on the standard care for the induced disease. As yet, no prospective trials
have been conducted to help determine optimal management of neurologic
immune-related adverse events.
INTRODUCTION TO CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL

THERAPY
CAR T-cell therapy is one of the most exciting recent therapy developments in
oncology. Whereas CAR T cells have been engineered against many tumor
antigens, the greatest success to date has been in B-cell malignancies. CAR
T-cell therapy targeting the B-cell antigen CD19 has shown impressive results
in relapsed and refractory acute lymphoblastic leukemia and diffuse large
TABLE 10-1 Common Terminology Criteria for Adverse Eventsa–c
Grade 1
◆ Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention
not indicated
Grade 2
◆ Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental activities of daily livingd
Grade 3
◆ Severe or medically significant but not immediately life-threatening; hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily livinge
Grade 4
◆ Life-threatening consequences; urgent intervention indicated
Grade 5
◆ Death related to adverse event
a
Modified from US Department of Health and Human Services.6
b
Grade refers to the severity of the adverse event. The Common Terminology Criteria for Adverse Events
displays Grades 1 through 5 with unique clinical descriptions of severity for each adverse event based on this
general guideline.
c
A semicolon indicates “or” within the description of the grade.
d
Instrumental activities of daily living refer to activities such as preparing meals, shopping for groceries or
clothes, using the telephone, and managing money.
e
Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet,
taking medications, and not bedridden.
734 JUNE 2020

B-cell lymphoma, leading to the FDA approval of two CD19 CAR T-cell KEY POINTS
products, tisagenlecleucel and axicabtagene ciloleucel. The therapy consists
● Early detection of
of collecting a patient’s own T cells, genetically modifying them with a neurologic immune-related
CAR transgene, expanding the cells, and reinfusing them into the patient adverse events is essential
after preconditioning chemotherapy, usually with fludarabine and as prompt therapeutic
cyclophosphamide. Binding of the CAR to the cancer surface antigen then intervention is likely to be
associated with better
initiates killing of the malignant cells.15 However, in addition to its high
recovery.
efficacy, CAR T-cell treatment is frequently complicated by the unique
toxicities cytokine release syndrome and neurotoxicity. Cytokine release ● Chimeric antigen receptor
syndrome manifests with fever, hypotension, and vascular leak resulting (CAR) T-cell therapy induces
from supraphysiologic cytokine elevations that occur in the hours to days after oncologic responses but is
associated with unique
CAR T-cell infusion as a result of the CAR T cells engaging the tumor and toxicities, cytokine release
myeloid cells in the tumor microenvironment. Neurotoxicity is also referred to syndrome, and immune
as immune effector cell–associated neurotoxicity syndrome (ICANS)16; it may occur effector cell–associated
in up to 40% of patients, with manifestations ranging from mild delirium and neurotoxicity syndrome.
tremor to global aphasia, seizures, obtundation, and diffuse cerebral edema that
may be fatal.
Although ICANS has been primarily studied in CD19-specific CAR T-cell
therapy, similar neurotoxicity has been reported with blinatumomab, a
CD19/CD3-bispecific T-cell receptor–engaging antibody that stimulates
endogenous CD19-specific T cells.17 ICANS appears to be less common with
CD22-specific CAR for B-cell malignancies and B-cell maturation antigen–specific
CARs that are under investigation for the treatment of multiple myeloma.
Certain host and tumor factors may be associated with the risk of severe ICANS,
including acute lymphoblastic leukemia tumor type more than diffuse large
B-cell lymphoma, high tumor burden, elevated baseline inflammation, intensity
of conditioning therapy, and CAR design (eg, CD28 more than 4-1BB
costimulatory domains). Severe ICANS is also more likely to occur in patients
who have previously developed severe cytokine release syndrome.
FIGURE 10-1
The clinical spectrum of neurologic immune-related adverse events.
Image reprinted from Biga LM, et al.12

ANTICANCER DRUGS
GENERAL PRINCIPLES OF TOXICITY EVALUATION

The first step in determining whether a neurotoxicity symptom is due to cancer
therapy is to ask if a temporal relationship exists between drug administration
and symptom onset. Treatment-related neurologic effects should be considered a
diagnosis of exclusion, with the neurologist ruling out symptoms related directly
to the cancer, such as from metastases, and those related to other neurologic
disorders. For example, frequent causes of peripheral neuropathy include diabetes
mellitus and alcohol use disorder. For the patient presenting with encephalopathy or
delirium, a wide differential exists, including metabolic and infectious causes.
Patients with cancer are at risk for new metastatic dissemination into the brain,
leptomeninges, spinal cord, plexus, peripheral nerves, or epidural space, with
resulting spinal cord compression; these should be considered. MRI can identify
parenchymal, leptomeningeal, intramedullary, and epidural metastases, and
fludeoxyglucose positron emission tomography (FDG-PET) can be helpful for
evaluating direct neoplastic infiltration of peripheral nerves or plexus compression
from tumor and for distinguishing tumor from radiation necrosis. Lumbar puncture
for CSF analysis can be particularly helpful for distinguishing leptomeningeal
disease, central nervous system (CNS) infection, and immune checkpoint
inhibitor–associated sterile inflammation. Finally, paraneoplastic neurologic
syndromes occurring in patients with cancer may present as a constellation of
neurologic symptoms that should be distinguished from treatment effect, with the
caveat that, in rare cases, immune checkpoint inhibitors have been reported to
trigger paraneoplastic syndromes along with the pathognomonic antibodies.18
TABLE 10-2 Spectrum of Peripheral Neurotoxicity Caused by Cancer Therapies
Neuromuscular Junction
Peripheral Neuropathy Disorder Myositis/Myalgia
Traditional chemotherapy 5-Azacytidine, brentuximab, Cisplatin Brentuximab, docetaxel,

cabazitaxel, cisplatin, cytarabine, gemcitabine, paclitaxel
docetaxel, eribulin, etoposide,
fludarabine, ifosfamide,
ixabepilone, nab-paclitaxel,
nelarabine, oxaliplatin, paclitaxel,
procarbazine, suramin, vinca
alkaloids
Small molecule inhibitors Bortezomib, carfilzomib, NA NA

larotrectinib, lorlatinib
Anti–vascular endothelial Sorafenib, sunitinib NA NA

growth factor (VEGF)
agents
Biologic agents/ Lenalidomide, thalidomide, Interferon alfa, IL-2 Interferon alfa

immunomodulatory agents brentuximab vedotin
Immunotherapy agents Atezolizumab, avelumab, Atezolizumab, avelumab, Atezolizumab, avelumab,

durvalumab, ipilimumab, durvalumab, ipilimumab, durvalumab, ipilimumab,
nivolumab, pembrolizumab nivolumab, pembrolizumab nivolumab, pembrolizumab
IL-2 = interleukin 2.
736 JUNE 2020

Early recognition of therapy-related neurotoxicity may result in improvement of KEY POINTS
adverse neurologic symptoms and avoidance of permanent neurologic damage. At
● Neurotoxicity from
the same time, consideration of alternative diagnoses when a complication is anticancer drugs is a
believed to be therapy related is imperative, since proper identification of an diagnosis of exclusion.
alternative cause for the patient’s neurologic condition may avoid dose reduction of
a needed anticancer drug or the premature cessation of treatment. Neurologic ● MRI and lumbar puncture
for CSF evaluation can be
immune-related adverse events from immune checkpoint inhibitors in particular
particularly helpful for
remain diagnoses of exclusion. When a patient receiving an immune checkpoint evaluating possible
inhibitor develops neurologic symptoms, investigations into potential alternative therapy-associated
diagnoses should be prioritized, including toxic-metabolic, vascular, and neurotoxicity by ruling out
infectious causes or metastatic spread into the nervous system in the form of other causes.
brain metastasis, leptomeningeal carcinomatosis, or spinal cord compression ● Recognition of

from epidural disease. neurotoxicity is important to
Determination of ICANS from CAR T-cell therapy is usually more prevent further neurologic
straightforward because classic symptoms are seen that typically follow a injury or the premature
cessation of a necessary
stereotyped progression within a defined time window (usually within the first anticancer treatment.
30 days) after CAR T-cell infusion. However, rarely, symptoms may occur
outside of the typical time frame or may be otherwise atypical. ● Determination of immune
This article addresses the main neurotoxic effects of cancer treatment on the effector cell–associated
neurotoxicity syndrome
central and peripheral nervous systems, including effects of the newer
from CAR T-cell therapy is
immunotherapies. Since the neurologist typically has some knowledge of the usually more straightforward
specific cancer treatment the patient received as well as the patient’s symptom(s), because classic symptoms
this article is organized accordingly. are seen that typically follow
a stereotyped progression
within a defined time
PERIPHERAL NERVOUS SYSTEM COMPLICATIONS OF window (usually within the
ANTICANCER DRUGS first 30 days) after CAR T-cell
Peripheral nervous system complications of cancer therapies may involve nerves, infusion.
the neuromuscular junction, or muscle (TABLE 10-2).
● Chemotherapy-induced
peripheral neuropathy is
Peripheral Neuropathy typically dose dependent
Peripheral neuropathy is the most common neurologic complication of and cumulative.
traditional chemotherapy and a major dose-limiting toxicity, with painful and
disabling symptoms that can diminish quality of life. The incidence of
neuropathy is variable and generally ranges from 30% to 40% of patients with
cancer treated with chemotherapy, although some studies report an incidence
as high as 70%.19–21 Some traditional chemotherapy agents are commonly
associated with chemotherapy-induced peripheral neuropathy, with those most
likely to be associated including platinum-based compounds (cisplatin,
oxaliplatin), antitubulins (eg, taxanes such as paclitaxel and docetaxel and vinca
alkaloids such as vincristine), proteasome inhibitors (bortezomib), and
antiangiogenic agents (thalidomide) (TABLE 10-3). Newer targeted biologic
agents and immunotherapies may also induce peripheral neuropathy despite
different modes of action.
Determination of whether a patient has chemotherapy-induced peripheral
neuropathy requires analysis of the administered drugs and the cumulative
dosage along with the clinical characteristics and time course of the neuropathy
symptoms. For most of the traditional chemotherapies, toxicity is dose or
duration dependent. Most chemotherapy-induced peripheral neuropathy
develops during the first 2 months of treatment, progresses while chemotherapy
continues, and stabilizes soon after treatment is completed. Whereas most

