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  2. 2. CNI REVIEW Official Publication of the Colorado Neurological Institute Contents Medical Editor John H. McVicker, MD Letter From the Editor 1 Guest Editor Lauren C. Seeberger, MD CNI Board of Directors Cognitive Processes in Parkinson’s Disease: 3 Don Johnson Chairman From Dopamine to Behavior John McVicker, MD Vice Chairman Michael J. Frank, PhD and Randall C. O’Reilly, PhD Walter Berger Treasurer Peter Ricci, MD Secretary Dan Weyland Past Chairman Visual Disturbances in Parkinson’s Disease 10 Cynthia Acree and Intervention Theron Bell Norman Dyer Thomas Politzer, O.D, FCOVD, FAAO Barbara Farley Lucille (Lucky) Gallagher Lynda Gumeson Richard Kelley, MD David C. Kelsall, MD Douglas Kerbs Surgical Treatment of Movement Disorders 14 Artemis Khadiwala-Donian Steven G. Ojemann, M.D. Bonnie Mandarich Charleen (Char) Merlo Dennis O’Malley Barbara Lynne Phillips, MD Roselyn Saunders Richard E. Schaler, MD Michael Schmidt, Esq. Community Resources and Practical Pointers 20 Douglas Tisdale, Esq. Mary White for Parkinson’s Disease Luanne Williams, CFRE Josette Pressler, LPN World Wide Web Address: www.TheCNI.org About the Colorado Neurological Institute (CNI) The Colorado Neurological Institute Huntington’s Disease 25 (CNI), a not-for-profit organization, enhances neurologic patient care Pinky Agarwal, M.D. and Lauren C. Seeberger, M.D. through its education, research and outreach activities. As the largest, most comprehensive neuroscience center in the Rocky Mountain area, CNI provides extensive interdisciplinary programs throughout the region. This medical review journal is Cerebellar Tremor – Definition and Treatment 29 one of CNI’s many educational offerings to the medical community. Lauren C. Seeberger, M.D. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means – electronic, mechanical, photocopying, recording, or otherwise — without the prior written permission of the Colorado CNI Program and Services 36 Neurological Institute. The CNI is grateful for the generous support of Swedish Medical Center. © Colorado Neurological Institute, 2005. Publication Design: TheParksGroup, Boulder, CO
  3. 3. From the Editor The tarantella is an ancient southern Italian dance form, characterized by feverish, writhing, jerking movements of the limbs, ostensibly danced to fend off the poisonous effects of a spider bite. It bears a striking resemblance to the dyskinesia experienced by a Parkinson’s patient with full-blown motor fluctuations associated with their medication regimen. But when the same patient’s medication level drops transiently between doses, the very opposite occurs. In his compelling book Awakenings, Dr. Oliver Sacks vividly describes patients with a post-infectious parkinson-like syndrome, living in the rigid prison of their own unresponsive frame, and the dramatic “awakening” of these patients given Levo-dopa. The advent of Levo-dopa therapy was hailed as a medical miracle, and indeed it is, freeing Parkinson’s patients from the rigidity, tremor, and difficulty initiating movement that are the hallmarks of the disease very effectively. But as the disease progresses and medication regimens escalate, the huge and often sudden swings from dyskinesia to rigidity and “freezing” can make the uncertainty of daily living a huge functional problem. Smoothing out these motor fluctuations is just one goal of movement disorders neurologists. This issue of the CNI REVIEW takes a look at a few of the things these very special neurologists are doing to fight disorders of movement and bring a modicum of functional ability and independence back into the lives of our patients. Take a moment to look at the words we use to describe movement disorders. We characterize these disorders using terms such as chorea, bradykinesia, dystonia, dyskinesia, tremor, dysmetria, dysdiadochokinesis, nystagmus, oscillopsia. The common denominator is kinesis—movement. These disorders change the way we move. Not only arms and legs, but fine motor control, voice, swallowing, head control, and eye motion can be affected. Like a rock in a pond, these disorders can interrupt more than just motor function in ever expanding circles. Rigidity of muscle tone, inability to initiate movement, incoordination of movement, loss of smoothness and fluidity, diminished speed of movement, loss of movement control, even violent uncontrollable movement can occur. Beyond motor function, the epiphenomenon of the underlying disease processes may induce cognitive deterioration and dementia, behavioral changes, attentional disorders, and obsessive thoughts and behaviors. These present additional challenges to our patients as they relentlessly and progressively steal independence and ability. Our contributors to this issue span a wide breadth of expertise in the neurology of movement. Pinky Agarwal, MD, and Lauren C. Seeberger, MD, describe Huntington’s disease and the current treatment options available for this dramatically disabling disease. Michael J. Frank, PhD and Randall C. O’Reilly, PhD summarize their research in computer modeling of basal ganglia, arriving at surprising and novel predictions about how this impacts a Parkinson’s patient’s cognition. Steven G. Ojemann, MD, updates us on the surgical management of Parkinsons Disease and Essential Tremor, outlining the indications, contraindications, complications and outcomes that can be expected with implantation of deep brain stimulators for these disorders. Thomas Politzer, OD, FCOVD, FAAO, describes the sometimes subtle but potentially disabling ocular effects of Parkinsons Disease, and what can be done to improve the affected Parkinson’s patient’s visual function. Josette Pressler, LPN, presents the many Fall 2005 1 www.thecni.org
  4. 4. community resources available to patients with movement disorders with an emphasis on Parkinson’s disease. Lauren C. Seeberger, MD defines the characteristics of cerebellar tremor, outlines the etiology of this disorder, and reports on the effectiveness of new interventions for this disabling affliction. I hope you will find this issue of the CNI REVIEW enlightening and interesting. I’m sure it will give you useful information on the availability and effectiveness of new treatments for these disorders, as well as the clinical, research and community resources available to your patients with movement disorders through the CNI Movement Disorder Center and Thompson Center for Restorative Neurosurgery at the Colorado Neurologic Institute. And if you have never had the opportunity, I invite you to read Dr. Sack’s book, Awakenings, to get a vivid picture of the battle our movement disorders neurologists are waging every day. John H. McVicker, MD, FACS President, Colorado Neurological Institute CNI REVIEW 2
