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Parkinsn Current Topics

Abstracts Authored or Co-authored by Dr. M.S. Okun through 2009

1. J Neurol. 2009 Oct 8. [Epub ahead of print]

The number and nature of emergency department encounters in patients with deep
brain stimulators.

Resnick AS, Foote KD, Rodriguez RL, Malaty IA, Moll JL, Carden DL, Krock NE,
Medley MM, Burdick A, Haq IU, Okun MS.

Department of Neurology, University of Florida, Gainesville, USA,
aresnick@ufl.edu.

Deep brain stimulation (DBS) has become an increasingly common modality for
control of several neurological disorders such as Parkinson's disease, dystonia, 
essential tremor (ET), and others. Our experience has demonstrated the need for
emergency physicians to familiarize themselves with the potential complications
of the DBS device as well as the device itself. Therefore, our aim in this paper 
was to elucidate the number and nature of DBS and non-DBS presentations to the
emergency department (ED) and to educate and familiarize ED physicians about DBS 
devices and their potential complications. We also aimed to devise a simple
protocol for DBS management so that all ED physicians would have access to the
knowledge or referral capabilities when managing a DBS patient. The objective of 
the present study was to review the number and nature of ED encounters in
patients with deep brain stimulation (DBS) devices implanted for movement and
neuropsychiatric disorders. Methods: The series of encounters reviewed included
215 unique patients with DBS implantation who were identified using an IRB
approved database and a paper chart review. Patients in the study included those 
implanted at University of Florida (UF), as well as those implanted at outside
institutions, so long as they were followed at UF. The cohort included n = 215
DBS patients. 25.6% of all 215 patients presented to the ED at least once, with
the most common presentation occurring as a result of a decline in mental status 
when taking into account all visits (6%). Reasons for presentation to the ED
included neurological (54.6%), infections/hardware issues (27.9%),
orthopedic/focal problems (10.5%), and medical issues (7%). In total, 29 patients
arrived at the ED for DBS related issues (23.2%). Of those who presented to the
ED (n = 55), the average age was 53.1 (range 10-80 years). Headache was the most 
common complaint within the neurological category (22.1%), followed by change in 
mental status (15.1%), and syncope (9.3%). When examining the data by ED
diagnosis, change in mental status occurred most commonly in Parkinson's disease 
(19.6%). Falls were most common in essential tremor (27.2%), and headache
occurred most commonly in the dystonia group (52.1%). Across all diseases, mental
status change was the most common indication for an ED encounter (6%). Parkinson 
disease patients most commonly presented with altered mental status (8%),
essential tremor patients revealed a high preponderance of falls (6.5%), and
dystonia patients tended to present with headache (7.1%). It was concluded that a
large number of patients with DBS will present to the ED for many reasons, the
majority of which will not be direct complications of their DBS device.
Neurological issues were the most common chief complaint, with individual
differences depending on the underlying disease. It is important for ED
physicians to consider non-DBS related complaints in the presentation of these
unique patients since these issues comprise the majority of the ED visits.
However, when properly evaluating these patients, management of their DBS device,
or referrals to neurosurgery and neurology, if necessary, are imperative. In
addition to device management, regular ED standards of care should apply to this 
special cohort of patients.

PMID: 19813069 [PubMed - as supplied by publisher]


2. Neurol Clin. 2009 Aug;27(3):633-77, v.

Surgical treatment of movement disorders.

Kluger BM, Klepitskaya O, Okun MS.

University of Colorado Denver and Health Sciences Center, Aurora, CO 80045, USA. 
benzi.kluger@ucdenver.edu

Surgical approaches are an important consideration in the management of many
movement disorders, particularly for patients refractory to medications. In this 
article, we review the history, pathophysiology, risks and indications for
surgical treatment. Summaries of case studies, case series and clinical trials
performed using deep brain stimulation are provided for Parkinson's disease,
dystonia, essential tremor and other movement disorders.

PMID: 19555825 [PubMed - indexed for MEDLINE]


3. Parkinsonism Relat Disord. 2009 May 14. [Epub ahead of print]

Side onset influences motor impairments in Parkinson disease.

Stewart KC, Fernandez HH, Okun MS, Rodriguez RL, Jacobson CE, Hass CJ.

Department of Applied Physiology and Kinesiology, University of Florida,
Gainesville, FL, USA; Movement Disorders Center, University of Florida,
Gainesville, FL, USA.