ANTICANCER DRUGS
chemotherapy-induced peripheral neuropathy occurs in a dose-dependent

fashion, drug-specific features exist, such as the acute neurotoxicity of
oxaliplatin and paclitaxel or the worsening of neuropathy after the
discontinuation of chemotherapy, which is known as the coasting phenomenon.
Chemotherapy-induced peripheral neuropathy can be enhanced by preexisting
peripheral neuropathy from a non–cancer-related cause,22,23 such as diabetes
mellitus,23 smoking history,24 and decreased creatinine clearance,24 or may be
amplified by the sequential or combined use of neurotoxic agents, such as
vinorelbine following bortezomib25 or platinum-based treatment. In particular,
patients who have Charcot-Marie-Tooth disease or other underlying hereditary
TABLE 10-3 Anticancer Drugs Associated With Peripheral Neuropathy
Drug Pathology Type Clinical Symptoms Outcome
Platinum-based
agents
Cisplatin Platinum products Large fiber, Distal symmetric Reversible; may progress
accumulate in dorsal sensory numbness or painful after discontinuation; may
root ganglion paresthesia, loss of be permanent
proprioception (sensory
ataxia common), loss of
deep tendon reflexes
Oxaliplatin Dorsal root ganglion, Acute neuropathy, Acute dysesthesia, Acute: subsides within
sodium ion channels chronic large fiber particularly of the face, hours
sensory, mouth and throat;
Chronic: reversible
autonomic allodynia, cold
months after cessation
hypersensitivity,
persistent sensory
neuropathy
Vinca alkaloids
Vincristine, Dorsal root ganglion, Sensorimotor with Numbness, pain, extensor Symptoms resolve within
vinblastine, microtubules, nerve small fiber, weakness predominantly 3 months but may be
vindesine, terminals autonomic, and affecting legs, permanent with
vinorelbine cranial nerves constipation, dizziness, vincristine; a dose-limiting
ocular palsy, facial toxicity, particularly in
weakness, vocal cord older patients; reversible
paralysis; vincristine is the after cessation
most neurotoxic
Taxanes
Paclitaxel, Dorsal root ganglion, Sensorimotor Feet more affected than Symptoms improve after
docetaxel, microtubules, nerve large and small hands, painful paresthesia, treatment discontinuation
nab-paclitaxel, channels fibers myalgia, occasional mild but may persist after
cabazitaxel weakness 1 year; time to improvement
typically shorter for
nab-paclitaxel
CONTINUED ON PAGE 739
738 JUNE 2020

neuropathies are predisposed to develop severe chemotherapy-induced
peripheral neuropathy.
Chemotherapy-induced peripheral neuropathy may present as sensory
symptoms in the feet or hands, typically in a stocking-glove distribution; pain,
numbness, or tingling; motor symptoms, manifested as weakness; cranial nerve
deficits; or autonomic neuropathy.26 Different chemotherapies affect different
parts of the peripheral nervous system from the dorsal root ganglion to the distal
axon, and the signs and symptoms of chemotherapy-induced peripheral
neuropathy depend on the type of nerve fiber affected: sensory, motor, or
autonomic. Sensory neuropathy may involve large fibers alone (platinum drugs)
CONTINUED FROM PAGE 738
Drug Pathology Type Clinical Symptoms Outcome
Bortezomib Mitochondria, Painful sensory Distal painful paresthesia Reversible with dose
endoplasmic reticulum reduction or drug
in Schwann cells cessation usually 3–4
months after
discontinuation
Thalidomide Dorsal root ganglion, Sensorimotor, Painful paresthesia, Reversible

nerve blood supply, autonomic in weakness and tremor,
dysregulation of elderly myalgia
neurotrophin
Alkylating agents
Ifosfamide, Not known Sensory Gradual onset of Not known

procarbazine paresthesia in feet with
loss of deep tendon
reflexes
Antimetabolites
Cytarabine Not known Sensory Rare Not known
Gemcitabine Not known Sensory Rare
Nelarabine Not known Autonomic, Rare

sensorimotor
mimicking Guillain-
Barré syndrome
Epothilones
Ixabepilone, Inhibits microtubules Sensory, motor, Painful paresthesia, Resolves with drug
eribulin autonomic weakness (10%–16%), rare discontinuation
autonomic changes
Hormonal agents
Anastrozole, Possibly related to Sensory Carpal tunnel syndrome Not known

exemestane, estrogen deprivation
letrozole and sex hormone
effects on transverse
carpal ligament or
carpal tunnel contents

ANTICANCER DRUGS
or both large and small fibers (taxanes). Common sensory symptoms include
symmetric paresthesia or abnormal dermal sensation in the feet and hands,
allodynia, loss of deep tendon reflexes, and diminished proprioception with loss
of vibration sense (typical of large fiber loss alone). Sensorimotor
polyneuropathy affecting axons may occur, in which paresthesia appears
initially, followed by motor weakness. This can classically be seen in vincristine
neuropathy. Autonomic neuropathy, typically seen with vinca alkaloids, may
present with constipation, abdominal discomfort, orthostatic hypotension, and
syncope. The predominance of sensory over motor symptoms in chemotherapy-
induced peripheral neuropathy is believed to be due to the greater exposure of
the dorsal root ganglion of primary sensory neurons to circulating chemotherapy
drugs because of the permeability of the blood-nerve barrier as opposed to motor
neuron cell bodies residing in the spinal cord sequestered behind the less
permeable blood-brain barrier.
Measures to assess chemotherapy-induced peripheral neuropathy include
objective measures of neurologic examination and neurophysiologic testing and
subjective measures, including the National Cancer Institute Common
Terminology Criteria for Adverse Events (CTCAE)6 and patient-reported
outcome measures. Variability exists between patient-reported outcomes and
those reported by clinicians, with the latter typically underreporting.
Many interventions have been studied for chemotherapy-induced peripheral
neuropathy prevention and treatment; however, only for the treatment of
existing oxaliplatin neuropathy is there intermediate strength of evidence
supporting the use of duloxetine for symptomatic relief.19
Peripheral neuropathy is also seen with immune checkpoint inhibitor therapy,
sometimes in severe form. For neurologic immune-related adverse events, the
peripheral nervous system is more commonly affected than the CNS, and serious
and fatal cases have been described.10 Although immune checkpoint inhibitors
share the potential for triggering different kinds of neuropathy (eg, sensory,
sensorimotor, autonomic) with the more traditional chemotherapeutics, the
timing of onset related to the start of therapy may differ from the classic
chemotherapies, and a distinct workup and management are recommended.
Unlike chemotherapy-induced peripheral neuropathy, which is often dose or
duration related, neuropathy related to immune checkpoint inhibitors may
develop very soon after treatment starts, even within the first one to three doses.
Neuropathy presentations from immune checkpoint inhibitors may be diverse,
ranging from painful small fiber sensory type to sensorimotor presentations
more typical of classic immune-mediated phenomena, such as Guillain-Barré
syndrome (GBS) or chronic inflammatory demyelinating polyradiculoneuropathy
(CIDP).27–29 Unlike chemotherapy-induced peripheral neuropathy, in which
holding or discontinuing the drug is the mainstay of management, peripheral
neuropathies from immune checkpoint inhibitors are managed by holding therapy
plus often initiating corticosteroids. For severe cases, other immunosuppressants
may be used.
The drugs most commonly associated with neuropathy are discussed in
greater detail in the following sections.
CISPLATIN. Platinum agents cause long-term peripheral sensory damage,

specifically a neuronopathy, due to formation of adducts (binding of the
chemotherapy to nuclear and mitochondrial DNA), which damage dorsal root
740 JUNE 2020

ganglia neurons. Cisplatin produces more adducts in dorsal root ganglia than KEY POINTS
oxaliplatin, consistent with its slightly higher neurotoxicity.30 Cisplatin typically
● With most chemotherapy
causes numbness, tingling, and pain in the extremities, beginning in the feet and drugs, chemotherapy-
spreading proximally with subsequent involvement of the arms.31,32 Strength is induced peripheral
spared. The neuropathy is dose dependent, and, although initial symptoms neuropathy has a symmetric,
usually begin during treatment, they can continue to progress for several months distal, stocking-glove
distribution. Chemotherapy-
after completion of therapy or discontinuation of therapy (coasting). Although
induced peripheral
symptoms can improve slowly, some patients are left with permanent sensory neuropathy predominantly
deficits, particularly a sensory ataxia because the large fiber modalities are consists of sensory rather
preferentially affected, leading to impaired position sense. No treatments or than motor symptoms,
although motor symptoms
preventive interventions have been proven effective for chemotherapy-induced
can occur.
peripheral neuropathy from cisplatin or the other chemotherapies outlined
below.33 The neuropathy is only preventable with dose reduction or cessation ● Autonomic neuropathy is
of drug. rare in chemotherapy-
Cisplatin can also cause ototoxicity, resulting in high-frequency hearing induced peripheral
neuropathy with the
loss and, less commonly, imbalance due to vestibular dysfunction. Tinnitus exception of vinca alkaloids,
often presents before hearing loss. Ototoxicity can be particularly severe in particularly vincristine. A
children, with risk factors including younger age, use of concurrent cranial typical presentation of
radiation, diagnosis of a CNS tumor, decreased renal function, high autonomic neuropathy is
constipation.
cumulative doses, and use of carboplatin in addition to cisplatin.34 Ototoxicity
results from the drug causing hair cell damage in the organ of Corti and is ● Unlike chemotherapy-
irreversible. Multiple prophylactic and therapeutic treatments are being induced peripheral
investigated. The addition of sodium thiosulfate to cisplatin-based chemotherapy neuropathy, which is often
dose or duration related,
has shown promise in reducing the incidence of ototoxicity in children in
neuropathy related to
investigational studies,35 but insufficient evidence is available to support this immune checkpoint
approach for adults or for any other pharmacologic agent. inhibitors may develop very
soon after treatment starts,
OXALIPLATIN. Two distinct peripheral neuropathy syndromes can develop in even within the first one to
three doses.
patients receiving oxaliplatin. In addition to the chronic cumulative dose-dependent
late-onset neuropathy observed with all platinum-based compounds, oxaliplatin ● Neuropathy presentations
may cause a transient acute neurotoxicity within 24 to 72 hours after each dose. from immune checkpoint
These acute neuropathy symptoms consist of cold-induced dysesthesia that is inhibitors may be diverse.
most severe in the hands, face, and mouth; it is likely due to the drug’s effect on
● Unlike chemotherapy-
voltage-gated sodium channels.36 More chronic symptoms may persist for induced peripheral
several months and necessitate drug discontinuation. Although oxaliplatin neuropathy, in which
neurotoxicity typically improves after discontinuation of therapy, the coasting holding or discontinuing the
drug is the mainstay of
phenomenon may be seen. Calcium and magnesium supplementation were
management, peripheral
thought to prevent oxaliplatin neuropathy but failed confirmation in a neuropathies from immune
randomized controlled trial.37 checkpoint inhibitors are
managed by holding therapy
CARBOPLATIN. Carboplatin is generally less neurotoxic than cisplatin or plus initiating corticosteroids.
For severe cases, other
oxaliplatin, and peripheral neuropathy has only been rarely reported. In adults, immunosuppressants may
carboplatin is less ototoxic than cisplatin, although ototoxicity can still occur be used.
with high-dose therapy.38
TAXANES. Taxanes are antimicrotubule agents that are widely used in oncology.
They cause a length-dependent, painful, sensory neuropathy due to dying-back
axonopathy. The neuropathy may be partially reversible after treatment is
discontinued. Additionally, an acute transient pain syndrome characterized by aching
musculoskeletal pain occurs in more than half of patients treated with paclitaxel.39

