Confused about Confusion

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Posted by Carla Rothaus

What are some of the features of immune effector cell–associated neurotoxicity syndrome?

When immune effector cell–associated neurotoxicity syndrome is suspected, immediate treatment with dexamethasone or methylprednisolone (at a dose of 1 to 2 g per day in severe disease) is recommended. Read the NEJM Clinical Problem-Solving Article here.

Clinical Pearls

Q: Name a cancer for which CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is increasingly used.

A: CD19-directed CAR-T therapy is increasingly used in the treatment of B-cell cancer. Its use results in 2-year progression-free survival in up to 40% of patients with relapsed or refractory diffuse large B-cell lymphoma; the prognosis for this patient population without CAR-T therapy is poor (2-year overall survival, 20%). A major drawback of CAR-T therapy is the occurrence of severe adverse effects, including cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome.

Q: Is magnetic resonance imaging (MRI) of the brain abnormal in immune effector cell–associated neurotoxicity syndrome?

A: Most often, no abnormalities are seen on MRI in immune effector cell–associated neurotoxicity syndrome, although several nonspecific MRI patterns have been described.


Morning Report Questions 

Q: What are some of the features of immune effector cell–associated neurotoxicity syndrome?

A: Immune effector cell–associated neurotoxicity syndrome affects two of three patients after treatment with the CAR-T therapy axicabtagene ciloleucel, on average 5 days after infusion, with an initial presentation characterized by acute encephalopathy with disorientation and difficulty in writing and finding words. Because immune effector cell–associated neurotoxicity syndrome can progress quickly, treatment with dexamethasone is advised as soon as this syndrome is suspected. If rapid resolution does not occur, a cranial MRI scan should be obtained. Both the rapid resolution of symptoms after initiation of treatment with dexamethasone and the early recurrence of symptoms are characteristic of immune effector cell–associated neurotoxicity syndrome. Most cases of immune effector cell–associated neurotoxicity syndrome are reversible, although rare fatal cases of cerebral edema and brain herniation despite treatment have been reported.

Q: What causes immune effector cell–associated neurotoxicity syndrome?

A: The pathogenesis of immune effector cell–associated neurotoxicity syndrome is incompletely understood. It is hypothesized that systemic inflammation and circulating cytokines trigger the activation of endothelial cells and disruption of the blood–brain barrier, which in turn cause an inflammatory cascade involving CAR-T and other immune-competent cells within the central nervous system, subsequently affecting cortical and subcortical functions. Cytokine release syndrome is considered a cofactor in immune effector cell–associated neurotoxicity syndrome because, in the vast majority of patients, cytokine release syndrome occurs shortly before the development of immune effector cell–associated neurotoxicity syndrome. Both the incidence and severity of immune effector cell–associated neurotoxicity syndrome are higher with greater tumor volume, higher levels of lactate dehydrogenase and inflammatory markers, lower platelet count, preceding cytokine release syndrome, and preexisting neurologic conditions.

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