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score, raised intracranial pressure and seizures or motor weakness. The neurological status is assessed with
CARTOX-10, a 10-point neurological assessment tool developed by the authors that evaluates attention,
speech and writing ability [Table 3].

It should be noted that direct CNS infusions of CAR-T have not resulted in the same toxicity (CRS or CRES),
though only a few patients have had this treatment at this point. As previously discussed, Brown et al. [28]
described a patient with glioblastoma who was treated with an intrathecal delivery of CAR-T cells. They
reported only grade 1-2 toxicity, the majority of which lasted less than 1 day. Grade 1 fatigue was the most
lasting adverse event (4 days). Headache, myalgias and lymphopenia were the worst higher grade toxicities
[28]
(Grade 2) .

MANAGEMENT OF CAR-T TOXICITY
Management of CAR-T associated toxicity is based on severity of symptoms. It begins with symptomatic
management and supportive care for milder symptoms - fever is treated with acetaminophen or cooling
blankets, acetaminophen is used for myalgias, anti-emetics for nausea, etc. Intravenous (IV) fluids may
be started for hydration in grade 1 toxicity. Organ systems are closely monitored with frequent laboratory
assessments and organ toxicities treated according to what is seen (for example, acute kidney injury or AKI
may be treated with hydration). Higher grades of CRS require greater intervention. Oxygen requirements
may need to be met with supplemental oxygen and/or even ventilation. Vasopressors may need to be started
and titrated to maintain a stable hemodynamic status. Ultrasound may be needed to assess hemodynamic
status, and frequency of vitals and assessments may need to be increased. For these reasons, patients who
are not yet in the intensive care unit (ICU) are often transferred when CRS or neurotoxicity is grade 2 or
higher [23,31,32,35] .

Similar to CRS, management of CRES is also escalated depending on the grade of the toxicity seen. Careful
and frequent neurological assessment by experienced providers is extremely important. In addition, it is also
important to use a scale such as the CARTOX-10 or a similarly sensitive tool that can pick up on subtle, early
neurological deficits. With even minimal signs of neurological impairment, the patient is generally placed on
aspiration precautions. The patient must be closely and frequently monitored from this point onwards with
careful neurological examinations by a neurologist, and regular funduscopic exams. CT head of the brain,
followed by MRI of the brain (and/or spine if appropriate and if deficits are present) is usually obtained
along with a lumbar puncture to assess opening pressure and rule out other conditions that these patients
may be at risk for (such as leukemic or infectious meningitis). If the patient is too unstable, a CT of the brain
can be obtained instead of MRI in this early stage. If patient is noted to be encephalopathic, an EEG should
[23]
be considered to rule out non-convulsive status epilepticus .

If the patient does develop increased intracranial pressure or has seizures (convulsive or non-convulsive),
management should be guided per the protocols for each of these conditions. An experienced neurology
team is thus quite necessary. Increased intracranial pressure may be managed with dexamethasone, man-
nitol or acetazolamide, bed elevation, hyperventilation, or hyperosmolar therapy, or even drainage of CSF.
Seizures, and possible status epilepticus, should be managed per nationally established guidelines that in-
clude lorazepam as a starting point with IV boluses of anti-epileptics such as levetiracetam and escalating
to additional medications or a drip of midazolam or phenobarbital if seizures continue despite early efforts.
Drugs such as fosphenytoin and lacosamide are typically avoided due to their potential for additional cardio-
toxicity. Some centers are using prophylactic levetiracetam (at 500 mg BID) prior to starting the treatment
[23]
process, though at this time no clear evidence supports the use of prophylactic anti-epileptics .
Tocilizumab is an IL-6 antagonistic monoclonal antibody that has been available on the market to treat
rheumatological disorders. Given the high levels of IL-6 seen with the toxicity of CAR-T, it was tried and