13.3 Chemo/Immune, SCT, CAR-T, Sickle Cell, and TMA (01.T.6–10)

The hematology consult in a modern neuro ICU is often not anemia. It is a chimeric antigen receptor T-cell (CAR-T) recipient who cannot write a sentence, a transplant patient who seizes on tacrolimus, or a young adult with sickle cell disease and a dense middle-cerebral-artery syndrome. This independent OpenExamPrep section covers chemotherapy and immune-effector toxicity, stem-cell transplant complications, CAR-T neurotoxicity, sickle cell cerebrovascular disease, and thrombotic microangiopathy (TMA) as listed in the ABPN Content Specifications (01.T.6–10). It is not an ABIM or ABPN product.

CAR-T: CRS versus ICANS

Cytokine release syndrome (CRS) is fever, hypotension, and hypoxia driven by interleukin-6 and other cytokines, usually in the first days after CAR-T infusion. Immune effector cell–associated neurotoxicity syndrome (ICANS) is the neurologic sibling: encephalopathy, aphasia, tremor, seizures, and, at the extreme, cerebral edema. ICANS often follows CRS by a few days (commonly around days 4–10 for CD19 products) but can overlap. CD28-costimulated products such as axicabtagene ciloleucel have historically produced more ICANS than 4-1BB products such as tisagenlecleucel; the examination cares more about recognition and first drugs than about brand-level epidemiology.

Grade ICANS with the American Society for Transplantation and Cellular Therapy (ASTCT) system. The Immune Effector Cell–Associated Encephalopathy (ICE) score is 10 points:

ICE 7–9 is consistent with grade 1 encephalopathy, 3–6 with grade 2, and 0–2 with grade 3, provided the patient can be tested. An unarousable patient who cannot perform ICE is grade 4. Seizures, motor weakness, depressed consciousness, and radiographic cerebral edema upgrade the grade even if ICE is only moderately reduced. Record ICE at least every 8 hours while toxicities are active. Work-up competing causes: infection, methotrexate if the patient also received it, electrolyte shifts, nonconvulsive seizures (EEG), and intracranial hemorrhage on CT or MRI.

Tocilizumab is an interleukin-6 receptor antagonist. It is first-line treatment for CRS (typical adult dose 8 mg/kg IV, maximum 800 mg per dose, repeatable every 8 hours with a cap on total doses per CRS episode). Blocking the receptor can raise circulating interleukin-6, which may worsen isolated neurotoxicity. Therefore isolated ICANS is treated with corticosteroids (dexamethasone for grade 2–3; high-dose methylprednisolone for fulminant cerebral edema), not with tocilizumab as monotherapy. If CRS and ICANS coexist, give both tocilizumab (for the CRS) and steroids (for the ICANS). Anakinra (interleukin-1 blockade) appears in refractory algorithms; it is not the first multiple-choice answer. Seizure prophylaxis is used in many CAR-T protocols (levetiracetam is common). Airway protection, osmotherapy, and ICP care follow ordinary neurocritical practice if edema develops.

PRES after transplant, and PML as a rare extra

Posterior reversible encephalopathy syndrome (PRES) is vasogenic edema, classically in parieto-occipital white matter, presenting with headache, visual change, seizures, and hypertension. After solid-organ or hematopoietic stem-cell transplant (SCT), calcineurin inhibitors (tacrolimus, cyclosporine) are leading drug triggers; sirolimus and VEGF-pathway cancer drugs (including bevacizumab) also appear. MRI shows T2/FLAIR hyperintensity that is usually not diffusion-restricted the way an infarct is (though mixed patterns exist). Treatment is blood-pressure control, reduction or substitution of the calcineurin inhibitor, and seizure care. Most cases reverse; infarction and hemorrhage are the exceptions that make “reversible” a hope rather than a guarantee.

Progressive multifocal leukoencephalopathy (PML) from JC virus is a rare neuro ICU admission compared with PRES and ICANS. It belongs on the differential in a patient with AIDS, natalizumab, rituximab, or chronic transplant immunosuppression who has subacute multifocal white-matter disease, scalloped U-fiber involvement, and little mass effect. There is no reliable antiviral. Restore immunity and watch for immune reconstitution inflammatory syndrome. Do not treat PML as PRES with a tacrolimus dose reduction alone, and do not treat PRES as PML with a lumbar puncture for JC virus as the first and only step when the MRI is classic vasogenic edema on day 10 of tacrolimus.

Other chemo-neurotoxic patterns worth a sentence: ifosfamide encephalopathy (methylene blue in selected cases), fludarabine leukoencephalopathy, and intrathecal or high-dose methotrexate (below). None of these is tPA-eligible “stroke” without imaging that actually shows a treatable arterial occlusion, and the history of the drug is the clue.

