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COLORADONEUROLOGICAL INSTITUTE
F A L L
CN
IREV
IEW
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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Activa® Parkinson’s Control Therapy, Tremor Control Therapy, and DystoniaTherapy: Product technical manual must be reviewed prior to use for detailed dis-closure.
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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
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Sleep Disorders Center 303/788-4600Ronald E. Kramer, M.D.
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Functional Surgery ProgramCNI Thompson Center for Restorative NeurosurgeryWilliam McK. & Marcia W. Thompson 303/788-4000John McVicker, M.D.
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