R E V I E W

COLORADONEUROLOGICAL INSTITUTE

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05 Movement Disorders

CNI REVIEWOfficial Publication of theColorado Neurological Institute

Medical EditorJohn H. McVicker, MD

Guest EditorLauren C. Seeberger, MD

CNI Board of DirectorsDon JohnsonChairman

John McVicker, MDVice Chairman

Walter BergerTreasurer

Peter Ricci, MDSecretary

Dan WeylandPast Chairman

Cynthia AcreeTheron BellNorman DyerBarbara FarleyLucille (Lucky) GallagherLynda GumesonRichard Kelley, MDDavid C. Kelsall, MDDouglas KerbsArtemis Khadiwala-DonianBonnie MandarichCharleen (Char) MerloDennis O’MalleyBarbara Lynne Phillips, MDRoselyn SaundersRichard E. Schaler, MDMichael Schmidt, Esq.Douglas Tisdale, Esq.Mary WhiteLuanne Williams, CFRE

World Wide Web Address:www.TheCNI.org

About the Colorado NeurologicalInstitute (CNI)

The Colorado Neurological Institute(CNI), a not-for-profit organization,enhances neurologic patient carethrough its education, research andoutreach activities. As the largest, mostcomprehensive neuroscience center inthe Rocky Mountain area, CNIprovides extensive interdisciplinaryprograms throughout the region.

This medical review journal is one of CNI’s many educationalofferings to the medical community.

All rights reserved. No part of thispublication may be reproduced, storedin a retrieval system, or transmitted, inany form or by any means – electronic,mechanical, photocopying, recording,or otherwise — without the priorwritten permission of the ColoradoNeurological Institute.

© Colorado Neurological Institute, 2005.Publication Design: TheParksGroup, Boulder, CO

The CNI is grateful for the generoussupport of Swedish Medical Center.

ContentsLetter From the Editor 1

Cognitive Processes in Parkinson’s Disease: 3 From Dopamine to BehaviorMichael J. Frank, PhD and Randall C. O’Reilly, PhD

Visual Disturbances in Parkinson’s Disease 10 and InterventionThomas Politzer, O.D, FCOVD, FAAO

Surgical Treatment of Movement Disorders 14Steven G. Ojemann, M.D.

Community Resources and Practical Pointers 20for Parkinson’s DiseaseJosette Pressler, LPN

Huntington’s Disease 25Pinky Agarwal, M.D. and Lauren C. Seeberger, M.D.

Cerebellar Tremor –Definition and Treatment 29Lauren C. Seeberger, M.D.

CNI Program and Services 36

Fall 2005 1 www.thecni.org

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

CNI REVIEW 2

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

Fall 2005 3 www.thecni.org

Michael Frank is a

postdoctoral fellow at the

University of Colorado.

His research involved

computational modeling

of neural mechanisms

underlying implicit

learning, working

memory, and attention.

He received a PhD in

neuroscience and

psychology from CU and

his dissertation title was

“Dynamic dopamine

modulation in the basal

ganglia: Converging

neuropsychological,

pharmacological and

computational studies.”

He has published more

than 10 articles in peer-

review scientific journals.

Introduction. Parkinson’s disease (PD)

is a progressive neurodegenerative disease

that selectively damages dopaminergic cells

that target the basal ganglia (BG). The most

obvious behavioral change associated with

PD is characterized by muscular rigidity,

slowness of movements, and tremor.

Nevertheless, a number of cognitive changes

have been documented as well, which are the

focus of this review. These cognitive

impairments are often complex and

seemingly unrelated, ranging from deficits in

reinforcement learning and decision making

(ie, choosing among multiple menu items at

a restaurant and learning from the outcome

of this decision) to working memory (holding

and manipulating information in mind, as in

mental arithmetic) and attentional control

(directing attention to task-relevant versus

distracting information). In the present

review we present our ongoing theoretical

account of these phenomena. Rather than

proposing separate mechanisms for the

various cognitive and motor impairments in

PD, our approach unites the diverse pattern

of results by adopting a mechanistic

approach that attempts to decipher the

underlying roles of the basal ganglia/

dopamine system. We begin by describing

the general aspects of our model of this

system, and then describe how cognitive

impairments in PD are consistent with

this model.

Relating Basal Ganglia Roles in MotorControl and Cognitive Function. In the

context of motor control, various authors

have suggested that the role of the BG is to

selectively facilitate the execution of a single

motor command, while suppressing all

others.1-3 Thus, the BG is thought to act as a

brake on competing motor actions that are

represented in motor cortex. Only the most

appropriate motor command is able to

release the brake and get executed at any

point in time. Further, the BG does not

come up with the motor responses itself, but

instead modulates the execution of cortical

responses by signaling “Go” or “No-Go”.4

This functionality also helps to string simple

motor commands together to form a

complex motor sequence, by selecting the

most appropriate command at any given

portion of the sequence and inhibiting the

other ones until the time is appropriate.1

A simplified analysis of BG anatomy helps

clarify the basis for this functional

characterization. In brief, 2 BG pathways are

Cognitive Processes in Parkinson’s Disease:From Dopamine to BehaviorMichael J. Frank, PhD and Randall C. O’Reilly, PhD

We present a summary of our ongoing research into the cognitive functions of the basal gangliaand their implication in Parkinson’s disease (PD). Diverse cognitive functions are impaired inPD, which are sometimes enhanced, but sometimes worsened, by dopaminergic medication.Computer modeling of the basal ganglia dopamine system and its involvement in cognition hasbeen useful for understanding these effects and for making novel predictions regarding corecognitive deficits in PD.

CNI REVIEW 4

Randall O’Reilly is an

associate professor in the

Department of

Psychology at the

University of Colorado.

He also holds appoint-

ments in the Institute of

Cognitive Science and

the Center for Neuro-

sciences. His research

interests include

specialization of function

in and interactions

between hippocampus,

prefrontal cortex, and

posterior neocortex in

learning, memory,

attention, and controlled

processing. He received a

PhD in Psychology at

Carnegie Mellon

University.

thought to independently facilitate or

suppress cortical motor commands. More

specifically, 2 main projection pathways

from the striatum go through different basal

ganglia output structures on the way to

thalamus and up to cortex (Figure 1).

Activity in the direct pathway sends a “Go”

signal to facilitate the execution of a

response considered in cortex, whereas

activity in the indirect pathway sends a “No-

Go” signal to suppress competing responses.

Dopamine modulates the relative balance of

these pathways by exciting “Go” cells while

inhibiting “No-Go” cells. This effect is

dynamic, such that transient increases in DA

leads to more “Go” and less “No-Go”, and

vice versa for decreases. 3 Note that in PD,

motor neurons themselves are not damaged,

and patients can in fact perform movements

quite smoothly under some circumstances

(eg, externally driven motor commands).

Instead, these patients may have difficulty

selecting among various competing motor

actions and executing the most appropriate

one. It is often suggested that depleted

dopamine in PD leads to an imbalance of

the direct and indirect pathways.5

Specifically, PD is thought to be associated

with too much “No-Go” and not enough

“Go”, leading to slowness of movements or

bradykinesia. In essence, depleted DA in the

BG may result in raising the threshold for

facilitating a motor program while

continuing to suppress competing actions.1, 6

The observation that treatment with DA

agonists and L-Dopa sometimes lead to

jerking movements, or dyskinesia 7 is

consistent with this hypothesis by shifting

the balance the other way and making the

threshold for motor execution too low,

rather than too high.8 How does the above

depiction of BG involvement in motor

control relate to cognition in Parkinson’s

disease? As described above, it is generally

accepted that the BG acts as the motor

controller by dynamically modulating

activity in frontal motor cortex. Similarly,

various researchers now propose a key role of

parallel circuits linking the BG, thalamus,

and PFC that are essentially identical to

those involved in the motor circuit.9

Working Memory. Based on the

general suggestions of basal ganglia

involvement in prefrontal circuits made by

Alexander and colleagues, we developed a

computational model that explicitly

formulated the role of the BG in working

memory.2 We suggested that just as the BG

facilitates motor command execution in

premotor cortex by disinhibiting or

“releasing the brakes” it may also facilitate

the updating of working memory in

prefrontal cortex. For task-relevant stimuli

that are suitable for working memory

maintenance, the BG direct pathway may

activate a “Go” signal to disinhibit the

thalamus and gate the updating of PFC.

In contrast, due to “No-Go” BG output,

task-irrelevant information would not be

robustly maintained. For example, when

someone is telling you their telephone

number, you have learned to activate “Go”

signals to encode this into working memory,

while also being able to have “No-Go”

signals to ring to distracting information (eg,

if your pesky friend later tries to distract you

with other numbers).

Reinforcement Learning / DecisionMaking. When faced with a decision, such

as which menu item to order at a restaurant,

people often use implicit, “gut-level”

strategies. They simply “know” they want to

choose the steak in favor of the salmon,

often without being able to explicitly state

the basis of their decision. In fact, in such

situations, the implicit value of alternative

decisions has been integrated over multiple

prior experiences—your intuition is really

just the integration of your experience in a

very generalized way.

Given that the BG are thought to

participate in selecting among various

competing low-level motor responses, it is

natural to extend this functionality to

include higher-level decisions. The question

is, how do the BG learn which decision has

the highest value? Insight comes from

various experiments showing that when

monkeys are rewarded following a correct

choice, transient increases in BG dopamine

firing are observed.10 Conversely, choices

that do not lead to reward are associated

with dopamine dips that drop below

baseline. These changes in dopamine are

adaptive, and are thought to lead to the

learning of rewarding behaviors. In our

models, transient dopamine increases

preferentially activate “Go” cells in the direct

pathway via D1 receptors, while suppressing

“No-Go” cells in the indirect pathway via

D2 receptors.3 This change in activity

modifies synaptic plasticity, such that on

subsequent trials the model is more likely to

respond “Go” to a decision that has been

recently rewarded. Conversely, dopamine

dips lead to “No-Go” learning to avoid non-

reinforced incorrect decisions. See below for

a more detailed description of how this

model functions, and its implications for

Parkinson’s disease.

Cognitive Impairments in Parkinson’sDisease. Next, we review the evidence for

cognitive deficits in PD and how it can be

understood within the context of our model.

We divide the cognitive deficits in PD into

2 general classes and address them in turn.

The first class concerns “frontal-like”

deficits, and the second is related to

impairments in implicit reinforcement

learning.

Frontal Deficits. Frontal-like cognitive

deficits have long been attributed to patients

with PD. Anecdotally, patients report

difficulty with manipulating information in

memory, such as counting backwards from

100. In the laboratory, PD patients are

Fall 2005 5 www.thecni.org

Figure 1aThe cortico-striato-thalamo-cortical loops, including thedirect (“Go”) and indirect(“No-Go”) pathways of thebasal ganglia. The “Go” cellsdisinhibit the thalamus viaGPi, thereby facilitating theexecution of an actionrepresented in cortex. The“No-Go” cells have anopposing effect by increasinginhibition of the thalamus,suppressing actions fromgetting executed. Dopaminefrom the SNc projects to thedorsal striatum, causingexcitation of “Go” cells viaD1 receptors, and inhibitionof “No-Go” via D2receptors. GPi: internalsegment of globus pallidus;GPe: external segment ofglobus pallidus; SNc:substantia nigra parscompacta; SNr: substantianigra pars reticulata.

Figure 1bThe Frank (2005) neuralnetwork model of thiscircuit (squares representunits, with height and colorreflecting neural activity;yellow = most active, red =less active, grey = not active).The Premotor Cortex selectsan Output response viadirect projections from thesensory Input, and ismodulated by the BGprojections from Thalamus.Go units are in the left halfof the Striatum layer; “No-Go” in the right half, withseparate columns for the 2responses R1 (left button),R2 (right button). In thecase shown, striatum “Go” isstronger than “No-Go” forR1, inhibiting GPi,disinhibiting Thalamus, andfacilitating execution of theresponse in cortex. A toniclevel of dopamine is shownin SNc; a burst or dip ensuesin a subsequent errorfeedback phase (not shown),causing correspondingchanges in “Go”/“No-Go”unit activations, which drivelearning.

Figure 1a and 1b

CNI REVIEW 6

impaired at many of the same tasks as

observed in patients with damage to

prefrontal cortex.11 The theoretical account

for these observations consistently implicates

a damaged BG that is interconnected in a

functional circuit with prefrontal cortex.12

Our framework holds that diminished DA

in the BG results in a higher threshold for

updating information in PFC, which leads

to working memory impairments and

rigidity, as is also observed in primates with

selective striatal DA depletion. Specifically, a

lack of BG DA in PD would lead to too

little updating of relevant information into

PFC, just as it leads to too little execution of

motor commands. Conversely, too much

DA in the BG would lead to excessive

updating of PFC, just as it leads to L-Dopa

induced motor tics and dyskinesia. Finally, a

suboptimal level of DA in the PFC would

lead to insufficient maintenance of task-

relevant information. Any of these DA

dysfunctions would lead to “frontal-like”

cognitive deficits.

Implicit/Reinforcement LearningDeficits. In support of the “multiple

memory system” hypothesis, researchers

have found that different patient

populations have different kinds of memory

impairments. Amnestics with medial

temporal lobe damage have impaired

episodic, but intact procedural memory—

that is, they cannot remember individual

trials but nevertheless successfully integrate

error feedback across multiple trials and

perform normally in trial-and-error tasks.13

PD patients show the opposite pattern of

results: they can remember individual

experiences but have difficulty integrating

error feedback across multiple trials.14-15

These deficits are typically studied with

probabilistic classification or “cognitive

procedural learning” tasks, in which

participants have to classify stimuli into

different categories using trial-and-error.

