Drug/Chemical Infusions

Drug infusion therapy directly into the central nervous system (CNS) is an attractive treatment modality in movement disorder patients with advanced disease. In PD, for example, the effectiveness of oral L-dopa therapy is limited due to its relatively short half-life, and the pulsatile stimulation of dopaminergic neurons can cause significant motor fluctuations and dyskinesias.³ Focal infusion of therapy to the area of dysfunction, however, could help achieve more constant striatal dopaminergic stimulation, and more closely mimic the body’s normal physiologic state.

The first demonstration of the effectiveness of focal infusion of medications within the brain parenchyma was conducted in PD patients, who were tested prior to stereotactic lesioning or electrode placement. These patients were infused with small-volume, low-dose muscimol, a GABA-A agonist, into the globus pallidus just prior to pallidotomy,⁴ and they displayed a rapid onset of improvement in finger motor speed, reduced extremity tone, and decreased muscle fatigue, which all returned to baseline slowly after approximately 30 minutes. Following subsequent pallidotomy, the patients displayed a similar improvement in motor symptoms. In addition, studies in MPTP-treated nonhuman primates have demonstrated that local inactivation of neurons in the subthalamic nucleus results in an improvement in parkinsonian symptoms.^5–7 These observations prompted intraoperative exploration of microinjections of either lidocaine, an anesthetic that selectively blocks axonal sodium channels, or muscimol into the STN of six PD patients to study the effects of local STN inactivation. This resulted in transient improvement in akinesia, rigidity, and limb tremor in patients with PD. Electrophysiologic recordings were also performed, which confirmed inhibition of electrical activity in the nucleus following drug infusion as it spread from the injection site to more distant tissue.

Although muscimol microinjection and electrical stimulation by STN deep brain stimulation (DBS) have the same effects on PD motor symptoms, their mechanisms of action are quite different. The precise mechanism of action of electrical stimulation on symptomatic improvement in movement disorders is still unclear, there is support for one or more functions, including excitation of neighboring axons, activation of recurrent inhibitory circuits, and direct inhibition of neuronal firing.⁸ As opposed to these more indirect mechanisms, muscimol acts by specifically activating chloride-dependent GABA-A receptors and thereby inhibiting neurons presynaptically. It is still unknown whether continuous infusion of muscimol is superior to stimulation, since the specificity of action provides opportunities for more direct conclusions regarding the relationship between neurotransmitter receptor action and symptomatic improvements, but there may as yet be unknown benefits of some more nonspecific or broader actions of electrical stimulation. In addition, a crucial question that must still be answered is whether patients will develop tolerance to the drug with time. In animals, one unpublished study has demonstrated that parkinsonian rats with unilateral 6OHDA lesions show sustained effects when muscimol is administered by an implanted osmotic pump for 2 weeks,⁹ but longer-term consequences remain to be seen. However, it is clear to every practitioner of DBS that some patients can have adverse effects due to spread of electrical stimulation outside the STN or to nonmotor areas of the STN despite proper electrode location, and this could be less problematic with a biologically specific therapy such as muscimol infusion. The development of appropriate technology for chronic infusions into brain parenchyma, which have yet to be fully developed, would help facilitate development and ultimate determination of the value of continuous muscimol infusion into basal ganglia targets as a therapy.

In addition, patients with essential tremor (ET) have also been studied through a local drug infusion modality, and one study demonstrated the cessation of tremor in patients microinjected with muscimol into the ventralis intermedius thalamus (Vim).¹⁰ In this study, six ET patients undergoing unilateral stereotactic thalamic procedures for relief of tremor refractory to medications were given either saline and/or muscimol intracerebral microinjections prior to thalamotomy or thalamic DBS electrode placement. The patients displayed suppression of tremor for an average of 9 minutes, following a mean latency of 9 minutes to allow for sufficient drug diffusion to influence enough neurons for a therapeutic effect. This not only provides further support for the belief that inhibition of Vim and STN activity can improve symptoms of ET and PD, respectively, but this presents another opportunity for application of direct intraparenchymal drug infusion for a second movement disorder, should technology permit further development of this therapy.

In addition to the therapeutic benefit of local microinjection of drugs such as lidocaine or muscimol, selective infusion of dopamine or dopaminergic medications into the basal ganglia has also been considered, in order to bypass the systemic side effects seen with conventional oral intake of these medications. Chronic intraventricular or intrastriatal dopamine infusions was investigated in 6-OHDA lesioned rats, which demonstrated improvement in motor symptoms following 7 days of continuous dopamine infusion compared to controls.¹¹ However, local examination of the striatum adjacent to the point of intrastriatal dopamine infusion revealed a barrier, which limited diffusion of medication to only 1 to 2 mm from the catheter. In an effort to increase the size of the perfused region, convection techniques have been attempted that move both fluid and drug into the extracellular space by bulk flow driven by a pressure gradient (Fig. 117-1).^12–14 The data are still rather limited, and ideal flow rates, catheter diameter, and infusion volume have not yet been determined.¹⁵

FIGURE 117-1 Convection-enhanced delivery of drug.

