Brainstem Infusions Research Articles

Infusion-related side-effects during convection enhanced delivery for brainstem-diffuse midline glioma/diffuse intrinsic pontine glioma

IntroductionSide-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 h.MethodsChildren with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review.Results55 infusions were performed in 8 children (3–11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value > 0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted > 24 h. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094–4.976; p-value = 0.028) and 2.155 (1.029–4.513; p-value = 0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist > 24 h, OR 0.473 (95% CI 0.177–0.948; p-value = 0.037). Most side-effects developed within the first three millilitre of infusion.ConclusionsSide-effects during brainstem infusion are common, can be transient or persist longer than 24 h. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.

Use of a novel ball-joint guide array for magnetic resonance imaging-guided cannula placement and convective delivery: technical note.

The objective of this study was to assess the feasibility, accuracy, effectiveness, and safety of an MRI-compatible frameless stereotactic ball-joint guide array (BJGA) as a platform for cannula placement and convection-enhanced delivery (CED). The authors analyzed the clinical and imaging data from consecutive patients with aromatic l-amino acid decarboxylase (AADC) deficiency who underwent infusion of adeno-associated virus (AAV) containing the AADC gene (AAV2-AADC). Eleven patients (7 females, 4 males) underwent bilateral MRI-guided BJGA cannula placement and CED of AAV2-AADC (22 brainstem infusions). The mean age at infusion was 10.5 ± 5.2 years (range 4-19 years). MRI allowed for accurate real-time planning, confirmed precise cannula placement after single-pass placement, and permitted on-the-fly adjustment. Overall, the mean bilateral depth to the target was 137.0 ± 5.2 mm (range 124.0-145.5 mm). The mean bilateral depth error was 0.9 ± 0.7 mm (range 0-2.2 mm), and the bilateral radial error was 0.9 ± 0.6 mm (range 0.1-2.3 mm). The bilateral absolute tip error was 1.4 ± 0.8 mm (range 0.4-3.0 mm). Target depth and absolute tip error were not correlated (Pearson product-moment correlation coefficient, r = 0.01). Use of the BJGA is feasible, accurate, effective, and safe for cannula placement, infusion MRI monitoring, and cannula adjustment during CED. The low-profile universal applicability of the BJGA streamlines and facilitates MRI-guided CED.

CONVECTION-ENHANCED DELIVERY OF NIMUSTINE HYDROCHLORIDE FOR BRAINSTEM MALIGNANT GLIOMA: CURRENT STUDY AND DEVELOPMENT OF NEW DEVICE

BACKGROUND: Convection-enhanced delivery (CED) is a technique that delivers therapeutic agents directly and effectively into the brain parenchyma. Glioma affecting brainstem is one of the important candidates that could be targeted with CED. In this report, we describe our recent effort to develop novel CED based therapeutic approach for gliomas affecting brainstem. METHODS: Direct local convection-enhanced delivery of nimustine hydrochloride (ACNU) monitored with real-time MRI is our strategy. We are now in clinical trial against recurrent malignant glioma cases affecting brainstem. Pilot feasibility study recruited three patients. Subsequently, until today, we have recruited 7 patients as Phase I trial. On the other hand, we have developed an ultrasound assisted infusion device for brainstem infusion. RESULTS: In the pilot study, CED of ACNU demonstrated an efficacy against a patient suffering recurrent glioblastoma at brainstem. Succeeding phase I study is still ongoing, but so far, CED of ACNU is safe and feasible even against brainstem disease. Although the new device we developed is still in pre-clinical development, improved distribution was achieved using this device. CONCLUSIONS: CED of ACNU can be safely performed with real-time MRI monitoring. This strategy can be a novel therapeutic approach for gliomas affecting brainstem. New ultrasound assisted device achieved improved distribution in animal brain. Clinical application is warranted. SECONDARY CATEGORY: Pediatrics.

