Incidence of Neurological Complications Secondary to Intrathecal Chemotherapy Used As Either Prophylaxis or Treatment of Leptomeningeal Carcinomatosis
Authors: Byrnes Diana M , Dermarkarian Christopher R , Kahn Ryan , Kwon Deukwoo , Vargas Fernando , Hurley Judith , Watts Justin M. , Schatz Jonathan H. , Swords Ronan T 
Published: November 2019

Abstract
Purpose:
To examine the incidence and frequency of neurological complications secondary to intrathecal chemotherapy.
Introduction:
Intrathecal (IT) chemotherapeutic agents have a narrow therapeutic index and high potential for toxicity. Though severe side effects are considered rare, consequences of IT chemotherapy administration can be catastrophic. The most common neurotoxic side effect is chemical arachnoiditis, manifesting typically as headache and/or fever, but more severe symptoms have also been reported including paraplegia, cranial nerve palsies, and seizures. The true incidence of neurological complications is not well quantified, and many cases of toxicity may go unrecognized or unreported. Here we detail neurologic complications of IT chemotherapy in adult patients over a two-year time period at our institution.
Patients and Methods:
Sixty-three patients received IT chemotherapy between January 2014 and December 2015 at Jackson Memorial Hospital and were included in this analysis. We cataloged all neurological complications within four days of IT chemotherapy. We defined minor neurological complications as headache, backache, nuchal rigidity, fever, nausea, or vomiting. Major neurological complications were defined as paresthesia, cranial nerve palsy, paralysis, or asthenia. For each administration of IT chemotherapy we recorded the type and dose of chemotherapy, and results of associated CSF cytology and flow cytometry.
Results:
Of the 63 patients who received IT chemotherapy treatment, 44 (70%) were male. 20 (32%) patients identified as non-Hispanic, 41 (65%) identified as Hispanic, and 2 (3%) identified as Haitian. The average age at time of treatment was 47.87 years (median: 49, range 22-72). 14 (22%) of patients were HIV positive. At time of IT chemotherapy treatment, 18 (29%) patients had known malignancy present in the CNS.
Of the 208 recorded administrations of IT chemotherapy, 197 (95%) included methotrexate and 122 (59%) included cytarabine. The incidence of major neurologic adverse events for all patients receiving IT chemotherapy was 6.8%. The rate of major events was 9.2% for methotrexate with or without hydrocortisone, 9.1% for cytarabine with or without hydrocortisone, and 5.4% for methotrexate and cytarabine combined with or without hydrocortisone. There was no statistically significant difference in rate of major events when the three drug combinations were compared (p=0.562). The rate of minor neurologic events was 38.3% for all cases of patients receiving IT chemotherapy, 42.4% for methotrexate with or without hydrocortisone, 36.4% for cytarabine with or without hydrocortisone, and 35.5% for methotrexate and cytarabine combined with or without hydrocortisone. There was no statistically significant difference in rate of minor events when comparing the three different drug combinations (p=0.604). The adverse events encountered most frequently were headache (15.9%), nausea (13.6%), vomiting (9.6%), back pain (5.8%), and fever (5.8%). The most frequent major adverse events were asthenia (4.3%) and paresthesia (3.8%).
Discussion and Conclusion:
More than one third of all IT chemotherapy administration events resulted in at least one minor side effect, with roughly 7% resulting in at least one major effect. Headache, nausea, vomiting, back pain, and fever were the most common events encountered-all of which are common sequelae of chemical arachnoiditis.
In the cases of major neurologic events we considered potential contamination of the IT methotrexate. Though never confirmed at our institution, Zeng et. al. (J Clin Oncol, 2011) investigated the development of paraplegia amongst patients who received IT methotrexate, discovering trace amounts of vincristine that contaminated intrathecal drugs produced by a manufacturing plant in China causing a large outbreak of severe neurological damage. Murata et al. (J Med Case Rep, 2015) reported a case of demyelination secondary to myelopathy attributed to an IT methotrexate dose. Outbreaks of severe adverse reactions to IT chemotherapy, especially when temporally related, should prompt suspicion of potential chemotherapy contamination.
It is important for clinicians to be aware of the adverse events described in this study and consider them seriously when treating patients with IT chemotherapy.
* Byrnes D, Dermarkarian C, and Kahn R contributed equally to this work

Disclosures
No relevant conflicts of interest to declare.