ANTICANCER DRUGS
VINCA ALKALOIDS. Vinca alkaloids such as vincristine, usually used for

hematologic malignancies, typically cause a length-dependent sensory
neuropathy that often progresses to some degree of motor involvement.40
A dose-limiting axonal sensorimotor neuropathy is almost universal and is
characterized by paresthesia and distal weakness, especially wrist drop and
footdrop. Long-term permanent and late effects may be seen, particularly in
the pediatric and young adult population. Vincristine primarily affects
peripheral nerves but can also cause cranial neuropathies and autonomic nervous
system dysfunction. Symptoms such as hoarseness, ptosis, vision loss, facial
weakness, and hearing loss are suggestive of cranial neuropathy from vincristine.
The major differential diagnosis is tumor recurrence in the CNS. Autonomic
neuropathy may occur, characterized by constipation and colicky abdominal
pain. Diurnal muscle cramps of the arms and legs may be the first sign of
neurotoxicity. Neuropathy is generally reversible but may require months
to improve after vincristine discontinuation. Symptoms can progress for
several weeks after stopping the drug, and patients may have incomplete
recovery.
Vinblastine, vindesine, and vinorelbine tend to be used more in the treatment
of solid tumors and are less neurotoxic than vincristine. All have been reported to
cause similar neuropathy, especially when combined with or used sequentially
after other neurotoxic agents such as taxanes.
ERIBULIN AND IXABEPILONE. Eribulin and ixabepilone are two new antimicrotubule
agents used to treat breast cancer that can cause an axonal neuropathy.41 Peripheral
neuropathy develops in approximately 30% of patients treated with eribulin and
is severe in 4%. Although symptoms are generally reversible with discontinuation,
neuropathy can last beyond a year in approximately 5% of patients.42 The
neuropathy of ixabepilone is a dose-dependent primarily sensory distal
neuropathy, although motor (and rarely autonomic) neuropathies have also
been reported.43 Overall, up to 71% of patients exposed develop a sensory
neuropathy of any grade, which is severe in 6% to 21%.44 Symptoms are typically
reversible and resolve after dose reduction.
BORTEZOMIB. Bortezomib is a proteasome inhibitor used to treat multiple

myeloma. It can induce peripheral neuropathy that is severe, with grade 3 to
grade 4 toxicity occurring in approximately 15% of patients.45 Patients typically
present with a painful, length-dependent small fiber predominant axonal
sensory neuropathy. Occasionally mild weakness in the legs (approximately
10% of patients) or autonomic symptoms such as constipation and orthostatic
hypotension may occur. The painful small fiber neuropathy is thought to arise
from effects on the activity of the endoplasmic reticulum and mitochondria
in Schwann cells, leading to damage to the dorsal root ganglia and, less
commonly, the axons. Neuropathy occurs in 60% to 70% of patients receiving
twice-weekly therapy and is decreased if the dose is given weekly, if the
medication is administered via a subcutaneous rather than IV route, if the total
dose is reduced, and possibly with concomitant use of dexamethasone.46,47
Patients are particularly susceptible to pressure-point neuropathies, which can
be superimposed upon the diffuse neuronal injury. Nerve conduction studies
reveal either a demyelinating or mixed axonal-demyelinating neuropathy.
A small proportion of patients receiving bortezomib develop a severe
742 JUNE 2020

polyradiculopathy, which appears to be immune mediated. CSF protein may KEY POINTS
be elevated, and nerve roots may sometimes enhance on MRI. Some patients
● With several
respond to glucocorticoids or IVIg, and some symptomatic improvement may be chemotherapies, such as
provided by topical menthol or agents for neuropathic pain such as duloxetine. cisplatin and paclitaxel,
The newer-generation proteasome inhibitors carfilzomib and ixazomib are although initial symptoms
reported to have a lower incidence of chemotherapy-induced peripheral usually begin during
treatment, they can
neuropathy.
continue to progress for
several months after
LORLATINIB. Lorlatinib is a third-generation inhibitor of anaplastic lymphoma completion of therapy or
receptor tyrosine kinase (ALK) and ROS1 tyrosine kinases that is approved for may worsen for several
months following the
ALK mutation–positive non–small cell lung cancers that are refractory to other
discontinuation of therapy
ALK inhibitors. In a phase 2 study, 30% of patients developed peripheral (coasting).
neuropathy.48
● Vincristine primarily
THALIDOMIDE. Thalidomide is an antiangiogenic therapy used for the treatment affects peripheral nerves
but can also cause cranial
of multiple myeloma. A sensory-predominant neuropathy may develop with neuropathies and autonomic
thalidomide treatment in 50% of patients with typical doses and is related to the nervous system dysfunction.
duration rather than the total dose of the treatment.49 Thalidomide reduces Symptoms such as
blood supply to the nerve, resulting in wallerian degeneration.50 Patients report hoarseness, ptosis, vision
loss, facial weakness, and
painful dysesthesia and sensory loss but may also develop weakness, cramps, hearing loss are suggestive
fasciculations, and tremor. Incidence is increased in older patients, and 10% of of cranial neuropathy from
patients have severe symptoms, commonly leading to dose reduction or vincristine. The major
cessation. Constipation is also common, particularly in elderly patients,51 and has differential diagnosis is
tumor recurrence in the
been attributed to autonomic nerve fiber injury. With cessation of treatment,
central nervous system.
symptoms are partially reversible but may persist for several months.49
Lenalidomide and pomalidomide are newer-formulation antiangiogenic agents
that appear to have less toxicity than thalidomide.
BRENTUXIMAB VEDOTIN. Brentuximab vedotin is an antibody-drug conjugate

against the CD30 marker found on B lymphocytes and T lymphocytes used to
treat relapsed or refractory Hodgkin lymphoma and anaplastic large cell
lymphoma. It causes a peripheral neuropathy by disturbing axonal transport.
Peripheral neuropathy occurs in 36% to 53% of patients and is severe in 10% to
14% of patients.52,53 The neuropathy is predominantly sensory, but some patients
can have motor symptoms. The median time of onset is 7 months into treatment,
and symptoms resolve with treatment discontinuation. Neuropathy is related to
cumulative dose, so treatment can be continued at a lower dose once a more
severe neuropathy improves to grade 1.
ADO-TRASTUZUMAB EMTANSINE. Ado-trastuzumab emtansine, also known as

T-DM1, is used to treat HER2-positive breast cancer refractory to trastuzumab
and can cause a predominantly sensory neuropathy.
ANASTROZOLE. Anastrozole, a hormonal agent used for the treatment of breast

cancer, may rarely be associated with compression of the median nerve in the
carpal tunnel.54 The resulting carpal tunnel syndrome is generally mild to
moderate and usually does not require surgery.
NELARABINE. Nelarabine, a purine analogue used for T-cell acute lymphoblastic

leukemia, is associated with a peripheral neuropathy that can mimic GBS.55

ANTICANCER DRUGS
IMMUNE CHECKPOINT INHIBITORS. Immune checkpoint inhibitors can result

in several types of peripheral neuropathy. In rare cases, a GBS-like or
polyradiculoneuropathy syndrome can develop soon after immune checkpoint
inhibitor treatment is started, usually within the first three cycles of therapy
and sometimes after just one cycle (CASE 10-1).28 Similar to idiopathic GBS,
patients may develop early lower back pain followed by ascending paralysis,
sensory loss, and areflexia as the main symptoms. Facial weakness and
extraocular movement impairment may occur.29 Nerve conduction studies
and EMG may show a demyelinating polyneuropathy or an axonal pattern.56
CSF analysis reveals elevated protein, but, unlike classic GBS in which
albuminocytologic dissociation is seen, a lymphocytic pleocytosis is usually
seen as well.27,56 MRI of the spine (and brain in cases of cranial neuropathy)
may show abnormal leptomeningeal enhancement or may be normal. CSF
evaluation should be performed to rule out leptomeningeal metastasis.
Management involves discontinuation of the immune checkpoint inhibitor and
treatment with IVIg or plasma exchange plus high-dose corticosteroids.5,13,28,57
Although corticosteroids are usually not used in idiopathic GBS, they appear
to be beneficial in immune checkpoint inhibitor–associated cases. After
acute treatment, corticosteroids should be tapered slowly because of
the long half-life of at least 6 weeks of the immune checkpoint inhibitor
antibodies.
Other acute neuropathies may develop with immune checkpoint inhibitors,
including painful sensory neuropathy and isolated cranial mononeuropathies,
especially of the facial and abducens nerves.8,29,57,58 Patients with painful
neuropathy may have an axonal pattern on electrodiagnostic studies.58 Unlike
chemotherapy-induced peripheral neuropathy, immune-related neuropathies
are more likely to have an acute or subacute and non–length-dependent
presentation.29 Vasculitic neuropathy has also been described after anti-PD1,
presenting as a rapidly progressive symmetric lower limb weakness59 or
asymmetric mononeuritis multiplex,11 with biopsy showing epineural
perivascular inflammation composed primarily of lymphocytes. Sensory
neuronopathies with inflammation of the dorsal root ganglion have also
been described.29 Immune-related neuropathies typically occur early in the
treatment course29 but may occur many months after the start of immune
checkpoint inhibitor therapy and may persist after the immune checkpoint
inhibitor is discontinued. It is unclear whether prior chemotherapy-induced
peripheral neuropathy or the presence of baseline neuropathy from another
cause increases the risk of immune checkpoint inhibitor neuropathy.
Management of mild cases includes holding the immune checkpoint inhibitor
and treatment with corticosteroids and neuropathic pain medication such
as duloxetine.
Cranial Neuropathy
A variety of chemotherapies can induce cranial neuropathies. Vincristine can
cause cranial neuropathies as part of a more diffuse peripheral neuropathy
syndrome. BRAF inhibitors, including encorafenib and vemurafenib,60,61 which
are used for the treatment of melanoma, can cause a rare transient facial palsy
that may be bilateral; treatment with oral corticosteroids can lead to complete
resolution of the deficits. Cranial neuropathies, especially of the facial nerve, may
occur with immune checkpoint inhibitor treatment.
744 JUNE 2020