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

Coinfused surrogate imaging tracers can provide direct insight into the properties of convection-enhanced delivery (CED) in the nervous system. To better understand the distributive properties of CED in a clinical circumstance, the authors analyzed the imaging findings in pediatric diffuse intrinsic pontine glioma (DIPG) patients undergoing coinfusion of Gd-DTPA and interleukin-13-Pseudomonas exotoxin (IL13-PE). Consecutive patients undergoing CED (maximal rates of 5 or 10 μl/minute) of Gd-DTPA (1 or 5 mM) and IL13-PE (0.125 μg/ml or 0.25 μg/ml) for DIPG were included. Real-time MRI was performed during infusions, and imaging results were analyzed. Four patients (2 males, 2 females; mean age at initial infusion 13.0 ± 5.3 years; range 5-17 years) underwent 5 infusions into DIPGs. Brainstem infusions were clearly identified on T1-weighted MR images at 1-mM (1 infusion) and 5-mM (4 infusions) coinfused Gd-DTPA concentrations. While the volume of distribution (Vd) increased progressively with volume of infusion (Vi) (mean volume 2.5 ± 0.9 ml; range 1.1-3.7 ml), final Vd:Vi ratios were significantly reduced with lower Gd-DTPA concentration (Vd:Vi for 1 mM of 1.6 compared with a mean Vd:Vi ratio for 5 mM of 3.3 ± 1.0) (p = 0.04). Similarly, anatomical distribution patterns were affected by preferential flow along parallel axial fiber tracts, into prior infusion cannula tracts and intraparenchymal air pockets, and leak back around the infusion cannula at the highest rate of infusion. Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. Part of clinical trial no. NCT00880061 ( ClinicalTrials.gov ).

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Gene replacement therapy for the neurological deficits caused by lysosomal storage disorders, such as in Niemann-Pick disease type A, will require widespread expression of efficacious levels of acid sphingomyelinase (ASM) in the infant human brain. At present there is no treatment available for this devastating pediatric condition. This is partly because of inherent constraints associated with the efficient delivery of therapeutic agents into the CNS of higher order models. In this study we used an adeno-associated virus type 2 (AAV2) vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA) to transduce highly interconnected CNS regions such as the brainstem and thalamus. On the basis of our data showing global cortical expression of a secreted reporter after thalamic delivery in nonhuman primates (NHPs), we set out to investigate whether such widespread expression could be enhanced after brainstem infusion. To maximize delivery of the therapeutic transgene throughout the CNS, we combined a single brainstem infusion with bilateral thalamic infusions in naive NHPs. We found that enzymatic augmentation in brainstem, thalamic, cortical, as well subcortical areas provided convincing evidence that much of the large NHP brain can be transduced with as few as three injection sites.

Ototoxicity of Carboplatin Delivered Locally in a Monkey Brainstem

Ototoxicity is a common side effect of platinum-based chemotherapy. Intratumoral drug delivery theoretically could reduce the ototoxic effects of systemic drug infusions. However, local delivery to central nervous system (CNS) tumors might promote ototoxicity through drug release into cerebrospinal fluid (CSF). This report describes an examination of the cytoarchitecture of vestibular cells of cynomolgus monkeys that had chronic brainstem infusions with the maximum tolerated dose (MTD) of carboplatin. The brainstems of adult monkeys were infused for 30 days at 0.42 mu l/h with 0.025 to 0.25 mg/kg (MTD) of carboplatin. The vestibular sensory epithelia of eight drug-treated animals were isolated for microscopic examination of vestibular hair cells and support cells. Local infusions produced chronic elevated CSF levels of platinum, neurological symptoms, and radiographic evidence of pontine injury. Histology revealed significant cell damage at the infusion sites. Microscopic examinations of vestibular support cells and hair cells demonstrate a small reduction in cell counts in the drug-treated monkeys compared to a noninfused control animal. Parametric and nonparametric tests show no effect of dose in predicting the vestibular cell counts. In this single study of eight monkeys, a dose-dependent reduction of vestibular hair cells or support cells was not observed in animals infused with brainstem infusions of 0.025 to 0.25 mg/kg of carboplatin.