  5. 5. Cognitive Processes in Parkinson’s Disease: From Dopamine to Behavior Michael J. Frank, PhD and Randall C. O’Reilly, PhD We present a summary of our ongoing research into the cognitive functions of the basal ganglia and their implication in Parkinson’s disease (PD). Diverse cognitive functions are impaired in PD, which are sometimes enhanced, but sometimes worsened, by dopaminergic medication. Computer modeling of the basal ganglia dopamine system and its involvement in cognition has been useful for understanding these effects and for making novel predictions regarding core cognitive deficits in PD. Introduction. Parkinson’s disease (PD) the general aspects of our model of this is a progressive neurodegenerative disease system, and then describe how cognitive that selectively damages dopaminergic cells impairments in PD are consistent with that target the basal ganglia (BG). The most this model. Michael Frank is a obvious behavioral change associated with postdoctoral fellow at the PD is characterized by muscular rigidity, Relating Basal Ganglia Roles in Motor University of Colorado. slowness of movements, and tremor. Control and Cognitive Function. In the His research involved Nevertheless, a number of cognitive changes context of motor control, various authors computational modeling have been documented as well, which are the have suggested that the role of the BG is to of neural mechanisms focus of this review. These cognitive selectively facilitate the execution of a single underlying implicit impairments are often complex and motor command, while suppressing all learning, working seemingly unrelated, ranging from deficits in others.1-3 Thus, the BG is thought to act as a memory, and attention. reinforcement learning and decision making brake on competing motor actions that are He received a PhD in (ie, choosing among multiple menu items at represented in motor cortex. Only the most neuroscience and a restaurant and learning from the outcome appropriate motor command is able to psychology from CU and of this decision) to working memory (holding release the brake and get executed at any his dissertation title was “Dynamic dopamine and manipulating information in mind, as in point in time. Further, the BG does not modulation in the basal mental arithmetic) and attentional control come up with the motor responses itself, but ganglia: Converging (directing attention to task-relevant versus instead modulates the execution of cortical neuropsychological, distracting information). In the present responses by signaling “Go” or “No-Go”.4 pharmacological and review we present our ongoing theoretical This functionality also helps to string simple computational studies.” account of these phenomena. Rather than motor commands together to form a He has published more proposing separate mechanisms for the complex motor sequence, by selecting the than 10 articles in peer- various cognitive and motor impairments in most appropriate command at any given review scientific journals. PD, our approach unites the diverse pattern portion of the sequence and inhibiting the of results by adopting a mechanistic other ones until the time is appropriate.1 approach that attempts to decipher the A simplified analysis of BG anatomy helps underlying roles of the basal ganglia/ clarify the basis for this functional dopamine system. We begin by describing characterization. In brief, 2 BG pathways are Fall 2005 3 www.thecni.org
  6. 6. thought to independently facilitate or disease? As described above, it is generally suppress cortical motor commands. More accepted that the BG acts as the motor specifically, 2 main projection pathways controller by dynamically modulating from the striatum go through different basal activity in frontal motor cortex. Similarly, ganglia output structures on the way to various researchers now propose a key role of thalamus and up to cortex (Figure 1). parallel circuits linking the BG, thalamus, Activity in the direct pathway sends a “Go” and PFC that are essentially identical to signal to facilitate the execution of a those involved in the motor circuit.9 response considered in cortex, whereas activity in the indirect pathway sends a “No- Working Memory. Based on the Go” signal to suppress competing responses. general suggestions of basal ganglia Dopamine modulates the relative balance of involvement in prefrontal circuits made by these pathways by exciting “Go” cells while Alexander and colleagues, we developed a inhibiting “No-Go” cells. This effect is computational model that explicitly dynamic, such that transient increases in DA formulated the role of the BG in working leads to more “Go” and less “No-Go”, and memory.2 We suggested that just as the BG vice versa for decreases. 3 Note that in PD, facilitates motor command execution in Randall O’Reilly is an motor neurons themselves are not damaged, premotor cortex by disinhibiting or associate professor in the and patients can in fact perform movements “releasing the brakes” it may also facilitate Department of quite smoothly under some circumstances the updating of working memory in Psychology at the (eg, externally driven motor commands). prefrontal cortex. For task-relevant stimuli University of Colorado. Instead, these patients may have difficulty that are suitable for working memory He also holds appoint- selecting among various competing motor maintenance, the BG direct pathway may ments in the Institute of actions and executing the most appropriate activate a “Go” signal to disinhibit the Cognitive Science and one. It is often suggested that depleted thalamus and gate the updating of PFC. the Center for Neuro- dopamine in PD leads to an imbalance of In contrast, due to “No-Go” BG output, sciences. His research interests include the direct and indirect pathways.5 task-irrelevant information would not be specialization of function Specifically, PD is thought to be associated robustly maintained. For example, when in and interactions with too much “No-Go” and not enough someone is telling you their telephone between hippocampus, “Go”, leading to slowness of movements or number, you have learned to activate “Go” prefrontal cortex, and bradykinesia. In essence, depleted DA in the signals to encode this into working memory, posterior neocortex in BG may result in raising the threshold for while also being able to have “No-Go” learning, memory, facilitating a motor program while signals to ring to distracting information (eg, attention, and controlled continuing to suppress competing actions.1, 6 if your pesky friend later tries to distract you processing. He received a The observation that treatment with DA with other numbers). PhD in Psychology at agonists and L-Dopa sometimes lead to Carnegie Mellon jerking movements, or dyskinesia 7 is Reinforcement Learning / Decision University. consistent with this hypothesis by shifting Making. When faced with a decision, such the balance the other way and making the as which menu item to order at a restaurant, threshold for motor execution too low, people often use implicit, “gut-level” rather than too high.8 How does the above strategies. They simply “know” they want to depiction of BG involvement in motor choose the steak in favor of the salmon, control relate to cognition in Parkinson’s often without being able to explicitly state CNI REVIEW 4
  7. 7. Figure 1a and 1b Figure 1a The cortico-striato-thalamo- cortical loops, including the direct (“Go”) and indirect (“No-Go”) pathways of the basal ganglia. The “Go” cells disinhibit the thalamus via GPi, thereby facilitating the execution of an action represented in cortex. The “No-Go” cells have an opposing effect by increasing inhibition of the thalamus, suppressing actions from getting executed. Dopamine from the SNc projects to the dorsal striatum, causing excitation of “Go” cells via D1 receptors, and inhibition of “No-Go” via D2 receptors. GPi: internal segment of globus pallidus; GPe: external segment of globus pallidus; SNc: substantia nigra pars the basis of their decision. In fact, in such modifies synaptic plasticity, such that on compacta; SNr: substantia situations, the implicit value of alternative subsequent trials the model is more likely to nigra pars reticulata. decisions has been integrated over multiple respond “Go” to a decision that has been Figure 1b The Frank (2005) neural prior experiences—your intuition is really recently rewarded. Conversely, dopamine network model of this just the integration of your experience in a dips lead to “No-Go” learning to avoid non- circuit (squares represent units, with height and color very generalized way. reinforced incorrect decisions. See below for reflecting neural activity; Given that the BG are thought to a more detailed description of how this yellow = most active, red = less active, grey = not active). participate in selecting among various model functions, and its implications for The Premotor Cortex selects competing low-level motor