Immune effector cell-associated neurotoxicity syndrome (ICANS)

Immune effector cell-associated neurotoxicity syndrome (ICANS), previously known as cytokine release encephalopathy syndrome (CRES) or chimeric antigen receptor (CAR) T-cell-related encephalopathy syndrome, is a neuropsychiatric syndrome that can occur days to weeks following the administration of certain types of immunotherapy, especially immune effector cell and T-cell engaging therapies (e.g. chimeric antigen receptor–engineered (CAR) T-cell therapy, bispecific T-cell engagers (BiTE)) ^1-4. It can result in life-threatening cerebral edema.

Epidemiology

The incidence of ICANS varies depending on the type and dose of immunotherapy, the underlying malignancy, and the patient characteristics. It has been reported to occur in 10-66% of patients receiving CAR T-cell therapy for hematologic malignancies, making it the second most common complication of CAR T-cell therapy after cytokine release syndrome ^1-3. Although ICANS can occur without preceding or concurrent cytokine release syndrome, more severe cases appear together ¹.

Clinical presentation

ICANS has a heterogeneous and non-specific clinical presentation and may manifest as headache, delirium, encephalopathy, aphasia, lethargy, difficulty concentrating, agitation, tremor, seizures, and symptoms of increased cranial pressure ^1,4. In a minority of cases, progression to obtundation, coma and death can be rapid ¹. Onset tends to be within days or weeks (most within 1 week) of CAR T-cell infusion ¹.

Grading

The severity of ICANS can be graded according to a a number of systems developed most frequently that proposed by the American Society for Transplantation and Cellular Therapy (ASTCT) ⁴. The grading system is based on a modified Mini-Mental Test, combined the a number of clinical features and imaging evidence of cerebral edema ^1,4.

Pathology

The pathophysiology of ICANS is not fully understood but it is thought to involve cytokine-mediated inflammation and disruption of the blood-brain barrier ^1,3. Some of the cytokines that have been implicated in ICANS include interleukin-6 (IL-6), interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and IL-213. These cytokines may activate microglia and astrocytes in the central nervous system and cause neuroinflammation ³.

Radiographic features

Although usually negative, imaging is recommended in cases of suspected ICANS to assess for the presence of edema (used in the ASTCT grading system) and for rare complications such as hemorrhage or stroke ¹.

CT

CT imaging of the brain is often normal. When abnormal cerebral edema may be evident along with features of raised intracranial pressure (e.g. sulcal effacement, ventricular compression). Only rarely is hemorrhage present.

MRI

MRI findings are also variable and nonspecific. They may include ^1,4:

• T2/FLAIR:

  • focal cerebral edema (ASTCT grade 3)

    • typically initially of the thalami and brainstem ¹

  • diffuse cerebral edema (ASTCT grade 4)

• T1 C+:

  • leptomeningeal enhancement

• SWI:

  • microhemorrhages ¹

• DWI/ADC:

  • areas of ischemia/cystotoxic edema result in restricted diffusion

• CBF:

  • increased perfusion

• MR spectroscopy:

  • increased choline/creatine ratio

  • increased lactate

Treatment and prognosis

The treatment of ICANS depends on its severity and on the underlying cause. Many therapies are supportive and aimed to control specific manifestations (e.g. antiseizure medications for seizures).

Anti-inflammatory therapies include corticosteroids (e.g. dexamethasone or methylprednisolone) or, in more severe cases particularly if concurrent cytokine release syndrome is present, with anti-cytokine agents such as tocilizumab (an anti-IL-6 receptor antibody) or anakinra (an IL-1 receptor antagonist) ¹.

The prognosis of ICANS depends on its severity and response to treatment and most patients recover fully within days to weeks after treatment initiation ¹.

Some patients may have residual neurological deficits or die from complications such as cerebral hemorrhage, uncontrolled cerebral edema leading to cerebral herniation or multiorgan failure ³.

The mortality rate of ICANS has been reported to range from 0-11% depending on the study population and definition used. Factors that have been associated with poor outcome include older age higher grade longer duration and delayed onset.

Differential diagnosis

• toxic leukoencephalopathy