Long-term Effects of Carboplatin Brainstem Infusions on Hearing Thresholds in Monkeys

To isolate the central auditory neurotoxicity of carboplatin from its well-established ototoxic effects. The "best-case scenario" of targeted drug delivery to brain cancer was simulated by infusing carboplatin directly into the brainstem of cynomolgus monkeys with chronically implanted catheters. Because this manner of drug administration produced low levels of carboplatin in spinal fluid and blood, it was assumed that resulting deficits were dictated by the central auditory neurotoxicity of platinum compounds and not peripheral ototoxic effects. The magnitude of this hearing loss was estimated by comparing the auditory brainstem response thresholds of treated monkeys with results from normal controls. Six adult male cynomolgus monkeys (Macaca fascicularis) weighing 4 to 6 kg (3 received carboplatin treatment and 3 served as normal controls). Brainstem infusions of carboplatin. The average threshold of carboplatin-treated monkeys was elevated 8.8 dB (SD = 7.3 dB) relative to normal controls 6 months after the termination of drug delivery and increased to 10.7 dB with less variation between subjects (SD = 5.6 dB) 1 year after drug treatment. Although small in magnitude, the hearing loss was statistically significant (P<.05). Brainstem infusions of carboplatin induced some degree of hearing impairment in all treated monkeys. These threshold elevations were modest compared with the ototoxic effects that have been reported after systemic doses of carboplatin. Our findings suggest that the neurotoxic sensitivity of cochlear hair cells is not shared by neurons in the central auditory pathways. As a result, methods for reducing the ototoxic effects of chemotherapy remain a viable strategy for preserving auditory function in patients with brain cancer.

Prolonged Convection-enhanced Delivery into the Rat Brainstem

Prolonged convection-enhanced delivery was used in an attempt to achieve large volumes of distribution (V(d)) in the rat brainstem. Clinical assessment and histological analysis were performed to establish the safety of this approach. For evaluation of V(d,), 10 rats underwent stereotactic cannula placement into the brainstem. Five rats underwent a 24-hour infusion (volume of infusion [V(i)], 200 microl), and 5 rats underwent a 7-day infusion (V(i), 2 ml) of fluorescein isothiocyanate-dextran. Serial brainstem sections were imaged with ultraviolet illumination, and V(d) was assessed. For assessment of clinical tolerance, 30 additional rats underwent chronic infusions of an isotonic saline solution into the brainstem. Serial neurological examinations were performed, followed by histological analysis after the animals' death. No animal demonstrated clinically recognized neurological deficits. Foci of organizing necrosis were limited to the site of infusion and cannula tract. V(d) increased linearly with increasing V(i) (range, 24.8-130.6 mm(3)). Maximal cross sectional area of fluorescence and craniocaudal extent of fluorescence increased with increasing V(i). Fluorescence was detected throughout the entire brainstem beyond the compact area of highly concentrated tracer. Prolonged convection-enhanced delivery can be applied safely in the rat brainstem with no recognized limitations of V(d) and minimal histological changes beyond the site of infusion. Chronic brainstem infusions may enhance the potential application of convection-enhanced delivery for therapeutic purposes in treating diffuse pontine gliomas.

Avian locomotion activated by brainstem infusion of neurotransmitter agonists and antagonists. II. gamma-Aminobutyric acid.

The companion article (Sholomenko et al. 1991) described the brainstem locomoter regions in the bird where direct intracerebral injection of a number of putative excitatory neurochemicals, including cholinergic agonists, N-methyl-d-aspartate (NMDA) and Substance P, evoke locomotion. Using the same experimental protocol, this study focuses on the locomotor effects following discrete brainstem injections of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and some of GABA agonists and antagonists. Brainstem regions that were electrically and chemically stimulated included the ventromedial medullary reticular formation, the pontobulbar locomotor strip of the dorsolateral pons and medulla, the pontine reticular formation, and the mesencephalic reticular formation. Locomotion was evoked after the injection of the GABA antagonists picrotoxin (a GABAA receptor antagonist) and bicuculline (GABAA antagonist) into several brainstem locomoter regions. Brainstem stimulated locomotion (both chemically and electrically induced) could be transiently blocked by intracerebral infusion of GABA and irreversibly blocked by muscimol (GABAA agonist). Our avian results are similar to those described for mammals and provide support for the suggestion that motor circuitry, at least at brainstem levels, is similar in all vertebrates.

