Date Published: March 20, 2017
Publisher: Public Library of Science
Author(s): Vesa Kiviniemi, Vesa Korhonen, Jukka Kortelainen, Seppo Rytky, Tuija Keinänen, Timo Tuovinen, Matti Isokangas, Eila Sonkajärvi, Topi Siniluoto, Juha Nikkinen, Seppo Alahuhta, Osmo Tervonen, Taina Turpeenniemi-Hujanen, Teemu Myllylä, Outi Kuittinen, Juha Voipio, Damir Janigro.
Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery.
The blood-brain barrier (BBB) inhibits the penetrance of hydrophilic and polar drugs into brain tissue and hinders effective use of treatments like methotrexate chemotherapy in the otherwise drug sensitive primary central nervous system lymphoma (PCNSL). It was recently shown that PCNSL relapses within 5 years in all subjects and over half of the subjects within 2 years with BONN intra-thecal reservoir treatment combined with multi-drug intravenous treatment and has dismal prognosis in a few months . However, numerous preclinical [2–10] and clinical [1,11–15] studies have shown that transiently disrupting the BBB with hyperosmolar intra-arterial mannitol infusion during chemotherapy holds much promise as a therapeutic intervention for PCNSL  and markedly increases survival . Results obtained using our modified BBB disruption (BBBD) method combined with a high-dose treatment protocol indicate 40-50% survival even in relapsed PCNSL for additional 7 years, and 100% disease free survival for 3 years in first-line cases with the treatment starting with BBBD .
In this study 47 consecutive BBBD treatments were monitored in 9 PCNSL patients (mean age ±SD = 55±16 years, range = 20-68, 5 females). Sixteen of the infusions were introduced into the right internal carotid artery, thirteen into the left internal carotid artery and eighteen into the dominant vertebral artery. Patients were recruited in the study during 2014 and a written informed consent was obtained from each patient prior to the procedure in addition to routine clinical BBBD information. The study was carried out in accordance with the Declaration of Helsinki and approved by the Ethical Committee of Northern Ostrobothnia Hospital District, Oulu University Hospital (number 5/2014).
The results of this study demonstrate for the first time real-time monitoring of human therapeutic BBBD using scalp-recorded DC-EEG. BBBD was induced with intra-arterial mannitol infusion in anesthetized patients receiving chemotherapy for PCNSL. DC-EEG detected robust mV-level shifts providing spatiotemporal information on the course of the induced BBBD. Simultaneously measured NIRS detected dilution of blood upon intra-arterial mannitol infusion followed by marked alteration in oxygen extraction fraction. Since the intact BBB makes the brain parenchyma inaccessible to hydrophilic drugs, new diagnostic and therapeutic innovations involving BBBD may benefit from the methods described here.
Our results demonstrate the feasibility of DC-EEG for real-time monitoring of induced transient BBBD in anesthetized human patients receiving chemotherapy for PCNSL. In addition to providing valuable real-time information on BBBD during PCNSL treatment, our present results and the DC-EEG method may be exploited when devising novel therapeutic strategies involving BBBD-aided pharmacotherapy of brain diseases.