Patients perform as well as controls in other

implicit learning tasks, such as those learned

by simple observation not involving error

feedback.15-16 In implicit categorization tasks,

successful integration of information

depends on both error feedback and BG

integrity.17 Perhaps the most well known

cognitive impairment in PD is that of the

“weather prediction” categorization task in

which category members are determined

probabilistically and participants have to

figure out statistical regularities by trial-and-

error.14 Healthy participants implicitly

integrate information over multiple trials,

progressively improving, despite not being

able to explicitly state the basis of their

choices. PD patients are reliably impaired in

the early stages of the task. At first glance,

implicit learning deficits might appear

unrelated to the frontal impairments of PD

patients described above. While frontal tasks

demand manipulation of information in

conscious awareness, implicit learning tasks

specifically measure the ability of partici-

pants to pick up on regularities that do not

reach conscious awareness. The current

framework provides a unified account for

both classes of deficits: diminished DA in

the BG causes a lack of working memory

updating in PFC, but through interactions

with premotor cortex it also reduces the

implicit learning of stimulus-response

relationships.3 Stimulus-response execution

requires facilitating some responses while

suppressing others, and the learning of these

mappings depends on dynamic modulatory

properties of DA in the BG.

A Model of Reinforcement Learningin PD. Computational modeling of the

Figure 2a Example stimulus pairs(Hiragana characters) usedin the cognitive probabilisticlearning task, designed tominimize verbal encoding.One pair is presented pertrial, and the participantmakes a forced choice. Thefrequency of positivefeedback for each choice isshown.

Figure 2b Novel test pair performancein Parkinson patients onand off medication tested atthe Colorado NeurologicalInstitute (Frank, Seebergerand O’Reilly, 2004). Notethat choosing A depends onhaving learned from positivefeedback, while avoiding Bdepends on having learnedfrom negative feedback.

Figure 2cThis pattern of results waspredicted by the Frank(2005) model. The figureshows “Go” - “No-Go”associations for stimulus A,and “No-Go” - “Go”associations for stimulus B,recorded from the model’sstriatum after having beentrained on the same taskused with patients. Errorbars reflect standard erroracross 25 runs of the modelwith random initial weights.

1. Mink J. The basalganglia: Focusedselection and inhibitionof competing motorprograms. Progress inNeurobiology.1996;50:381-425.

2. Frank MJ, Loughry B,O’Reilly RC.Interactions betweenthe frontal cortex andbasal ganglia in workingmemory: Acomputational model.Cognitive, Affective, andBehavioral Neuroscience.2001;1:137-160.

Fall 2005 7 www. thecni.org

3. Frank M. Dynamicdopamine modulationin the basal ganglia: Aneurocomputationalaccount of cognitivedeficits in medicatedand non-medicatedParkinsonism. Journalof Cognitive Neuro-sciene. 2005;17:51-72.

4. Hikosaka O. Role ofbasal ganglia in initia-tion of voluntarymovements. In: ArbibMA, Amari S, Eds.Berlin: Springer-Verlag. Dynamicinteractions in neuralnetworks: Models anddata. 1989; 153-167.

5. Albin R, Young A,Penney J. The func-tional anatomy of basalganglia disorders.Trends in Neurosciences.1989;12:366-375.

6. Wichmann T, DeLongM. Pathophysiology ofParkinson’s disease:The MPTP primatemodel of the humandisorder. Annals of theNew York Academy ofSciences. 2003;991:199-213.

7. McAuley J. Thephysiological basis ofclinical deficits inParkinson’s disease.Progress inNeurobiology.2003;69:27-48.

8. Gerfen C. D1 dopa-mine receptorsupersensitivity in thedopamine-depletedstriatum animal modelof Parkinson’s disease.Neuroscientist.2003;9:455-462.

9. Alexander, GE,DeLong MR, StrickPL. Parallel organiza-tion of functionallysegregated circuitslinking basal gangliaand cortex. AnnualReview of Neuroscience.1986;9:357-381.

10. Schultz W. Gettingformal with dopamineand reward. Neuron.2002;36: 241-263.

Figure 2

dynamics of BG-cortical interactions

provided an explicit formulation for how the

BG is involved in cognitive reinforcement

learning, and how this is impaired in PD.3

Specifically, the model (Figure 1b)

addressed how phasic changes in DA during

error feedback are critical for modulating

“Go/No-Go” representations in the BG that

facilitate or suppress the execution of motor

commands. The main assumption is that

during positive and negative feedback (eg,

correct or incorrect), bursts and dips of DA

occur that drive learning for the response.

This assumption was motivated by a large

amount of evidence for bursts and dips of

DA during rewards or their absence in

monkeys,10 which have also been inferred to

occur in humans for positive and negative

feedback.18 These phasic changes in DA

modulate neuronal excitability, and may

therefore act to reinforce the efficacy of

recently active synapses, leading to the

learning of rewarding behaviors. Thus in the

model, “correct” responses are followed by

transient increases in simulated DA that

enhance synaptically driven activity in the

direct/“Go” pathway, while concurrently

suppressing the indirect/“No-Go” pathway.

This drives “Go” learning, and enables the

model to facilitate responses that on average

result in positive feedback. Conversely, after

incorrect responses phasic dips in DA release

the “No-Go” pathway from suppression,

increasing its activity and driving “No-Go”

learning. Over the course of training, this

model learns how to respond in the weather

prediction task, with performance levels

similar to that of healthy human participants.

When 75 percent of simulated dopamine

neurons were removed (to model the

approximate amount of damage in PD

patients), the model was impaired similarly

to patients.

Modeling Dopaminergic MedicationEffects on Cognitive Function in PD. The

same model was used to explain certain

negative effects of dopaminergic medication

on cognition in PD.3 While medication

improves performance in task-switching, it

actually tends to impair performance in

probabilistic reversal.19 These authors noted

that the task-dependent medication effects

are likely related to the fact that different

tasks recruit different parts of the striatum.

Dopaminergic damage in early stage PD is

restricted to the dorsal striatum, leaving the

ventral striatum with normal levels of DA.20

This explains why DA medication alleviates

deficits in taskswitching, which relies on

CNI REVIEW 8

11. Nieoullon A. (2002).Dopamine and theregulation of cognitionand attention. Progress inNeurobiology.2002;67:53-83.

12. Middleton FA, StrickPL. Basal ganglia outputand cognition: Evidencefrom anatomical,behavioral, and clinicalstudies. Brain and Cogni-tion. 2000;42:183-200.

13. Knowlton BJ, SquireLR, Gluck MA.Probabilistic categorylearning in amnesia.Learning and Memory.1994;1:1-15.

14. Knowlton BJ, MangelsJA, Squire LR. Aneostriatal habit learningsystem in humans.Science. 1996;273:1399.

15. Shohamy D, Myers C,Grossman S, Sage J,Gluck M, Poldrack R.Cortico-striatalcontributions tofeedback-based learning:converging data fromneuroimaging andneuropsychology. Brain.2004;127:851-859.

16. Reber PJ, Squire LR.(1999). Intact learningof artificial grammarsand intact categorylearning by patients withParkinson’s disease.Behavioral Neuroscience.1999;113:235.

17. Ashby F, Alfonso-ReeseL, Turken A, WaldronE. A neuropsychologicaltheory of multiplesystems In categorylearning. PsychologicalReview. 1998;105:442-481.

18. Holroyd CB, ColesMGH. The neural basisof human errorprocessing: Reinforce-ment learning,dopamine, and theerror-related negativity.Psychological Review.2002;109:679-709.

dorsal striatal interactions with dorsolateral

prefrontal cortex. However, the amount of

medication necessary to replenish the dorsal

striatum might “overdose” the ventral stria-

tum with DA, and is therefore detrimental

to tasks that recruit it.

In order to simulate medication

effects, it was hypothesized that medication

increases the tonic level of DA, but that this

interferes with the natural biological system’s

ability to dynamically regulate phasic DA

changes. Specifically, phasic DA dips during

negative feedback may be partially blocked

by DA agonists that continue to bind to

receptors. When this was simulated in the

model, selective deficits were observed

during probabilistic reversal, despite

equivalent performance in the acquisition

phase,3 mirroring the results found in

medicated patients. Because increased tonic

levels of DA suppressed the indirect/“No-

Go” pathway, networks were unable to learn

“No-Go” to override the prepotent response

learned in the acquisition stage. This

account is consistent with similar reversal

deficits observed in healthy participants

administered an acute dose of

bromocriptine, a D2 agonist.21

Empirical Tests of the Model.Recently, we have tested various aspects of

the hypothesized roles of the basal ganglia/

dopamine system across both reinforcement

learning and working memory processes.

First, we demonstrated striking support for a

central prediction of our model regarding

dopamine involvement in “Go” and “No-

Go” cognitive reinforcement learning.3, 22 We

tested Parkinson’s patients on and off

medication, along with healthy senior

control participants matched for age, educa-

tion and a measure of verbal IQ. We

predicted that decreased levels of dopamine

in Parkinson’s disease would lead to spared

“No-Go” learning, but impaired “Go”

learning (which depends on DA bursts). We

further predicted that dopaminergic medica-

tion should alleviate the “Go” learning

deficit, but would block the effects of

dopamine dips needed to support “No-Go”

learning, as was simulated to account for

other medication-induced cognitive deficits

in Parkinson’s disease.3 Results were consis-

tent with these predictions (Figure 2). In a

probabilistic learning task, all patients and

aged-matched controls learned to make

choices that were more likely to result in

positive rather than negative reinforcement.

The difference was in their strategy: patients

taking their regular dose of dopaminergic

medication implicitly learned more about the

positive outcomes of their decisions (ie, they

were better at “Go” learning), whereas those

who had abstained from taking medication

implicitly learned to avoid negative outcomes

(better “No-Go” learning). Age-matched

controls did not differ in their tendency to

learn more from the positive/negative

outcomes of their decisions.

We have also tested predictions for a

more a general role for BG/dopamine in

cognitive function by administering low

doses of dopamine agonists/antagonists to

young, healthy participants.23-24 The drugs

used (cabergoline and haloperidol) were

selective for D2 receptors, which are by far

most prevalent in the BG. By acting on

presynaptic D2 receptors, cabergoline

reduces, while haloperidol enhances, the

amount of phasic dopamine that is released

during dopaminergic cell bursting.25 Again,

results were consistent with our model.

Increases in dopamine during learning

caused participants to learn more about the

positive outcomes of their decisions (as in

medicated Parkinson’s patients), whereas

decreases in dopamine caused the same

participants to learn more about negative

Fall 2005 9 www. thecni.org

19. Cools R, Barker R, Saha-kian B, Robbins T. (2001).Enhanced or impairedcognitive function inParkinson’s disease as afunction of dopaminergicmedication and taskdemands. Cerebral Cortex.2001;11:1136-1143.

20. Kish S, Shannak K, Horn-ykiewicz O. Unevenpattern of dopamine loss inthe striatum of patientswith idiopathic Parkinson’sdisease. New EnglandJournal of Medecine.1988;318:876-880.

21. Mehta M, Swainson R,Ogilvie A, Sahakian B,Robbins T. Improvedshort-term spatial memorybut impaired reversallearning following thedopamine D2 agonistbromocriptine in humanvolunteers. Psycho-pharmacology.2000;159:10-20.

22. Frank M, Seeberger L,O’Reilly R. By carrot or bystick: Cognitive reinforce-ment learning inParkinsonism. Science.2004;306:1940-1943.

23. Frank M, O’Reilly R.(submitted-a). Individualdifferences in learning andattention: Opposing D2drug effects.

24. Frank M, and O’Reilly R.(submitted-b). Amechanistic account ofstriatal dopamine functionin cognition: Psycho-pharmacological studieswith cabergoline andhaloperidol.

25. Wu Q, Reith M, WalkerQ, Kuhn C, Caroll F,Garris P. Concurrentautoreceptor-mediatedcontrol of dopamine releaseand uptake duringneurotransmission: an invivo voltammetric study.Journal of Neuroscience.2002;22:6272-6281.

26. Kimberg DY, D’EspositoM, and Farah MJ. Effectsof bromocriptine onhuman subjects depend onworking memory capacity.Neuroreport. 1997;8:3581-3585.

outcomes (as in non-medicated patients).

Notably, these same effects were borne

out in the context of a working memory and

attentional task. Specifically, increases in

dopamine by haloperidol enhanced selective

working memory updating of task-relevant

(ie, “positively-valenced”), but not distracting

(“negatively-valenced”) information. By our

model’s account, dopamine release evoked

during the presentation of task-relevant

information reinforces BG “Go” firing to

update this information. Consistent with this

analysis, increased dopamine release also

caused difficulty not updating (ie, ignoring)

this information when it subsequently

became distracting in the set-shift. Finally,

and perhaps most suggestive for a role of BG

dopamine in working memory, participants

with low baseline working memory span

were most subject to the effects of increases

in dopamine by haloperidol, while those

with high span were most subject to

decreases in dopamine by cabergoline.23- 24

These latter results are consistent with the

notion that individual differences in working

memory span are partially characterized by

underlying differences in dopamine levels,26

but extend this hypothesis in a more

mechanistic fashion consistent with our

modeling.

Taken together, these results provide

strong support that BG signals, under

modulation by dopamine, are critical for the

updating of PFC working memory repre-

sentations. Further, the model’s success in

capturing subtle cognitive effects in both

Parkinson’s disease and controlled dopamine

manipulation suggests that it can also be

applied to mechanistically understand cogni-

tive deficits in those with more complex

disorders involving BG/dopamine dysfunc-

tion, such as attention deficit hyperactivity

disorder (ADHD) and schizophrenia.

