. 2021 Jul 8;40(3):949–982. doi: 10.1007/s10555-021-09976-0

Table 19.

All-grade adverse events of nervous system origin in cancer patients treated with ICI [71, 74, 76, 77, 79–81]

System	Symptoms	Abnormalities in diagnostic test results	Suspected pathology
Nervous system	Bilateral motor/ sensory/bowel and bladder signs/symptoms-loss of bowel/bladder function Pain in the lower back, neck, arm, or leg Tingling, numbness, or weakness Difficulty walking Abnormal/increased reflexes in extremities Decreased fine motor skills, balance and coordination	Lumbar puncture for CSF analysis— cytology/flow cytometry of the cerebrospinal fluid (normal/lymphocytosis with elevated proline) Spine/brain MRI (including axial sections through the region of suspected abnormality)	Myelopathy
Fatigable/fluctuating muscle weakness (more proximal) Ocular/bulbar involvement (ptosis, extra ocular movement) Double vision Dysphagia Dysarthria Facial muscle weakness neck/respiratory muscle weakness Myositis Myocarditis	Brain MRI (no leptomeningeal or cranial nerve enhancement, parenchymal alterations) EMG (pathological jitter)	Myasthenia gravis Myasthenia-like syndrome
Acute polyneuropathy Symmetrical muscle weakness Sensory symptoms Neuropathic pain localized to lower back and thighs Dysregulation of autonomic nerves	Anti-ganglioside, anti-acetylcholine receptor, and anti-strained muscle antibodies can be present Lumbar puncture (elevated WBC)	Guillain-Barre syndrome
Asymmetric/symmetric sensory, motor, sensory-motor deficit Focal mononeuropathies Numbness Paresthesia Hypo-/areflexia Sensory ataxia	Nerve biopsy (to distinguish from direct tumor infiltration) MRI (to evaluate cranial neuropathies/nerve root abnormality) EMG	Peripheral neuropathy
Symptoms related to nerves involved (proximal/distal peripheral sensory and motor nerves, autonomic nervous system), e.g., arrhythmias, silent angina due to damage to nerve fibers and disruption of pain transmission, gastroparesis, severe constipation, bladder paralysis Sweating abnormalities Sluggish pupil reaction Orthostatic hypertension	Abnormal electrophysiological tests	Autonomic neuropathy (sensory-motor)
Headache Photophobia Neck stiffness Nausea/vomiting	Lumbar puncture for CSF analysis—cytology/flow cytometry of the cerebrospinal fluid (WBC <500, normal glucose)	Aseptic meningitis
Confusion Fatigue Spastic tremors Fever Vomiting Altered behavior Headache Seizures Short-term memory loss Lowered level of consciousness Focal weakness Speech abnormality Cerebral symptoms (gait disturbance, tremor, altered movements)	Lumbar puncture for CSF analysis—cytology/flow cytometry of the cerebrospinal fluid (WBC <250, mononuclear pleocytosis, normal glucose, increased protein level) Brain MRI (diffuse dural enhancement without parenchymal abnormalities) EEG (diffuse non-specific slowing) Anti-NMDA receptor antibodies positive in some cases	Encephalitis
Acute/ subacute weakness Bilateral sensory changes Increased deep tendon reflex	MRI (inflammation of the spinal cord and other potential causes) Lumbar puncture (± abnormally high numbers of white blood cells or immune system proteins that indicate inflammation) Blood tests (± antibodies associated with neuromyelitis optica, a condition in which inflammation occurs both in the spinal cord and in the optic eye)	Transverse myelitis

System

Symptoms

Abnormalities in diagnostic test results

Suspected pathology

Nervous system

Bilateral motor/ sensory/bowel and bladder signs/symptoms-loss of bowel/bladder function

Pain in the lower back, neck, arm, or leg

Tingling, numbness, or weakness

Difficulty walking

Abnormal/increased reflexes in extremities

Decreased fine motor skills, balance and coordination

Lumbar puncture for CSF analysis— cytology/flow cytometry of the cerebrospinal fluid (normal/lymphocytosis with elevated proline)

Spine/brain MRI (including axial sections through the region of suspected abnormality)

Myelopathy

Fatigable/fluctuating muscle weakness (more proximal)

Ocular/bulbar involvement (ptosis, extra ocular movement)

Double vision

Dysphagia

Dysarthria

Facial muscle weakness

neck/respiratory muscle weakness

Myositis

Myocarditis

Brain MRI (no leptomeningeal or cranial nerve enhancement, parenchymal alterations)

EMG (pathological jitter)

Myasthenia gravis

Myasthenia-like syndrome

Acute polyneuropathy

Symmetrical muscle weakness

Sensory symptoms

Neuropathic pain localized to lower back and thighs

Dysregulation of autonomic nerves

Anti-ganglioside, anti-acetylcholine receptor, and anti-strained muscle antibodies can be present

Lumbar puncture (elevated WBC)

Guillain-Barre syndrome

Asymmetric/symmetric sensory, motor, sensory-motor deficit

Focal mononeuropathies

Numbness

Paresthesia

Hypo-/areflexia

Sensory ataxia

Nerve biopsy (to distinguish from direct tumor infiltration)

MRI (to evaluate cranial neuropathies/nerve root abnormality)

EMG

Peripheral neuropathy

Symptoms related to nerves involved (proximal/distal peripheral sensory and motor nerves, autonomic nervous system), e.g., arrhythmias, silent angina due to damage to nerve fibers and disruption of pain transmission, gastroparesis, severe constipation, bladder paralysis

Sweating abnormalities

Sluggish pupil reaction

Orthostatic hypertension

Abnormal electrophysiological tests

Autonomic neuropathy (sensory-motor)

Headache

Photophobia

Neck stiffness

Nausea/vomiting

Lumbar puncture for CSF analysis—cytology/flow cytometry of the cerebrospinal fluid (WBC <500, normal glucose)

Aseptic meningitis

Confusion

Fatigue

Spastic tremors

Fever

Vomiting

Altered behavior

Headache

Seizures

Short-term memory loss

Lowered level of consciousness

Focal weakness

Speech abnormality

Cerebral symptoms (gait disturbance, tremor, altered movements)

Lumbar puncture for CSF analysis—cytology/flow cytometry of the cerebrospinal fluid (WBC <250, mononuclear pleocytosis, normal glucose, increased protein level)

Brain MRI (diffuse dural enhancement without parenchymal abnormalities)

EEG (diffuse non-specific slowing)

Anti-NMDA receptor antibodies positive in some cases

Encephalitis

Acute/ subacute weakness

Bilateral sensory changes

Increased deep tendon reflex

MRI (inflammation of the spinal cord and other potential causes)

Lumbar puncture (± abnormally high numbers of white blood cells or immune system proteins that indicate inflammation)

Blood tests (± antibodies associated with neuromyelitis optica, a condition in which inflammation occurs both in the spinal cord and in the optic eye)

Transverse myelitis