Convection-enhanced selective excitotoxic ablation of the neurons of the globus pallidus internus for treatment of parkinsonism in nonhuman primates.

OBJECT: Selective treatment of central nervous system (CNS) structures holds therapeutic promise for many neurological disorders, including Parkinson's disease (PD). The ability to inhibit or augment specific neuronal populations within the CNS reliably by using present therapeutic techniques is limited. To overcome this problem, the authors modeled and developed a method in which convection was used to deliver compounds to deep brain nuclei in a reproducible, homogeneous, and targeted manner. To determine the feasibility and clinical efficacy of convective drug delivery for treatment of a neurological disorder, the investigators selectively ablated globus pallidus internus (GPi) neurons with quinolinic acid (QA), an excitotoxin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model of primate parkinsonism. METHODS: After the parameters of convective distribution to the GPi were confirmed by infusion of biotinylated albumin into the GPi of a primate (Macaca mulatta), seven adult monkeys of this species were rendered either fully parkinsonian by intravenous injections of MPTP (five animals) or hemiparkinsonian by a right-sided intracarotid injection of this agent (two monkeys). Using convection-enhanced delivery to the GPi, animals were infused with either QA (three fully parkinsonian, two hemiparkinsonian) or saline (two fully parkinsonian). The three fully parkinsonian animals that underwent GPi lesioning with QA had substantial improvement of PD symptoms, manifested by a marked increase in activity (34 +/- 2.5%; mean +/- standard deviation) and dramatic improvement of parkinsonian clinical scores. In contrast, the control animals did not improve (activity monitor change = -1.5 +/- 0.5%). The two hemiparkinsonian animals that underwent QA lesioning of the GPi had dramatic recovery of extremity use. Histological examination revealed selective neural ablation of GPi neurons (mean loss 87%) with sparing of surrounding gray and white matter structures. No animal developed worsening signs of PD or neurological deficits after infusion. CONCLUSIONS: Convection-enhanced delivery of QA permits selective, region-specific (GPi), and safe lesioning of neuronal subpopulations, resulting in dramatic improvement in parkinsonian symptomatology. The properties of convection-enhanced delivery indicate that this method could be used for chemical neurosurgery for medically refractory PD and that it may be ideal for cell-specific therapeutic ablation or trophic treatment of other targeted structures associated with CNS disorders.

Partial denervation of the whiskerpad in adult mice: altered patterns of metabolic activity in barrel cortex.

One hundred days after unilateral C-row nerve transection in the adult mouse whiskerpad, the caudal follicles of row C are reinnervated with approximately 80 % of the original number of axons [Corthésy, M.-E., Bronchti, G. & Welker, E. (1999) Eur. J. Neurosci. , 11, 2835-2846]. To what extent is this reinnervation functional, and how does it interact with the enlargement of the functional representation of neighbouring rows subsequent to the denervation? Using the autoradiographic deoxyglucose method, we studied the whisker representation at the level of the barrel cortex 100 days post lesionem. We stimulated whiskers belonging to the denervated row C, the neighbouring rows B and D, or to all five rows A-E. The deoxyglucose uptake was measured in tangential sections through layer IV. The results indicate that, 100 days post lesionem, whiskers of row C reactivate their cortical barrels. However, (i) the magnitude of this cortical response was reduced; (ii) row C barrels were equivalently activated by the stimulation of the neighbouring rows; and (iii) when all whiskers were stimulated, we observed a significantly reduced deoxyglucose uptake over the representation of nonlesioned whiskers of rows D and E. Therefore, 100 days after the peripheral nerve lesion the reinnervation of the whiskerpad had not restored a normal pattern of activation at the level of the barrel cortex. We propose that this is due to a modified interaction between the representations of the various rows of follicles at the cortical level that does not return to normal.

Partial denervation of the whiskerpad in adult mice: pattern and origin of reinnervation.

We studied sensory organ reinnervation after nerve transection in the mouse whisker-to-barrel pathway. In one set of adult mice, we determined at light microscopy level the number of fibres reaching the caudal whisker follicles 5, 15, 20, 60, 100 days and 1 year after transection of the sensory nerve of row C. Regenerated fibres were first detected 15 days post lesionem (p.l.) and myelin first observed at 20 days. Between 60 and 100 days, the number of fibres stayed at approximately 80% of the values obtained in control animals. At that time, myelinated fibres reached only 58% of their number in controls. At the electron microscopy level, these fibres differ from control ones by a smaller fibre diameter. The innervation of follicles of adjacent rows was not modified, indicating that follicular reinnervation is row specific. We checked this feature by injecting in another set of mice the denervated follicles and the adjacent ones with distinct retrograde tracers 45 days and 1 year after nerve transection. The percentage of double-labelled neurons in the Gasserian ganglion did not increase in experimental animals. This confirms the absence of colonization of intact follicles by regenerating fibres and indicates that reinnervation of the whisker follicles takes place by regeneration of the degenerated axons without collateral reinnervation. The companion paper describes the pattern of activation of the barrel cortex relative to the present findings.