Conclusions and PracticalImplications. In summary, we have

presented a mechanistic account of how

dopamine in the basal ganglia may play a

functionally similar role across multiple

cognitive processes. We have showed that

while dopaminergic medication used to treat

PD sometimes enhances cognitive function,

it can also worsen or even cause cognitive

deficits. At this stage it is far too preliminary

to recommend changing medication

prescriptions based on these results, especially

considering their important benefits for

treating the more profound and debilitating

motor impairments associated with the

disease. Nevertheless, we expect that this

research will lead to a better understanding

of the dopaminergic system, and ultimately

better design of medications that can

specifically target underlying neural dysfunc-

tion without causing unwanted side effects.

Finally, because our approach is based on

low-level neural mechanisms which are not

specific to PD per se, we are hopeful that this

basic science will lead to a better under-

standing of, and ultimately better medica-

tions to treat, other pathological conditions

involving the BG/DA system, including

schizophrenia, obsessive compulsive disorder,

ADHD, and Huntington’s disease.

Address questions and comments to:Michael J. Frank, PhD

Randall C. O’Reilly, PhD

Department of Psychology

Center for Neuroscience

University of Colorado at Boulder

345 UCB

Boulder, CO 80309

CNI REVIEW 10

Visual Disturbances in Parkinson’s Diseaseand InterventionThomas 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 selectiveocclusion, prism and lenses are discussed.

Dr. Politzer is an

optometrist specializing

in vision rehabilitation

for patients with double

vision, visual field loss,

dizziness and imbalance,

and binocular disorders.

He graduated from

Pacific University in

1981. He consults at

Craig Rehabilitation

Hospital, Swedish

Hospital, and Spalding

Rehabilitation Hospital.

He has Fellowships in

the College of Optome-

trists in Vision Develop-

ment and the American

Academy of Optometry.

Introduction. Parkinson’s disease (PD)

is a progressive degeneration of the neurons

in the central nervous system that produce

the neurotransmitter dopamine. Located in

the substantia nigra, these neurons innervate

the Caudate Nucleus and Putamen. The

symptoms of PD are a direct result of

dopamine depletion.

Primary symptoms of PD include

tremor, rigidity, bradykinesia, difficulty in

gait and ambulation, and difficulty in

balance. Secondary issues include respiratory

problems, dysphagia, dysarthria, depression,

sleep disorders, speech disturbance, and

visual problems.

Patients with PD may complain of

vision problems. Common complaints

include reading problems, double vision,

abnormal perception of motion (oscillopsia),

and problems with eye tracking. Since vision

is our dominant sense, these symptoms can

be quite troubling and interfere with many

activities of daily living. Appropriate vision

intervention can often help compensate for

the problem and improve functional

outcomes.

Review of Literature. Biousse et al1

noted that patients with Parkinson’s would

commonly complain of impaired visual

function and difficulty with reading. Their

study found that visual symptoms suggesting

ocular surface irritation, altered tear film,

visual hallucinations, decreased blink rate,

and decrease convergence were more

common in Parkinson’s patients than in

control subjects. Newman2 writes that ocular

signs in Parkinson’s may mimic, but should

not be confused with progressive supra-

nuclear palsy. Clinical presentation includes

blepharospasm and eye movement

abnormality. Verhagen and Schimsheimer3

note abnormalities of the electro-retinogram

and visual evoked potential in patients with

Parkinson’s. Muchnick writes that

Parkinson’s “may cause a loss of upward gaze,

followed by downward gaze, and finally

horizontal eye movements. Convergence

may fail producing diplopia at near.”4

Examination. A comprehensive

ophthalmic exam with careful evaluation of

ocular fixations, eye movements, and

binocular vision is indicated for patients

with PD. Signs of problems may include

nystagmus, ataxic ocular pursuits, slow and

inaccurate saccades, reduced convergence,

and strabismus.

Nystagmus connotes an instability, or

ataxia of ocular fixation. There are many

Fall 2005 11 www. thecni.org

1. Biousse V, et al.Ophthalmologic featuresof Parkinson’s disease.Neurology. 2004;62:177-180.

2. Newman N. Neuro-Ophthalmology APractical Text. Appleton& Lange. 1992:190,366.

3. Verhagen W,Schimsheimer R.Current Neuro-Ophthalmology, Vol. 3.Eds. Lessell and VanDalen. Mosby1991:368-369.

4. Muchnick B. OcularManifestations ofNeurologic Disease. Ed.Blaustein. Mosby1996:101.

different types of nystagmus including, but

not limited to rhythmic, horizontal, vertical,

rotary, vestibular, congenital, and central.

The name refers to a description of the

disorder, or source of origin. If nystagmus is

acquired, such as in PD from a central

dysfunction, the patient is generally not able

to suppress the image generated from the

abnormal eye movements. This results in

oscillopsia, which is the abnormal

perception of movement.

Ocular motor dysfunction (OMD)

can manifest as ataxia of ocular pursuit, or

slow and inaccurate saccades. When OMD

is acquired such as in patients with PD, it is

from a central cause. Associated symptoms

include impairment of fine motor

coordination and reading problems such as

loss of place when reading and words

appearing to move and jump when reading.

Convergence describes the ability of

the eyes to accurately align on, and track an

object as it moves closer to and away from

the person viewing it. In convergence

insufficiency the eyes lag behind the viewed

object and are not able to track it as it

approaches to closer than approximately 8

inches from the person. In mild cases this

may cause only blurring and eye strain. As it

becomes more pronounced there will likely

be double vision at near.

Strabismus is a misalignment of the

eyes. It can manifest intermittently, or

constant, at distance and/or near, inward

(eso), outward (exo), vertical (hyper, or

hypo), or rotary (cyclo). It is commonly

found with a Cranial Nerve III, IV, or VI

ophthalmoparesis, or ophthalmoplegia and

also with progressive external ophthlmo-

plegia. When acquired, such as in patients

with PD, there will typically be double

vision because of the inability to suppress

central vision from the deviating eye.

Exotropia at near is the most common

finding in patients with PD.

Treatment. The goal of treatment

for vision problems is to find a functional

solution to the patient’s symptoms

(double vision, oscillopsia, reading

difficulty). Treatment should be relatively

easy to employ, cost effective and

functionally based.

Double Vision. Double vision is a

serious and intolerable condition that is

caused by strabismus, ophthalmoplegia, gaze

palsy, and decompensated binocular skills.

Prism, visual rehabilitation therapy, and

surgery are options to help the patient

recover binocular vision and alleviate the

diplopia. Some patients may adapt to their

strabismus by suppressing the vision of one

eye, but this is rare in adult acquired onset.

As a general rule, vision rehabilitation and

surgery are not as helpful as prism for

patients with PD because of the variable

nature and central cause of motor

dysfunction in PD.

Prism is an ophthalmic device that

bends light. It is effective in compensating

for diplopia in patients with PD because it

can be prescribed to offset the amount of eye

deviation. If the diplopia is only with near

vision, then reading lenses with prism are

indicated. This authors’ experience is that an

amount of prism between one half and two

thirds of the measured ocular deviation is

usually a sufficient and appropriate amount

to prescribe. Using more than is necessary is

counterproductive and may perpetuate the

diplopia. If the double vision is only with far

vision, then distance lenses with prism are

prescribed. If there is double vision both

distance and near, then either two separate

prescriptions can be fabricated, or a Ben

Franklin bifocal can be used. This is a lens

that is manufactured from two separate

lenses with different prism and lens prescrip-

tions. One is made for far vision and the

other for near vision. They are then cut in

half and glued together to make a single

bifocal lens.

If prisms and/or therapy are not

successful and the patient does not suppress,

intractable diplopia may occur. In these

cases, and before current treatment

strategies, complete patching of one eye has

been used. While effective in eliminating

diplopia, patching renders the patient

monocular.

Monocular as opposed to binocular

vision will affect the individual primarily in

2 ways; absence of stereoscopic depth

perception and a roughly 25 percent

reduction of the peripheral field of vision.

These in turn cause problems in eye hand

coordination, depth judgments, orientation,

balance, mobility, and many activities of

daily living such as playing sports, driving,

climbing stairs, crossing the street, threading

a needle, etc.

A new method of treating diplopia

that does not have these limitations has been

successfully developed by this author. It is

called the “spot patch” and is a method used

to eliminate intractable diplopia without

compromising peripheral vision. It is a

small, usually round or oval, patch made of

Transpore tape, 3-M blurring film, or any

other such translucent tape. It is placed on

the lens of glasses directly in the line of sight

of the deviating eye. The diameter is

generally about 1 centimeter, but will vary

on the individual angular subtense required

for the particular strabismus, or gaze palsy.

The spot patch works by blurring central

vision, where diplopia is perceived, to a

point where it is eliminated while preserving

peripheral vision.

Oscillopsia. Oscillopsia is the

symptom of abnormal perception of

movement, usually related to nystagmus, or

abnormal pursuits without retinal

suppression. Patients may acquire a varied

head position and direction of gaze to help

compensate by finding a null point where

the nystagmus is decreased. Partial selective

occlusion with bi-nasal, and/or bi-temporal

patching can help dampen the perception of

oscillopsia by enhancing a stable frame of

reference. Rigid contact lenses can be used

in a type of biofeedback mechanism to

sometimes reduce nystagmus.

Reading Difficulties. Reading

problems are one of the main causes for

people seeking vision care. There are many

causes and types of reading problems, and

the specific treatment depends on an

accurate diagnosis.

Convergence insufficiency may also

impair reading ability. It can cause double

vision, eyestrain, fatigue, or the appearance

of words seeming to move and swim on the

page when reading. For patients with PD

effective treatment options include lenses

and prism.

Accommodative deficiency may also

cause reading problems. It can cause

symptoms of blur, eyestrain, fatigue, or the

appearance of words seeming to pulse and

float on the page when reading. Lenses to

assist accommodation are a good

intervention.

Double vision will impair reading and

should be treated as noted above.

Saccadic (scanning) movements are

required for efficient reading. When slow

and/or inaccurate they will impair reading.

This can cause loss of place, skipping lines,

CNI REVIEW 12

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

CNI REVIEW 14

Surgical Treatment of Movement DisordersSteven G. Ojemann, M.D.

The surgical treatment of movement disorders has evolved considerably over the last decade interms of the scope of the indications for surgery, and in terms of technique. Deep BrainStimulation (DBS) has an established role in the treatment of Parkinson’s disease and essentialtremor. As a surgical procedure, it offers inherent advantages over ablative therapies, as thetherapeutic and side effects of stimulation can be modulated by adjustment of multiplestimulation parameters. DBS is finding increasing application for the treatment of dystonias, andfor tremor disorders other than essential tremor. These conditions, many of which are notoriouslydifficult to treat medically, are reviewed in this article. The objective is to focus on the conditionsfor which surgical treatments may be beneficial, the indications and contraindications to theseprocedures, and on the surgical techniques and outcomes.

Steven G. Ojemann is

an Assistant Professor of

Neurosurgery at the

University of Colorado,

and Director of Stereo-

tactic and Functional

Neurosurgery. He

completed his neuro-

surgical training at the

University of California,

San Francisco in 2002.

His clinical interests

include the surgical

treatment of movement

disorders, epilepsy, brain

tumors, and chronic

pain disorders.

Overview of Surgical Procedures.Surgical techniques can be roughly divided

into ablative procedures, neurostimulation

procedures, and procedures aimed at the

enhancement of drug delivery. Added to this

scheme more recently are the trials of

augmentative and restorative therapies, such

as transplantation of fetal mesencephalic

tissue into the striatum of patients with

Parkinson’s disease. The different surgical

strategies are summarized in Table I.

Currently, Deep Brain Stimulation (DBS)

represents the most commonly employed

procedure, with an extensive literature that

supports efficacy for the treatment of

Parkinson’s disease and essential tremor. It

possesses an inherent advantage over ablative

procedures, because of the ability to

modulate both therapeutic and adverse

effects of stimulation—effects are typically

fixed following lesioning. Several restorative

therapies have been subjected to controlled

studies to date; none have demonstrated

efficacy similar to that seen with DBS.

Targets of surgical treatments consist

largely of the structures of the basal ganglia

and thalamus, specifically the internal

segment of the Globus Pallidus (GPi), the

subthalamic nucleus (STN), and the

Ventralis intermedius nucleus of the

thalamus (Vim). The modern targets for

surgical treatment of movement disorders

were discovered somewhat serendipitously,

with the observation over 50 years ago that

an iatrogenic infarct in the basal ganglia

produced effective tremor control in a

Parkinsonian patient. Further exploration of

the effects of lesions in multiple sites within

the basal ganglia gave rise to the stereotactic

thalamotomy and pallidotomy. Lesions of

the subthalamic region were complicated by

hemiballismus, and bilateral lesions of the

thalamus or pallidum were frequently

accompanied by fixed corticobulbar or

corticospinal deficits. The ability to

modulate the majority of therapeutic and

side effects with adjustable stimulation has

overcome these serious limitations of lesion

surgery. Deep Brain Stimulation has

generally supplanted ablative techniques,

because DBS makes possible bilateral

surgery, and surgery employing the

subthalamic nucleus as a target. While the

risks specific to the creation of a lesion (ie,

Fall 2005 15 www.thecni.org

1. Binder DK, Rau G,Starr PA. Hemorrhagiccomplications ofmicroelectrode-guideddeep brain stimulation.Stereotact FunctNeurosurg. 2003; 80(1-4): 28-31.

2. Lyons KE, Pahwa R.Deep brain stimulationand essential tremor. JClin Neurophysiol.2004:21(1); 2-5.

3. Pahwa R, et al. Bilateralthalamic stimulation forthe treatment ofessential tremor.Neurology.1999;53(7):1447-1450.

4. Deep-brain stimulationof the subthalamicnucleus or the parsinterna of the globuspallidus in Parkinson’sdisease. N Engl J Med.2001; 345(13):956-963.

