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  • Author or Editor: John A. Butman x
  • By Author: Jagannathan, Jay x
  • By Author: Lonser, Russell R. x
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Jay Jagannathan, Stuart Walbridge, John A. Butman, Edward H. Oldfield and Russell R. Lonser

Object

Convection-enhanced delivery (CED) is increasingly used to investigate new treatments for central nervous system disorders. Although the properties of CED are well established in normal gray and white matter central nervous system structures, the effects on drug distribution imposed by ependymal and pial surfaces are not precisely defined. To determine the effect of these anatomical boundaries on CED, the authors infused low MW and high MW tracers for MR imaging near ependymal (periventricular) and pial (pericisternal) surfaces.

Methods

Five primates underwent CED of Gd-diethylenetriamine pentaacetic acid (Gd-DTPA; MW 590 D) or Gd-bound albumin (Gd-albumin; MW 72,000 D) during serial real-time MR imaging (FLAIR and T1-weighted sequences). Periventricular (caudate) infusions were performed unilaterally in 1 animal (volume of infusion [Vi] 57 μl) and bilaterally in 1 animal with Gd-DTPA (Vi = 40 μl on each side), and bilaterally in 1 animal with Gd-albumin (Vi = 80 μl on each side). Pericisternal infusions were performed in 2 animals with Gd-DTPA (Vi = 190 μl) or with Gd-albumin (Vi = 185 μl) (1 animal each). Clinical effects, MR imaging, and histology were analyzed.

Results

Large regions of the brain and brainstem were perfused with both tracers. Intraparenchymal distribution was successfully tracked in real time by using T1-weighted MR imaging. During infusion, the volume of distribution (Vd) increased linearly (R2 = 0.98) with periventricular (mean Vd/Vi ratio ± standard deviation; 4.5 ± 0.5) and pericisternal (5.2 ± 0.3) Vi, but did so only until the leading edge of distribution reached the ependymal or pial surfaces, respectively. After the infusate reached either surface, the Vd/Vi decreased significantly (ependyma 2.9 ± 0.8, pia mater 3.6 ± 1.0; p < 0.05) and infusate entry into the ventricular or cisternal cerebrospinal fluid (CSF) was identified on FLAIR but not on T1-weighted MR images.

Conclusions

Ependymal and pial boundaries are permeable to small and large molecules delivered interstitially by convection. Once infusate reaches these surfaces, a portion enters the adjacent ventricular or cisternal CSF and the tissue Vd/Vi ratio decreases. Although T1-weighted MR imaging is best for tracking intraparenchymal infusate distribution, FLAIR MR imaging is the most sensitive and accurate for detecting entry of Gd-labeled imaging compounds into CSF during CED.

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Jay Jagannathan, John A. Butman, Russell R. Lonser, Alexander O. Vortmeyer, Christopher K. Zalewski, Carmen Brewer, Edward H. Oldfield and H. Jeffrey Kim

✓ Endolymphatic sac tumors (ELSTs) are locally invasive neoplasms that arise in the posterior petrous bone and are associated with von Hippel–Lindau (VHL) disease. These tumors cause symptoms even when microscopic in size (below the threshold for detectability on imaging studies) and can lead to symptoms such as hearing loss, tinnitus, vertigo, and facial nerve dysfunction. While the mechanisms of audiovestibular dysfunction in patients harboring ELSTs are incompletely understood, they have critical implications for management. The authors present the case of a 33-year-old man with VHL disease and a 10-year history of progressive tinnitus, vertigo, and left-sided hearing loss. Serial T1-weighted magnetic resonance (MR) imaging and computed tomography scans revealed no evidence of tumor, but fluid attenuated inversion recovery (FLAIR) MR imaging sequences obtained after hearing loss demonstrated evidence of left intralabyrinthine hemorrhage. On the basis of progressive disabling audiovestibular dysfunction (tinnitus and vertigo), FLAIR imaging findings, and VHL disease status, the patient underwent surgical exploration of the posterior petrous region, and a small (2-mm) ELST was identified and completely resected. Postoperatively, the patient had improvement of the tinnitus and vertigo. Intralabyrinthine hemorrhage may be an early and the only neuroimaging sign of an ELST in patients with VHL disease and audiovestibular dysfunction. These findings support tumor-associated hemorrhage as a mechanism underlying the audiovestibular dysfunction associated with ELSTs.