Neurologic adverse events of cancer immunotherapy

Brito, Marcelo Houat de

doi:10.1590/0004-282X-ANP-2022-S116

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NEURO-ONCOLOGY • Arq. Neuro-Psiquiatr. 80 (5 Suppl 1) • May 2022 • https://doi.org/10.1590/0004-282X-ANP-2022-S116 copy

Neurologic adverse events of cancer immunotherapy

Eventos adversos neurológicos da imunoterapia contra o câncer

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

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

Keywords:
Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Drug-Related Side Effects and Adverse Reactions; Neurologic Manifestations; Neuromuscular Diseases

Syndrome	% of nirAE¹⁰	Clinical manifestations	Diagnostic workup	Mortality rate¹⁰
Myositis	32%	-Proximal muscular weakness with myalgia -Ptosis, dysphagia -Facial and neck weakness -Respiratory dysfunction -Myocarditis	-↑ serum CK and aldolase -EMG: myopathic pattern -Ab: SM, AChr (not frequent) -Muscle biopsy: lymphocyte infiltration -MNM, EKG, Echo: assess concomitant myocarditis	17%
Myasthenic syndromes	14%	-Ocular myasthenia -Generalized myasthenia -Myositis / myocarditis overlap -LEMS	-NCS with repetitive nerve stimulation -EMG with single-fiber evaluation -Ice pack test (when ptosis is present) -Ab: AChr, VGCC	28%
Peripheral neuropathy	22%	-Acute polyradiculoneuropathy (GBS-like) -CIDP -Sensory neuronopathy -Miller-Fisher syndrome -Others: Phrenic neuropathy, vasculitic neuropathy, small fiber neuropathy, enteric neuropathy, neuralgic amyotrophy, motor neuropathy, Mononeuritis multiplex	-NCS -CSF: albuminocytologic dissociation or pleocytosis with high protein -Ab: rarely positive, GM1 more common -MRI: contrast enhancement in nerve roots, plexus, and/or cranial nerves in polyradiculoneuropathy	11%
Cranial neuropathy	7%	-Facial nerve palsy -Vestibulocochlear nerve impairment -Trigeminal nerve impairment -Oculomotor nerve palsy. -Multiple cranial neuropathy simultaneously	-CSF: albuminocytologic dissociation or pleocytosis with high protein -MRI: contrast enhancement in affected cranial nerves -NCS (facial palsy)	0%
Encephalitis	13%	-Altered mental status, cognitive impairment, seizures, psychiatric disturbances and/or movement disorders	-MRI: Mesial temporal lobes, basal ganglia, cortico-subcortical, and/or brainstem areas of increased signal in T2/FLAIR -CSF: mild pleocytosis, elevated protein, OCB+ -EEG: diffuse slow activity; epileptic or slow-wave activity involving focal cerebral regions -Ab (CSF and serum): Ma2, Hu, others	21%
CNS demyelination / myelopathy	3,5%	-MS relapse -NMOSD -Isolated optic neuritis -Isolated myelitis -Atypical demyelination	-MRI: periventricular, juxtacortical, infratentorial, spinal cord, and/or optic nerve involvement characteristic of MS or NMOSD -CSF: mild pleocytosis, elevated protein, OCB+ -Ab: AQP4 (NMOSD)	12%
Aseptic meningitis	3%	- headache, neck stiffness, fever and/or nausea	-MRI: meningeal contrast enhancement -CSF: mild pleocytosis and elevated protein	0%

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

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

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

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[1] Correspondence:
Marcelo Houat de Brito; Email: marcelohbrito@gmail.com.