5. Pinter MM, et al.Apomorphine test: apredictor for motorresponsiveness to deepbrain stimulation of thesubthalamic nucleus. JNeurol.1999;246(10):907-913.

6. Tarsy D, et al. Adverseeffects of subthalamicnucleus DBS in apatient with multiplesystem atrophy.Neurology.2003;61(2):247-249.

7. Chou KL, et al.Subthalamic nucleusdeep brain stimulationin a patient withlevodopa-responsivemultiple system atrophy.Case report. J Neurosurg.2004;100(3):553-556.

8. Vidailhet M, et al.Bilateral deep-brainstimulation of theglobus pallidus inprimary generalizeddystonia. N Engl J Med.2005;352(5):459-467.

dysarthria, ataxia) are clearly lower with

DBS, there remains with this surgery a risk

of hemorrhagic complications, and of

hardware-related complications, including

infection. The risk of intracranial hemorr-

hage with DBS surgery is typically cited at

around 3 percent in large series, though in

general, less than half of these are

symptomatic.1

Essential Tremor. Thalamic DBS for

the treatment of medically refractory

essential tremor (ET) is extremely effective

in the treatment of upper extremity tremor,

Table 1. Summary of Neurosurgical Procedures Used for the Treatment of Movement Disorders

PROCEDURE CURRENT STATUS

Lesioning and Ablative Procedures

Thalamotomy Proven benefit for tremor only, not recommended for use on both sides

of the brain.

Pallidotomy Proven benefit up to 5 years for tremor, rigidity, bradykinesia, and

levodopa induced dyskinesias. Not recommended for use on both sides

of the brain.

Denervation Procedures Examples include partial denervation of the accessory nerve for cervical

dystonia, selective dorsal rhizotomy for spasticity. As with lesioning

procedures, denervation does not afford the opportunity to modulate

either the therapeutic or adverse effects.

Deep Brain Stimulation

Chronic thalamic stimulation (Vim DBS) Reduces tremor but not the other signs of PD; approved by U.S. Food

and Drug Administration in 1997 for unilateral use in the treatment of

tremor. Commonly used off-label for the treatment of bilateral essential

tremor. Growing literature on the use of thalamic stimulation for the

treatment of non essential tremor, such as tremor from MS, and

Holmes’ tremor.

Chronic pallidal stimulation (GPi DBS) Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by

FDA in 2002 for use in Parkinson’s disease. FDA granted Humanitarian

Device Exemption in 2003 for use in the treatment of dystonia.

Chronic stimulation of subthalamic Reduces tremor, rigidity, bradykinesia, and gait disorder; approved by

nucleus (STN DBS) FDA in 2002 for use in Parkinson’s disease. FDA granted Humanitarian

Device Exemption in 2003 for use in the treatment of dystonia.

“Restorative” Therapies & Drug Delivery Strategies

Human fetal cell transplantation Experimental; human trials have not shown overall efficacy. One recent

trial showed only modest benefit in a subgroup of younger patients, and

production of uncontrollable dyskinesias was an adverse effect in some

patients.

Stem cell transplantation Studied in laboratory animals only; not yet applicable in humans

Intracerebral injection of growth factors Experimental; Most recent trial of intracerebral administration of Glial

cell. Derived Neurotrophic Factor (GDNF) halted by manufacturer due to

safety concerns.

Gene therapy by intracerebral injection Studied in laboratory animals, initial human studies (Phase I) are being

of genetically modified viral vectors conducted.

often with secondary improvement in head

tremor, and sometimes in voice tremor.

Surgical treatment is reasonable to consider

in patients with a clear diagnosis of ET, who

have substantial disability and impairment

in quality of life despite therapy with beta-

blockers and primidone. Additional medical

therapy including topirimate, baclofen, or

clonazepam may be attempted prior to

considering surgery, though some estimates

have as many as 50 percent of patients with

persistence of disabling symptoms despite

maximal medical therapy.2 While the FDA

has approved the device for unilateral

implantation for the treatment of disabling

tremor, it is not unusual that patients with

bilateral symptoms require bilateral

stimulator placement for effective treatment.

The risks of irreversible dysarthria and gait

disorder, which proved to be serious

limitation to bilateral thalamotomy are

much less seriuos with bilateral DBS surgery,

as such side effects are largely subject to

modulation with changes in stimulation

parameters. 3

Parkinson’s Disease. Parkinson’s

disease is characterized by the cardinal

symptoms of tremor, rigidity, bradykinesia,

and postural instability. For patients with

early Parkinson’s disease, levodopa and other

antiparkinsonian medications are usually

effective for maintaining a good quality of

life. As the disorder progresses, however,

most patients develop a fluctuating response

to levodopa, often vacillating between “on”

and “off ” states many times a day. Addition-

ally, levodopa-induced dyskinesias,

consisting of involuntary, often choreo-

athetotic movements, can occur with the

peak dose or with the onset and wearing-off

of the dose (diphasic dyskinesias). Dosing

changes, sustained-release preparations of

levodopa, dopaminergic agonists, and other

medications can often address these motor

fluctuations and complications of levodopa

therapy for a period of time. Continued

difficulties with fluctuations in motor

symptoms and/or levodopa-induced

dyskinesas are the primary indications for

surgical treatment. Table 2, adapted from the

University of California, San Francisco,

summarizes the selection criteria employed

for DBS surgery at the University of

Colorado, along with the rationale for

each criterion.

The selection criteria are largely

derived from the observed benefits of DBS

surgery. Stimulation of both the

Subthalamic nucleus (STN) and the internal

segment of the Globus Pallidus (GPi)

produce significant improvement in the off-

medication severity of all of the cardinal

symptoms of Parkinson’s disease (widely

accepted criteria for selecting between the

GPi and STN targets do not exist as yet).

The degree of benefit is rarely greater than

that afforded by medication, but the same

level of benefit achieved by medications can

often be achieved surgically. Thus, benefits

of stimulation can be maintained with a

substantial reduction or even elimination of

medications, which in turn contributes to a

reduction of levodopa-induced dyskinesias.

As well, the benefit achieved with surgery is

typically sustained over the course of the

day, and thus addresses the problems related

to frequent “on-off ” fluctuations in motor

symptoms experienced by most patients as

the course of their disease progresses.4

Other selection criteria are also derived

from outcomes data. The few reports of DBS

as a treatment for “atypical” parkinsonism,

such as multiple systems atrophy, suggest

little or no benefit of surgery for these

patients.5-7 Thus, the certainty of the diag-

16CNI REVIEW

9. Starr PA, et al.Microelectrode-guidedimplantation of deepbrain stimulators intothe globus pallidusinternus for dystonia:techniques, electrodelocations, andoutcomes. NeurosurgFocus. 2004;17(1):E4.

10. Wishart HA, et al.Chronic deep brainstimulation for thetreatment of tremor inmultiple sclerosis:review and casereports. J NeurolNeurosurg Psychiatry.2003;74(10):1392-1397.

11. Kim MC, et al. Vimthalamotomy forHolmes’ tremorsecondary to midbraintumour. J NeurolNeurosurg Psychiatry.2002;73(4):453-455.

12. Nikkhah G. et al.Deep brainstimulation of thenucleus ventralisintermedius forHolmes (rubral)tremor and associateddystonia caused byupper brainstemlesions. Report of twocases. J Neurosurg.2004;100(6):1079-1083.

13. Samadani U, et al.Thalamic deep brainstimulation fordisabling tremor afterexcision of a midbraincavernous angioma.Case report.J Neurosurg.2003;98(4):888-890.

14. Goto S, Yamada K.Combination ofthalamic Vim stimula-tion and GPi pallido-tomy synergisticallyabolishes Holmes’tremor. J NeurolNeurosurg Psychiatry.2004;75(8):1203-1204.

nosis of idiopathic Parkinson’s disease is

important. Observations of the potential for

negative neuropsychological sequelae of

surgery have highlighted the importance of

identifying cognitive impairment in surgical

candidates, and counseling those with signi-

ficant impairment against the procedure.

Dystonia. Dystonia is a heterogeneous

disorder, classified roughly according to etio-

logy, insofar as this is known. It consists of

primary dystonias, secondary dystonias,

heredodegenerative dystonias, and “dystonia-

plus” syndromes. It can also be described as

focal, segmental, or generalized. As a symp-

tom, it consists of simultaneous, sustained

contraction of agonist and antagonist

muscles, resulting in a fixed, abnormal, and

often painful postures. Surgical experience

with DBS for many different forms of dys-

tonia has grown significantly over the last 5

years, and the Food and Drug Administration

(FDA) granted DBS therapy a “Humani-

tarian Device Exemption” status in 2003 for

implantation of the Globus Pallidus Interna

or Subthalamic Nucleus for the whole spec-

trum of disorders characterized as dystonia.

This designation has led to improvement in

third party payer reimbursement for the

procedure, making it an increasingly

accessible option for patients. As this surgical

experience grows, recommendations are likely

to evolve regarding patient selection criteria,

ideal surgical target, and efficacy.

As with all other surgical therapies,

medical therapies and alternatives should be

thoroughly explored before undertaking the

potentially irreversible risks of surgery. For

dystonia, the anticholinergic drug trihey-

phenidyl and oral or intrathecal baclofen are

typically employed prior to consideration of

surgery. Medical therapy may be deemed

ineffective due to lack of efficacy, or due to

side effects. If the most disabling dystonic

symptoms are quite focal, then intramuscular

injections of botulinum toxin can be an

effective treatment. Care should be taken

when labeling symptoms refractory to

botulinum toxin, as reasons for lack of

efficacy can include technical factors, and the

procedure is ideally performed with electro-

myographic recording. Another reason for

lack of efficacy may be the development of

neutralizing antibodies to specific serotypes

of the toxin, and the use of alternative

serotypes can sometimes restore benefit.

Consideration of surgery should be

offered to patients with disabling dystonic

symptoms that are not effectively treated

with the above measures. DBS of the GPi

target has been employed for a variety of

dystonias, and this has shown dramatic

results in the treatment of primary

generalized dystonias, especially when the

patient harbors the DYT-1 genetic

mutation.8 The results of GPi DBS in the

case of secondary dystonias, including adult-

onset cervical dystonias, are more mixed,

though some patients do make impressive

gains with this surgery.9 Selective denervation

or rhizotomy of the spinal accessory nerve is

another procedure sometimes employed in

the treatment of cervical dystonias. The

irreversible nature of any resultant weakness,

the tendency of symptoms to progress

through this treatment, and the frequency of

bilateral involvement of the disorder make

denervation a less attractive option than DBS

in many cases.

Surgery for Non-Essential Tremor.Increasingly, DBS is being applied to the

treatment of tremor disorders other than

Parkinson’s disease and ET. The tremor

associated with multiple sclerosis (MS) can

produce severe disability, and can be difficult

Fall 2005 17 www. thecni.org

15. Romanelli P, et al.Possible necessity fordeep brain stimulationof both the ventralisintermedius andsubthalamic nuclei toresolve Holmes tremor.Case report. J Neurosurg.2003;99(3):566-571.

CNI REVIEW 18

Table 2. Selection Criteria for Deep Brain Stimulation (DBS) surgery at the University of Colorado

CRITERION RATIONALE

Clear diagnosis of Idiopathic

Parkinson’s disease

Clear evidence of motor

improvement with levodopa

(Sinemet), with good motor

function in the best on-medication

state

Degree of disability

Lack of comorbidity

Realistic expectations

Screening MRI of the brain

Intact cognitive function

Patient Age

Ability to remain calm and

cooperative

Patients with atypical parkinsonism or “parkinson’s plus” syndromes do not

respond to DBS. If there are features in the history and physical that are suggestive

of atypical parkinsonism (such as very rapid progression of symptoms, autonomic

failure or postural instability as early features of the disease, signs of cerebellar or

pyramidal dysfunction) or an MRI suggesting an atypical syndrome, surgery is

contraindicated.

A good screening test is the Unified Parkinson’s disease Rating Scale (UPDRS) part

III, performed in 12 hours off of medication and repeated following a

supratherapeutic sinemet dose. An improvement of 30% or more in this score with

sinemet is desirable. The patient should be ambulatory in the best on state without

much assistance. In general surgery makes the “off” states more like the “on”

states but rarely does better than the best “on” state, so a patient with poor

function in best “on” state (for example, nonambulatory in best “on”) is a poor

surgical candidate. Patients who fluctuate between good motor function while

“on” and poor motor function while “off” are usually good surgical candidates.

DBS is a poor procedure to rescue someone with end stage PD, although these can

be the most desperate patients. It is also not appropriate for early PD when the

symptoms are very well controlled on medical therapy. Patients should have an off-

medication UPDRS-III score of > 25. The best time to intervene surgically is when

the patient is just beginning to lose the ability to perform activities meaningful to

him/her, in spite of optimal medical therapy. In a patient who is still working, the

time to intervene is before the patient is forced to retire on disability.

Serious cardiac disease, uncontrolled hypertension, or any major other chronic

systemic illness increases the risk and decreases the benefit of surgery.

People who expect a sudden miracle are disappointed with the results, and become

frustrated with the complexity of the therapy.

This should be free of severe vascular disease, atrophy that is out of proportion to

age, or signs of atypical parkinsonism.

A good screening test is the mini-mental status test. A score of >26 is ideal, < 24 an

absolute contraindication. Patients with cognitive dysfunction have difficulty

tolerating awake surgery, may have permanent worsening of cognitive function

postoperatively, deal poorly with the intrinsic complexity of DBS therapy, and

realize little overall functional gain even if motor performance is improved. Formal

neuropsychological testing is often obtained as part of the preoperative evaluation

process.