Sickle cell disease and stroke

In sickle cell disease (SCD), especially HbSS and HbS/β0-thalassemia, ischemic stroke is a large-vessel and small-vessel disease of sickled blood, endothelial injury, and anemia. The disease-specific emergency treatment is transfusion, not a debate about a 7 g/dL TRICC trigger. The American Society of Hematology (ASH) 2020 cerebrovascular guideline recommends prompt transfusion within 2 hours of presentation for children or adults with SCD and acute neurologic deficits, including TIA. Exchange transfusion is preferred over simple transfusion. If exchange cannot start within 2 hours and hemoglobin is ≤8.5 g/dL, simple transfusion can proceed as a bridge toward a hemoglobin near 10 g/dL while apheresis is arranged. If hemoglobin is already above about 8.5 g/dL, simple transfusion risks hyperviscosity; wait for exchange. Post-exchange targets are typically HbS well below 30% (many apheresis orders use 15–20%) with a total hemoglobin around 10–12 g/dL, not 14 g/dL.

Do not delay transfusion while a tPA discussion unfolds. Intravenous thrombolysis in adults with SCD is a shared decision when ordinary eligibility is met; it is not a reason to skip exchange. Primary prevention in children with abnormal transcranial Doppler velocities is chronic transfusion to keep HbS below 30% (STOP trial logic). Adults with prior ischemic stroke often remain on a chronic transfusion or exchange program. Avoid hypoxia, acidosis, hypothermia, and hypotonic dehydration that provoke sickling. Meperidine is a poor analgesic choice because of normeperidine seizures.

TTP, HUS, and other TMA

Thrombotic microangiopathy means microangiopathic hemolytic anemia (MAHA: schistocytes, high LDH, low haptoglobin) plus thrombocytopenia, with organ injury. The neuro ICU’s job is to separate TTP, hemolytic uremic syndrome (HUS), DIC, malignant hypertension, and transplant-associated TMA in time to start the right first therapy.

TTP is severe ADAMTS13 deficiency (activity <10%), usually autoantibody-mediated in adults. Uncleaved ultra-large von Willebrand factor multimers platelet-occlude the microcirculation. Neurologic injury (fluctuating mental status, stroke, seizure) often outweighs renal injury. Do not wait for the historical pentad (MAHA, thrombocytopenia, fever, renal injury, neurologic change); fever and renal failure may be absent. Draw ADAMTS13 before plasma is infused, then start therapeutic plasma exchange (PLEX) as soon as TTP is the leading diagnosis. PLEX removes autoantibody and replaces ADAMTS13. Glucocorticoids, rituximab, and caplacizumab enter contemporary protocols; they do not replace PLEX as the first move. Do not lead with platelet transfusion. Platelets can feed microvascular thrombi. Reserve platelets for life-threatening bleeding or an immediately necessary invasive procedure after PLEX has started.

The PLASMIC score estimates the chance of ADAMTS13 <10% while the send-out assay is pending. One point each for: platelets <30 × 10^9/L, hemolysis, no active cancer, no solid-organ or stem-cell transplant, MCV <90 fL, INR <1.5, and creatinine <2.0 mg/dL. Scores 0–4 are low probability, 5 intermediate, and 6–7 high. High PLASMIC plus MAHA and thrombocytopenia is a PLEX-now stem. Low PLASMIC pushes you toward DIC, transplant TMA, or cancer-associated TMA instead.

Typical (STEC) HUS follows Shiga-toxin-producing E. coli diarrhea. Renal failure dominates; PLEX is not routine. Antibiotics and antimotility drugs are generally avoided in suspected STEC infection. Atypical HUS is complement dysregulation (often after a trigger) and may need eculizumab or ravulizumab once TTP is judged unlikely. Transplant-associated TMA is driven by calcineurin inhibitors, graft-versus-host disease, infection, and complement; it is not PLEX-first TTP unless ADAMTS13 is truly deficient. DIC, taught in section 13.1, shows a coagulopathy (high INR, low fibrinogen) that TTP usually lacks.

Methotrexate leukoencephalopathy, conceptually

High-dose intravenous methotrexate (CNS lymphoma, acute lymphoblastic leukemia) and intrathecal methotrexate can produce an acute or subacute leukoencephalopathy: stroke-like aphasia, hemiparesis, or encephalopathy with white-matter T2/FLAIR change and variable diffusion restriction that does not respect a single arterial territory. Delayed methotrexate clearance (acute kidney injury, third-space fluid, interacting drugs such as NSAIDs) raises risk. This is not an indication for tPA. Hold methotrexate, give leucovorin rescue as oncology directs, and consider glucarpidase when high-dose methotrexate remains in the toxic range with delayed clearance and renal failure. Intrathecal drug can also cause chemical meningitis or myelopathy. The examination needs the pattern and the “not a vascular occlusion” distinction, not a dosing nomogram.

Exam traps

Do not give tocilizumab as the sole treatment for isolated ICANS. Do not miss PRES on tacrolimus because the MRI “looks like PCA infarcts.” Do not simple-transfuse an already well-hemoglobinized SCD patient into hyperviscosity. Do not treat TTP with platelets and a wait-and-see ADAMTS13. Do not call every post-transplant TMA TTP. Do not give thrombolysis for methotrexate leukoencephalopathy.