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

Restricted access

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.

Article Information

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.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flowchart illustrating the NHP study design. Twelve NHPs (Macaca mulatta) were divided into a toxicity group and a distribution group. Gd-albumin distribution following infusion into the hippocampus was compared with 125I-BoNT/A distribution measured by QAR in the 3 NHPs from the distribution study.

  • View in gallery

    MR images obtained in an NHP that underwent coinfusion of Gd-albumin and 125I-BoNT/A to the right hippocampus. The images are thresholded to demonstrate signal intensity 10% above background intensity. There is gadolinium signal backtracking (white) along the catheter trajectory within the hippocampus with a volume of distribution of 208 mm3, shown in the axial (A), coronal (B), and sagittal (C) planes.

References

  • 1

    Allergan: Botulinum Toxin Type A Prescribing Information. Madison, NJ: Allergan (https://www.allergan.com/assets/pdf/botox_pi.pdf) [Accessed May 29 2019]

    • Search Google Scholar
    • Export Citation
  • 2

    Alvarez-Royo PClower RPZola-Morgan SSquire LR: Stereotaxic lesions of the hippocampus in monkeys: determination of surgical coordinates and analysis of lesions using magnetic resonance imaging. J Neurosci Methods 38:2232321991

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Araque ALi NDoyle RTHaydon PG: SNARE protein-dependent glutamate release from astrocytes. J Neurosci 20:6666732000

  • 4

    Benoliel REliav EMannes AJCaudle RMLeeman SIadarola MJ: Actions of intrathecal diphtheria toxin-substance P fusion protein on models of persistent pain. Pain 79:2432531999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Bobo RHLaske DWAkbasak AMorrison PFDedrick RLOldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:207620801994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Bozzi YCostantin LAntonucci FCaleo M: Action of botulinum neurotoxins in the central nervous system: antiepileptic effects. Neurotox Res 9:1972032006

  • 7

    Brown DCAgnello KIadarola MJ: Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain 156:101810242015

  • 8

    Caleo MRestani L: Exploiting botulinum neurotoxins for the study of brain physiology and pathology. Toxins (Basel) 10:E1752018

  • 9

    Carruthers ACarruthers J: Botulinum toxin type A. J Am Acad Dermatol 53:2842902005

  • 10

    Carruthers ACarruthers J: Toxins 99, new information about the botulinum neurotoxins. Dermatol Surg 26:1741762000

  • 11

    Costantin LBozzi YRichichi CViegi AAntonucci FFunicello M: Antiepileptic effects of botulinum neurotoxin E. J Neurosci 25:194319512005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12

    Davis KANanga RPDas SChen SHHadar PNPollard JR: Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy. Sci Transl Med 7:309ra1612015

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Fisher RSChen DK: New routes for delivery of anti-epileptic medications. Acta Neurol Taiwan 15:2252312006

  • 14

    Gasior MTang RRogawski MA: Long-lasting attenuation of amygdala-kindled seizures after convection-enhanced delivery of botulinum neurotoxins A and B into the amygdala in rats. J Pharmacol Exp Ther 346:5285342013

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15

    Gasior MWhite NARogawski MA: Prolonged attenuation of amygdala-kindled seizure measures in rats by convection-enhanced delivery of the N-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIA. J Pharmacol Exp Ther 323:4584682007

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Hampton RRBuckmaster CAAnuszkiewicz-Lundgren DMurray EA: Method for making selective lesions of the hippocampus in macaque monkeys using NMDA and a longitudinal surgical approach. Hippocampus 14:9182004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Heiss JDArgersinger DPTheodore WHButman JASato SKhan OI: Convection-enhanced delivery of muscimol in patients with drug-resistant epilepsy. Neurosurgery 85:E4E152019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Heiss JDJamshidi AShah SMartin SWolters PLArgersinger DP: Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma. J Neurosurg Pediatr 23:3333422018

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Heiss JDWalbridge SArgersinger DPHong CSRay-Chaudhury ALonser RR: Convection-enhanced delivery of muscimol into the bilateral subthalamic nuclei of nonhuman primates. Neurosurgery 84:E420E4292019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20

    Heiss JDWalbridge SAsthagiri ARLonser RR: Image-guided convection-enhanced delivery of muscimol to the primate brain. J Neurosurg 112:7907952010