responses, it is Parkinson’s disease. an Output response via direct projections from the natural to extend this functionality to sensory Input, and is include higher-level decisions. The question Cognitive Impairments in Parkinson’s modulated by the BG projections from Thalamus. is, how do the BG learn which decision has Disease. Next, we review the evidence for Go units are in the left half the highest value? Insight comes from cognitive deficits in PD and how it can be of the Striatum layer; “No- Go” in the right half, with various experiments showing that when understood within the context of our model. separate columns for the 2 monkeys are rewarded following a correct We divide the cognitive deficits in PD into responses R1 (left button), R2 (right button). In the choice, transient increases in BG dopamine 2 general classes and address them in turn. case shown, striatum “Go” is firing are observed.10 Conversely, choices The first class concerns “frontal-like” stronger than “No-Go” for R1, inhibiting GPi, that do not lead to reward are associated deficits, and the second is related to disinhibiting Thalamus, and with dopamine dips that drop below impairments in implicit reinforcement facilitating execution of the response in cortex. A tonic baseline. These changes in dopamine are learning. level of dopamine is shown adaptive, and are thought to lead to the in SNc; a burst or dip ensues in a subsequent error learning of rewarding behaviors. In our Frontal Deficits. Frontal-like cognitive feedback phase (not shown), models, transient dopamine increases deficits have long been attributed to patients causing corresponding changes in “Go”/“No-Go” preferentially activate “Go” cells in the direct with PD. Anecdotally, patients report unit activations, which drive pathway via D1 receptors, while suppressing difficulty with manipulating information in learning. “No-Go” cells in the indirect pathway via memory, such as counting backwards from D2 receptors.3 This change in activity 100. In the laboratory, PD patients are Fall 2005 5 www.thecni.org
  8. 8. Figure 2a Example stimulus pairs impaired at many of the same tasks as procedural learning” tasks, in which (Hiragana characters) used observed in patients with damage to participants have to classify stimuli into in the cognitive probabilistic learning task, designed to prefrontal cortex.11 The theoretical account different categories using trial-and-error. minimize verbal encoding. for these observations consistently implicates Patients perform as well as controls in other One pair is presented per trial, and the participant a damaged BG that is interconnected in a implicit learning tasks, such as those learned makes a forced choice. The functional circuit with prefrontal cortex.12 by simple observation not involving error frequency of positive feedback for each choice is Our framework holds that diminished DA feedback.15-16 In implicit categorization tasks, shown. in the BG results in a higher threshold for successful integration of information Figure 2b updating information in PFC, which leads depends on both error feedback and BG Novel test pair performance to working memory impairments and integrity.17 Perhaps the most well known in Parkinson patients on and off medication tested at rigidity, as is also observed in primates with cognitive impairment in PD is that of the the Colorado Neurological selective striatal DA depletion. Specifically, a “weather prediction” categorization task in Institute (Frank, Seeberger and O’Reilly, 2004). Note lack of BG DA in PD would lead to too which category members are determined that choosing A depends on little updating of relevant information into probabilistically and participants have to having learned from positive feedback, while avoiding B PFC, just as it leads to too little execution of figure out statistical regularities by trial-and- depends on having learned motor commands. Conversely, too much error.14 Healthy participants implicitly from negative feedback. DA in the BG would lead to excessive integrate information over multiple trials, Figure 2c This pattern of results was updating of PFC, just as it leads to L-Dopa progressively improving, despite not being predicted by the Frank induced motor tics and dyskinesia. Finally, a able to explicitly state the basis of their (2005) model. The figure shows “Go” - “No-Go” suboptimal level of DA in the PFC would choices. PD patients are reliably impaired in associations for stimulus A, lead to insufficient maintenance of task- the early stages of the task. At first glance, and “No-Go” - “Go” associations for stimulus B, relevant information. Any of these DA implicit learning deficits might appear recorded from the model’s dysfunctions would lead to “frontal-like” unrelated to the frontal impairments of PD striatum after having been trained on the same task cognitive deficits. patients described above. While frontal tasks used with patients. Error demand manipulation of information in bars reflect standard error across 25 runs of the model Implicit/Reinforcement Learning conscious awareness, implicit learning tasks with random initial weights. Deficits. In support of the “multiple specifically measure the ability of partici- 1. Mink J. The basal memory system” hypothesis, researchers pants to pick up on regularities that do not ganglia: Focused have found that different patient reach conscious awareness. The current selection and inhibition of competing motor populations have different kinds of memory framework provides a unified account for programs. Progress in impairments. Amnestics with medial both classes of deficits: diminished DA in Neurobiology. 1996;50:381-425. temporal lobe damage have impaired the BG causes a lack of working memory 2. Frank MJ, Loughry B, episodic, but intact procedural memory— updating in PFC, but through interactions O’Reilly RC. that is, they cannot remember individual with premotor cortex it also reduces the Interactions between the frontal cortex and trials but nevertheless successfully integrate implicit learning of stimulus-response basal ganglia in working error feedback across multiple trials and relationships.3 Stimulus-response execution memory: A computational model. perform normally in trial-and-error tasks.13 requires facilitating some responses while Cognitive, Affective, and PD patients show the opposite pattern of suppressing others, and the learning of these Behavioral Neuroscience. 2001;1:137-160. results: they can remember individual mappings depends on dynamic modulatory experiences but have difficulty integrating properties of DA in the BG. error feedback across multiple trials.14-15 These deficits are typically studied with A Model of Reinforcement Learning probabilistic classification or “cognitive in PD. Computational modeling of the CNI REVIEW 6
