Convection-enhanced delivery of botulinum toxin serotype A into the nonhuman primate cisterna magna and hippocampus

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  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;
  • 2 Neurological & Spinal Surgery, The Iowa Clinic, Des Moines, Iowa;
  • 3 Department of Pathology, Indiana University Health Pathology Laboratory, Indianapolis, Indiana;
  • 4 Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and
  • 5 Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland
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OBJECTIVE

Botulinum toxin serotype A (BoNT/A) was reported to raise the seizure threshold when injected into the seizure focus of a kindled rodent model. Delivering BoNT/A to the nonhuman primate (NHP) central nervous system via convection-enhanced delivery (CED) has not been performed. The objective of this study was to determine the toxicity and distribution characteristics of CED of BoNT/A into the NHP hippocampus and cisterna magna.

METHODS

Escalating BoNT/A doses were delivered by CED into the NHP hippocampus (n = 4) and cisterna magna (n = 5) for behavioral and histological assessment and to determine the highest nonlethal dose (LD0) and median lethal dose (LD50). Hippocampal BoNT/A was coinfused with Gd-albumin, a surrogate MRI tracer. Gd-albumin and radioiodinated BoNT/A (125I-BoNT/A) were coinfused into the hippocampus of 3 additional NHPs to determine BoNT/A distribution by in vivo MRI and postmortem quantitative autoradiography. Scintillation counting of CSF assessed the flow of 125I-BoNT/A from the hippocampus to CSF postinfusion.

RESULTS

LD0 and LD50 were 4.2 and 18 ng/kg, and 5 and > 5 ng/kg for the NHP hippocampus and cisterna magna, respectively. Gd-albumin and 125I-BoNT/A completely perfused the hippocampus (155–234 mm3) in 4 of 7 NHPs. Fifteen percent of BoNT/A entered CSF after hippocampal infusion. The MRI distribution volume of coinfused Gd-albumin (VdMRI) was similar to the quantitative autoradiography distribution of 125I-BoNT/A (VdQAR) (mean VdMRI = 139.5 mm3 [n = 7]; VdQAR = 134.8 mm3 [n = 3]; r = 1.00, p < 0.0001). No infusion-related toxicity was identified histologically except that directly attributable to needle placement.

CONCLUSIONS

Gd-albumin accurately tracked BoNT/A distribution on MRI. BoNT/A did not produce CNS toxicity. BoNT/A LD0 exceeded 10-fold the dose administered safely to humans for cosmesis and dystonia.

ABBREVIATIONS BoNT/A = botulinum neurotoxin serotype A; CED = convection-enhanced delivery; DRE = drug-resistant epilepsy; LD0 = nonlethal dose; LD50 = median lethal dose; NHP = nonhuman primate; QAR = quantitative autoradiography; VdMRI = distribution volume on MRI; VdQAR = distribution volume on QAR.

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Contributor Notes

Correspondence John D. Heiss: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. heissj@ninds.nih.gov.

INCLUDE WHEN CITING Published online July 19, 2019; DOI: 10.3171/2019.4.JNS19744.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

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