Muscle Symptoms KEY POINTS
Myalgia and muscle cramps are common in patients treated with cisplatin but
● Unlike classic Guillain-
also may occur with several biologic agents, such as brentuximab and rituximab. Barré syndrome, in which
Muscle cramps occur in 20% to 50% of patients receiving imatinib, the albuminocytologic
BCR-ABL, c-kit tyrosine kinase inhibitor. Myalgia may also occur in 14% to 19% dissociation is seen, a
of patients being treated with combined BRAF and MEK inhibition for lymphocytic pleocytosis is
usually seen in the
melanoma.62 Rarely, patients may develop elevated creatine kinase, muscle
polyradiculoneuropathy
edema, or rhabdomyolysis. Muscle cramps usually respond to supplementation resulting from immune
with calcium or magnesium. checkpoint inhibitor
An inflammatory myopathy or myositis may be caused by gemcitabine. This is treatment.
manifested by painful weakness, typically of proximal muscles, that resolves
● Unlike chemotherapy-
with discontinuation of the drug. Gemcitabine myositis also preferentially affects induced peripheral
muscle contained in previously irradiated areas and in unusual locations such as neuropathy, immune-
the abdominal wall.63 related neuropathies are
A “dropped head syndrome” has been rarely observed after exposure to MEK more likely to have an acute
or subacute and non–length-
inhibitors used to treat melanoma and other solid tumors. This is a focal dependent presentation.
noninflammatory myopathy that is characterized by neck extensor weakness and
neck pain. Diagnostic workup reveals moderately elevated serum creatine kinase ● Immune-related
levels, and abnormal uptake can be seen on FDG-PET imaging. Because this is a neuropathies typically occur
early in the treatment course
noninflammatory process, steroids are not helpful for treatment and can actually
but may occur many months
exacerbate myopathic symptoms. Resolution usually occurs after discontinuation after the start of immune
of the agent.64 checkpoint inhibitor therapy
Myositis/inflammatory myopathies are being increasingly recognized as a and may persist after the
immune checkpoint inhibitor
complication of immune checkpoint inhibitor therapy. The triggering therapy is
is discontinued.
most often anti-PD1/PD-L1 containing, and symptoms usually occur early in the
course of treatment.65 Patients present with symptoms of muscle pain, mixed ● Myalgia and muscle
axial and limb-girdle weakness, difficulty speaking/swallowing, ptosis, or ocular cramps are common in
weakness. Myalgia is usually an early sign, preceding muscle weakness in the patients treated with
cisplatin and vincristine but
majority of patients.66 Reported cases of myositis often resemble clinical may also occur with several
manifestations of myasthenia gravis (MG), with involvement of oculobulbar other agents, such as
muscles, including extraocular muscles such as levator palpebrae superioris, neck brentuximab, rituximab,
muscles, and diaphragm.66 Myositis can also occur simultaneously with MG and imatinib, and the
combination of BRAF and
myocarditis; therefore, all three toxicities should be evaluated in a patient on an MEK inhibitors.
immune checkpoint inhibitor presenting with ocular, bulbar, or respiratory
symptoms. All patients with myositis should be evaluated for heart involvement ● Myositis is a complication
with troponin and ECG. In a series of 19 cases of immune checkpoint of immune checkpoint
inhibitor therapy that usually
inhibitor–induced myositis, 32% had concurrent myocarditis and 5% had
occurs early in the course of
concomitant MG. treatment, most often
Diagnostic workup for myositis often shows elevated creatine kinase or triggered by anti-PD1/PD-
aldolase and a myopathic pattern on EMG. Antistriational antibodies may be L1–containing therapy. It
present and appear to be associated with a more severe necrotizing myositis. may affect oculobulbar
muscles and resemble
Muscle biopsies demonstrate multifocal necrotic myofibers and endomysial myasthenia gravis.
inflammation consisting of CD68+ cells and CD8+ T lymphocytes.66 In one
prospective serologic study of patients with thymoma who were treated with ● Immune checkpoint
anti–PD-L1, myositis developed only in those who had preexisting acetylcholine inhibitor–induced myositis
must be distinguished from
receptor antibodies and not in patients who were seronegative.67 immune checkpoint
Whereas a short course of prednisone therapy may be suitable for patients inhibitor–induced
with mild symptoms and non-necrotizing myopathy, patients with necrotizing myasthenia gravis.
myopathy can be more refractory to immunotherapy.65 In severe cases
(CTCAE grade 3 to grade 4), the immune checkpoint inhibitor should be

ANTICANCER DRUGS
CASE 10-1 A 72-year-old man received ipilimumab plus nivolumab at diagnosis for
widely metastatic melanoma including a left frontal brain metastasis.
Two weeks after receiving his first and only dose of immunotherapy, he
developed right lower motor neuron facial weakness. MRI of the brain
showed a stable left frontal brain metastasis but no other change
(FIGURE 10-2). Steroids were not initially administered for what was thought
to be Bell’s palsy but were started 4 days later when his facial weakness
persisted and he developed new thigh and lower back pain with difficulty
climbing stairs. He was advised to come to the hospital for urgent
evaluation.
His neurologic examination on admission was notable for dense right
lower motor neuron facial paralysis, mild ophthalmoparesis resulting in
horizontal diplopia, bilateral lower limb weakness (right slightly worse
than left), decreased sensation in his legs up to his knees to all modalities,
and absent deep tendon reflexes throughout. He was unable to walk
because of the leg weakness. He had no muscle tenderness or
fatigability.
Creatine kinase, aldolase, and myasthenia gravis antibodies were
normal. Pulmonary function tests showed no respiratory compromise.
MRI of the spine was normal without evidence of compression or
abnormal leptomeningeal enhancement. CSF showed mild protein
elevation (68 mg/dL), a mild pleocytosis of 41 cells/mm3, and negative
cytology and infectious panel. Antiganglioside antibody panel was
negative, including anti-GQ1b. Nerve conduction studies and EMG
showed a moderately severe polyneuropathy with demyelinating
features.
Based on the clinical presentation, he was diagnosed with presumed
Guillain-Barré syndrome (GBS) and started on IV immunoglobulin (IVIg)
0.4 g/kg/d along with pulse methylprednisolone 1 g/d for 5 days.
Four days later, his facial weakness and ophthalmoplegia had completely
resolved, and by 1 week, his leg strength had improved so that he was
able to walk with a walker. He was discharged to acute rehabilitation with
a 6-week prednisone taper.
After 6 weeks, he was ambulating normally without assistance with a
mild sensory deficit in his feet. After tapering off steroids, he developed
a maculopapular rash and pruritis, presumed to be a skin immune-related
adverse event, and he was placed back on prednisone 20 mg/d for
2 weeks. He achieved a remission of his melanoma, including regression
of the brain metastasis. He remained on active surveillance only and
received no further doses of immune checkpoint inhibitor.
746 JUNE 2020

FIGURE 10-2
Imaging of the patient in CASE 10-1. Axial postcontrast T1-weighted MRIs demonstrate an
enhancing left frontal metastasis at diagnosis (A, arrow) and resolution of the metastasis at
2 months (B, arrow).
This patient developed a severe peripheral neuropathy resembling GBS COMMENT

(progressive, fairly symmetric ascending muscle weakness accompanied by
absent deep tendon reflexes) after receiving combination immune
checkpoint inhibitor treatment. Potential neurologic causes of weakness in
patients receiving immune checkpoint inhibitors include myositis,
myasthenia gravis, and peripheral neuropathy. It can be difficult to
distinguish between these clinical entities based on symptom report alone;
clinical examination is necessary. Ancillary testing, including blood tests and
CSF analysis, can be very helpful. Immune checkpoint inhibitor–associated
cases of GBS resemble idiopathic cases; however, because they occur in
patients with known cancer, MRI and CSF analysis are important to rule out
cord compression and leptomeningeal metastasis. Severe neurologic
immune-related adverse events typically occur within the first 8 weeks of
therapy and can occur after only a single dose. In immune checkpoint
inhibitor–associated GBS, CSF may show elevated cell count in addition to
elevated protein. Because elevated cell counts can be found in CSF,
corticosteroids are typically added to IVIg or plasma exchange. Nerve
conduction studies and EMG may show a demyelinating or axonal pattern.
Despite concern in this case that a high dose of corticosteroids in the acute
setting and a prolonged taper might negatively affect the melanoma
treatment response, this patient had a complete and durable antitumor
response, including regression of the brain metastasis, that has been
ongoing for more than 6 months. The presence of an immune-related
adverse event affecting another organ system in addition to the nervous
system is common.