  9. 9. Figure 2 3. Frank M. Dynamic dopamine modulation in the basal ganglia: A neurocomputational account of cognitive deficits in medicated and non-medicated Parkinsonism. Journal of Cognitive Neuro- sciene. 2005;17:51-72. 4. Hikosaka O. Role of basal ganglia in initia- tion of voluntary movements. In: Arbib MA, Amari S, Eds. Berlin: Springer- Verlag. Dynamic interactions in neural networks: Models and data. 1989; 153-167. dynamics of BG-cortical interactions result in positive feedback. Conversely, after 5. Albin R, Young A, provided an explicit formulation for how the incorrect responses phasic dips in DA release Penney J. The func- tional anatomy of basal BG is involved in cognitive reinforcement the “No-Go” pathway from suppression, ganglia disorders. learning, and how this is impaired in PD.3 increasing its activity and driving “No-Go” Trends in Neurosciences. 1989;12:366-375. Specifically, the model (Figure 1b) learning. Over the course of training, this 6. Wichmann T, DeLong addressed how phasic changes in DA during model learns how to respond in the weather M. Pathophysiology of Parkinson’s disease: error feedback are critical for modulating prediction task, with performance levels The MPTP primate “Go/No-Go” representations in the BG that similar to that of healthy human participants. model of the human disorder. Annals of the facilitate or suppress the execution of motor When 75 percent of simulated dopamine New York Academy of commands. The main assumption is that neurons were removed (to model the Sciences. 2003;991: 199-213. during positive and negative feedback (eg, approximate amount of damage in PD 7. McAuley J. The correct or incorrect), bursts and dips of DA patients), the model was impaired similarly physiological basis of occur that drive learning for the response. to patients. clinical deficits in Parkinson’s disease. This assumption was motivated by a large Progress in amount of evidence for bursts and dips of Modeling Dopaminergic Medication Neurobiology. 2003;69:27-48. DA during rewards or their absence in Effects on Cognitive Function in PD. The 8. Gerfen C. D1 dopa- monkeys,10 which have also been inferred to same model was used to explain certain mine receptor supersensitivity in the occur in humans for positive and negative negative effects of dopaminergic medication dopamine-depleted feedback.18 These phasic changes in DA on cognition in PD.3 While medication striatum animal model of Parkinson’s disease. modulate neuronal excitability, and may improves performance in task-switching, it Neuroscientist. therefore act to reinforce the efficacy of actually tends to impair performance in 2003;9:455-462. recently active synapses, leading to the probabilistic reversal.19 These authors noted 9. Alexander, GE, DeLong MR, Strick learning of rewarding behaviors. Thus in the that the task-dependent medication effects PL. Parallel organiza- model, “correct” responses are followed by are likely related to the fact that different tion of functionally segregated circuits transient increases in simulated DA that tasks recruit different parts of the striatum. linking basal ganglia enhance synaptically driven activity in the Dopaminergic damage in early stage PD is and cortex. Annual Review of Neuroscience. direct/“Go” pathway, while concurrently restricted to the dorsal striatum, leaving the 1986;9:357-381. suppressing the indirect/“No-Go” pathway. ventral striatum with normal levels of DA.20 10. Schultz W. Getting formal with dopamine This drives “Go” learning, and enables the This explains why DA medication alleviates and reward. Neuron. model to facilitate responses that on average deficits in taskswitching, which relies on 2002;36: 241-263. Fall 2005 7 www. thecni.org
  10. 10. 11. Nieoullon A. (2002). “No-Go” learning, but impaired “Go” Dopamine and the dorsal striatal interactions with dorsolateral regulation of cognition prefrontal cortex. However, the amount of learning (which depends on DA bursts). We and attention. Progress in further predicted that dopaminergic medica- Neurobiology. medication necessary to replenish the dorsal 2002;67:53-83. striatum might “overdose” the ventral stria- tion should alleviate the “Go” learning 12. Middleton FA, Strick tum with DA, and is therefore detrimental deficit, but would block the effects of PL. Basal ganglia output and cognition: Evidence to tasks that recruit it. dopamine dips needed to support “No-Go” from anatomical, In order to simulate medication learning, as was simulated to account for behavioral, and clinical studies. Brain and Cogni- effects, it was hypothesized that medication other medication-induced cognitive deficits tion. 2000;42:183-200. increases the tonic level of DA, but that this in Parkinson’s disease.3 Results were consis- 13. Knowlton BJ, Squire tent with these predictions (Figure 2). In a LR, Gluck MA. interferes with the natural biological system’s Probabilistic category ability to dynamically regulate phasic DA probabilistic learning task, all patients and learning in amnesia. aged-matched controls learned to make Learning and Memory. changes. Specifically, phasic DA dips during 1994;1:1-15. negative feedback may be partially blocked choices that were more likely to result in 14. Knowlton BJ, Mangels by DA agonists that continue to bind to positive rather than negative reinforcement. JA, Squire LR. A neostriatal habit learning receptors. When this was simulated in the The difference was in their strategy: patients system in humans. model, selective deficits were observed taking their regular dose of dopaminergic Science. 1996;273:1399. during probabilistic reversal, despite medication implicitly learned more about the 15. Shohamy D, Myers C, Grossman S, Sage J, equivalent performance in the acquisition positive outcomes of their decisions (ie, they Gluck M, Poldrack R. phase,3 mirroring the results found in were better at “Go” learning), whereas those Cortico-striatal contributions to medicated patients. Because increased tonic who had abstained from taking medication feedback-based learning: levels of DA suppressed the indirect/“No- implicitly learned to avoid negative outcomes converging data from neuroimaging and Go” pathway, networks were unable to learn (better “No-Go” learning). Age-matched neuropsychology. Brain. “No-Go” to override the prepotent response controls did not differ in their tendency to 2004;127:851-859. 16. Reber PJ, Squire LR. learned in the acquisition stage. This learn more from the positive/negative (1999). Intact learning account is consistent with similar reversal outcomes of their decisions. of artificial grammars and intact category deficits observed in healthy participants We have also tested predictions for a learning by patients with administered an acute dose of more a general role for BG/dopamine in Parkinson’s disease. Behavioral Neuroscience. bromocriptine, a D2 agonist.21 cognitive function by administering low 1999;113:235. doses of dopamine agonists/antagonists to 17. Ashby F, Alfonso-Reese L, Turken A, Waldron Empirical Tests of the Model. young, healthy participants.23-24 The drugs E. A neuropsychological Recently, we have tested various aspects of used (cabergoline and haloperidol) were theory of multiple systems In category the hypothesized roles of the basal ganglia/ selective for D2 receptors, which are by far learning. Psychological dopamine system across both reinforcement most prevalent in the BG. By acting on Review. 1998;105:442- 481. learning and working memory processes. presynaptic D2 receptors, cabergoline 18. Holroyd CB, Coles First, we demonstrated striking support for a reduces, while haloperidol enhances, the MGH. The neural basis central prediction of our model regarding amount of phasic dopamine that is released of human error processing: Reinforce- dopamine involvement in “Go” and “No- during dopaminergic cell bursting.25 Again, ment learning, Go” cognitive reinforcement learning.3, 22 We results were consistent with our model. dopamine, and the error-related negativity. tested Parkinson’s patients on and off Increases in dopamine during learning Psychological Review. medication, along with healthy senior caused participants to learn more about the 2002;109:679-709. control participants matched for age, educa- positive outcomes of their decisions (as in tion and a measure of verbal IQ. We medicated Parkinson’s patients), whereas predicted that decreased levels of dopamine decreases in dopamine caused the same in Parkinson’s disease would lead to spared participants to learn more about negative CNI REVIEW 8
