ICANS or TIAN? Neurologic Toxicity Following CAR T-Cell Therapy in a Patient With Primary Central Nervous System Lymphoma

Presentation 

A 63-year-old female with recurrent primary central nervous system (CNS) lymphoma was admitted for CAR T-cell therapy on a clinical trial. Prior to admission, she developed worsening altered mental status and was found to have acute hydrocephalus. She underwent shunt placement and received MATRix chemotherapy (methotrexate, cytarabine, thiotepa, and rituximab) as bridging therapy prior to CAR T-cell infusion. 

She subsequently presented for treatment with lisocabtagene maraleucel. Her CAR T-cell infusion was administered on Day 0 without complication. 

Given her history of CNS lymphoma, recent hydrocephalus, and shunt placement, she was considered to be at high risk for neurologic complications during the post–CAR T period. 

Workup, Diagnosis, and Treatment 

Day +8 

The patient developed a severe 10/10 headache. Despite the headache, there were initially no new focal neurologic findings or changes in mental status. Her Immune Effector Cell Encephalopathy (ICE) score remained at baseline. 

• A computed tomography (CT) scan of the head was obtained and demonstrated: 

• Diffusely increased ventricular caliber, 

• Progressive periventricular edema, and 

• Findings suspicious for progressive obstructive hydrocephalus. 

Given the radiographic progression and her history of acute hydrocephalus, neurosurgery was consulted. The differential diagnosis included progressive CNS lymphoma involving the ventricular system, CAR T-associated inflammation or neurotoxicity, and ineffective drainage from the existing shunt. 

Neurosurgery felt the hydrocephalus was most likely related to the patient's known third-ventricular tumor; however, they could not definitively exclude progression of disease or a contribution from CAR T-associated inflammation. 

The patient was transferred to the neuro intensive care unit (ICU) for close monitoring, including hourly neurologic examinations, with a plan for additional shunt intervention. 

Day +9 

The patient developed a sustained fever to 100.76°F. Her vital signs were otherwise stable, and her ICE score remained at baseline. A comprehensive infectious workup was obtained, and empiric piperacillin/tazobactam was initiated. 

Later that day, the patient underwent shunt revision with neurosurgery. 

Following the procedure, she developed recurrent fever accompanied by increasing tachypnea with respiratory rates in the 20s–30s and a new oxygen requirement of 2L via nasal cannula. 

Given the timing after CAR T-cell infusion and the combination of fever and hypoxia, the treating team elected to treat the patient for grade 2 cytokine release syndrome (CRS). 

Treatment included: 

• Anakinra 100 mg every 6 hours 

•  Dexamethasone 10 mg IV × 1 

Day +10 

The patient's fever and hypoxia resolved; however, her neurologic status worsened significantly. She became increasingly lethargic, with an ICE score of 0/10. 

A repeat head CT demonstrated stable hydrocephalus without evidence of acute worsening. 

Given the acute change in mental status in the setting of CAR T-cell therapy and the absence of radiographic progression of hydrocephalus, the patient was treated as having grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS). 

Treatment was escalated to:  

• Dexamethasone 20 mg IV every 6 hours  

• Anakinra 100 mg every 6 hours  

• Levetiracetam increased to 1 g twice daily for seizure prophylaxis 

Day +11 

The patient's mental status continued to deteriorate. She became responsive only to painful stimuli. 

Anakinra was increased to 200 mg every 6 hours. Corticosteroid therapy was escalated from dexamethasone to methylprednisolone 250 mg IV every 6 hours. 

The clinical presentation remained concerning for severe CAR T-associated neurotoxicity, although distinguishing ICANS from other causes of neurologic deterioration remained challenging because of her underlying CNS lymphoma and recent hydrocephalus. 

Day +12 

The patient developed significant hypoxia requiring bilevel positive airway pressure. Despite her respiratory deterioration, her mental status began to improve. She was able to follow some simple commands, and her ICE score improved to 3/10. 

Given concern for ongoing grade 3 CRS, siltuximab was administered × 1. Neurologic status continued to be closely monitored with ongoing high-dose corticosteroids and anakinra. 

Day +14 

The patient's neurologic and respiratory status continued to improve. She was transferred from the neuro ICU back to the floor. 

Day +15 

The patient was receiving 4L oxygen via nasal cannula, and her ICE score had returned to baseline. Given sustained clinical improvement, corticosteroids and anakinra were gradually tapered over the subsequent days. 