The benefits of DBS for PD decline with advancing age, and the risks go up. Patients

over 75 are informed that their benefits are likely to be modest, though

“physiological age,” and disease status described above are perhaps more

significant considerations.

The patient remains awake during neurosurgery lasting about 2-3 hours per side of

brain. Patient cooperation and feedback during surgery contributes to technical

success. A helpful “screening test” for this is how well the patient tolerates an MRI

scan.

to treat medically. A reasonable set of criteria

for considering surgery are the presence of a

severely disabling tremor, clinically stable or

worsening for at least 6 months despite

optimal medical treatment, with lack of

significant weakness, sensory impairment,

dysarthria, swallowing difficulties, severe

cognitive impairement, or significant cerebral

atrophy on MRI. A review of 75 previously

published cases of DBS for the treatment of

MS tremor revealed that surgery resulted in

tremor reduction and improvement in some

measure of daily functioning respectively in

87.7 percent and 76.0 percent of patients.10

As with many studies of tremor, standardized,

qualitative outcomes measures were not used

in most of these reports, and few reports

involved follow-up beyond 1 year. The

majority of these patients were treated with

stimulators implanted in the Vim nucleus of

the thalamus, as for essential tremor, and it

appears that distal limb tremor is more easily

treated than either proximal limb tremors or

axial tremors.

A disabling tremor can result from

lesions of the dentato-rubro-thalamic path-

way (so-called “cerebellar outflow tremor”),

particularly in the vicinity of the red nucleus.

The term “rubral tremor”, also called Holmes’

tremor, refers to a 2 Hz to 5 Hz rest, postural,

and kinetic tremor, usually of an upper

extremity in the presence of such a lesion. In

a handful of reported cases, unilateral Vim

thalamotomy or Vim DBS has provided

effective control of tremor.11-13 Two case

reports detail the efficacy of Vim DBS in

controlling the distal component of the

postural and kinetic tremor, with control of

the axial and proximal appendicular compo-

nents achieved with the addition of a lesion

in the GPi in one case,14 and control of the

resting component of the tremor with a

stimulator implanted into the STN contrala-

teral to the tremulous extremity in another.5

Conclusion. The surgical treatment

of movement disorders has advanced signifi-

cantly over the last decade. Many patients

whose symptoms have not been well

controlled medically now have surgical

options, as in the cases of several non-

essential tremor conditions and dystonias.

With increasing collective experience, it is

becoming clearer which subsets of these

patients are likely to derive benefit from

surgery and which are not. When dealing

with relatively rare conditions, or with

diagnostic categories that encompass a

heterogeneous group of patients, it is less

likely that data from large, prospective,

randomized trials will be available or that

reasonable inferences can be made in

applying such results to individual patients.

In some instances, anecdotal and case reports

constitute the only available support for the

application of DBS to treat a patient whose

disabling symptoms do not respond to

medical therapy. Third party payers may

draw their own conclusions in regard to the

level at which efficacy must be demonstrated

in order to justify treatment, potentially

limiting patients’ access to this therapy.

Careful study and reporting of the results of

treatments of these unusual conditions, as

well as regular reviews of the state of the art

are therefore critical to the development of

surgical selection criteria and the rational

application of these techniques as treatments.

Address questions and comments to:Steven G. Ojemann M.D.

Assistant Professor, Department of

Neurological Surgery

University of Colorado School of Medicine

4200 East 9th Avenue

Denver, CO 80262

Fall 2005 19 www. thecni.org

Community Resources and Practical Pointersfor Parkinson’s DiseaseJosette Pressler, LPN

Due to time constraints, it is difficult for physicians and their office staff to know all of thevarious resources available for the many complex issues that may arise for the individual withParkinson’s disease. There are numerous national and local organizations available to assist thepatient and family. A list of Parkinson’s disease organizations and other useful resources is listed atthe end of the article.

Introduction. Parkinson’s disease (PD)

is a progressive neurodegenerative disease

and at this time, there is no cure, however, it

is one of the few neurological disorders

whose symptoms can be medically managed

for many years with proper medications.

Disease progression and severity varies

greatly between individuals. As the disease

progresses, many aspects of the patient’s and

their families lives may be affected. Rigidity,

bradykinesia, tremor, and balance issues are

not the only difficulties that a patient may

have. There are numerous non-motor

symptoms that may affect ones

independence. Due to the wide range of

challenges that one may face, accessibility to

many different types of resources may be

needed. This article intends to provide a

general cross-section of resources available

for the individual with PD and to provide a

few practical pointers that may ease some

daily tasks. By no means does this article

contain all resources available.

PD Education and Social Support. It is always important with any illness to

educate yourself and family members. For

Parkinson’s disease, there are many

educational resources available both

nationally and locally. Locally, CNI’s

Movement Disorders Center has

neurologists, nurse practitioners, and nurses

that are specifically trained in Parkinson’s

disease. The Center has numerous research

studies that encompass all stages of disease.

Support groups prove to be quite beneficial

for many individuals; we are fortunate in

Colorado to have Parkinson’s Association of

the Rockies (PAR) which not only has a

wonderful PD library, but has over 30 PD

support groups in Colorado, western

Nebraska, and Wyoming. Such support

groups allow patients and families to

network with others who have the same

disease and to share coping strategies with

the physical, social, and psychological

challenges that are faced on a daily basis.

Mobility and Safety. As the disease

progresses, a shuffling quality of gait,

decreased balance and freezing episodes may

interfere with ambulation. A single point

cane or a walker with 4 wheels or casters

may be helpful. Basic aluminum walkers and

4-pronged canes are not appropriate for the

individual with PD. To avoid falls from

tripping, it is recommended that scatter rugs

be removed from the home. To decrease

freezing episodes, rooms should not be

cluttered or crowded. For people with PD

CNI REVIEW 20

Ms. Pressler has more

than 25 years experience

working with neuro-

logical disease and the

past 8 years of working

specifically with

Parkinson’s disease at

CNI’s Movement

Disorders Center. As a

nurse educator, Josette

provides inservices to

many healthcare

providers including

nursing personnel at

hospitals, extended care

facilities, assisted living

facilities and also

provides education to

many different

community groups.

Josette is a member of the

Parkinson Association of

the Rockies (PAR)

education team which

provides information to

Parkinson support groups

in Colorado, Wyoming,

and western Nebraska.

Fall 2005 www. thecni.org21

that have difficulty standing from a chair, it

is helpful to have couches and chairs at a

level where it is easier to stand, preferably

with armrests to push up from. There are

“lift chairs” which have proven to be quite

helpful for the patient with PD who has

difficulty arising from a chair.

Personal Hygiene/Grooming.Regarding safety with bathing and toileting,

install handrails in the shower and toilet

areas. A shower bench or tub/transfer bench

may be quite helpful as is a hand held

shower head. Please remember to put non-

skid rubber mats in the bottom of showers.

If mobility is a problem, particularly at night

when one awakens and has the need to use

the bathroom, make sure the area to the

bathroom is well lit or use a urinal or

bedside commode. Rigidity, decreased

dexterity and tremor may make it difficult to

handle toothbrushes, razors etc. Electric

razors and electric toothbrushes help the

individual to remain independent with these

daily tasks.

Home Evaluations. It may be helpful

to have a home evaluation by a physical

therapist or occupational therapist to

maximize safety and independence. They

can give helpful suggestions and recommend

the appropriate adaptive equipment for the

patient and family. They may also be able to

let the doctor know if the patient can no

longer stay safely in the home.

Feeding/Eating. For the advanced PD

patient, it is better to eat meals during the

“on” times. Food may need to be cut into

smaller bite-size pieces which will be easier

to chew and swallow. Alternating liquids and

solids can help with swallowing. If the

patient chokes on thin liquids, then a

thickening agent may be requested. If the

patient experiences frequent coughing or

choking while eating, consider a swallow

evaluation by a speech-language pathologist.

Dressing. Due to decreased balance, it

is safer to sit down while dressing. It may be

helpful to use a footstool to put on socks

and shoes. Clothing with Velcro closures and

elastic waistbands for pants and skirts make

dressing easier. There are now many

different types of shoes with Velcro fasteners

instead of laces or there are “curly fries”

elastic-type shoelaces available.

Sleep Environment. Bed mobility may

be significantly impaired due to medications

wearing off at night. For easier bed mobility,

satin sheets or pajamas can help. Avoid

flannel sheets and heavy comforters, as they

may impair mobility further. Keep items off

the bedroom floor to avoid tripping. Some

patients benefit from a rope around the head

board for leverage or a floor to ceiling pole

next to the head of the bed. Many patients

with PD who have severe mobility problems

resort to a recliner for sleeping.

Communication/Speech. The most

common speech problem associated with

PD is lowered volume of speech. It may be

difficult to hear the person with PD,

however, many times the PD person thinks

they are talking at a normal volume. The

Lee Silverman Voice Therapy (LSVT) that is

used successfully for Parkinson’s disease voice

improvement internationally was developed

at the National Center for Voice and Speech

right here in Denver.

Driving. The issue of driving should

be addressed, particularly with the

individual who has motor fluctuations.

CNI REVIEW 22

Reaction times may be diminished, especially

when the patient is “off ”, making driving

more dangerous. Patients with PD also may

have problems with task shifting so it is

recommended that they drive with minimal

distractions in well lit, low traffic situations.

Driving evaluations are recommended if

there is any question about ones ability to

remain safe on the road.

Medications and Affordability. People

with PD are usually on multiple medications

for symptomatic control. These medications

are quite costly and, if one does not have an

insurance medication plan, may be

prohibitive to obtain. If the patient does not

have a medication plan and if purchasing the

medications out of pocket is a financial hard-

ship, most pharmaceutical companies have

patient assistance programs that upon

qualification, provide the drugs free of

charge. If the patient is a US Veteran, by all

means, have them contact their local VA. If

the patient is experiencing financial

difficulties, it may be appropriate to have

them contact their County of residence,

Human/Social Services department to see if

they would qualify for any programs.

Caregivers. Caregiving 24/7 is

extremely difficult. Access the caregiver for

“burn out” or depression during your

patients interview. Have the caregiver call in

“the troops”, whether it is a family member,

friend, or local senior organization, have

them get some respite!! Sometimes just a few

hours a week may help keep the patient at

home. Other families may need a few days

which many extended care facilities can

provide. Touring the facility first is

recommended. Today, there are many adult

day-care facilities that have different

programs for different levels of care.

Encourage continued activities that they find

enjoyable. Encourage rest, regular exercise

and a healthy diet.

Conclusion. Due to the numerous

challenges that the patient and family may

face as Parkinson’s disease advances,

accessibility to many different organizations

may be needed and/or helpful. We are

fortunate in the state of Colorado to have

access to many of these organizations both

locally and nationally. Many of the listed

organizations provide reading materials and

handouts free of charge. If you are a

physician, please do not hesitate to have your

patients contact the various organizations.

Address questions and comments to:Josette Pressler, LPN

National Parkinson Foundation

Center of Excellence Coordinator

701 E. Hampden Avenue, #330

Englewood, CO 80113

Fall 2005 23 www. thecni.org

Parkinson’s organizations:

Colorado Neurological Institute

Movement Disorders Center

701 E. Hampden Ave., Suite 530

Englewood, CO 80113

www.thecni.org

National Parkinson Foundation

1501 NW 9th Ave/Bob Hope Road

Miami, FL 33136-1494

1 (800) 327-4545

www.parkinson.org

Parkinson Association of the Rockies

1420 Ogden St.

Denver, CO 80218

(303) 830-1839

www.parkinsonrockies.org

Colorado Parkinson Foundation

Colorado Springs, CO

Ric Pfarrer

(719) 495-1853

Parkinson’s Disease Foundation

710 West 168th St.

NY, NY 10032-9982

1 (800) 457-6676

www.PDF.org

American Parkinson Disease Association

1250 Hylan Blvd. #48

Staten Island, NY 10305

1 (800) 223-2732

www.APDAParkinson.org

Michael J. Fox Foundation

Grand Central Station

PO Box 4777

NY, NY 10163

1 (800) 708-7644

www.michaeljfox.org

Worldwide Education & Awareness for

Movement Disorders

www.wemove.org

Parkinson’s disease advocacy:

Parkinson’s Action Network

1000 Vermont Ave. NW # 900

Washington DC 20005

1 (800) 850-4726

www.parkinsonaction.org

Patient Advocate Foundation

www.patientadvocate.org

Financial Assistance-Human Services:Contact your county of residence:

Adams County (303) 287-8831

Arapahoe County (303) 636-1130

Boulder County (303) 441-1000

Broomfield County (720) 887-2200

Denver County (720) 944-3666

Douglas County (303) 688-4825

Jefferson County (303) 271-1388

Adaptive Driving Programs:

“Behind the Wheel”

Spalding Rehabilitation Hospital

900 Potomac St.

Aurora, CO 80011

(303) 363-5321

www.SpaldingRehab.com

Master Drive of Colorado Springs

3280 E. Woodmen Rd.

Colorado Springs, CO 80920

(719) 260-0999

www.masterdrive.com

Parkinson’s Disease Resource ListThe following is a list of resources available, as mentioned earlier in this article, this by no means

is a list of all resources but a general cross-section.

CNI REVIEW 24

Master Drive of Denver, Inc.

15659 E. Hinsdale Dr.

Englewood, CO 80112

(303) 627-4447

www.masterdrive.com

Master Drive of Ft. Collins and Loveland

5609 Goldco Dr.

Loveland, CO 80538

(970) 593-6362

www.masterdrive.com

Speech Therapy:

National Center for Voice and Speech

DCPA Administration Building

1245 Champa St.

Denver, CO 80204

(303) 893-4000

www.lsvt.org

Physical therapy, Occupational therapy,Speech therapy:

Most local hospitals have outpatient

departments, or there may be free-standing

therapy centers in your community.