  11. 11. outcomes (as in non-medicated patients). Conclusions and Practical 19. Cools R, Barker R, Saha- kian B, Robbins T. (2001). Notably, these same effects were borne Implications. In summary, we have Enhanced or impaired out in the context of a working memory and presented a mechanistic account of how cognitive function in Parkinson’s disease as a attentional task. Specifically, increases in dopamine in the basal ganglia may play a function of dopaminergic dopamine by haloperidol enhanced selective functionally similar role across multiple medication and task demands. Cerebral Cortex. working memory updating of task-relevant cognitive processes. We have showed that 2001;11:1136-1143. (ie, “positively-valenced”), but not distracting while dopaminergic medication used to treat 20. Kish S, Shannak K, Horn- ykiewicz O. Uneven (“negatively-valenced”) information. By our PD sometimes enhances cognitive function, pattern of dopamine loss in model’s account, dopamine release evoked it can also worsen or even cause cognitive the striatum of patients with idiopathic Parkinson’s during the presentation of task-relevant deficits. At this stage it is far too preliminary disease. New England information reinforces BG “Go” firing to to recommend changing medication Journal of Medecine. 1988;318:876-880. update this information. Consistent with this prescriptions based on these results, especially 21. Mehta M, Swainson R, analysis, increased dopamine release also considering their important benefits for Ogilvie A, Sahakian B, caused difficulty not updating (ie, ignoring) treating the more profound and debilitating Robbins T. Improved short-term spatial memory this information when it subsequently motor impairments associated with the but impaired reversal became distracting in the set-shift. Finally, disease. Nevertheless, we expect that this learning following the dopamine D2 agonist and perhaps most suggestive for a role of BG research will lead to a better understanding bromocriptine in human dopamine in working memory, participants of the dopaminergic system, and ultimately volunteers. Psycho- pharmacology. with low baseline working memory span better design of medications that can 2000;159:10-20. were most subject to the effects of increases specifically target underlying neural dysfunc- 22. Frank M, Seeberger L, O’Reilly R. By carrot or by in dopamine by haloperidol, while those tion without causing unwanted side effects. stick: Cognitive reinforce- with high span were most subject to Finally, because our approach is based on ment learning in Parkinsonism. Science. decreases in dopamine by cabergoline.23- 24 low-level neural mechanisms which are not 2004;306:1940-1943. These latter results are consistent with the specific to PD per se, we are hopeful that this 23. Frank M, O’Reilly R. (submitted-a). Individual notion that individual differences in working basic science will lead to a better under- differences in learning and memory span are partially characterized by standing of, and ultimately better medica- attention: Opposing D2 drug effects. underlying differences in dopamine levels,26 tions to treat, other pathological conditions 24. Frank M, and O’Reilly R. but extend this hypothesis in a more involving the BG/DA system, including (submitted-b). A mechanistic fashion consistent with our schizophrenia, obsessive compulsive disorder, mechanistic account of striatal dopamine function modeling. ADHD, and Huntington’s disease. in cognition: Psycho- pharmacological studies Taken together, these results provide with cabergoline and strong support that BG signals, under haloperidol. modulation by dopamine, are critical for the Address questions and comments to: 25. Wu Q, Reith M, Walker Q, Kuhn C, Caroll F, updating of PFC working memory repre- Michael J. Frank, PhD Garris P. Concurrent sentations. Further, the model’s success in Randall C. O’Reilly, PhD autoreceptor-mediated control of dopamine release capturing subtle cognitive effects in both Department of Psychology and uptake during Parkinson’s disease and controlled dopamine Center for Neuroscience neurotransmission: an in vivo voltammetric study. manipulation suggests that it can also be University of Colorado at Boulder Journal of Neuroscience. applied to mechanistically understand cogni- 345 UCB 2002;22:6272-6281. 26. Kimberg DY, D’Esposito tive deficits in those with more complex Boulder, CO 80309 M, and Farah MJ. Effects disorders involving BG/dopamine dysfunc- of bromocriptine on human subjects depend on tion, such as attention deficit hyperactivity working memory capacity. disorder (ADHD) and schizophrenia. Neuroreport. 1997;8:3581- 3585. Fall 2005 9 www. thecni.org
  12. 12. Visual Disturbances in Parkinson’s Disease and Intervention Thomas Politzer, O.D, FCOVD, FAAO Patients with Parkinson’s disease may complain of vision problems such as reading problems, double vision, abnormal perception of motion (oscillopsia), and problems with eye tracking. Signs of problems may include nystagmus, ataxic ocular pursuits, slow and inaccurate saccades, reduced convergence and strabismus. Treatment options that include the use of partial selective occlusion, prism and lenses are discussed. Introduction. Parkinson’s disease (PD) function and difficulty with reading. Their is a progressive degeneration of the neurons study found that visual symptoms suggesting in the central nervous system that produce ocular surface irritation, altered tear film, Dr. Politzer is an the neurotransmitter dopamine. Located in visual hallucinations, decreased blink rate, optometrist specializing the substantia nigra, these neurons innervate and decrease convergence were more in vision rehabilitation the Caudate Nucleus and Putamen. The common in Parkinson’s patients than in for patients with double symptoms of PD are a direct result of control subjects. Newman2 writes that ocular vision, visual field loss, dopamine depletion. signs in Parkinson’s may mimic, but should dizziness and imbalance, Primary symptoms of PD include not be confused with progressive supra- and binocular disorders. tremor, rigidity, bradykinesia, difficulty in nuclear palsy. Clinical presentation includes He graduated from gait and ambulation, and difficulty in blepharospasm and eye movement Pacific University in 1981. He consults at balance. Secondary issues include respiratory abnormality. Verhagen and Schimsheimer3 Craig Rehabilitation problems, dysphagia, dysarthria, depression, note abnormalities of the electro-retinogram Hospital, Swedish sleep disorders, speech disturbance, and and visual evoked potential in patients with Hospital, and Spalding visual problems. Parkinson’s. Muchnick writes that Rehabilitation Hospital. Patients with PD may complain of Parkinson’s “may cause a loss of upward gaze, He has Fellowships in vision problems. Common complaints followed by downward gaze, and finally the College of Optome- include reading problems, double vision, horizontal eye movements. Convergence trists in Vision Develop- abnormal perception of motion (oscillopsia), may fail producing diplopia at near.”4 ment and the American and problems with eye tracking. Since vision Academy of Optometry. is our dominant sense, these symptoms can Examination. A comprehensive be quite troubling and interfere with many ophthalmic exam with careful evaluation of activities of daily living. Appropriate vision ocular fixations, eye movements, and intervention can often help compensate for binocular vision is indicated for patients the problem and improve functional with PD. Signs of problems may include outcomes. nystagmus, ataxic ocular pursuits, slow and inaccurate saccades, reduced convergence, Review of Literature. Biousse et al1 and strabismus. noted that patients with Parkinson’s would Nystagmus connotes an instability, or commonly complain of impaired visual ataxia of ocular fixation. There are many CNI REVIEW 10