ANTICANCER DRUGS
discontinued and patients should be treated with IV corticosteroids with or

without IVIg or plasma exchange. Based on the prominent finding of
CD8 T lymphocytes in the biopsies, a role may exist for tacrolimus and
cyclosporine in cases refractory to steroids and IVIg, although this has not
been studied.68
Neuromuscular Junction Symptoms

A myastheniclike syndrome affecting the neuromuscular junction has been
reported in patients receiving cisplatin for malignant thymoma, with symptoms
including ptosis, diplopia, muscle weakness, and respiratory difficulty that
worsen with fatigue or repetitive activity. In addition, the cytokine therapies
interferon alfa69 and IL-2 have been reported to induce MG. The most common
cause of cancer treatment–related MG, however, is immune checkpoint
inhibitor therapy.
MG usually occurs within the first 3 months after treatment with immune
checkpoint inhibitor therapy (average onset in week 6 after initiation). The
incidence of MG was 0.12% among a large set of patients treated with the
anti-PD1 drug nivolumab.70 Similar to myositis, most cases are associated with
anti-PD1 monotherapy or combination therapy.70,71 Patients often present with
the classic manifestations of ptosis, diplopia, muscle weakness, dyspnea, and
dysphagia. Acetylcholine receptor antibodies are positive in many, but not all,
patients,70,71 although cases that were reported clinically as MG and not
associated with antibodies may actually have been oculobulbar myositis.
Supporting the difficulty of relying on clinical features alone, cases of immune
checkpoint inhibitor–associated MG have been seen with normal repetitive nerve
stimulation and single-fiber EMG despite severe weakness.72 In other cases,
myositis may occur simultaneously with MG.71
Immune checkpoint inhibitor–associated MG is treated with discontinuation
of the immune checkpoint inhibitor and initiation of symptomatic treatment
with pyridostigmine along with immunosuppressive treatment with
corticosteroids plus IVIg or plasma exchange. However, despite aggressive
treatment with immune checkpoint inhibitor discontinuation, pyridostigmine,
steroids, IVIg, or plasma exchange, one case series showed a 30% MG-related
mortality rate.71 Compared to patients developing MG independently of
immunotherapy, patients with immune checkpoint inhibitor–associated MG
seem to have a higher rate of respiratory failure (up to 42%) necessitating
respiratory support.70,71,73,74 Since MG may overlap with myositis or
myocarditis,70,74 immune-related adverse event management guidelines
recommend that creatine kinase, antistriational antibodies, and troponin be
tested and ECG obtained in cases of immune checkpoint inhibitor–associated
MG regardless of cardiac symptoms.5,10,66 Of note, nearly all reported fatal cases
of PD-1 inhibitor–associated MG had elevated creatine kinase.
CENTRAL NERVOUS SYSTEM COMPLICATIONS OF

ANTICANCER DRUGS
Although generally considered to be protected by the blood-brain barrier, the
CNS is susceptible to chemotherapy toxicity. The newer cancer therapies that
work by activating immune cells may be associated with CNS toxicity because
activated immune cells and cytokines may be better able to cross the blood-brain
barrier.
748 JUNE 2020

For many of the conventional chemotherapies, the occurrence of drug-related KEY POINTS
CNS toxicity depends on the dose and delivery method of the drug. Toxicity may
● The diagnostic workup for
result from direct damage to CNS tissue, such as vascular or white matter injury. myositis resulting from
Cancer treatments may also cause secondary CNS toxicity by a number of immune checkpoint inhibitor
mechanisms, such as cancer therapy–related immunosuppression leading to therapy often shows
meningitis, JC virus reactivation, or coagulopathies associated with hormonal elevated creatine kinase or
aldolase and a myopathic
therapies leading to ischemic events. TABLE 10-4 describes some of the clinical
pattern on EMG.
signs and symptoms of CNS neurotoxicity associated with anticancer drugs. Antistriational antibodies
may be present and appear
Headache to be associated with a more
severe necrotizing myositis.
Headache may occur as a complication of several chemotherapeutic agents
(TABLE 10-4). The exact mechanisms of headache are unknown, but among ● In severe cases of
traditional chemotherapy agents, headache occurs more frequently with agents myositis, the immune
that penetrate the blood-brain barrier, particularly temozolomide, nelarabine, checkpoint inhibitor should
and either intrathecal or high-dose methotrexate. Headache may also occur with be discontinued and
patients should be treated
biologic treatments, such as rituximab, and rarely with trastuzumab used to treat with IV corticosteroids
HER2-positive breast cancer. Cetuximab for advanced colorectal cancer is also with or without IV
associated with headache.75 immunoglobulin or plasma
Cancer treatment can also induce intracranial processes, such as aseptic exchange.
meningitis, that can result in headache. Aseptic meningitis is common after
● When myasthenia gravis
intrathecal treatment with any chemotherapy or biologic therapy. Patients occurs with immune
typically present within hours of drug administration with headache, neck checkpoint inhibitor
stiffness, nausea and vomiting, low-grade fever, and lethargy and are found to therapy, it usually occurs
within the first 3 months
have a CSF pleocytosis with negative CSF bacterial and viral cultures. The
after treatment.
chemotherapeutic agents that most commonly cause aseptic meningitis after
intrathecal administration are methotrexate, cytarabine, thiotepa, and topotecan. ● Since myasthenia gravis
Dexamethasone treatment should be given prophylactically with intrathecal use may overlap with myositis or
of liposomal cytarabine as many patients will develop significant aseptic myocarditis, immune-
related adverse event
meningitis with this agent. management guidelines
Headache associated with immune checkpoint inhibitor therapy may suggest recommend that creatine
aseptic meningitis or hypophysitis. Aseptic meningitis occurs most often kinase, antistriational
with ipilimumab (anti-CTLA4) monotherapy or combination therapy with antibodies, and troponin be
tested and ECG obtained in
anti-CTLA4 and anti-PD1.76 Symptoms typically develop within the first 7 weeks cases of immune checkpoint
after therapy initiation and include headache, neck stiffness, photophobia, inhibitor–associated
low-grade fever, and nausea.76,77 Mental status is normal. CSF evaluation is myasthenia gravis
important to rule out infectious etiologies and leptomeningeal metastasis and, in regardless of cardiac
symptoms.
aseptic meningitis, reveals a sterile CSF with negative cytology, elevated protein,
and an elevated cell count that is typically lymphocyte predominant. Meningeal ● Headache associated
enhancement may be seen on MRI.78 Aseptic meningitis from immune with immune checkpoint
checkpoint inhibitor therapy is typically very responsive to oral corticosteroids, inhibitor therapy may
such as prednisone 0.5 to 1 mg/kg/d.5,8,9,13 suggest aseptic meningitis
or hypophysitis.
Clinical manifestations of hypophysitis include headache, fatigue, and
weakness. The incidence is 3.2% in patients treated with ipilimumab and 6.4% in ● Aseptic meningitis from
patients treated with combination therapy79; anti-PD1/PD-L1 monotherapy is immune checkpoint inhibitor
rarely implicated. The reason for the strong association of hypophysitis with therapy is typically very
responsive to oral
anti-CTLA4 therapy is thought to be the direct targeting of CTLA4 expressed on corticosteroids.
the pituitary gland. The diagnosis of hypophysitis is established by the finding of
low levels of hormones produced by the pituitary or panhypopituitarism.
Laboratory findings differentiate hypophysitis from primary adrenal
insufficiency, which is characterized by low cortisol and high adrenocorticotropic

ANTICANCER DRUGS
TABLE 10-4 Central Nervous System Neurotoxicity Caused by Cancer Therapies
Acute
Encephalopathy Tremor or Cerebellar
Headache (Delirium) Seizures Myoclonus Dysfunction
Traditional Temozolomide, 5-Azacytidine, Busulfan, Ifosfamide, Capecitabine,

chemotherapy nelarabine, IT capecitabine, carmustine, nelarbine, cyclosporine,
methotrexate (aseptic cisplatin, chlorambucil, thalidomide cytarabine,
meningitis), high-dose corticosteroids, cisplatin, high-dose 5-fluorouracil,
methotrexate, IT cyclophosphamide cyclophosphamide, nelarabine,
cytarabine (aseptic (PRES), cyclosporine cytarabine, high- procarbazine
meningitis), IT (PRES), etoposide, dose etoposide,
liposomal cytarabine fludarabine, high-dose
(aseptic meningitis), IT 5-fluorouracil, fludarabine,
thiotepa (aseptic gemcitabine (PRES), gemcitabine,
meningitis), IT hexamethylmelamine, ifosfamide,
topotecan (aseptic ifosfamide (isolated methotrexate,
meningitis) encephalopathy or nelarabine,
PRES), methotrexate, thalidomide,
mitomycin C, vincristine
nelarabine,
nitrosoureas,
procarbazine,
tamoxifen, thiotepa,
vincristine (isolated
encephalopathy or
PRES)
Small molecule NA Bortezomib, NA NA NA

inhibitors larotrectinib, lorlatinib
Anti–vascular NA Bevacizumab (PRES), NA NA NA

endothelial sorafenib (PRES),
growth factor sunitinib (PRES)
(VEGF) agents
Biologic agents IT rituximab, Rituximab (PRES), NA Interferon NA

trastuzumab, retinoid interferon alfa, IL-2 alfa
treatment
Immunotherapy Atezolizumabc (aseptic Blinatumomab, CAR T Blinatumomab, Blinatumomab, Blinatumomab,

agents meningitis), avelumabc cells, atezolizumab,c CAR T cells CAR T cells CAR T cells
(aseptic meningitis), avelumabc (isolated
durvalumabc (aseptic encephalopathy),
meningitis), durvalumabc (isolated
ipilimumaba encephalopathy),
(hypophysitis or ipilimumaba (isolated
aseptic meningitis), encephalopathy and
nivolumabb (aseptic PRES), nivolumabb
meningitis), (isolated
pembrolizumabb encephalopathy),
(aseptic meningitis), pembrolizumabb
blinatumomab, CAR T (isolated
cells encephalopathy)
CAR = chimeric antigen receptor; IL-2 = interleukin 2; IT = intrathecal; PRES = posterior reversible encephalopathy syndrome.
a
Ipilimumab is an anti-CTLA4 antibody.
b
Nivolumab and pembrolizumab are anti-PD1 antibodies.
c
Atezolizumab, avelumab, and durvalumab are anti-PD-L1 antibodies.
750 JUNE 2020