Adaptive Equipment:

You Can Too Can

2223 S. Monaco Pkwy

Denver, CO 80222

(303) 759-9525

www.youcantoocan.com

Pathways Homecare Center

11091 E. Mississippi Ave.

Aurora, CO 80012

(720) 207-9540

www.pathwayshomecare.org

AAA Medical

2095 W. Hampden Ave.

Englewood, CO 80110

(303) 781-1474

www.AAAmedical.com

The following is a wonderful organization

that publishes a free booklet loaded with

information for where to contact or go for

many different services available:

Seniors Resource Guide

(303) 642-2232

www.SeniorsResourceGuide.com

Fall 2005 25 www.thecni.org

Dr. Agarwal did her

neurology training at NJ

Neuroscience Institute.

She did fellowship in

movement disorders at

Columbia University,

NY. She has been

practicing subspecialty

movement disorders at

the Colorado Neuro-

logical Institute since

2003. Her special areas

of interest are

Parkinson’s disease and

parkinsonism, tremor,

dystonia including

botulinum toxin

injections, restless leg

syndrome and

tics/tourette’s syndrome.

Introduction. Huntington’s disease is

an autosomal dominant neurodegenerative

disorder characterized by abnormal move-

ments manifested as chorea, bradykinesia

and dystonia. There are also cognitive

abnormalities characterized by disorders of

attention and obsessive thoughts. The

mutation is an expansion of a trinucleotide

repeat in a gene on chromosome 4.

Clinical Manifestations. Huntington’s

disease is a fully penetrant, autosomal

dominantly inherited, progressive

neurodegenerative disease that causes

disorders of motor control, emotional

control, cognitive ability, and involuntary

movements, classically choreic. The mean

age of onset is approximately 40 years.

Several signs may portend onset of

clinically manifest Huntington’s disease:

increased motor restlessness, slowing of

saccadic eye movements, and slowing or

dysrhythmic production of rapid, repetitive

movements of the fingers or tongue. A

number of individuals have prominent

mood, thought, or personality disorders that

present in the years prior to onset of

definitive motor signs. Cognitive changes

may also precede onset of motor definitive

symptoms. In the earliest stages of

Huntington’s disease, disturbances of

problem-solving abilities, memory deficits,

visuospatial skills, and attention disorders

often lead to a decline in performance at

work or in the home.1

Because of its serious implications, the

diagnosis of manifest Huntington’s disease is

reserved for at-risk persons who have

developed chorea or another movement

disorder. Juvenile cases (less than 20 years of

age at onset) constitute about 5.4 percent of

all cases of Huntington’s disease.2 Juvenile

cases and occasional young adult cases can

present with prominent parkinsonism or

rigidity-dystonia with little or no chorea.

Motor Disorder. Chorea, from the

Greek meaning “to dance,” is an involuntary

movement around multiple joints.

Huntington’s disease displays generalized

choreiform movements. The mouth, trunk,

and proximal as well as distal muscles are

prominently affected. More flowing and

somewhat slower choreoathetotic

movements also often occur with more

advanced disease as do fast, large amplitude,

flinging movements resembling ballism.

Huntington’s disease is a disorder of

Huntington’s DiseasePinky Agarwal, M.D. and Lauren C. Seeberger, M.D.

Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized byabnormal movements manifested as chorea, bradykinesia and dystonia. There are also cognitiveabnormalities characterized by disorders of attention and obsessive thoughts. The mutation is anexpansion of a trinucleotide repeat in a gene on chromosome 4. This article outlines currenttreatment options.

CNI REVIEW 26

Dr. Seeberger earned her

undergraduate degree

from Vanderbilt

University and received

her MD from the

University of Alabama.

Her fellowship training

is in movement disorders

at UMDNJ - Robert

Wood Johnson Medical

School and she is Board

Certified in neurology.

Dr. Seeberger has

written and lectured

extensively on movement

disorder and is currently

involved in CNI research

projects to develop

treatments for

Huntington’s disease and

Parkinson’s disease.

voluntary motor control that causes

progressive physical disability. There is a

serious impairment in sequential movement.

Mimical apraxia is common although

language skills remain mostly intact. Patients

are unable to learn complicated motor skills.

Other motor signs include

bradykinesia, dystonia, imbalance, and

speech disturbances. Bradykinesia generally

coexists with chorea in the adult form of

illness. A parkinsonian state with marked

slowing of eye movements is seen in the

juvenile onset cases (Westphal variant);

seizures and myoclonus commonly

complicate the course of juvenile onset

Huntington’s disease. Deep tendon reflexes

are hyperactive in Huntington’s disease. Poor

balance manifests in mid to late stages of

disease for both adult and juvenile forms

with frequent falling and eventual wheelchair

or bed-bound state. On examination, broad

based stance and gait are common, and

tandem walking is often impaired. Speech

and swallowing dysfunction develop

midstage of the illness and ultimately lead to

inability to communicate and swallow. The

movement disorder in adult onset

Huntington’s disease changes with time.

Chorea tends to slow and may be

replaced by dystonia-rigidity in the end

stages. Careful reviews of medications

should be undertaken as the clinical picture

changes to ensure that neuroleptic or other

drug use is not contributing to motor

dysfunction.

Psychiatric Disorder. Psychiatric

disorders are prevalent in patients with

Huntington’s disease; including psychosis

with rare visual hallucinations, a delusional

thought disorder, mood lability, anxiety,

irritability, mania, obsessive behavior, or

rigidity of thought. Disabling or over-

whelming apathy from frontal lobe

dysfunction is not unusual. Depression is the

most common psychiatric manifestation of

Huntington’s disease and may be

accompanied by emotional irritability with

outbursts of disruptive behavior. Suicide

occurs in 5 percent to 10 percent of

Huntington’s disease patients, and there is an

increased risk of suicide for those at-risk for

the disease. 3 Frank psychosis is relatively

unusual, though delusions may occur.

Obsessive ideation is common and may

respond to SSRIs.

Cognitive decline occurs in all patients

and may be more, less, or equally as disabling

as the motor disorder in different patients1.

Patients tend to be disorganized and suffer

from lack of initiative. Some may show no

awareness of their movement or cognitive

disorder. There is usually a more rapid

decline in visuospatial as compared to verbal

skills. Also, a more dramatic drop in

performance IQ as opposed to verbal IQ

scores is seen4.

Etiology. Huntington’s disease results

from an expanded and unstable trinucleotide

repeat in the IT15 gene on the short arm of

chromosome 4. There is a 50 percent chance

of inheriting the gene from an affected

parent. The gene produces a protein called

huntingtin. Three nucleotides, cytosine-

adenine-guanine, form a trinucleotide and

are repeated over and over in this gene

normally. A person may have as many as 35

repetitions of the CAG trinucleotide in the

Huntington’s disease gene. Persons with more

than 39 repeats will develop Huntington’s

disease, and those with 36 to 39 repeats are

“indeterminate” and may or may not develop

the disease. Such indeterminate individuals

may have offspring with clinical

Huntington’s disease who have a more

Fall 2005 27 www.thecni.org

expanded CAG repeat length in the gene.6

Epidemiology. The prevalence of

affected individuals in the United States is

estimated at 5 to 10 per 100,000.7

Approximately 2 to 4 times as many

individuals have inherited the mutation but

are as yet asymptomatic.

Diagnostic Workup. The diagnosis can

be made on the basis of the clinical

presentation described above in the context

of a confirmed family history of

Huntington’s disease. MRI and CT scans

show prominent caudate atrophy in young

patients with moderate disability but may be

within the normal range of patients with

early signs of Huntington’s disease. DNA

diagnostic testing can now determine

whether a patient with a suspicious clinical

syndrome has Huntington’s disease and is

invaluable in clarifying uncertain situations.

Appropriate genetic counseling should be

available. Neuropsychological testing can be

helpful in delineating the patient’s degree of

cognitive disability.

Prognosis and Complications.Huntington’s disease is a progressive

neurodegeneration that leads to death via

medical complications. Complications

during the course of illness include speech

and swallowing problems, imbalance,

incoordination, and falling, as well as

impaired judgment and cognition. Death

usually is caused by infectious complications

of immobility in the late stages of the illness.

Management. Treatment of patients

with Huntington’s disease requires a

coordinated effort on the part of a medical,

psychiatric, social service and physical

therapy team. For those who are gene

positive and asymptomatic or early

symptomatic, focus should be on treatments

that may potentially slow disease

progression. A national trial showed neither

remacemide nor coenzyme Q10 given alone

or in combination has any significant effect

on progressive functional decline.

Minoclycline study in delaying disease

progression, showed that it was well

tolerated and had no serious adverse events.8

A 1-year placebo-controlled clinical

trial of creatine supplementation (5mg/day)

in Huntington’s disease did not improve

functional, neuromuscular, or cognitive

status in patients with early disease.9

Depression often responds partially to

treatment with standard antidepressants.

Carbamazepine or valproate may improve

patients with a manic disorder. Delusions

and paranoia often respond to low dose

neuroleptics. Carbamazepine, SSRIs, clona-

zepam, propranolol, valproate, and clomi-

pramine are just some of the medications

that may be helpful for irritability and

emotional dyscontrol. Risperidone may be

useful for management of psychiatric dis-

orders in patients with Huntington’s disease.

Chorea in Huntington’s disease may

be treated effectively with neuroleptics.

Other agents used include tetrabenazine,

benzodiazepines, and propranolol. In a

randomized trial, amantadine hydrochloride

treatment at doses of 300mg/day had no

effect on Huntington’s chorea, although

most patients felt subjectively better.10

In a multicenter placebo-controlled

trial, riluzole 200mg/day decreased the

intensity of chorea without improving

functional capacity. It caused reversible liver

transaminase abnormalities that require

long-term monitoring.11 Dystonia and

rigidity may complicate end stage disease

and can be treated with local injections of

1. White FR, Vasterling JJ,Koroshetz WJ, Myers R.Neuropsychology ofHuntington’s’s disease.In: White R, editor.Clinical syndromes inadult neuropsychology; thepractitioner’s handbook.Amsterdam: Elsevier,1992:213-248.

2. Nance MA. Genetictesting of children at riskfor Huntington’s’sdisease. Neurology.1997;49:1048-1053.

3. Sorensen S, Fenger K.Causes of death inpatients withHuntington’s’s diseaseand in unaffected firstdegree relatives. J MedGenetics. 1992;29:911-914.

4. Zakzanis KK. Thesubcortical dementia ofHuntington’s’s disease. JClin Exp Neuropsychol.1998;20:565-578.

5. Rubinsztein DC, LeggoJ, et al. Phenotypiccharacterization ofindividuals with 30-40CAG repeats in theHuntington’s’s genereveals HD cases with36 repeats andapparently normalelderly individuals with36-39 repeats. Am JHum Genet .1996;59:16-22.

6. Sanchez A, Mila M,Castellvi-Bel S, et al.Maternal transmissionin sporadicHuntington’s’s disease. JNeurol NeurosurgPsychiatry. 1997;62:535-537.

7. Conneally PM.Huntington’s’s disease:genetics andepidemiology. Am JHum Genet.1984;36:506-526.

botulinum toxin type A.

Juvenile cases of Huntington’s disease

are often treated with carbidopa and

levodopa to reduce prominent bradykinesia,

posture abnormalities, rigidity, and dystonia.

Nutrition is important in

Huntington’s disease patients as their caloric

requirements may be increased. At end stage,

patients are bed-bound, mute and rigid.

Eventually dysphagia and aspiration become

problematic.The patient’s wishes regarding

gastric tube feeding should be ascertained in

preparation for this stage of illness.

Pregnancy. Those who carry the gene

should also have genetic counseling prior to

conception. Prenatal diagnostic testing is

available at some centers.

Conclusion. The last decade has seen

exciting advances in the understanding of

Huntington’s disease.

Continuing research will also improve

our ability to treat and possibly slow

progression of the disease.

Address questions and comments to:Pinky Agarwal, M.D.

Lauren C. Seeberger, M.D.

CNI Movement Disorders Center

701 E. Hampden Avenue, #530

Englewood, CO 80113

8. Thomas M, AshizawaT, Jankovic J.Minocycline inHuntington’s’s disease:a pilot study. MovDisord.2004;19(6):692-695.

9. Verbessem P, LemiereJ, Eijnde BO, et alCreatinesupplementation inHuntington’s’s disease:a placebo-controlledpilot trial. Neurology.2003;61(7):925-930.

10. O’Suilleabhain P,Dewey RB Jr. Arandomized trial ofamantadine inHuntington’s disease.Arch Neurol.2003;60(7):996-998.

11. Huntington’s StudyGroup. Dosage effectsof riluzole inHuntington’s’s disease:a multicenter placebo-controlled study.Neurology.2003;61(11):1551-1556.

Spring 2005 28 www. thecni.org

Acknowledgements anddisclosures published inMedlink

Fall 2005 29 www.thecni.org

Dr. Seeberger earned her

undergraduate degree

from Vanderbilt

University and received

her MD from the

University of Alabama.

Her fellowship training

is in movement disorders

at UMDNJ - Robert

Wood Johnson Medical

School and she is Board

Certified in neurology.

Dr. Seeberger has

written and lectured

extensively on movement

disorder and is currently

involved in CNI research

projects to develop

treatments for

Huntington’s disease and

Parkinson’s disease.