  13. 13. 1. Biousse V, et al. different types of nystagmus including, but Exotropia at near is the most common Ophthalmologic features not limited to rhythmic, horizontal, vertical, finding in patients with PD. of Parkinson’s disease. Neurology. 2004;62:177- rotary, vestibular, congenital, and central. 180. The name refers to a description of the Treatment. The goal of treatment 2. Newman N. Neuro- disorder, or source of origin. If nystagmus is for vision problems is to find a functional Ophthalmology A Practical Text. Appleton acquired, such as in PD from a central solution to the patient’s symptoms & Lange. 1992:190,366. dysfunction, the patient is generally not able (double vision, oscillopsia, reading 3. Verhagen W, Schimsheimer R. to suppress the image generated from the difficulty). Treatment should be relatively Current Neuro- abnormal eye movements. This results in easy to employ, cost effective and Ophthalmology, Vol. 3. Eds. Lessell and Van oscillopsia, which is the abnormal functionally based. Dalen. Mosby perception of movement. 1991:368-369. Ocular motor dysfunction (OMD) Double Vision. Double vision is a 4. Muchnick B. Ocular Manifestations of can manifest as ataxia of ocular pursuit, or serious and intolerable condition that is Neurologic Disease. Ed. slow and inaccurate saccades. When OMD caused by strabismus, ophthalmoplegia, gaze Blaustein. Mosby 1996:101. is acquired such as in patients with PD, it is palsy, and decompensated binocular skills. from a central cause. Associated symptoms Prism, visual rehabilitation therapy, and include impairment of fine motor surgery are options to help the patient coordination and reading problems such as recover binocular vision and alleviate the loss of place when reading and words diplopia. Some patients may adapt to their appearing to move and jump when reading. strabismus by suppressing the vision of one Convergence describes the ability of eye, but this is rare in adult acquired onset. the eyes to accurately align on, and track an As a general rule, vision rehabilitation and object as it moves closer to and away from surgery are not as helpful as prism for the person viewing it. In convergence patients with PD because of the variable insufficiency the eyes lag behind the viewed nature and central cause of motor object and are not able to track it as it dysfunction in PD. approaches to closer than approximately 8 Prism is an ophthalmic device that inches from the person. In mild cases this bends light. It is effective in compensating may cause only blurring and eye strain. As it for diplopia in patients with PD because it becomes more pronounced there will likely can be prescribed to offset the amount of eye be double vision at near. deviation. If the diplopia is only with near Strabismus is a misalignment of the vision, then reading lenses with prism are eyes. It can manifest intermittently, or indicated. This authors’ experience is that an constant, at distance and/or near, inward amount of prism between one half and two (eso), outward (exo), vertical (hyper, or thirds of the measured ocular deviation is hypo), or rotary (cyclo). It is commonly usually a sufficient and appropriate amount found with a Cranial Nerve III, IV, or VI to prescribe. Using more than is necessary is ophthalmoparesis, or ophthalmoplegia and counterproductive and may perpetuate the also with progressive external ophthlmo- diplopia. If the double vision is only with far plegia. When acquired, such as in patients vision, then distance lenses with prism are with PD, there will typically be double prescribed. If there is double vision both vision because of the inability to suppress distance and near, then either two separate central vision from the deviating eye. prescriptions can be fabricated, or a Ben Fall 2005 11 www. thecni.org
  14. 14. Franklin bifocal can be used. This is a lens peripheral vision. that is manufactured from two separate lenses with different prism and lens prescrip- Oscillopsia. Oscillopsia is the tions. One is made for far vision and the symptom of abnormal perception of other for near vision. They are then cut in movement, usually related to nystagmus, or half and glued together to make a single abnormal pursuits without retinal bifocal lens. suppression. Patients may acquire a varied If prisms and/or therapy are not head position and direction of gaze to help successful and the patient does not suppress, compensate by finding a null point where intractable diplopia may occur. In these the nystagmus is decreased. Partial selective cases, and before current treatment occlusion with bi-nasal, and/or bi-temporal strategies, complete patching of one eye has patching can help dampen the perception of been used. While effective in eliminating oscillopsia by enhancing a stable frame of diplopia, patching renders the patient reference. Rigid contact lenses can be used monocular. in a type of biofeedback mechanism to Monocular as opposed to binocular sometimes reduce nystagmus. vision will affect the individual primarily in 2 ways; absence of stereoscopic depth Reading Difficulties. Reading perception and a roughly 25 percent problems are one of the main causes for reduction of the peripheral field of vision. people seeking vision care. There are many These in turn cause problems in eye hand causes and types of reading problems, and coordination, depth judgments, orientation, the specific treatment depends on an balance, mobility, and many activities of accurate diagnosis. daily living such as playing sports, driving, Convergence insufficiency may also climbing stairs, crossing the street, threading impair reading ability. It can cause double a needle, etc. vision, eyestrain, fatigue, or the appearance A new method of treating diplopia of words seeming to move and swim on the that does not have these limitations has been page when reading. For patients with PD successfully developed by this author. It is effective treatment options include lenses called the “spot patch” and is a method used and prism. to eliminate intractable diplopia without Accommodative deficiency may also compromising peripheral vision. It is a cause reading problems. It can cause small, usually round or oval, patch made of symptoms of blur, eyestrain, fatigue, or the Transpore tape, 3-M blurring film, or any appearance of words seeming to pulse and other such translucent tape. It is placed on float on the page when reading. Lenses to the lens of glasses directly in the line of sight assist accommodation are a good of the deviating eye. The diameter is intervention. generally about 1 centimeter, but will vary Double vision will impair reading and on the individual angular subtense required should be treated as noted above. for the particular strabismus, or gaze palsy. Saccadic (scanning) movements are The spot patch works by blurring central required for efficient reading. When slow vision, where diplopia is perceived, to a and/or inaccurate they will impair reading. point where it is eliminated while preserving This can cause loss of place, skipping lines, CNI REVIEW 12
  15. 15. type of mask measuring about 10 centimeters long by 5 centimeters wide, and is made from heavy card stock paper. It has a slit cut in it approximately 8 centimeters long and 1 centimeter wide. It is placed over reading material to isolate the line being read. Conclusion. Parkinson’s disease mainly affects vision through motor dysfunction. Patients frequently complain of vision problems including difficulty with reading, double vision and the abnormal perception of movement. Examination may reveal the diagnoses of nystagmus, ocular motor dysfunction, convergence insufficiency and/or strabismus. Treatment options including lenses, prism and partial selective occlusion are effective and affordable means to treat these conditions. Address questions and comments to: Thomas Politzer, O.D. 333 S. Allison Parkway, #120 Lakewood, CO 80120 Fall 2005 13 www.thecni.org