hormone (ACTH). MRI may show swelling and enhancement of the pituitary KEY POINT
gland.80 Systemic high-dose steroid treatment beyond replacement
● Immune checkpoint
hydrocortisone is no longer recommended for hypophysitis unless the patient is inhibitors may result in
symptomatic with visual field deficits from optic chiasm compression; steroids encephalitis at an incidence
do not change the course of the pituitary damage, which is rapid and estimated to be 0.1% to
irreversible.81 Instead, supportive treatment of hypophysitis-related hormone 0.2%. Diagnosis is often
challenging as patients may
deficiencies with the corresponding hormone replacement is recommended; in
present with a wide range of
this setting, immune checkpoint inhibitor therapy can be resumed. symptoms, including altered
Retinoid treatment used as part of the treatment for acute promyelocytic mental status, confusion,
leukemia may also cause headache by inducing idiopathic intracranial short-term memory
impairment, agitation,
hypertension (pseudotumor cerebri), with an elevated CSF opening pressure in
aphasia, and seizures.
the absence of a space-occupying lesion in the brain. Headache may also occur in
these patients when intracranial pressure is not apparently elevated.
Acute Encephalopathy
Acute altered mental status is the most common CNS toxicity after a number of
cancer treatments. Acute encephalopathy occurs commonly after agents with
good penetration of the blood-brain barrier, such as high-dose cytarabine or
methotrexate. Immunotherapies are likely associated with acute encephalopathy
in some cases because of the ability of immune cellular and cytokine mediators to
cross the blood-brain barrier. Many other agents can also induce encephalopathy
(TABLE 10-4). Encephalopathy varies in severity from somnolence and
inattentiveness to stupor and coma. Encephalopathy usually improves with drug
withdrawal, but, in some circumstances, it may require an antidote to reverse.
For example, the encephalopathy that occurs after high-dose ifosfamide may
reverse with methylene blue. The encephalopathy occurring with immune
checkpoint inhibitors requires immunosuppression, and the global
encephalopathy that occurs with CAR T-cell therapy may be managed with
corticosteroids when severe.
ENCEPHALOPATHY RELATED TO IMMUNE CHECKPOINT INHIBITORS AND CAR

T-CELL THERAPY. Immune checkpoint inhibitors may result in encephalitis at an
incidence estimated to be 0.1% to 0.2%.8 Diagnosis is often challenging as
patients may present with a wide range of symptoms, including altered mental
status, confusion, short-term memory impairment, agitation, aphasia, and
seizures. Patients may have a low-grade fever and focal neurologic deficits,
especially difficulty standing and gait changes. Early in the course, symptoms
may be mild, consisting of fatigue, syncope, or brief episodes of confusion. Many
patients have concomitant non-neurologic immune-related adverse events or a
history of immune-related adverse events in previous cycles of treatment.78 The
diagnosis of immune checkpoint inhibitor–associated encephalitis is one of
exclusion. The typical diagnostic workup should include brain MRI to exclude
brain parenchymal or leptomeningeal metastases, EEG, CSF studies to exclude
leptomeningeal metastases or infectious etiologies, a review of medications, and
electrolyte and thyroid evaluation, including antithyroid peroxidase antibodies.
Empiric antiviral treatment should be started until viral encephalitis is ruled out.
The CSF profile may show slightly elevated cell count or protein or may be bland
other than the finding of CSF-specific oligoclonal bands. Patients may have
positive onconeuronal or autoimmune encephalitis antibodies; cases have been
reported with Hu antigen D (HuD),82 contactin-associated proteinlike 2

ANTICANCER DRUGS
(CASPR2), glutamic acid decarboxylase (GAD), and N-methyl-D-aspartate

(NMDA) receptor–specific antibodies. If clinical suspicion is high, autoimmune
encephalopathy and paraneoplastic panels can be checked from blood and CSF.
CSF-specific oligoclonal bands may be present even when paraneoplastic
antibodies are negative, suggesting common pathogenesis despite absence of an
identifiable antibody. Two patients with cancer who went on to develop immune
checkpoint inhibitor–associated encephalitis were shown to have circulating Hu
antibodies before the initiation of the immune checkpoint inhibitor.82,83 Rapid
management of encephalitis with immune checkpoint inhibitor discontinuation
and initiation of high-dose corticosteroids is crucial for better outcome. Unlike
aseptic meningitis, in which intermediate-dose steroids may be effective,
pulse-dose steroids are often required for severe symptoms, and IVIg, plasma
exchange, or rituximab should be considered.
The acute global encephalopathy known as immune effector cell–associated
neurotoxicity syndrome (ICANS) can be seen in up to 40% of patients treated
with CD19-specific CAR T cells.84 In contrast to immune checkpoint
inhibitor–associated encephalopathy, CAR T-cell toxicity is more temporally
related to the CAR infusion, typically occurring within the first 28 days after
infusion and often overlapping with cytokine release syndrome. Cytokine
release syndrome, the most common acute event associated with CAR T-cell
therapy, is a systemic inflammatory response triggered by the release of
cytokines by CAR T cells and bystander immune cells, such as macrophages,
following the CAR recognition of tumor in vivo. Cytokine release syndrome
typically manifests as constitutional symptoms of fever, myalgia, rigors, and
fatigue but can lead to hypotension, vascular leak, and multiorgan
dysfunction in severe cases. Cytokine release syndrome is completely
reversible if managed appropriately. Serum IL-6 levels are elevated during
cytokine release syndrome, and blockade of IL-6 receptor with tocilizumab
can reverse cytokine release syndrome. Tocilizumab is now FDA approved as
standard care for treatment for this complication.85 Other cytokines and
chemokines are also elevated during cytokine release syndrome; therefore, if
IL-6 receptor blockade alone is not sufficient to manage cytokine release
syndrome, corticosteroids are used.86
ICANS is the second most common acute toxicity observed with CAR
T-cell therapy.84 ICANS can occur during cytokine release syndrome or, more
commonly, shortly after cytokine release syndrome has subsided. It typically
presents as a global toxic encephalopathy with confusion, tremor, and
word-finding difficulty progressing to global aphasia and, in more severe cases,
seizures, depressed level of consciousness, motor weakness, and diffuse cerebral
edema.16 Encephalopathy symptoms may be mild and initially waxing and
waning, consisting of disorientation, attentional deficits, stuttering/hesitant
speech, apraxia, and difficulty following multistep commands. Mild symptoms
may evolve over the course of hours or days to more severe symptoms. Aphasia is
one of the more specific symptoms, and mild dysfluency may progress to global
aphasia or mutism.87 EEG monitoring is helpful to rule out nonconvulsive status
epilepticus, which is known to occur with the treatment, although EEG findings
are most often nonspecific with generalized slowing in the theta-delta range or
frontally predominant rhythmic delta. Unlike cytokine release syndrome, which
is reasonably well understood, the pathophysiology and best management of
neurotoxicity has remained more elusive. Studies found that early treatment
752 JUNE 2020

with tocilizumab decreased the incidence of severe cytokine release syndrome, KEY POINTS
but it was not associated with decreased incidence or severity of ICANS88; in fact,
● Studies found that early
severe ICANS rates may have been slightly higher.89 Therefore, tocilizumab is treatment with tocilizumab
not recommended for management of isolated ICANS. Cytokine and chemokine decreased the incidence of
elevations and the degree of CAR T-cell expansion are associated with the severe cytokine release
severity of neurotoxicity. In addition, CAR T cells are frequently found in the syndrome, but it was not
associated with decreased
CSF of patients, although they do not correlate with the degree of toxicity and
incidence or severity of
can be found in the CSF of patients who did not develop neurotoxicity. immune effector cell–
Endothelial cell activation90 and blood-CSF barrier disruption87 are associated associated neurotoxicity
with the degree of neurotoxicity. Other reports have suggested a role for myeloid syndrome (ICANS); in fact,
severe ICANS rates may
cell activation in the CNS. Elevated CSF levels of excitatory glutamate and
have been slightly higher.
quinolinic acid have been observed during ICANS.87 These are both implicated Therefore, tocilizumab is not
in epileptogenesis,91,92 and the increased levels may contribute to the seizures recommended for
seen in severe ICANS. Two recent studies in mouse models demonstrated a management of isolated
role for IL-1 in the pathophysiology of both cytokine release syndrome and ICANS.
neurotoxicity; blocking IL-1 with anakinra, an IL-1 receptor antagonist, ● ICANS is usually
abrogated both toxicities.93,94 This approach is now being explored in reversible but can be severe
clinical trials. or even fatal.
The bispecific T-cell engager blinatumomab, used for relapsed/refractory
acute lymphoblastic leukemia, can also cause ICANS, predominantly during the
first cycle and usually grade 1 or grade 2.
ICANS is primarily managed with supportive care for low-grade toxicity and
with corticosteroids for more severe grades. ICANS appears to have a
self-limited, completely reversible course in most patients, but the potential for a
serious and even fatal outcome mandates specialized multidisciplinary care,
including neurologists. It is unknown whether the treatment can cause long-term
subclinical neurologic sequelae.
The American Society for Transplantation and Cellular Therapy published an
objective and easy-to-use consensus grading system for ICANS and cytokine
release syndrome that is being adopted by institutions across the world for
reporting of adverse events associated with immune effector cell therapies in
both clinical trials and routine practice and will allow for better determination of
the best ICANS management strategies.16
Adult patients can be evaluated for encephalopathy using a 10-point scoring
system called the Immune Effector Cell–Associated Encephalopathy (ICE)
assessment tool, which is like a pared-down Mini-Mental State Examination
(MMSE) except focused on the critical CAR encephalopathy–specific domains
(TABLE 10-5, CASE 10-2). For children under age 12, instead of the ICE tool, the
Cornell Assessment of Pediatric Delirium (CAPD) is recommended to aid in the
overall grading of ICANS.16 The grading of ICANS requires assessment of ICE
score (or CAPD for children), level of consciousness, seizures, motor weakness,
and assessment for raised intracranial pressure/cerebral edema. The final grade of
toxicity is the highest score in any of these domains (TABLE 10-6).
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME. Posterior reversible

encephalopathy syndrome (PRES) is a specific encephalopathy syndrome that
manifests as seizures, headache, cortical blindness, and altered mental status.
Immunomodulatory agents used to treat graft versus host disease in allogeneic
stem cell transplant recipients, such as tacrolimus and cyclosporine, are common
causes of PRES. Bevacizumab, a monoclonal antibody against vascular