Other techniques that may allow for efficient delivery and monitoring of drug infusions locally within the brain include microdialysis and voltammetry (Table 117-1). Cerebral microdialysis is a modality that allows measurement of the concentration of extracellular neurochemicals within cerebral structures, locally and in vivo. Initially conducted in 1966 by using a dialysis membrane filled with dextran solution into canine cortex, with measurement of local amino acid concentrations,¹⁶ this method has also been applied to PD patients.¹⁷ Currently, cerebral microdialysis consists of a double-lumen probe containing an inlet and an outlet port, surrounded by a semipermeable membrane, and sealed above and below a point at which the two tubes are inserted into the membrane lumen. This dialysis probe can be inserted through a burr hole to a preset depth through the brain parenchyma, allowing for perfusion of solutions through the inlet port as well as analysis of the returning solution for extracellular molecule concentrations with techniques such as high-performance liquid chromatography with electrochemical detection (HPLC EC). HPLC EC provides high sensitivity and specificity for the measurement of molecules, such as biogenic amine, including noradrenaline, dopamine, and serotonin, as well as for amino acids, including glutamate, aspartate, and GABA.^18–20

Table 117-1 Drug or Chemical Infusion Modalities

Some limitations of microdialysis, however, include invasiveness, reports of complications in the literature, dependence of accuracy on factors such as flow rate and probe size, and a local fibrotic reaction to the probe tip seen during chronic microdialysis experiments.^19,21 In addition, the neurochemicals sampled during microdialysis are not only those released synaptically, but also include neurochemicals of local metabolism, capillary delivery, and neuronal release and uptake from groups of cells.^22,23 Despite these limitations, microdialysis has been used successfully in human patients, ranging from traumatic brain injury and subarachnoid hemorrhage to movement disorders and epilepsy.^18,22 In movement disorders, particularly PD, there have been published studies such as one demonstrating the changes in concentrations of GABA, cGMP, and glutamate before, during, and after 1 hour in the internal globus pallidus, anteroventral thalamus, and putamen of six patients with refractory PD undergoing DBS in the STN.^24,25 In addition, an in vivo microdialysis method was developed permitting the continuous, chronic sampling of local neurotransmitter concentrations in the STN and substantia nigra pars reticulata (SNr) of patients for several days after placement of STN DBS electrodes.²⁶ All six patients in this study had no complications, and the microdialysis probes were successfully removed without disrupting the DBS electrode location. In theory, microdialysis use may be extended to monitoring levels of a particular neurotransmitter in the region where the probe is implanted, which could then be attached to a pump that would administer a drug or chemical in response to a certain level, allowing for achievement of steady-state levels of that neurotransmitter. Microdialysis has in fact been used to monitor systemic drug levels and to infuse agents into the brain in epilepsy patients, and this could easily be extended to movement disorders if improved technology permitted chronic use of these devices.^27–29

In addition to microdialysis, voltammetry is another method that can detect changes in the concentration of certain neurotransmitters, and allows for excellent temporal and spatial resolution of their release in real-time.^30,31 Voltammetry is based on the principle that oxidation of certain chemicals leads to the release of electrons, and the resultant current can be measured with an electrode.³² Furthermore, a dialysis electrode was developed that combined microdialysis with voltammetry to measure glutamate,³³ which specifically contained a dialysis probe with an electrochemical detection system utilizing the enzyme glutamate oxidase to detect glutamate levels. Other systems have been designed that measure the concentrations of molecules such as glucose and oxygen.^34,35 Most applications have currently been in animal models, including the construction of a micromanipulator in rats that allowed for both infusion of drugs and voltammetry in freely moving rats³⁶ and mostly studied in tumors, cerebral ischemia, and traumatic brain injury. However, the application of voltammetry has also been extended to the measurement of dopamine in both rats and nonhuman primates. Voltammetry has been used to measure extracellular dopamine concentration changes in rats, such as during certain behaviors or in response to cocaine administration in the nucleus accumbens.³⁷ In regard to movement disorders, there was a recent study using carbon fiber voltammetry to measure the release of dopamine in MPTP-induced dopaminergic lesions in nonhuman primates.³⁸ In addition to its utilization in probing drug effects on dopamine release and uptake, there may also future applications of voltammetry to measuring dopamine release in patients, with tailored therapeutic release of medication by external or internal means in response to certain changes in levels. Although microdialysis can sample any neurotransmitter which can diffuse across the dialysis membrane, voltammetry is currently limited to monitoring a select population of neurotransmitters due to technical constraints of the voltammetry methodology to measure transmitter oxidation. However, because it does not involve a membrane or a tube, physical blockade of fluid diffusion due to luminal obstruction is not a concern and oxidation could be more easily measured by an implanted electrical device compared with chemical analysis of dialysate fluids. Therefore, voltammetry could represent an attractive prospect for long-term monitoring of brain neurotransmission as a component of a dynamic feedback mechanism to tailor intraparenchymal drug delivery to specific patient needs.