  16. 16. Surgical Treatment of Movement Disorders Steven G. Ojemann, M.D. The surgical treatment of movement disorders has evolved considerably over the last decade in terms of the scope of the indications for surgery, and in terms of technique. Deep Brain Stimulation (DBS) has an established role in the treatment of Parkinson’s disease and essential tremor. As a surgical procedure, it offers inherent advantages over ablative therapies, as the therapeutic and side effects of stimulation can be modulated by adjustment of multiple stimulation parameters. DBS is finding increasing application for the treatment of dystonias, and for tremor disorders other than essential tremor. These conditions, many of which are notoriously difficult to treat medically, are reviewed in this article. The objective is to focus on the conditions for which surgical treatments may be beneficial, the indications and contraindications to these procedures, and on the surgical techniques and outcomes. Steven G. Ojemann is Overview of Surgical Procedures. segment of the Globus Pallidus (GPi), the an Assistant Professor of Surgical techniques can be roughly divided subthalamic nucleus (STN), and the Neurosurgery at the into ablative procedures, neurostimulation Ventralis intermedius nucleus of the University of Colorado, procedures, and procedures aimed at the thalamus (Vim). The modern targets for and Director of Stereo- enhancement of drug delivery. Added to this surgical treatment of movement disorders tactic and Functional scheme more recently are the trials of were discovered somewhat serendipitously, Neurosurgery. He augmentative and restorative therapies, such with the observation over 50 years ago that completed his neuro- as transplantation of fetal mesencephalic an iatrogenic infarct in the basal ganglia surgical training at the University of California, tissue into the striatum of patients with produced effective tremor control in a San Francisco in 2002. Parkinson’s disease. The different surgical Parkinsonian patient. Further exploration of His clinical interests strategies are summarized in Table I. the effects of lesions in multiple sites within include the surgical Currently, Deep Brain Stimulation (DBS) the basal ganglia gave rise to the stereotactic treatment of movement represents the most commonly employed thalamotomy and pallidotomy. Lesions of disorders, epilepsy, brain procedure, with an extensive literature that the subthalamic region were complicated by tumors, and chronic supports efficacy for the treatment of hemiballismus, and bilateral lesions of the pain disorders. Parkinson’s disease and essential tremor. It thalamus or pallidum were frequently possesses an inherent advantage over ablative accompanied by fixed corticobulbar or procedures, because of the ability to corticospinal deficits. The ability to modulate both therapeutic and adverse modulate the majority of therapeutic and effects of stimulation—effects are typically side effects with adjustable stimulation has fixed following lesioning. Several restorative overcome these serious limitations of lesion therapies have been subjected to controlled surgery. Deep Brain Stimulation has studies to date; none have demonstrated generally supplanted ablative techniques, efficacy similar to that seen with DBS. because DBS makes possible bilateral Targets of surgical treatments consist surgery, and surgery employing the largely of the structures of the basal ganglia subthalamic nucleus as a target. While the and thalamus, specifically the internal risks specific to the creation of a lesion (ie, CNI REVIEW 14
  17. 17. Table 1. Summary of Neurosurgical Procedures Used for the Treatment of Movement Disorders 1. Binder DK, Rau G, Starr PA. Hemorrhagic complications of PROCEDURE CURRENT STATUS microelectrode-guided deep brain stimulation. Lesioning and Ablative Procedures Stereotact Funct Thalamotomy Proven benefit for tremor only, not recommended for use on both sides Neurosurg. 2003; 80 of the brain. (1-4): 28-31. Pallidotomy Proven benefit up to 5 years for tremor, rigidity, bradykinesia, and 2. Lyons KE, Pahwa R. Deep brain stimulation levodopa induced dyskinesias. Not recommended for use on both sides and essential tremor. J of the brain. Clin Neurophysiol. Denervation Procedures Examples include partial denervation of the accessory nerve for cervical 2004:21(1); 2-5. dystonia, selective dorsal rhizotomy for spasticity. As with lesioning 3. Pahwa R, et al. Bilateral thalamic stimulation for procedures, denervation does not afford the opportunity to modulate the treatment of either the therapeutic or adverse effects. essential tremor. Neurology. Deep Brain Stimulation 1999;53(7):1447-1450. Chronic thalamic stimulation (Vim DBS) Reduces tremor but not the other signs of PD; approved by U.S. Food 4. Deep-brain stimulation and Drug Administration in 1997 for unilateral use in the treatment of of the subthalamic tremor. Commonly used off-label for the treatment of bilateral essential nucleus or the pars interna of the globus tremor. Growing literature on the use of thalamic stimulation for the pallidus in Parkinson’s treatment of non essential tremor, such as tremor from MS, and disease. N Engl J Med. Holmes’ tremor. 2001; 345(13):956-963. Chronic pallidal stimulation (GPi DBS) Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by 5. Pinter MM, et al. Apomorphine test: a FDA in 2002 for use in Parkinson’s disease. FDA granted Humanitarian predictor for motor Device Exemption in 2003 for use in the treatment of dystonia. responsiveness to deep Chronic stimulation of subthalamic Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by brain stimulation of the subthalamic nucleus. J nucleus (STN DBS) FDA in 2002 for use in Parkinson’s disease. FDA granted Humanitarian Neurol. Device Exemption in 2003 for use in the treatment of dystonia. 1999;246(10):907-913. 6. Tarsy D, et al. Adverse “Restorative” Therapies & Drug Delivery Strategies effects of subthalamic Human fetal cell transplantation Experimental; human trials have not shown overall efficacy. One recent nucleus DBS in a trial showed only modest benefit in a subgroup of younger patients, and patient with multiple system atrophy. production of uncontrollable dyskinesias was an adverse effect in some Neurology. patients. 2003;61(2):247-249. Stem cell transplantation Studied in laboratory animals only; not yet applicable in humans 7. Chou KL, et al. Intracerebral injection of growth factors Experimental; Most recent trial of intracerebral administration of Glial Subthalamic nucleus deep brain stimulation cell. Derived Neurotrophic Factor (GDNF) halted by manufacturer due to in a patient with safety concerns. levodopa-responsive Gene therapy by intracerebral injection Studied in laboratory animals, initial human studies (Phase I) are being multiple system atrophy. of genetically modified viral vectors conducted. Case report. J Neurosurg. 2004;100(3):553-556. 8. Vidailhet M, et al. Bilateral deep-brain stimulation of the dysarthria, ataxia) are clearly lower with general, less than half of these are globus pallidus in DBS, there remains with this surgery a risk symptomatic.1 primary generalized dystonia. N Engl J Med. of hemorrhagic complications, and of 2005;352(5): hardware-related complications, including Essential Tremor. Thalamic DBS for 459-467. infection. The risk of intracranial hemorr- the treatment of medically refractory hage with DBS surgery is typically cited at essential tremor (ET) is extremely effective around 3 percent in large series, though in in the treatment of upper extremity tremor, Fall 2005 15 www.thecni.org