ANTICANCER DRUGS
endothelial growth factor (VEGF); the small molecule tyrosine kinase inhibitors
sunitinib and sorafenib; and rituximab may also cause PRES in less than 1% of
treated patients.95,96 PRES can also occur with traditional chemotherapies,
including cyclophosphamide, methotrexate, and, less commonly, cisplatin,
cytarabine, gemcitabine, and ifosfamide. PRES has been reported with the
immune checkpoint inhibitor ipilimumab97 and with CAR T-cell therapy.98
PRES is thought to be related to endothelial cell dysfunction that is preceded
by hypertension, immunosuppressive agents, or cytotoxic medication. MRI has
the typical appearance of bilateral white matter hyperintensities on
fluid-attenuated inversion recovery (FLAIR), typically involving the bilateral
parietooccipital or posterior circulation territories. PRES occurs more commonly
in patients with hypertension, fluid imbalance, electrolyte abnormalities,
baseline organ dysfunction, and preexisting CNS insults during chemotherapy,
such as CNS infection. Hypertension may occur with these therapies, but it is also
possible that the cerebral endothelium is directly affected. Once PRES develops,
discontinuation of the offending agent and strict blood pressure control are
critical. The clinical and radiographic changes are usually reversible unless
cerebral infarction has occurred. Antiepileptic medication is recommended if
PRES is associated with seizure activity and should be continued until the
MRI normalizes.
Seizures
Seizures occur with a variety of IV chemotherapy agents (TABLE 10-4). Seizures
may be convulsive or may manifest as encephalopathy with nonconvulsive status
epilepticus demonstrated on EEG. High-dose busulfan, used for conditioning for
hematopoietic cell transplantation, carries a high risk of seizure, and antiepileptic
TABLE 10-5 Encephalopathy Assessment Tool for Grading of Immune Effector

Cell–Associated Neurotoxicity Syndrome (ICANS)a
Immune Effector Cell–Associated Encephalopathy

◆ Orientation: Orientation to year, month, city, hospital: 4 points
◆ Naming: Name three objects (eg, point to clock, pen, button): 3 points
◆ Following commands: Ability to follow commands (eg, “Show me two fingers” or “Close your
eyes and stick out your tongue”): 1 point
◆ Writing: Ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point
◆ Attention: Count backward from 100 by ten: 1 point
Scoring
◆ 10: No impairment
◆ 7–9: Grade 1 immune effector cell–associated neurotoxicity syndrome (ICANS)
◆ 3–6: Grade 2 ICANS
◆ 0–2: Grade 3 ICANS
◆ 0 due to patient unarousable and unable to perform assessment: Grade 4 ICANS
a
Modified with permission from Lee DW, et al, Biol Blood Marrow Transplant.16 © 2018 American Society for
Blood and Marrow Transplantation.
754 JUNE 2020

prophylaxis is recommended with drug administration. Seizures are more KEY POINT
common with intrathecal administration of chemotherapy, particularly with
● Many centers use
cytarabine and methotrexate.99 prophylactic levetiracetam
Clinical and subclinical seizures can be seen as part of ICANS associated with or another antiepileptic drug
CD19 CAR T-cell therapy. Many centers use prophylactic levetiracetam or starting on the day of
another antiepileptic drug starting on the day of infusion for CAR T-cell agents infusion for CAR T-cell
agents associated with high
associated with high incidence of ICANS.
incidence of immune
effector cell–associated
Chronic Encephalopathy neurotoxicity syndrome
A chronic encephalopathy or dementia may occur with chemotherapies such as (ICANS).
methotrexate, cytarabine, carmustine, fludarabine, thalidomide, or vincristine.100
Any intrathecal drug, including rituximab and topotecan, can also cause a chronic
encephalopathy. Chemotherapy may cause a leukoencephalopathy on its own or
can potentiate the toxicity associated with cranial radiation therapy, whether the
chemotherapy is given before or after. Leukoencephalopathy is a delayed
complication of intrathecal methotrexate, usually occurring after 6 months of
therapy and when the cumulative dose exceeds 140 mg.101 The administration of
methotrexate through an Ommaya reservoir can cause leukoencephalopathy if the
flow of the drug from the ventricular system is blocked. Therefore, CSF flow
studies are important to assure normal CSF flow in patients with leptomeningeal
metastases. Rarely, capecitabine may cause a multifocal leukoencephalopathy.102
Clinical manifestations range from nausea and vomiting to seizures and coma, and
diagnosis is based on MRI findings of diffusion restriction along white matter
tracts. Discontinuation of the drug leads to resolution of the clinical and
radiographic findings.
Some patients with cancer experience milder chronic findings of cognitive
dysfunction after receiving chemotherapy.103 These changes are commonly
referred to as “chemobrain,” and many studies report subtle impairment in
executive function, processing speed, and memory in patients receiving
chemotherapy, particularly with high-dose regimens. Deficits are more likely to
be permanent if they are associated with structural changes in the brain seen on
MRI. Hippocampal neurogenesis may be affected by chemotherapy and is one
potential cause of these mild cognitive changes.104 Other recent studies on the
cognitive effects of chemotherapy demonstrate deleterious effects of
chemotherapeutic agents on glial-glial and neuron-glial interactions in the CNS.
Certain traditional chemotherapies, such as methotrexate, induce microglial
activation, which leads to dysfunction of both neural precursor cells and mature
neurons via a network of interactions involving multiple cell types.105,106
Progressive multifocal leukoencephalopathy (PML) is another cause of
chronic mental status change that can occur with chemotherapy. The risk of PML
increases with administration of agents that can cause immunosuppression, such
as fludarabine, and the B-cell targeting agents rituximab (CD20 inhibitor),
alemtuzumab (CD52 inhibitor), and brentuximab (CD30 inhibitor). The diseases
for which these agents are used, such as chronic lymphocytic leukemia, are
independently associated with PML; therefore, increased PML risk may derive
from the combination of long-standing disease with immunosuppressive drug
administration. Management of PML involves trying to reconstitute the immune
system by withdrawal of the offending agent. Previously no effective treatment
was available for this condition, but recent investigational approaches using
anti-PD1 or off-the-shelf virus-specific T-cell therapy have shown promise.107,108

ANTICANCER DRUGS
Central Nervous System Demyelinating Disease

A variety of inflammatory demyelinating syndromes have been reported
following treatment with immune checkpoint inhibitors, including optic
neuritis, transverse myelitis, and acute tumefactive demyelinating inflammatory
lesions.109 Exacerbations of multiple sclerosis (MS) following treatment with
ipilimumab (anti-CTLA4) have also been described.110 In a retrospective study of
the FDA Adverse Event Reporting System database, 14 patients with flares of MS
under treatment with an immune checkpoint inhibitor were identified. Of those,
eight had preexisting MS and four were under active treatment, although three
had their treatment interrupted just before the initiation of the immune
checkpoint inhibitor. Most patients with flares responded to immune checkpoint
inhibitor interruption and high-dose steroids, but two patients had rapid
progression and poor response to MS therapy.111
CASE 10-2 A 54-year-old man with diffuse large B-cell lymphoma had been
previously treated with two courses of chemotherapy and autologous
stem cell transplantation, but the disease recurred 3 years later. He was
deemed a candidate for axicabtagene ciloleucel CD19 chimeric antigen
receptor (CAR) T cells and underwent leukapheresis and cell
manufacture. He received fludarabine and cyclophosphamide
preconditioning followed by the CD19 CAR T-cell infusion.
Forty-eight hours later, he developed a fever of 39.6°C (103.3°F). He was
pancultured, and antibiotics were started. Later that same day, his fever
continued despite antipyretics, and he developed tachycardia to the 130s,
fluid-responsive hypotension, and increased oxygen requirement
consistent with grade 2 cytokine release syndrome. He had some slight
disorientation to date and reported mild headache during febrile episodes.
His mental status and neurologic examination were otherwise normal. His
Immune Effector Cell–Associated Encephalopathy (ICE) assessment tool
score was 10. He received a dose of tocilizumab for grade 2 cytokine
release syndrome, which led to rapid resolution of the fever, tachycardia,
and hypoxia. He remained well until 2 days later, when he developed
perseverative stuttering speech, bilateral arm tremor, inattention, and
slight lethargy; his ICE score was 6, consistent with grade 2 immune
effector cell–associated neurotoxicity syndrome (ICANS). A brain MRI was
performed and was negative for an acute process. EEG was negative for
seizures. He was transferred to the intensive care unit for closer
monitoring. Over the next 2 hours, his transient word-finding difficulty
progressed to his being completely nonverbal (mute) while awake (ICE
score of 0). He was not able to follow commands. He was started on
dexamethasone 10 mg; however, his level of consciousness started to
decline, and he was arousable only to persistent tactile stimulus. He
received another bolus of dexamethasone 20 mg, followed by
dexamethasone 10 mg every 6 hours. He underwent a lumbar puncture that
showed normal opening pressure and cell count, negative microbial panel,
and elevated protein. He became more alert but still had global aphasia
and myoclonus. EEG during this time showed lateralized rhythmic delta
waves, and his anticonvulsants were escalated.
756 JUNE 2020

Cerebrovascular Disease
Patients with cancer have an increased risk of stroke and other cerebrovascular
disease because of the underlying hypercoagulability of malignancy as well as
the treatments they receive. Chemotherapeutic agents such as L-asparaginase
and platinum-based treatments increase the risk of stroke. The risk of
cisplatin-induced stroke increases if the drug is used in combination with other
chemotherapeutic agents. The exact pathophysiology of this increased stroke risk
is unknown. In addition to arterial thrombosis, cisplatin-based chemotherapy
and L-asparaginase increase the risk of venous sinus thrombosis, which may lead
to stroke, intracranial hemorrhage, and seizures. Bevacizumab significantly
increases the risk of cerebrovascular thrombosis and intracranial hemorrhage.
Rare cases of giant cell arteritis and polymyalgia rheumatica have been described
after immune checkpoint inhibitor treatment.112
By the next morning, his mental status had markedly improved and his
ICE score was 8, so the corticosteroids were tapered rapidly over 2 days.
He continued to have mild word-finding difficulty and confusion and tremor
over the next 4 days but was ambulatory. By day 12 postinfusion, he had
returned to his neurologic baseline. Disease assessment by positron
emission tomography (PET) at day 30 showed a complete response, and this
remained durable at 6-month follow-up.
Aphasia (especially expressive aphasia), confusion, and tremor/myoclonus COMMENT

are common symptoms of ICANS. The ICE score is a rapid objective measure
of severity of encephalopathy in adult patients who have received CAR
T-cell therapy (TABLE 10-5). Fever is the first sign of cytokine release
syndrome, and cytokine release syndrome almost always precedes ICANS.
This case demonstrates the common scenario that ICANS often develops
after cytokine release syndrome has resolved or while it is resolving.
Whereas the IL-6 receptor blocker tocilizumab can rapidly resolve many
cases of cytokine release syndrome, it does not improve ICANS.
Corticosteroids are used for the management of severe ICANS, typically
grade 3 or higher. Reassessment of response to steroids is important, with
dose escalation or weaning based on response. Lumbar puncture can be
helpful for measuring opening pressure and ruling out infectious etiologies.
EEG often shows rhythmic or periodic electrical activity in the ictal-interictal
continuum, and clinical seizurelike activity without EEG correlate may occur,
which should be treated with antiepileptic drug escalation.