Growth Factors/Recombinant Proteins

As an alternative to infusion of drugs into the CNS for the treatment of movement disorders, another potential strategy employs the infusion of growth factors or recombinant proteins. Since the central feature of patients with PD is the loss of dopaminergic neurons in the substantia nigra, researcher proposed the idea of administrating neurotrophic factors to degenerating neurons in order to promote their survival. Specifically, the leading candidate neurotrophic factor was glial cell–line derived neurotrophic factor (GDNF), discovered in 1993³⁹ and shown to enhance the survival of dopaminergic neurons in vitro.⁴⁰ In animal models, the goal of GDNF was to prevent further neuronal loss while encouraging reinnervation of the striatum from any surviving, intact terminal within the striatum. Since GDNF is a 134–amino acid peptide, it does not efficiently cross the blood brain barrier, and thus it must be delivery locally into the CNS either by administration into the ventricular system or directly into the brain parenchyma. In preclinical studies with both 6-OHDA- and MPTP-lesioned animal models, GDNF was delivered using both approaches into the CNS, and it indeed did show some benefit.^41–43

Eventually, infusion of a recombinant form of GDNF was administered in human clinical trials (Table 117-2). Initially, 50 patients with moderately advanced PD were treated with intraventricular GDNF; however, the infusion trial was stopped early due to excessive complications from toxicity to the periventricular structures.⁴⁴ Furthermore, there was a lack of therapeutic efficacy, potentially due to failure of GDNF diffusion across the greater distance between the ventricular system and substantia nigra when compared to nonhuman animal models. Subsequently, this led to direct intraparenchymal infusion of GDNF into the striatum (postcommissural putamen) in an open-label phase 1 study that demonstrated both encouraging safety and efficacy results.⁴⁵ Five PD patients were treated, with a resulting significant decrease in total Unified Parkinson’s Disease Rating Scale (UPDRS) score in the “off” state at 3 months, as well as mean reduction in UPDRS motors score at 12 months of 48%. There were also correlational ¹⁸F-dopa PET scans showing an increased uptake in the area of the GDNF infusion. Since ¹⁸F-dopa PET measures dopamine synthetic capacity and by extension dopaminergic innervation of the striatum, these results did support potential enhancement of dopaminergic function in the remaining viable nigrostriatal neurons, and a postmortem case from the study later did demonstrate sprouting of dopaminergic fibers around the GDNF infusion site.⁴⁶

Table 117-2 Infusion of Recombinant GDNF into CNS of Parkinson Disease Patients

These initial promising results did not translate into success in a phase II double-blind, placebo controlled trial that subsequently followed.⁴⁷ In this study, 34 patients with moderately advanced PD were bilaterally implanted with a single port catheter to infuse either drug or placebo continuously into the putamen, and no significant effect of GDNF was reported in either primary or secondary outcome measures (except for ¹⁸F-dopa PET scan data), leading to considerable debate regarding the reasons for the conflicting results between the open-label and double-blind, placebo-controlled studies. There has long been concern about potential placebo effects confounding trials of new therapies for PD, but the relative absence of substantial benefit in either the treatment or control groups suggests that placebo was not a cause of the different results observed in the two trials. It is possible that the change in the type of infusion catheter and mechanism of infusion (differences in diameter and total amount of GDNF delivered) may have negatively affected the therapy and led to a false-negative result. The study may also not have been adequately powered to demonstrate an effect. This highlights the difficulties that can limit successful translation of promising and potentially efficacious therapies. Given the expense and limited likelihood of success for any new therapy, it can be difficult to develop optimal technology for phase 1 studies. However, when results justify later-phase trials, an incentive is created to improve technology so that the methodology used in the more advanced trial can be more readily extrapolated for general use. Furthermore, patient recruitment and financial considerations often limit the size of randomized studies. These understandable and often unavoidable issues may nonetheless compromise later phase trials and can create difficulties resolving discrepancies with early phase data when subsequent results do not justify continued development. This is not unique to growth factor infusion, and has plagued other promising surgical therapies, including cell transplantation and gene therapy. But these issues must be considered when evaluating results of surgical trials for new molecular therapies, in order to improve future studies and to not automatically reject treatments that may have genuine promise due to disappointing results from a single study.

Gene Therapy

Gene therapy in the CNS has been the molecular therapy with perhaps the largest number of clinical trials for different diseases, including Alzheimer’s disease, Canavan and Batten diseases, and PD. The basic premise behind gene therapy involves introduction of a modified genetic vector, which serves as a delivery system for a potentially therapeutic gene, into a host target brain region in order to allow production of the desired gene product. Since these agents do not effectively circumvent the blood–brain barrier at present, and if this were possible, then restricting gene expression to a particular brain region following global delivery is even more difficult, gene therapy in the brain for the foreseeable future is conducted with the aid of stereotactic and functional neurosurgery. Since the neuroanatomy and physiologic consequences of nigral degeneration in PD are better understood than for most disorders, PD has been a primary target of gene therapy for many years. The earliest applications of gene therapy in animals were in PD models, and although gene therapy has been tested in human patients for a variety of neurologic diseases, the first and largest number of gene therapy trials in the CNS have been in PD patients. Thus, movement disorders have been a leading application in the emerging field of gene therapy for neurologic diseases.