Chapter 8 - l-DOPA- and graft-induced dyskinesia following transplantation
Introduction
Key motor symptoms of Parkinson's disease (PD), namely bradykinesia/akinesia and rigidity, have been directly associated with nigrostriatal pathway degeneration and consequent dopaminergic depletion in the striatum. As well as a significant contributor to the disease phenotype, this lack of nigral dopamine is a major pathological hallmark of PD along with the presence of specific protein inclusions known as Lewy bodies. Most of the current therapeutic strategies revolve around dopamine replacement, and a range of pharmacological approaches are now available to increase endogenous dopamine (e.g., monoamine oxidase inhibitors or catechol-O-methyl transferase inhibitors), support dopamine receptor stimulation (dopamine receptor agonists), and last, and most simply, to directly replace the missing dopamine (l-DOPA). The last of these, l-DOPA (administered in combination with a peripheral decarboxylase inhibitor), has been the “gold standard” in antiparkinsonian therapeutics since the 1960s, effectively alleviating most of the motor deficits. It can be used alone or can be supported by and administered with dopamine agonists, monoamine oxidase inhibitors, and catechol-O-methyl transferase inhibitors. However, because l-DOPA is the most efficacious treatment and the disease is of such a prolonged nature, long-term treatment is necessary and often requires steadily increasing doses of l-DOPA. In the early days of treatment, this is not problematic, and patients enjoy the renewed freedom of movement they can achieve once l-DOPA therapy commences. However, with time l-DOPA becomes less friend and more foe as motor complications develop which include wearing off (the dose of l-DOPA is effective for a shorter period of time), “on–off” motor fluctuations (in which l-DOPA can suddenly cease to be effective, therefore also called “sudden-off”), and l-DOPA-induced dyskinesia (LID). LID typically emerges in the majority of patients during the course of the disease and with ongoing l-DOPA treatment, taking the form of choreic or dystonic abnormal involuntary movements often affecting the upper limbs and orofacial area but sometimes also affecting the torso and lower limbs, causing significant disability, and importantly, limiting the dose of l-DOPA that can be used. Lowering the dose of l-DOPA reduces the severity of the LID but may result in a compromise between the presence of the abnormal movement and an effective therapeutic dose. New developments such as deep brain stimulation, pump therapies infusing apomorphine subcutaneously, or l-DOPA intrajejunally have improved therapeutic options for these patients and improved their motor responding, but only a small number of patients are eligible for these therapies. The lack of effective long-term symptom management and development of treatment-induced side effects necessitate the search for alternative strategies.
Transplantation of dopaminergic neurons into the caudate–putamen has been proposed as such an alternative and explored since the late 1970s when two groups demonstrated that catecholaminergic neurons could restore function following dopamine depletion in a rat model of PD (Björklund and Stenevi, 1979, Perlow et al., 1979). A series of early preclinical studies illustrated the significant potential of this approach in both restoring dopaminergic innervation to the striatum and resulting in functional recovery (Björklund et al., 1980, Björklund et al., 1981, Björklund et al., 1982, Herrera-Marschitz et al., 1984, Nadaud et al., 1984, Strömberg et al., 1984). This success translated into open-label clinical trials in the late 1980s in Mexico (Machado-Salas et al., 1990), Europe (Backlund et al., 1985, Lindvall and Björklund, 1989, Widner et al., 1992), and the United States (Freed et al., 1990) in which adrenal medullary tissue and/or fetal ventral mesencephalon was transplanted into PD patients. Positive outcomes were described for many patients, improvement in symptoms and reductions in PD medication, with no evidence of side effects or significant safety issues; the most abundant success centered on the use of the dopaminergic ventral mesencephalon obtained from elective terminations of pregnancy (Brundin et al., 2000, Hauser et al., 1999, Jacques et al., 1999, Lindvall, 1998). On this basis, two double-blind placebo-controlled clinical trials funded by NIH started in the United States (Freed et al., 2001, Olanow et al., 2003). Unfortunately, these trials did not echo the success of the open-label trials, and early reports at 1 year posttransplantation suggested minimal functional benefit was gained by the patients. However, the most significant part of the reports, particularly in terms of the public perception of the procedure, was that several patients had developed debilitating dyskinesia specifically related to the graft (now called graft-induced dyskinesia, GID) and unrelated to their antiparkinsonian medication (Freed et al., 2001, Greene et al., 1999, Olanow et al., 2003).
This review focuses on how transplantation and dyskinesia interact, exploring both the consequences of cell transplantation on LID, as well as the origins of GID. We will assimilate the preclinical and clinical evidence in support of the different hypotheses for GID development, consider how these two behavioral phenomena may be connected, and suggest how GID may be avoided in future trials.
Section snippets
The clinical phenomena of LID
The use of l-DOPA has long been associated with the development of abnormal, excessive involuntary movements. After the introduction of l-DOPA into clinical use, there were soon observations of motor fluctuations including LID, which later were linked to the very high doses of l-DOPA administered prior to the development of decarboxylase inhibitors. Nowadays, even with lower doses of l-DOPA plus a decarboxylase inhibitor, LID can appear as early as 2–3 years after the initiation of treatment,
The clinical phenomena of GID
The development of abnormal involuntary movements posttransplantation was first described in a published abstract by Greene et al. in 1999 and followed-up in a full report in 2001 (Freed et al., 2001, Greene et al., 1999). The authors described 33 patients who had bilateral transplantation of embryonic ventral mesencephalon obtained from elective terminations of pregnancy; this study was in two phases, as half the group served as a sham treatment group for the initial part of the study and were
Conclusion
Understanding both transplantation effects on LID and the phenomena of GID are classic examples of the nonlinear, circular route from bench-to-bedside-to-bench-to-bedside. Transplantation went to the clinic with strongly supportive preclinical evidence, and the problems that emerged have been explored in more detail preclinically, allowing us to consider a return to the clinic. New clinical trials are now imminent in the TransEUro trial to be undertaken in several European countries using an
Acknowledgments
The authors acknowledge funding support through the European Commission under the 7th Framework Programme—HEALTH 2009—Collaborative Project TransEUro (Contract # 242003).
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2017, Progress in Brain ResearchCitation Excerpt :In a few cases, these adverse effects have been so severe that the patients have required additional neurosurgical intervention (Richardson et al., 2011). The reasons behind this emergence of GIDs are still debated but may relate to the tissue composition of the graft and its uneven placement, and thus uneven pattern of innervation, across the striatal complex (Lane and Winkler, 2012). The GIDs were particularly severe in the Freed et al. study which transplanted “noodles” of VM tissue along the anteroposterior axis of the striatum using a novel transfrontal approach—an approach that was adopted following a significant hemorrhage in one of their open label patients grafted using the more standard neurosurgical approach (Freed and LeVay, 2002).
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