  18. 18. 9. Starr PA, et al. Microelectrode-guided often with secondary improvement in head levodopa, dopaminergic agonists, and other implantation of deep tremor, and sometimes in voice tremor. medications can often address these motor brain stimulators into the globus pallidus Surgical treatment is reasonable to consider fluctuations and complications of levodopa internus for dystonia: in patients with a clear diagnosis of ET, who therapy for a period of time. Continued techniques, electrode locations, and have substantial disability and impairment difficulties with fluctuations in motor outcomes. Neurosurg in quality of life despite therapy with beta- symptoms and/or levodopa-induced Focus. 2004;17(1):E4. blockers and primidone. Additional medical dyskinesas are the primary indications for 10. Wishart HA, et al. Chronic deep brain therapy including topirimate, baclofen, or surgical treatment. Table 2, adapted from the stimulation for the clonazepam may be attempted prior to University of California, San Francisco, treatment of tremor in multiple sclerosis: considering surgery, though some estimates summarizes the selection criteria employed review and case have as many as 50 percent of patients with for DBS surgery at the University of reports. J Neurol Neurosurg Psychiatry. persistence of disabling symptoms despite Colorado, along with the rationale for 2003;74(10): maximal medical therapy.2 While the FDA each criterion. 1392-1397. 11. Kim MC, et al. Vim has approved the device for unilateral The selection criteria are largely thalamotomy for implantation for the treatment of disabling derived from the observed benefits of DBS Holmes’ tremor secondary to midbrain tremor, it is not unusual that patients with surgery. Stimulation of both the tumour. J Neurol bilateral symptoms require bilateral Subthalamic nucleus (STN) and the internal Neurosurg Psychiatry. 2002;73(4):453-455. stimulator placement for effective treatment. segment of the Globus Pallidus (GPi) 12. Nikkhah G. et al. The risks of irreversible dysarthria and gait produce significant improvement in the off- Deep brain disorder, which proved to be serious medication severity of all of the cardinal stimulation of the nucleus ventralis limitation to bilateral thalamotomy are symptoms of Parkinson’s disease (widely intermedius for much less seriuos with bilateral DBS surgery, accepted criteria for selecting between the Holmes (rubral) tremor and associated as such side effects are largely subject to GPi and STN targets do not exist as yet). dystonia caused by modulation with changes in stimulation The degree of benefit is rarely greater than upper brainstem lesions. Report of two parameters. 3 that afforded by medication, but the same cases. J Neurosurg. level of benefit achieved by medications can 2004;100(6): 1079-1083. Parkinson’s Disease. Parkinson’s often be achieved surgically. Thus, benefits 13. Samadani U, et al. disease is characterized by the cardinal of stimulation can be maintained with a Thalamic deep brain stimulation for symptoms of tremor, rigidity, bradykinesia, substantial reduction or even elimination of disabling tremor after and postural instability. For patients with medications, which in turn contributes to a excision of a midbrain cavernous angioma. early Parkinson’s disease, levodopa and other reduction of levodopa-induced dyskinesias. Case report. antiparkinsonian medications are usually As well, the benefit achieved with surgery is J Neurosurg. 2003;98(4):888-890. effective for maintaining a good quality of typically sustained over the course of the 14. Goto S, Yamada K. life. As the disorder progresses, however, day, and thus addresses the problems related Combination of thalamic Vim stimula- most patients develop a fluctuating response to frequent “on-off ” fluctuations in motor tion and GPi pallido- to levodopa, often vacillating between “on” symptoms experienced by most patients as tomy synergistically abolishes Holmes’ and “off ” states many times a day. Addition- the course of their disease progresses.4 tremor. J Neurol ally, levodopa-induced dyskinesias, Other selection criteria are also derived Neurosurg Psychiatry. 2004;75(8):1203- consisting of involuntary, often choreo- from outcomes data. The few reports of DBS 1204. athetotic movements, can occur with the as a treatment for “atypical” parkinsonism, peak dose or with the onset and wearing-off such as multiple systems atrophy, suggest of the dose (diphasic dyskinesias). Dosing little or no benefit of surgery for these changes, sustained-release preparations of patients.5-7 Thus, the certainty of the diag- CNI REVIEW 16
  19. 19. 15. Romanelli P, et al. nosis of idiopathic Parkinson’s disease is side effects. If the most disabling dystonic Possible necessity for important. Observations of the potential for symptoms are quite focal, then intramuscular deep brain stimulation of both the ventralis negative neuropsychological sequelae of injections of botulinum toxin can be an intermedius and surgery have highlighted the importance of effective treatment. Care should be taken subthalamic nuclei to resolve Holmes tremor. identifying cognitive impairment in surgical when labeling symptoms refractory to Case report. J Neurosurg. candidates, and counseling those with signi- botulinum toxin, as reasons for lack of 2003;99(3):566-571. ficant impairment against the procedure. efficacy can include technical factors, and the procedure is ideally performed with electro- Dystonia. Dystonia is a heterogeneous myographic recording. Another reason for disorder, classified roughly according to etio- lack of efficacy may be the development of logy, insofar as this is known. It consists of neutralizing antibodies to specific serotypes primary dystonias, secondary dystonias, of the toxin, and the use of alternative heredodegenerative dystonias, and “dystonia- serotypes can sometimes restore benefit. plus” syndromes. It can also be described as Consideration of surgery should be focal, segmental, or generalized. As a symp- offered to patients with disabling dystonic tom, it consists of simultaneous, sustained symptoms that are not effectively treated contraction of agonist and antagonist with the above measures. DBS of the GPi muscles, resulting in a fixed, abnormal, and target has been employed for a variety of often painful postures. Surgical experience dystonias, and this has shown dramatic with DBS for many different forms of dys- results in the treatment of primary tonia has grown significantly over the last 5 generalized dystonias, especially when the years, and the Food and Drug Administration patient harbors the DYT-1 genetic (FDA) granted DBS therapy a “Humani- mutation.8 The results of GPi DBS in the tarian Device Exemption” status in 2003 for case of secondary dystonias, including adult- implantation of the Globus Pallidus Interna onset cervical dystonias, are more mixed, or Subthalamic Nucleus for the whole spec- though some patients do make impressive trum of disorders characterized as dystonia. gains with this surgery.9 Selective denervation This designation has led to improvement in or rhizotomy of the spinal accessory nerve is third party payer reimbursement for the another procedure sometimes employed in procedure, making it an increasingly the treatment of cervical dystonias. The accessible option for patients. As this surgical irreversible nature of any resultant weakness, experience grows, recommendations are likely the tendency of symptoms to progress to evolve regarding patient selection criteria, through this treatment, and the frequency of ideal surgical target, and efficacy. bilateral involvement of the disorder make As with all other surgical therapies, denervation a less attractive option than DBS medical therapies and alternatives should be in many cases. thoroughly explored before undertaking the potentially irreversible risks of surgery. For Surgery for Non-Essential Tremor. dystonia, the anticholinergic drug trihey- Increasingly, DBS is being applied to the phenidyl and oral or intrathecal baclofen are treatment of tremor disorders other than typically employed prior to consideration of Parkinson’s disease and ET. The tremor surgery. Medical therapy may be deemed associated with multiple sclerosis (MS) can ineffective due to lack of efficacy, or due to produce severe disability, and can be difficult Fall 2005 17 www. thecni.org