Older age (> 60)
Renal dysfunction
Type of transplant: allogeneic > autologous
Pre-transplant CNS
Total body irradiation
High-dose conditioning regimen
Acute myeloid malignancy
GVHD > grade II
Calcineurin inhibitor use
Table 25.2
Drug-induced neurotoxicity
Drug | Symptoms | Timing | Treatment |
|---|---|---|---|
HiDAC (high dose ara-C) | Cerebellar syndrome, polyneuropathy | Conditioning: acute, during administration | Discontinue infusion |
Fludarabine | Peripheral neuropathy, visual changes, delayed leukoencephalopathy | Conditioning | Discontinue drug |
Calcineurin inhibitors—tacrolimus, cyclosporine | PRES | Chronic | Discontinue drug |
Sirolimus | PRES | Chronic | Discontinue drug |
Busulfan | Seizures, encephalopathy, myoclonus, hallucinations | Conditioning | Prophylactic antiepileptics—phenytoin, klonipin, or levetiracetam |
Ifosfamide | Encephalopathy, myoclonus, hallucinations, seizures | Conditioning | Discontinue drug |
1.
High-dose cytarabine
a.
Neurotoxicity generally occurs in doses ≥ 2 g/m2 every 12 h
b.
Acute cerebellar syndrome, manifesting as dysarthria and ataxia, is the most common neurotoxic event from high-dose cytarabine
c.
Incidence is ~ 10 %
d.
First signs include nystagmus and ataxia with concurrent cerebral dysfunction (encephalopathy) and altered mental status
e.
Neuroimaging with magnetic resonance imaging (MRI) is initially unrevealing; however, imaging later in the course reveals cerebellar atrophy
f.
Risk factors may include
i.
Age ≥ 50
ii.
Total cumulative doses ³ 48 g/m2
iii.
Prior central nervous system (CNS) disease
iv.
Renal dysfunction, both prior to initiation of chemotherapy or development of acute kidney injury during the chemotherapy administration
g.
Mechanism of injury is likely related to accumulation of metabolites in the cerebrospinal fluid (CSF) leading to selective injury of the cerebellar Purkinje cells.
h.
Treatment includes discontinuing cytarabine (though symptoms onset may not become apparent until therapy completed). Steroids are often administered; however, benefit has not been proven.
i.
Daily monitoring for nystagmus, dysmetria on finger-to-nose, and unsteady gait should be performed and the infusion halted with detection of any sign.
j.
Though most symptoms resolve over 2 weeks, a small minority of patients have permanent deficits.
2.
Fludarabine
a.
Generally associated with doses higher than 50 mg/m2/day. At lower doses, this severe complication is less common.
b.
Risk factors may include
i.
Age ≥ 60
ii.
Renal dysfunction
iii.
Prior CNS disease
iv.
Dose
c.
Neurotoxicity may be delayed, potentially severe, and sometimes irreversible
d.
Symptoms, including cognitive changes, altered mental status , and visual changes, may evolve to coma and death
e.
MRI reveals nonenhancing periventricular white matter changes with restricted diffusion
3.
Calcineurin inhibitors (CNIs)
a.
CNIs are immunosuppressants used as graft-versus-host disease (GVHD) prophylaxis in allogeneic HSCT recipients and are notorious for instigating neurotoxicity
b.
Neurotoxicity with Cyclosporine is quoted at 4–30 %
i.
Less common with tacrolimus and newer generation CNIs
ii.
CNI levels should be monitored closely. However, there may not be a significant correlation between drug levels and the development of neurotoxicity
c.
Symptoms range from tremor (see Sect. 25.2) and mild changes in mental status to more significant visual changes, including cortical blindness, seizures, and coma.
d.
Posterior reversible leukoencephalopathy or posterior reversible encephalopathy syndrome (PRES) is the most common manifestation of CNIs (described in Sect. 25.D) .
4.
Busulfan
a.
Administered as part of many reduced-intensity and myeloablative conditioning regimens: high CNS penetration leads to cortical irritability and seizures (~ 10 %), which are usually generalized
b.
Antiepileptic prophylaxis is widely used.
i.
Phenytoin and phenobarbital are potent cytochrome P450 inducers leading to many drug interactions, variable plasma levels, and effect on busulfan metabolism.
ii.
New antiepileptics, such as levetiracetam (Keppra®), are better tolerated with fewer drug interactions and are becoming more widely used.
iii.
A typical seizure prophylaxis regimen combines levetiracetam 500 mg po BID and clonazepam 0.5 mg po BID, beginning 12 h prior to the first dose of busulfan and continuing for 24 h after the last dose.
5.
Ifosfamide
a.
Encephalopathy occurs during or shortly after infusion and manifests as confusion, hallucinations, and/or seizures; progression to coma and death is rare.
b.
Treatment includes discontinuation of the infusion.
i.
Use of methylene blue 50 mg q4 intravenous (IV) is anecdotally reported to be beneficial.
ii.
Metabolites can be removed with hemodialysis.
c.
Symptoms typically resolve within 7 days.
6.
Intrathecal methotrexate
a.
Neurotoxicity includes aseptic meningitis, occurring in ~ 10 % of cases and manifesting with fever and signs of increased intracranial pressure with headache, nausea/vomiting, and lethargy
b.
CSF shows increased protein and monocytic or lymphocytic pleocytosis; while infectious etiologies should be ruled out, the timing usually points to drug effect.
c.
Acute encephalopathy similar to PRES has been reported.
d.
Protracted use of intrathecal methotrexate , especially in patients treated with whole-brain radiation, may produce a chronic diffuse leukoencephalopathy.
i.
Symptoms typically present 6 months after treatment with progressive neurocognitive decline.
ii.
MRI reveals diffuse subcortical white matter T2/fluid attenuated inversion recovery (FLAIR) hyperintensity and cerebral atrophy.
e.
Patients treated via lumbar puncture (LP; rather than via Ommaya reservoir) may develop radicular symptoms and imaging suggestive of myeloradiculopathy.
25.2 Tremors
1.
Most common neurologic toxicity from CNIs, seen in up to 40 %, and may be associated with chronic GVHD
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