Reversal of experimental parkinsonism by using selective chemical ablation of the medial globus pallidus.

OBJECT: Symptoms from Parkinson's disease improve after surgical ablation of the medial globus pallidus (GPm). Although, in theory, selective chemical ablation of neurons in the GPm could preserve vital structures jeopardized by surgery, the potential of this approach is limited when using traditional techniques of drug delivery. The authors examined the feasibility of convection-enhanced distribution of a neurotoxin by high-flow microinfusion to ablate the neurons of the GPm selectively and reverse experimental Parkinson's disease (akinesia, tremor, and rigidity). METHODS: Initially, to test the feasibility of this approach, the GPms of two naive rhesus macaques were infused with kainic acid or ibotenic acid through two cannulas that had been placed using the magnetic resonance imaging-guided stereotactic technique. Two weeks later the animals were killed and their brains were examined histologically to determine the presence of neurons in the GPm and the integrity of the optic tract and the internal capsule. To examine the therapeutic potential of this paradigm, unilateral experimental Parkinson's disease was induced in six macaques by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and their behavior was studied for 12 weeks after chemopallidotomy was performed using kainic acid (three animals) or control infusion (three animals). CONCLUSIONS: Chemopallidotomy using kainic acid permanently reversed the stigmata of MPTP-induced parkinsonism. By contrast, the control animals exhibited a transient recovery following intrapallidal infusion and then relapsed back to their baseline state. The use of high-flow microinfusion of selectively active toxins has the potential for treatment of Parkinson's disease and, by expanding the range of approachable targets to include large nuclei, for broad applications in clinical and experimental neuroscience.

Pulmonary sequestration: a review of 26 cases.

OBJECTIVES: Pulmonary sequestration is a continuum of lung anomalies for which no single embryonic hypothesis is yet available. The aim of this study was to assess the diagnostic tools and treatment for the rare condition, pulmonary sequestration, in an unspecialised centre. METHODS: We performed an analysis of 26 cases of pulmonary sequestration (paediatric and adult) operated at the Centre Hospitalier Universitaire Vaudois between May 1959 and May 1997. A review of the extralobar and intralobar types of sequestrations is discussed. Angiography is compared to other diagnostic tools in this condition, and treatment is discussed. RESULTS: Twenty-six cases of pulmonary sequestrations, a rare congenital pulmonary malformation, were operated on in the defined time period. Seventy-three percent (19) of the cases were intralobar and 27% (seven) extralobar. Extralobar localisation was basal in 71% and situated between the upper and the lower lobe in 29%. In six cases, the diagnosis was made by exploratory thoracotomy. In the other 20 cases, diagnosis was evoked on chest X-ray and confirmed by angiography. Lobectomy (46%) was the most common treatment procedure. Segmental resection was performed in 30% of the cases and bilobectomy in 4%. Post-operative morbidity was low. The most significant complications were pleural empyema, haemothorax and haemopneumoperitoneum in case of extralobar sequestration. There was no evidence of metaplasia or pre-neoplastic changes. CONCLUSIONS: Despite its rarity, some radiological features are sufficiently suggestive of diagnosis of pulmonary sequestration. Investigations are necessary in order to avoid unexpected pathology at the time of operation. Resection of the involved lung leads to excellent results and the long-term outcome is highly favourable.

Chronic interstitial infusion of protein to primate brain: determination of drug distribution and clearance with single-photon emission computerized tomography imaging.

High-flow interstitial infusion into the brain, which uses bulk fluid flow to achieve a relatively homogeneous drug distribution in the extracellular space of the brain, has the potential to perfuse large volumes of brain. The authors report reproducible long-term delivery of 111In-diethylenetriamine pentaacetic acid-apotransferrin (111In-DTPA-Tf) (molecular mass 81 kD) to Macaca mulatta brain and monitoring with single-photon emission computerized tomography (SPECT). The 111In-DTPA-Tf was infused at 1.9 microl/minute over 87 hours into the frontal portion of the centrum semiovale using a telemetry-controlled, fully implanted pump. On Days 1, 3, 4, 8, 11, and 15 after beginning the infusion, planar and SPECT scans of 111In-DTPA-Tf were obtained. Spread of protein in the brain ranged from 2 to 3 cm and infusion volumes ranged from 3.9 to 6.7 cm3. Perfusion of over one-third of the white matter of the infused hemisphere was achieved. From brain SPECT images of (99m)Tc-hexamethylpropyleneamine oxime, which was administered intravenously before each 111In scan, the authors also found that blood perfusion in the infused region was reduced by less than 5% relative to corresponding noninfused regions. Histological examination at 30 days revealed only mild gliosis limited to the area immediately surrounding the needle tract. These findings indicate that long-term interstitial brain infusion is effective for the delivery of drugs on a multicentimeter scale in the primate brain. The results also indicate that it should be possible to perfuse targeted regions of the brain for extended intervals to investigate the potential utility of neurotrophic factors, antitumor agents, and other materials for the treatment of central nervous system disorders.