Definition. Cerebellar tremor is

defined as a proximal 3 to 5 Hertz action

tremor in the extremity ipsilateral to lesions

of the deep cerebellar nuclei or the outflow

tracts of these nuclei in the superior

cerebellar peduncle. Most commonly,

cerebellar tremor is a low frequency tremor,

that is, below 4 Hertz. Although, there is

some confusion regarding the nosology of

the types of tremor, it is generally accepted

that one calls the action tremor during

movement a “kinetic tremor”, the increase in

kinetic tremor amplitude at endpoint

“intention tremor” and the action tremor

during posture holding a “postural tremor”.1

Classically, the tremor amplitude of

cerebellar tremor increases as the limb is

visually guided to the target thus termed

“intention tremor.” It can be elicited by

performing finger-to-nose testing, finger-

chase testing or heel-knee-shin testing.

There may be a postural component of the

tremor. One must differentiate tremor from

the incoordinated ataxic movements of the

limb also seen with cerebellar dysfunction.

Limb ataxia is a general term that refers to

the gross irregular decomposition of

movements of the limb. Specifically, poor

performance in smooth, fluent, rapid

alternating movements is called

dysdiadochokinesis. Dyssynergia is the loss

of muscle coordination leading to

breakdown of ‘en mass’ movements into

individual parts and dysmetria is the

inability to measure properly range in

motion with hypometria (undershooting

target) as well as hypermetria (overshooting

target). Cerebellar tremor is usually

perpendicular to the direction of movement

and variable in amplitude. The dominant

feature of tremor should be its rhythmic

nature. The diagnosis of cerebellar tremor

may be made only when there is a pure or

predominant intention tremor (unilateral

or bilateral) of low frequency (usually

below 5 Hz) without the presence of a

resting tremor. 1

Pathophysiology of Cerebellar Tremor.There are 3 theories about how the normal

cerebellum guides and controls movement.2

The first is that the cerebellum acts through

a feedback system. This system uses constant

feedback to the cerebellum from the

peripheral receptors to adjust ongoing

movement. A lesion study in cats supports

the role of cerebellar outflow neurons in

correcting ongoing movement initiated by

the motor cortex.3 The second theory is that

the cerebellum uses feedforward control. In

this theory, the cerebellum has planned

motor sequences that are sent to the motor

cortex in anticipation of movement. This

enables movements to be accomplished

more quickly especially for learned

movements. Evidence shows that there is

Cerebellar Tremor – Definition and TreatmentLauren C. Seeberger, M.D.

One of the most difficult movement disorders to diagnose and treat is cerebellar tremor. This review serves to familiarize the clinician with basic definitions and treatment options for thistremor type.

1. Dueschl G, Bain P, BrinM, Committee AHS.Consensus Statement ofthe Movement DisorderSociety on Tremor.Movement Disorders.1998;13(Supplement3):2-23.

2. Johnson DS,Montgomery EB.Pathophysiology ofCerebellar Disorders. In:Watts RL, Koller WC,eds. Movement Disorders:Neurologic Principles andPractice. New York:McGraw-Hill;1997:587-610.

3. Li Volsi G, Pacitti C,Perciavalle V, SapienzaS, Urbano A.Interpositus NucleusInfluences OnPyramidal TractNeurons in the Cat.Neuroscience.1982;7(8):1929-1936.

4. Cooper IS. A cerebellarmechanism in restingtremor. Neurology.1966;16(10):1003-1015.

5. Dueschl G, Krack P,Lauk M, Timmer J.Clinical Neuro-physiology of Tremor.Journal of ClinicalNeurophysiology.1996;13(2):110-121.

6. Krauss JK, Trankle R,Kopp KH. Post-traumatic movementdisorders in survivors ofsevere head injury.Neurology.1996;47(6):1488-1492.

7. Lang AE, Weiner WJ,eds. Drug-InducedMovement Disorders.Mount Kisco: FuturaPublishing Company,Inc.; 1992.

8. Gilman S. ClinicalFeatures and Treatmentof Cerebellar Disorders.In: Watts RL, KollerWC, eds. MovementDisorders: NeurologicPrinciples and Practice.New York: McGraw-Hill; 1997:576-585.

CNI REVIEW 30

activation of the dentate nucleus that

proceeds intended movement.2 Lastly, there

is the idea of efferent copy in which the

motor cortex provides the cerebellum with a

‘copy’ of the motor plan that is being sent to

effector muscles prior to movement. The

cerebellum can then make short loop

corrections back to the motor cortex even

before movement is completed. It stands to

reason that the development of pathologic

tremor must involve dysfunction of one or

more of these control systems allowing

oscillation to occur. The most important

cerebellar pathways for movement control

involve the cerebello-dentato-rubro-thalamic

circuit. Cerebellar tremor is caused by a

lesion of these deep lateral cerebellar nuclei

or their outflow paths in the superior

cerebellar peduncle up to but not beyond

the red nucleus. 4 Injury to the cerebellar

cortex itself does not initiate tremor.

Electrophysiologic studies of tremor

frequency may be helpful in diagnosis of

cerebellar tremor as few types of tremor have

such low frequency. 5

Etiology of Cerebellar Tremor. There

are many causes of cerebellar tremor. The

most common causes are multiple sclerosis

(MS), trauma, and degenerative diseases of

the cerebellum. Tremor and other cerebellar

signs are often seen in MS, especially with

disease progression. After severe closed head

injury, tremor emerged between 2 weeks and

6 months in 19 percent of survivors in one

study with 58 percent of those experiencing

tremor of less than one year duration.6 The

cerebellar degenerative diseases may be

inherited or spontaneous (Table 1). Rarely

do any of these disorders present with

tremor as an isolated feature nor does the

tremor distinguish the etiology of cerebellar

disease. This tremor, like most others, is

never a sign of normal aging. As a general

rule, degenerative or toxic cerebellar

dysfunction cause bilateral tremor and a

focal unilateral disease process, such as a

mass, infarction, or plaque, causes unilateral

tremor. But there are a variety of other signs

of cerebellar dysfunction depending on the

areas of the cerebellum or outflow tracts that

are affected. The tremor in context with

history, neurological exam and evaluation

should lead the clinician to a working

diagnosis in most cases. Magnetic resonance

imaging (MRI) is very helpful to assess the

cerebellum for degeneration, white matter

disease and to show the plaques of multiple

sclerosis. MRI brain scanning can also define

traumatic injury, tumor formation or

cerebrovascular accident and is

recommended in any case of new onset

cerebellar tremor. Toxic causes of intention

tremor include: chronic alcoholism, lithium,

heavy metal intoxication, and some

medications 7 of the anticonvulsant,

antidepressant and neuroleptic classes. Other

causes of cerebellar tremor: neoplasm and

paraneoplastic syndromes, Wilson’s disease

and other inherited metabolic diseases,

endocrinopathies, and infections.8

Treatment of Cerebellar Tremor. As

our understanding of the pathophysiologic

basis of cerebellar tremor grows it is hoped

that better treatments for these potentially

disabling tremors will be developed. Open

label studies and case reports have suggested

several medications that may have some

benefit including propranolol, primidone,

glutethimide, carbamazepine, isoniazid,

clonazepam, buspirone and topiramate.

However, there have been few randomized

double-blind (DB) trials. Many of the

medications tried for cerebellar tremor have

been used to treat essential tremor. Braham

Fall 2005 31 www.thecni.org

et al.19 noted beneficial effects on ataxia and

intention tremor in 2 brothers with familial

ataxia treated with propranolol 120 mg/day.

However, in a crossover treatment trial of 6

patients, propranolol was not found to

benefit cerebellar tremor.18 In another report,

2 patients with MS-related tremor given

primidone experienced tremor reduction

and better hand control.14

In a 10 patient single-blind study,

carbamazepine significantly reduced

cerebellar tremor amplitude and clinical

tremor scores at 15 days (400 mg/day) and

30 days (600 mg/day). Improvement

correlated with mean carbamazepine plasma

levels.12 Seven of the 10 patients chose to

stay on long-term treatment and attempts to

lower the carbamazepine dose were

associated with worsening of tremor. An

open-label study of 3 patients with cerebellar

tremor following stroke noted marked

efficacy of carbamazepine at 600 mg/day

(serum levels between 5.8 - 9.6

micrograms/ml) with return of tremor

severity upon cessation of the agent.11

It has been postulated that the mechanism

by which carbamazepine ameliorates

cerebellar tremor is through reduction of

9. Andrew J, Fowler CJ,Harrison MJG.Tremor after headinjury and itstreatment bystereotaxic surgery. JNeurol NeurosurgPsychiatry.1982;45:815-819.

10. Sandyk R. Successfultreatment of cerebellartremor withclonazepam. ClinPharm. 1985;4(6):615,618.

11. Sechi GP, Pirisi A,Agnetti V, Piredda M,Zuddas M, Tanca S, etal. Efficacy ofcarbamazepine oncerebellar tremors inpatients with superiorcerebellar arterysyndrome. J Neurol.1989;236(8):461-463.

12. Sechi GP, Zuddas M,Piredda M, Agnetti V,Sau G, Piras ML, et al.Treatment ofcerebellar tremors withcarbamazepine: Acontrolled trial withlong-term follow-up.Neurology.1989;39:1113-1115.

13. Lou J-S, Goldfarb L,McShane L, Gatev P,Hallett M. Use ofBuspirone forTreatment ofCerebellar Ataxia. ArchNeurol. 1995;52:982-988.

14. Henkin Y, HerishanuYO. Primidone as aTreatment forCerebellar Tremor inMultiple Sclerosis-Two Case Reports. IsrJ Med Sci.1989;25(12):720-721.

15. Sechi GP, Agnetti V,Sulas FMI, Sau G,Corda D, Pitzolu MG,et al. Effects oftopiramate in patientswith cerebellar tremor.(Progress in Neuro-Psychopharmacology &Biological Psychiatry.2003;27:1023-1027.

Table 1. Causes of Cerebellar Tremor

CAUSE GENETIC TEST AVAILABLE

Trauma

Closed head injury, Hypoxia, Stroke,

Cerebellar neoplasm, Hypertherrmia

Inherited

Spinocerebellar ataxias SA1-SCA 17

SCA-12, SCA-16, SCA19

FXTAS Fragile X DNA

Diseases

Multiple Sclerosis, OPCA/MSA, Wilson’s Disease

Paraneoplastic syndrome Hu, Yo, CV2, TaTa, Ri,

CAR, LEMS

Creutzfeldt-Jacob disease

Guillain-Barre’ Syndrome

Endocrinopathy

Hyperthyroid

Hypoparathyroid

Hypoglycemia (insulinoma)

Cerebellar Neoplasm

Infections

Rubella, H. Influenzae, Rabies,

Varicella infection or vaccination

Drug effects

EtOH, Lithium, Heavy metal, Anticonvulsants,

Antidepressants, Neuroleptics,

Chemotherapeutic agents

FTXAS, Fragile X associated tremor and ataxia; OPCA, olivopontocerebellar atrophy; MSA, multiple system atrophy

CNI REVIEW 32

16. Trouillas P, Xie J,Adeleine P, Michel D,Vighetto A, HonnoratJ, et al. Buspirone, a 5-Hydroxytryptamine1A Agonist, Is Activein Cerebellar Ataxia.Arch Neurol.1997;54:749-752.

17. Bier JC, Dethy S,Hildebrand J, Jacquy J,Manto M, Martin JJ,et al. Effects of the oralform of ondansetronon cerebellardysfunction. A multi-center double-blindstudy. J Neurol.2003;250(6):693-697.

18. Koller WC.Pharmacologic Trialsin the Treatment ofCerebellar Tremor.Archives of Neurology.1984;41:280-281.

19. Braham J, Sadeh M,Turgman J, Sarova-Pinchas I. Beneficialeffect of propranolol infamilial ataxia. AnnNeurol. 1979;5(2):207.

20. Duquette P, Pleines J,du Souich P. Isoniazidfor tremor in multiplesclerosis: a controlledtrial. Neurology.1985;35(12):1772-1775.

21. Wasielewski PG, BurnsJM, Koller WC.Pharmacologictreatment of tremor.Mov Disord. 1998;13Suppl 3:90-100.

22. Weiss N, North RB,Ohara S, Lenz FA.Attenuation ofcerebellar tremor withimplantation of anintrathecal baclofenpump: the role ofgamma-aminobutyricacidergic pathways.Case report. JNeurosurg.2003;99(4):768-771.

repetitive neuronal firing in the VIM nucleus

of the thalamus.10

Evidence as to whether isoniazid can

reduce cerebellar tremor has been mixed.

Limited improvement from isoniazid up to

1000 mg/day was reported by Duquette in

13 MS patients with 10 patients showing

slight change on one or more assessments.20

However, other trials with isoniazid reported

better success with doses up to 1200

milligrams per day. Isoniazid inhibits γ-

aminobutyric acid-aminotransferase, the first

step in the enzymatic breakdown of GABA,

and therefore increases GABA concentration.

GABA is the major inhibitory neurotrans-

mitter of the efferent pathways of the

cerebellum and CSF levels of GABA are

known to be reduced in some degenerative

cerebellar ataxias.21 Isoniazid has many

adverse effects including the potential for

hepatic toxicity and liver function testing

should be done regularly.

Other treatments to enhance GABA

have been tried. Weiss et al, reported marked

improvement in upper extremity cerebellar

tremor in one case after an intrathecal

baclofen pump was placed for bilateral lower

extremity spasticity.22 In addition,

benzodiazepines have been reported shown to

improve some cases of cerebellar tremor 10, 23

by facilitating GABAergic transmission. In a

study by Sechi et al, the GABA agonist,

topiramate was employed in doses up to 200

mg per day (average 122 mg/day) in 9

patients (5 with MS, 2 with inherited

degenerative disease, 1 with paraneoplastic

syndrome, and 1 CVA) with 7 taking it as

monotherapy and 2 in combination with

carbamazepine.15 There were significant

reductions in both postural and intention

tremor in the treated group but 3 of 9

patients terminated early due to side effects.