  • 21

    Heiss JDWalbridge SMorrison PHampton RRSato SVortmeyer A: Local distribution and toxicity of prolonged hippocampal infusion of muscimol. J Neurosurg 103:103510452005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Jabbari BNey JSichani AMonacci WFoster LDifazio M: Treatment of refractory, chronic low back pain with botulinum neurotoxin A: an open-label, pilot study. Pain Med 7:2602642006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Jagannathan JWalbridge SButman JAOldfield EHLonser RR: Effect of ependymal and pial surfaces on convection-enhanced delivery. J Neurosurg 109:5475522008

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Jäncke LLiem FMerillat S: Scaling of brain compartments to brain size. Neuroreport 30:5735792019

  • 25

    Kawakami KKawakami MKioi MHusain SRPuri RK: Distribution kinetics of targeted cytotoxin in glioma by bolus or convection-enhanced delivery in a murine model. J Neurosurg 101:100410112004

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26

    Kodihalli SEmanuel ATakla THua YHobbs CLeClaire R: Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques. PLoS One 12:e01868922017

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Kokkinos VSisterson NDWozny TARichardson RM: Association of closed-loop brain stimulation neurophysiological features with seizure control among patients with focal epilepsy. JAMA Neurol 76:8008082019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Lonser RRCorthésy MEMorrison PFGogate NOldfield EH: Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates. J Neurosurg 91:2943021999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Lonser RRGogate NMorrison PFWood JDOldfield EH: Direct convective delivery of macromolecules to the spinal cord. J Neurosurg 89:6166221998

  • 30

    Lonser RRWalbridge SGarmestani KButman JAWalters HAVortmeyer AO: Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:9059132002

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Middlebrook JLFranz DR: Botulinum toxins in Sidell FRTakafuji ETFranz DR (eds): Medical Aspects of Chemical and Biological Warfare. Washington, DC: Department of the Army1997 pp 643654

    • Search Google Scholar
    • Export Citation
  • 32

    Morrison PFLaske DWBobo HOldfield EHDedrick RL: High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol 266:R292R3051994

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33

    Morrison PFLonser RROldfield EH: Convective delivery of glial cell line–derived neurotrophic factor in the human putamen. J Neurosurg 107:74832007

  • 34

    Murad GJWalbridge SMorrison PFGarmestani KDegen JWBrechbiel MW: Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to Pseudomonas exotoxin. Clin Cancer Res 12:314531512006

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    National Research Council Institute for Laboratory Animal Research: Guide for the Care and Use of Laboratory Animalsed 7. Washington, DC: National Academies Press1996

    • Search Google Scholar
    • Export Citation
  • 36

    Nguyen TTPannu YSSung CDedrick RLWalbridge SBrechbiel MW: Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 98:5845902003

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Nilsen KECock HR: Focal treatment for refractory epilepsy: hope for the future? Brain Res Brain Res Rev 44:1411532004

  • 38

    Paxinos GHuang XFToga AW: The Rhesus Monkey Brain in Stereotaxic Coordinatesed 1. Cambridge, MA: Academic Press1999

  • 39

    Ramey WLMartirosyan NLLieu CMHasham HALemole GM JrWeinand ME: Current management and surgical outcomes of medically intractable epilepsy. Clin Neurol Neurosurg 115:241124182013

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Sharma SKEblen BSBull RLBurr DHWhiting RC: Evaluation of lateral-flow Clostridium botulinum neurotoxin detection kits for food analysis. Appl Environ Microbiol 71:393539412005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Son EIHoward MAOjemann GALettich E: Comparing the extent of hippocampal removal to the outcome in terms of seizure control. Stereotact Funct Neurosurg 62:2322371994

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Sperling MRFeldman HKinman JLiporace JDO’Connor MJ: Seizure control and mortality in epilepsy. Ann Neurol 46:45501999

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Strickland BARennert RCBakhsheshian JBulic SCorrea AJAmar A: Botulinum toxin to improve vessel graft patency in cerebral revascularization surgery: report of 3 cases. J Neurosurg 130:5665722019

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Suzuki MHagino HNohara SZhou SYKawasaki YTakahashi T: Male-specific volume expansion of the human hippocampus during adolescence. Cereb Cortex 15:1871932005

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45

    Xavier ALRHauglund NLvon Holstein-Rathlou SLi QSanggaard SLou N: Cannula implantation into the cisterna magna of rodents. J Vis Exp (135):573782018

    • Search Google Scholar
    • Export Citation

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 195 195 40
Full Text Views 38 38 6
PDF Downloads 26 26 4
EPUB Downloads 0 0 0

PubMed

Google Scholar