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David I. Sandberg, M. Melissa Peet, Mark D. Johnson, Phaedra Cole, Tulay Koru-Sengul and Ali W. Luqman

Object

The authors hypothesized that chemotherapy infusions directly into the fourth ventricle might potentially play a role in treating malignant fourth ventricular tumors. The study tested the safety and pharmacokinetics of short- and long-term infusions of methotrexate into the fourth ventricle in a new nonhuman primate model.

Methods

Six rhesus monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In Group I (3 animals), catheters were externalized, and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term methotrexate infusions. In 2 animals, methotrexate (0.5 mg) was infused into the fourth ventricle daily for 5 days. Serial CSF and serum methotrexate levels were measured. The third animal had a postoperative neurological deficit, and the experiment was aborted prior to methotrexate administration. In Group II (3 animals), catheters were connected to a subcutaneously placed port for subsequent long-term methotrexate infusions. In 2 animals, 4 cycles of intraventricular methotrexate, each consisting of 4 daily infusions (0.5 mg), were administered over 8 weeks. The third animal received 3 cycles, and then the experiment was terminated due to self-inflicted wound breakdown. All animals underwent detailed neurological evaluations, MRI, and postmortem histological analysis.

Results

No neurological deficits were noted after intraventricular methotrexate infusions. Magnetic resonance images demonstrated catheter placement within the fourth ventricle and no signal changes in the brainstem or cerebellum. Histologically, two Group I animals, one of which did not receive methotrexate, had several small focal areas of brainstem injury. Two Group II animals had a small (≤ 1-mm) focus of axonal degeneration in the midbrain. Intraventricular and meningeal inflammation was noted in 4 animals after methotrexate infusions (one from Group I and all three from Group II). In all Group II animals, inflammation extended minimally into brainstem parenchyma. Serum methotrexate levels were undetectable or negligible in both groups, ranging from 0.00 to 0.06 μmol/L. In Group I, the mean peak methotrexate level in fourth ventricle CSF exceeded that in the lumbar CSF by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC (area under the concentration-time curve) were detected at peaks (p = 0.04) but not at troughs (p = 0.50) or at all time collection points (p = 0.12). In Group II, peak fourth ventricle CSF methotrexate levels ranged from 84.62 to 167.89 μmol/L (mean 115.53 ± 15.95 μmol/L [SD]). Trough levels ranged from 0.06 to 0.55 μmol/L (mean 0.22 ± 0.13 μmol/L).

Conclusions

Methotrexate can be infused into the fourth ventricle in nonhuman primates without clinical or radiographic evidence of injury. Observed inflammatory and other histological changes had no clinical correlate. This approach may have pharmacokinetic advantages over current treatment paradigms. Further experiments are warranted to determine if fourth ventricular chemotherapy infusions may benefit patients with malignant fourth ventricular tumors.

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Bradley Kolb, Hassan Fadel, Gary Rajah, Hamidreza Saber, Ali Luqman and Leonardo Rangel-Castilla

OBJECTIVE

Steno-occlusive diseases of the cerebral vasculature have been associated with cognitive decline. The authors performed a systematic review of the existing literature on intracranial steno-occlusive disease, including intracranial atherosclerosis and moyamoya disease (MMD), to determine the extent and quality of evidence for the effect of revascularization on cognitive performance.

METHODS

A systematic search of PubMed/MEDLINE, the Thomson Reuters Web of Science Core Collection, and the KCI Korean Journal Database was performed to identify randomized controlled trials (RCTs) in the English-language literature and observational studies that compared cognitive outcomes before and after revascularization in patients with steno-occlusive disease of the intracranial vasculature, from which data were extracted and analyzed.

RESULTS

Nine papers were included, consisting of 2 RCTs and 7 observational cohort studies. Results from 2 randomized trials including 142 patients with symptomatic intracranial atherosclerotic steno-occlusion found no additional benefit to revascularization when added to maximal medical therapy. The certainty in the results of these trials was limited by concerns for bias and indirectness. Results from 7 observational trials including 282 patients found some cognitive benefit for revascularization for symptomatic atherosclerotic steno-occlusion and for steno-occlusion related to MMD in children. The certainty of these conclusions was low to very low, due to both inherent limitations in observational studies for inferring causality and concerns for added risk of bias and indirectness in some studies.

CONCLUSIONS

The effects of revascularization on cognitive performance in intracranial steno-occlusive disease remain uncertain due to limitations in existing studies. More well-designed randomized trials and observational studies are needed to determine if revascularization can arrest or reverse cognitive decline in these patients.