ANTICANCER DRUGS
Movement Disorders/Cerebellar Dysfunction/Ataxia

The most common chemotherapy to induce a cerebellar syndrome is high-dose
cytarabine, usually at high cumulative dose. The effects are more pronounced in
elderly patients and in those with preexisting neurologic conditions or renal
dysfunction. Most of the symptoms resolve within 2 weeks of discontinuing
treatment, but some patients have permanent impairment secondary to loss of
Purkinje cells in the cerebellum. Despite marked symptoms, imaging is usually
normal. Other chemotherapeutic agents that can induce cerebellar dysfunction
include capecitabine, 5-fluorouracil, hexamethylmelamine, nelarabine,
oxaliplatin, procarbazine, and vincristine.
Tremor can be caused by several chemotherapies, blinatumomab, and CAR
T-cell therapy. Tremor or myoclonus associated with CAR T-cell therapy is
typically mild and transient; it may begin with the onset of cytokine release
syndrome and may be the last ICANS symptom to resolve, usually within a few
days of the start of the symptom.
TABLE 10-6 American Society for Transplantation and Cellular Therapy Immune Effector
Cell–Associated Neurotoxicity Syndrome Consensus Grading for Adultsa,b
Neurotoxicity
Domain Grade 1 Grade 2 Grade 3 Grade 4
c
ICE score 7–9 3–6 0–2 0 (patient is unarousable and
unable to perform ICE)
Depressed level of Awakens Awakens Awakens only to tactile stimulus Patient is unarousable and
consciousnessd spontaneously to voice requires vigorous or repetitive
tactile stimuli to arouse; stupor or
coma
Seizure NA NA Any clinical seizure, focal or Life-threatening prolonged

generalized, that resolves rapidly seizure (>5 min) or repetitive
or nonconvulsive seizures on EEG clinical or electrical seizures
that resolve with intervention without return to baseline in
between
Motor findingse NA NA NA Deep focal motor weakness such

as hemiparesis or paraparesis
Raised intracranial NA NA Focal/local edema on Diffuse cerebral edema on

pressure/cerebral neuroimagingf neuroimaging, decerebrate or
edema decorticate posturing, cranial
nerve VI palsy, papilledema, or
Cushing triad
EEG = electroencephalography; ICE = immune effector cell–associated encephalopathy; NA = not applicable.

a
Reprinted with permission from Lee DW, et al, Biol Blood Marrow Transplant.16 © 2018 American Society for Blood and Marrow Transplantation.
b
Immune effector cell–associated neurotoxicity syndrome (ICANS) grade is determined by the most severe event (ICE score, level of
consciousness, seizure, motor findings, raised intracranial pressure/cerebral edema) not attributable to any other cause; for example, a patient
with an ICE score of 3 who has a generalized seizure is classified as having grade 3 ICANS.
c
A patient with an ICE score of 0 may be classified as having grade 3 ICANS if the patient is awake with global aphasia, but a patient with an ICE
score of 0 may be classified as having grade 4 ICANS if unarousable.
d
Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication).
e
Tremors and myoclonus associated with immune effector cell therapies may be graded according to Common Terminology Criteria for Adverse
Events v5.0,6 but they do not influence ICANS grading.
f
Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may
be graded according to Common Terminology Criteria for Adverse Events v5.0.6
758 JUNE 2020

Spinal Cord Syndromes KEY POINTS
Myelopathy may occur after intrathecal administration of any chemotherapeutic
● A variety of inflammatory
agent, including methotrexate, cytarabine, or thiotepa. Symptoms may start demyelinating syndromes
within minutes of treatment or have a delayed onset after 2 weeks. Myelopathy have been reported
symptoms may include lower extremity weakness, sensory change, and following treatment with
alterations in bowel and bladder control. The risk of myelopathy is higher in immune checkpoint
inhibitors, including optic
patients who have received prior spinal radiation.
neuritis, transverse myelitis,
Spinal cord symptoms are generally uncommon with IV chemotherapy. and acute tumefactive
Cisplatin and oxaliplatin are exceptions that can cause Lhermitte phenomenon demyelinating inflammatory
during or after treatment. This manifests clinically as a transient electric lesions.
shock–like sensation down the back or limbs with neck flexion. The symptom
● Patients with cancer have
represents a transient demyelination of the posterior columns of the spinal cord. an increased risk of stroke
Imaging is usually negative, and symptoms resolve completely without and other cerebrovascular
permanent damage.113 Transverse myelitis has been reported with ipilimumab.77 disease because of the
underlying hypercoagulability
of malignancy as well as the
treatments they receive.
CONCLUSION
Anticancer drugs have very different toxicity profiles, and the neurologic ● The most common
toxicity presentations are becoming more diverse and common as new types of chemotherapy to induce a
cerebellar syndrome is
therapy and therapy combinations are developed and more widely used. The
high-dose cytarabine,
vulnerability of the central and peripheral nervous systems to these adverse usually at high cumulative
effects is often dependent on individual predisposition as well as therapy-related dose.
factors and comorbid conditions. For example, CAR T-cell–associated
neurotoxicity is more likely to occur in a patient with acute leukemia and a high ● Tremor or myoclonus
associated with CAR T-cell
disease burden being treated with a CD28-costimulatory domain containing therapy is typically mild and
CD19 CAR. A neurologic immune-related adverse event is most likely to occur in transient; it may begin with
a patient who is treated with dual immune checkpoint blockade with anti-CTLA4 the onset of cytokine
plus anti-PD1 who has had immune-related adverse events affecting other release syndrome and may
be the last immune effector
organs, such as the skin, the gastrointestinal tract, or pulmonary system. Diabetes cell–associated
mellitus enhances the risk of chemotherapy-induced peripheral neuropathy. neurotoxicity syndrome
Common to all toxicity is the recognition that early diagnosis is key to the symptom to resolve, usually
maximum preservation of neurologic function. within a few days of the start
of the symptom.
This is an exciting time in oncology, with many tumor types now seeing the
possibility of “cure.” Efforts are under way to identify patient risk factors for ● The risk of myelopathy in
toxicity from anticancer drugs and to develop preventive and therapeutic patients who have received an
strategies to minimize toxicity while enhancing oncologic outcomes. intrathecal chemotherapeutic
agent is higher in those who
have received prior spinal
radiation.
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REVIEW ARTICLE

RECENT FINDINGS:Whereas neurologic complications from traditional

732 JUNE 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

INTRODUCTION TO IMMUNE CHECKPOINT INHIBITOR THERAPY ● Neurologic immune-

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

checkpoint inhibitor while other potential causes are eliminated. Once a

INTRODUCTION TO CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL

TABLE 10-1 Common Terminology Criteria for Adverse Eventsa–c

734 JUNE 2020

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GENERAL PRINCIPLES OF TOXICITY EVALUATION

TABLE 10-2 Spectrum of Peripheral Neurotoxicity Caused by Cancer Therapies

Traditional chemotherapy 5-Azacytidine, brentuximab, Cisplatin Brentuximab, docetaxel,

Small molecule inhibitors Bortezomib, carfilzomib, NA NA

Anti–vascular endothelial Sorafenib, sunitinib NA NA

Biologic agents/ Lenalidomide, thalidomide, Interferon alfa, IL-2 Interferon alfa

Immunotherapy agents Atezolizumab, avelumab, Atezolizumab, avelumab, Atezolizumab, avelumab,

736 JUNE 2020

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brain metastasis, leptomeningeal carcinomatosis, or spinal cord compression ● Recognition of

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chemotherapy-induced peripheral neuropathy occurs in a dose-dependent

TABLE 10-3 Anticancer Drugs Associated With Peripheral Neuropathy

Drug Pathology Type Clinical Symptoms Outcome

CONTINUED ON PAGE 739

738 JUNE 2020

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CONTINUED FROM PAGE 738

Drug Pathology Type Clinical Symptoms Outcome

Thalidomide Dorsal root ganglion, Sensorimotor, Painful paresthesia, Reversible

Ifosfamide, Not known Sensory Gradual onset of Not known

Cytarabine Not known Sensory Rare Not known

Gemcitabine Not known Sensory Rare

Nelarabine Not known Autonomic, Rare

Anastrozole, Possibly related to Sensory Carpal tunnel syndrome Not known

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CISPLATIN. Platinum agents cause long-term peripheral sensory damage,

740 JUNE 2020

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

VINCA ALKALOIDS. Vinca alkaloids such as vincristine, usually used for

BORTEZOMIB. Bortezomib is a proteasome inhibitor used to treat multiple

742 JUNE 2020

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BRENTUXIMAB VEDOTIN. Brentuximab vedotin is an antibody-drug conjugate

ADO-TRASTUZUMAB EMTANSINE. Ado-trastuzumab emtansine, also known as

ANASTROZOLE. Anastrozole, a hormonal agent used for the treatment of breast

NELARABINE. Nelarabine, a purine analogue used for T-cell acute lymphoblastic

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

IMMUNE CHECKPOINT INHIBITORS. Immune checkpoint inhibitors can result

744 JUNE 2020

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

746 JUNE 2020

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This patient developed a severe peripheral neuropathy resembling GBS COMMENT

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

discontinued and patients should be treated with IV corticosteroids with or

Neuromuscular Junction Symptoms

CENTRAL NERVOUS SYSTEM COMPLICATIONS OF

748 JUNE 2020