Discussion 

Neurologic toxicity following CAR T-cell therapy can be particularly challenging to diagnose in patients with pre-existing CNS disease. ICANS is a well-described complication of CAR T-cell therapy and can range from mild confusion or language disturbance to severe encephalopathy, seizures, cerebral edema, and coma. 

The diagnosis of ICANS is primarily clinical and is graded using the American Society for Transplantation and Cellular Therapy ICANS grading system. The ICE score is an important component of assessment and evaluates orientation, naming, following commands, writing, and attention. 

In this patient, the decline in ICE score from baseline to 0/10, accompanied by profound lethargy, was highly concerning for severe ICANS. 

However, this case illustrates an important diagnostic dilemma: not every neurologic change after CAR T-cell therapy is ICANS. 

Progressive Hydrocephalus 

On Day +8, before the development of overt encephalopathy, the patient developed a severe headache, and CT imaging demonstrated increased ventricular caliber and progressive periventricular edema. This raised concern for worsening obstructive hydrocephalus, potentially related to her known third-ventricular tumor. 

The need for shunt revision immediately before the subsequent neurologic deterioration made it particularly difficult to determine how much of her presentation was attributable to mechanical obstruction versus CAR T-associated inflammation. 

ICANS 

The patient's subsequent deterioration occurred in the setting of CAR T-cell therapy and following an episode of CRS. Her ICE score fell to 0/10, and she developed profound encephalopathy without radiographic worsening of hydrocephalus. 

These findings supported a diagnosis of severe ICANS and prompted treatment with high-dose corticosteroids. Her neurologic status improved after escalation of corticosteroid therapy, supporting an immune-mediated component to her presentation. 

Tumor inflammation-associated neurotoxicity  

An additional consideration in patients receiving CAR T-cell therapy for CNS malignancies is tumor inflammation-associated neurotoxicity (TIAN) associated with CAR T-cell therapy. 

TIAN describes a spectrum of neurologic complications that may occur after CAR T-cell therapy for CNS malignancies and can overlap clinically with ICANS. In this patient, the distinction between ICANS and TIAN was particularly difficult because she had: 

• Active/recurrent primary CNS lymphoma, 

• Known third-ventricular disease, 

• Pre-existing hydrocephalus, 

• Recent shunt placement and revision, 

• CAR T-cell therapy directed against CD19 and CD22, 

• CRS preceding her neurologic deterioration, and 

• Severe encephalopathy without clear radiographic progression of hydrocephalus. 

Thus, it was not possible to definitively determine whether her neurologic decline represented classic ICANS, TIAN, worsening CNS lymphoma, hydrocephalus-related encephalopathy, or a combination of these processes. 

Fortunately, the initial treatment strategy for severe immune-mediated neurotoxicity converges on high-dose corticosteroids, making prompt recognition and treatment more important than establishing a perfectly precise diagnosis at the bedside. 

This case also highlights the importance of multidisciplinary management. Neurology, neurosurgery, critical care, and the cellular therapy team were required to simultaneously evaluate mechanical, malignant, infectious, and immune-mediated causes of neurologic deterioration. 

Clinical Pearls 

• Neurologic deterioration following CAR T-cell therapy is not always ICANS, particularly in patients with pre-existing CNS disease. 

• In patients with primary CNS lymphoma, consider ICANS, TIAN, progressive disease, hydrocephalus, infection, seizures, and treatment-related complications in the differential. 

• A declining ICE score should prompt immediate neurologic assessment and consideration of ICANS, but the ICE score alone does not establish the etiology. 

• New headache or neurologic symptoms in a patient with known CNS disease warrant appropriate neuroimaging and consideration of structural causes. 

• TIAN may overlap clinically with ICANS, making the distinction challenging in patients with CNS malignancies. 

• Improvement in hydrocephalus on imaging does not necessarily exclude an immune-mediated neurologic toxicity. 

• Severe ICANS requires prompt corticosteroid therapy; treatment should not be delayed while attempting to establish the precise mechanism of neurotoxicity. 

• Management may require simultaneous treatment of multiple toxicities, as demonstrated by this patient's concurrent CRS and neurologic toxicity. 

• Close collaboration among cellular therapy, neurology, neurosurgery, and critical care teams is essential in complex CNS CAR T-cell treatment scenarios.