These results suggest that a placebo-

controlled trial of topiramate using a slower

titration in an effort to lessen side effects is

warranted.

Buspirone hydrochloride, a serotonin

agonist, has been evaluated in one open-label

and one double-blind trial for cerebellar

ataxia. The open label trial of buspirone 60

mg/day found significant overall benefit in

clinical rating of ataxia in the mild-moderate

group, particularly for those with lower

extremity dysfunction.13 Similarly, a double-

blind study of buspirone16 for cerebellar

ataxia demonstrated improvement in kinetic

scores. Neither of these studies specifically

evaluated tremor, but overall functional

improvement may be more important than

isolated tremor reduction. The therapeutic

mechanism of action of buspirone in this

setting is unknown but is independent of any

anxiolytic or anti-depressant effect.

The intravenous and oral forms of

ondansetron, a 5-HT 3 receptor antagonist,

have been studied as possible treatments for

cerebellar tremor. A recent double-blind trial

evaluating oral ondansetron, 16 mg/day

versus placebo, for tremor in 45 patients with

various cerebellar disorders showed no

significant improvement in upper extremity

tremor in any group.17

Surgical Interventions. A wide variety

of tremor types improve after ventral

intermediate nucleus (Vim) thalamotomy,

reflecting this area’s role as a common

pathway for rhythmic activity in the brain.

Narabayashi described rhythmic, large-spiked

burst discharges in the Vim synchronous

with contralateral body tremor and proposed

that lesions of this nucleus would disrupt the

tremor circuit.24 He considered intention

tremor to be one of the movements most

successfully improved by thalamotomy based

on his many years of performing the surgery.

Thalamotomy. Thalamotomy has been

used to treat cerebellar tremor arising from

various causes, including trauma, multiple

sclerosis, stroke, and unknown. In a series of

7 mostly pediatric trauma-induced cases of

intention tremor, Marks reported

improvement in tremor and function in 6 of

7 patients who underwent thalamotomy.25

However, it should be noted there were no

specific measures of function or tremor

assessment reported and 2 of the seven

experienced transient hemiparesis following

surgery. Similarly, in 8 head trauma patients

with mixed tremor undergoing thalamotomy,

Andrew et al, described marked improvement

in all 8 due to resolution of postural tremor

and reduction of kinetic tremor but

temporary worsening of dysarthria, ataxia

and weakness.9 Again, there were no

measures of tremor or function used to

quantify these results. Because post-

traumatic movements can spontaneously

improve within the first year after injury,

patients should generally not be referred for

surgery within this time.9, 25

A larger study of thalamotomy for

cerebellar tremor of various etiologies (22 ET,

46 MS, 11 posttraumatic, 9 post stroke, and

7 idiopathic) found that most patients

experienced improvement in several domains

including tremor severity, motor dexterity

and ability to drink from a cup without

spilling.27 MS patients had a significant

number of post-operative complications (44

events in 53 surgeries including persistent

cognitive dysfunction, hemiparesis,

dysarthria, gait ataxia, arm ataxia and

numbness) and worsening of MS was

observed in 8.7 percent despite peri-operative

steroid treatment. The majority of MS

patients were evaluated for one year or less

with more than half exhibiting recurrence of

some tremor within the first year after

surgery. The risks of lack of sustained

improvement in tremor and possible relapse

of MS symptoms must be explained to

potential surgical candidates along with

possible benefits. Of the 25 patients who

underwent thalamotomy for other types of

cerebellar tremor in this series the best

improvement was observed for post-stroke

tremor. Bilateral thalamotomy is usually

avoided because of the high risk of dysarthria

and dysphagia.

Deep Brain Stimulation. Deep brain

stimulation (DBS) of the Vim nucleus has

now been used to treat cerebellar tremor.

DBS does not improve the associated signs of

dyssynergia and dysmetria which may be the

most disabling aspects of the cerebellar

dysfunction. Therefore, candidates for DBS

must be carefully selected and reasonable

expectations for outcomes set. Deep brain

stimulation has gained favor because of the

decline in tremor suppression with thalamo-

tomy over time. The advantages of DBS

include no permanent lesion, the potential

for bilateral placement in patients with

bilateral tremor, and adjustability of

stimulation settings if tremor control wanes.

In a study by Geny et al, 69.2 percent of 13

patients with MS related tremor undergoing

DBS had reduction in tremor amplitude

(mostly proximal), although none had

complete resolution of tremor.28 In 2 studies

of DBS for different tremor types, including

some individuals with MS-related tremor,

dysarthria was reported in about 30 percent

of those having bilateral DBS or a unilateral

DBS placed contralateral to a thalamotomy

lesions.30, 31 Change in stimulation parameters

was reported to help the dysarthria but

Spring 2005 www.thecni.org33

23. Trelles L, Trelles JO,Castro C, Altamirano J,Benzaquen M.Successful treatment oftwo cases of intentiontremor withclonazepam. AnnNeurol. 1984;16(5):621.

24. Narabayashi H. Analysisof intention tremor.Clin Neurol Neurosurg.1992;94 Suppl:S130-132.

25. Marks PV. Stereotacticsurgery for post-traumatic cerebellarsyndrome: an analysis ofseven cases. StereotactFunct Neurosurg.1993;60(4):157-167.

26. Critchley GR,Richardson PL. Vimthalamotomy for therelief of the intentiontremor of multiplesclerosis. British Journalof Neurosurgery.1998;12(6):559-562.

27. Shahzadi S, Tasker RR,Lozano A.Thalamotomy forEssential and CerebellarTremor. Stereotact FunctNeurosurg. 1995;65:11-17.

28. Geny C, Nguyen JP,Pollin B, Feve A, RicolfiF, Cesaro P, et al.Improvement of severepostural cerebellartremor in multiplesclerosis by chronicthalamic stimulation.Mov Disord.1996;11(5):489-494.

29. Schulder M, Sernas TJ,Karimi R. ThalamicStimulation in Patientswith Multiple Sclerosis:Long-Term Follow-up.Stereotact FunctNeurosurg. 2003;80:48-55.

30. Siegfried J, Lippitz B.Chronic electricalstimulation of the VL-VPL complex and of thepallidum in thetreatment of movementdisorders: personalexperience since 1982.Stereotact FunctNeurosurg. 1994;62(1-4):71-75.

resulted in less tremor control. Recently, a

long term (mean of 32 months) study of

DBS in 9 medically refractory multiple

sclerosis patients demonstrated a reduction of

tremor in all, though improvement was

greatest at the outset.29 Extended Disability

Status Scale (EDSS) scores worsened over

time and were on average, 6.7 before surgery,

6.8 at 6 months and 7.8 at late follow-up.

Improvement in tremor scores persisted

despite the fact that disability scores

worsened. This is consistent with continued

benefit for tremor despite progression of the

underlying disease. Within one month of

surgery, one-third had exacerbations of MS

symptoms, requiring steroid therapy. How-

ever, one-third, had long term restitution of

their ability to feed themselves and maintain

independent personal hygiene when stimu-

lated. The authors conclude after reviewing

other published accounts of DBS for MS-

related tremor that the surgery is safe and

effective for reducing tremor. In addition,

some patients may have sustained benefit but

the progressive nature of MS makes it

difficult to assess functional outcomes from

surgery over time. This finding is likely to

hold true for any neurodegenerative cause of

cerebellar tremor. Better outcome tools are

required to truly determine functional

outcome, disability, and quality of life

following DBS so these concerns should be

addressed in future trials of surgical treat-

ment for cerebellar tremor. Although there

are limitations in functional improvement as

currently measured, the resistance to medical

treatment and debilitating aspects of this

tremor along with the low morbidity and

mortality rate of DBS make the surgery an

acceptable option for those appropriately

selected patients with moderately to severely

disabling cerebellar tremor.

Conclusion. Cerebellar tremor is

remarkable in its presentation, can be

disabling for the patient, and is very difficult

to treat. Although the underlying cause is

usually able to be determined, the treatment

is based on amelioration of symptoms of

tremor rather than by change in tremor

expected by treatment of the disease. Over

the years many medications have been tried

for cerebellar tremor with mixed success.

New surgical techniques may be of benefit in

some patients who have failed attempts at

medical therapies.

Address questions and comments to:Lauren C. Seeberger, M.D.

Director, CNI Movement Disorders Center

701 E. Hampden Avenue, #530

Englewood, CO 80113

CNI REVIEW 34

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Dystonia Therapy: Unilateral or bilateral stimulation of the internal globus pallidus(GPi) or the subthalamic nucleus (STN) by the Medtronic Activa System is indicatedas an aid in the management of chronic, intractable (drug refractory) primary dys-tonia, including generalized and segmental dystonia, hemidystonia, and cervical dys-tonia (torticollis), for individuals 7 years of age and older.

Contraindications: Contraindications include patients who will be exposed to MRIusing a full body radio-frequency (RF) coil or a head transmit coil that extends overthe chest area, patients who are unable to properly operate the neurostimulator, orfor Parkinson’s disease and Essential Tremor, patients for whom test stimulation isunsuccessful. Also, diathermy (e.g., shortwave diathermy, microwave diathermy ortherapeutic ultrasound diathermy) is contraindicated because diathermy’s energycan be transferred through the implanted system (or any of the separate implantedcomponents), which can cause tissue damage and can result in severe injury ordeath. Diathermy can damage parts of the neurostimulation system.

Warnings/ Precautions/Adverse Events: There is a potential risk of tissue damageusing stimulation parameter settings of high amplitudes and wide pulse widths.Extreme care should be used with lead implantation in patients with a heightenedrisk of intracranial hemorrhage. Do not place the lead-extension connector in thesoft tissues of the neck. Placement in this location has been associated with anincreased incidence of lead fracture. Theft detectors and security screening devicesmay cause stimulation to switch ON or OFF, and may cause some patients to expe-rience a momentary increase in perceived stimulation. Although some MRI proce-dures can be performed safely with an implanted Activa System, clinicians shouldcarefully weigh the decision to use MRI in patients with an implanted Activa System.MRI can cause induced voltages in the neurostimulator and/or lead possibly causinguncomfortable, jolting, or shocking levels of stimulation. MRI image quality may bereduced for patients who require the neurostimulator to control tremor, because thetremor may return when the neurostimulator is turned off.

Severe burns could result if the neurostimulator case is ruptured or pierced. TheActiva System may be affected by, or adversely affect, medical equipment such ascardiac pacemakers or therapies, cardioverter/ defibrillators, external defibrillators,ultrasonic equipment, electrocautery, or radiation therapy. Safety and effectivenesshas not been established for patients with neurological disease other thanParkinson’s disease or Essential Tremor, previous surgical ablation procedures,dementia, coagulopathies, or moderate to severe depression; or for patients who arepregnant, under 18 years, over 75 years of age (Parkinson’s Control Therapy) or over80 years of age (Tremor Control Therapy). For patients with Dystonia, age of implantis suggested to be that at which brain growth is approximately 90% complete orabove. Additionally, the abrupt cessation of stimulation for any reason should beavoided as it may cause a return of disease symptoms. In some cases, symptomsmay return with an intensity greater than was experienced prior to system implant(“rebound” effect). Adverse events related to the therapy, device, or procedure caninclude: stimulation not effective cognitive disorders, pain, dyskinesia, dystonia,speech disorders including dysarthria, infection, paresthesia, intracranial hemor-rhage, electromagnetic interference, cardiovascular events, visual disturbances,sensory disturbances, device migration, paresis/asthenia, abnormal gait, incoordina-tion, headaches, lead repositioning, thinking abnormal, device explant, hemiplegia,lead fracture, seizures, respiratory events, and shocking or jolting stimulation.

Humanitarian Device (Dystonia Therapy): Authorized by Federal Law for the use asan aid in the management of chronic, intractable (drug refractory) primary dystonia,including generalized and segmental dystonia, hemidystonia, and cervical dystonia(torticollis), for individuals 7 years of age and older.

For further information, please call Medtronic at 1-800-633-8766.

CNI Programs & Services

CNI Center for Brain & Spinal TumorsEdward B. Arenson, M.D. 303/788-8675Timothy M. Fullagar, M.D. 303/788-4000

CNI Center for Hearing 303/783-9220David C. Kelsall, M.D.

CNI Epilepsy Center 303/788-4600Barbara Lynne Phillips, M.D.Kirsten Bracht, M.D.

CNI Movement Disorders Center 303/788-4010Lauren C. Seeberger, M.D. 303/788-4600

CNI Stroke Center 303/781-4485Don B. Smith, M.D.

Cranio-Facial Surgery 303/788-6632Richard E. Schaler, M.D.

Dizziness & Balance Disorders 303/788-7880Barbara A. Esses, M.D.

Head Pain Center 303/781-5505Judy C. Lane, M.D.

Interventional NeuroradiologyDonald Frei, Jr., M.D. 720/493-3406Wayne F. Yakes, M.D. 303/788-4280

Neuromuscular & Peripheral Nerve Disorders 303/788-1700Marc Treihaft, M.D.

Neurovascular SurgeryPaul D. Elliot, M.D. 303/788-4000

Sleep Disorders Center 303/788-4600Ronald E. Kramer, M.D.

Stereotactic RadiosurgeryJohn McVicker, M.D. 303/788-4000Marshall Davis, M.D. 303/788-5860

Voice & Swallow Disorders 303/781-0404Andre L. Reed M.D.

Functional Surgery ProgramCNI Thompson Center for Restorative NeurosurgeryWilliam McK. & Marcia W. Thompson 303/788-4000John McVicker, M.D.

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Movement Disorders