Avian locomotion activated by brainstem infusion of neurotransmitter agonists and antagonists

Previous studies have demonstrated that focal electrical stimulation of regions within the brainstem of a decerebrate bird will elicit all the normal patterns of avian locomotion. However, electrical stimulation can activate a variety of neuronal elements within the radius of effective current spread, including axons of passage traversing the stimulation point. To restrict activation to neuronal cell bodies within the immediate vicinity, we have utilized direct intracerebral injection of neurotransmitters, their agonists and antagonists, into identified brainstem locomotor regions. To undertake these studies, birds (geese or ducks) were placed in a stereotaxic frame and decerebrated under halothane anesthesia. After completion of surgery, several discrete locomotor regions were first identified with electrical microstimulation. Acetylcholine (ACh) and excitatory amino acid (EAA) agonists and antagonists, as well as Substance P were then slowly infused into each brainstem region. Any change in locomotor behavior was recorded by electromyographic techniques. When injected into a variety of sites, carbachol (an ACh nicotinic (AChN) and muscarinic (AChM) agonist) and pilocarpine (an AChM agonist) evoked locomotion, whereas atropine (an AChM antagonist) blocked locomotion. N-methyl-D-aspartate NMDA), but not glutamate, also elicited locomotion or reduced the current intensity threshold for electrically-evoked locomotion. The NMDA-induced locomotion evoked locomotion. The NMDA-induced locomotion could be blocked by the injection of glutamic acid diethyl ester (GDEE, an EAA antagonist) or D-2-amino-5-phosphonopentanoic acid (AP5) into the same site. Finally. Substance P also evoked locomotion. The above observations strongly suggest that brainstem electrically-stimulated locomotion in decerebrate birds is not due to activation of fibers traversing a brainstem locomotor region, but instead, is due to the activation of receptors located on neuronal cell bodies, dendrites or presynaptic terminals in the immediate vicinity of the micropipette tip. After correlating our findings with similar lamprey and mammalian studies, the comparable discoveries serve to underscore the suggestion that the neuroanatomical substrates underlying the brainstem control of locomotion appear to be highly conserved in all vertebrates.

Brain stem infusion of the gamma-aminobutyric acid antagonist bicuculline increases plasma insulin levels in the rat.

Previous neuroanatomical and physiological studies have indicated that nucleus ambiguus (Amb) is one source of vagal motoneurons in the brain stem that innervates the pancreas and which, when stimulated, increases insulin release. To investigate one of the neurotransmitter inputs to Amb neurons and its relation to insulin secretion, bicuculline, a specific gamma-aminobutyric acid (GABA) antagonist, was infused bilaterally into the Amb region as well as into a neighboring area, the rostral level of the lateral nucleus tractus solitarius (nts) of anesthetized male rats. Experiments were carried out in the presence or absence of the alpha-adrenergic blocker phentolamine. In the absence of phentolamine, no increases in plasma insulin levels were seen after bicuculline or vehicle infusion into the Amb region or after bicuculline infusion into the nts, while plasma glucose levels were significantly increased. In the presence of phentolamine, bicuculline infusion into the Amb region led to a prompt and significant increase in plasma insulin levels that could not be accounted for by changes in glycemia. The infusion of vehicle into Amb or of bicuculline into nts produced small or insignificant increases in plasma insulin levels. These results suggest that Amb neurons capable of modulating plasma insulin levels are under tonic GABA inhibition, an effect that appears to be specific for Amb neurons, since bicuculline infusion into another brain stem nucleus (nts) had no effect on insulin release. The fact that phentolamine pretreatment was necessary to reveal the bicuculline-induced effects corroborates previous studies showing that in addition to a central nervous system inhibition of vagal motoneurons by GABA, there is a tonic sympathetic inhibitory input to the endocrine pancreas capable of masking any disinhibition of vagal motoneurons. The physiological role of GABA inhibition of Amb neurons that innervate the pancreatic beta-cells remains to be determined.