In right-handers, the left hemisphere has greater ipsilateral control of the
upper extremities than the right hemisphere. This asymmetry is not as profound
among left-handers. We sought to determine whether Parkinson disease (PD)
maintains this pattern of ipsilateral control and affects motor impairment. Using
right- and left-hand sub-scores from the Unified Parkinson Disease Rating Scale
(UPDRS), we calculated a lateralized impairment score to compare ipsilateral
influence among four groups: right-handed-right-sided onset (RH-RSO),
right-handed-left-sided onset (RH-LSO), left-handed-right-sided onset (LH-RSO),
and left-handed-left-sided onset (LH-LSO). We hypothesized that right-handed
patients with RSO (left hemisphere dysfunction) would have lower scores, hence
more deficits in both hands, than the other groups. Among right-handers, the RSO 
patients (left dominant hemisphere dysfunction) had a significantly lower mean
lateralized impairment score than LSO patients (mu = 2.09 versus mu = 4.06; p <
0.001). Further, RHRSO also had lower scores than both the LHLSO (mu = 4.52, p < 
0.05) and LHRSO (mu = 4.27, p < 0.05) groups. The symmetry of impairments
indicates deficits in both hands and supports more ipsilateral involvement of the
affected left hemisphere in RH-RSO patients. Therefore, we suggest that PD does
retain an asymmetric ipsilateral influence. The low numbers of left-handed
subjects and the significant percentage of left-handers with a dominant left
hemisphere prevented a clear interpretation of our findings in left-handed
subjects.

PMID: 19447063 [PubMed - as supplied by publisher]


4. J Geriatr Psychiatry Neurol. 2009 May 8. [Epub ahead of print]

Depressive Symptoms in Parkinson Disease Correlate With Impaired Global and
Specific Cognitive Performance.

Fernandez HH, See RH, Gary MF, Bowers D, Rodriguez RL, Jacobson C 4th, Okun MS.

Consecutive patients in a Movement Disorders Center with Parkinson disease (PD)
were offered to undergo complete neuropsychological testing and to complete the
Beck Depression Inventory (BDI), regardless of their cognitive and behavioral
status. A total of 82 patients were included in this cross-sectional study and
had a mean age of 67.7 years, formal education of 14.8 years, PD duration of 101 
months, Unified Parkinson Disease Rating Scale-Motor "off" score of 36.96,
Mini-Mental State Examination (MMSE) score of 27.8 (range 19-30), and BDI score
of 10.23 (SD 8.65). Beck Depression Inventory scores did not correlate with
disease duration or motor scores but inversely correlated with the MMSE scores (r
= -0.40; P < .001) and total Dementia Rating Scale (DRS) scores (r = -0.33; P <
.01). Using a univariate regression analysis controlling for age, gender,
education, and total Unified Parkinson Disease Rating Scales (UPDRS) score, the
BDI scores had a significant and unique relationship with MMSE scores. However,
when the BDI scores were correlated with specific cognitive domains, only the
Boston Naming Test and the Hopkins Verbal Learning Test (HVLT) delayed recall
remained significant after Bonferroni correction. Similarly, when comparing the
cognitive performance of patients with PD who scored >14 on the BDI versus those 
who scored <14, only the mean score of the Boston Naming Test was different
between the 2 groups. Our study shows that while depressive symptoms correlated
with global cognitive performance, naming, verbal memory, and language are the
most susceptible cognitive domains affected with depressive symptoms.

PMID: 19429848 [PubMed - as supplied by publisher]


5. Neuropsychologia. 2009 Jul;47(8-9):1917-27. Epub 2009 Mar 13.

Startle reflex hyporeactivity in Parkinson's disease: an emotion-specific or
arousal-modulated deficit?

Miller KM, Okun MS, Marsiske M, Fennell EB, Bowers D.

Department of Clinical & Health Psychology, College of Public Health and Health
Professions, University of Florida, United States. Kimberly.Miller9@va.gov

We previously reported that patients with Parkinson's disease (PD) demonstrate
reduced psychophysiologic reactivity to unpleasant pictures as indexed by
diminished startle eyeblink magnitude [Bowers, D., Miller, K., Bosch, W., Gokcay,
D., Pedraza, O., Springer, U., et al. (2006). Faces of emotion in Parkinsons
disease: Micro-expressivity and bradykinesia during voluntary facial expressions.
Journal of the International Neuropsychological Society, 12(6), 765-773; Bowers, 
D., Miller, K., Mikos, A., Kirsch-Darrow, L., Springer, U., Fernandez, H., et al.
(2006). Startling facts about emotion in Parkinson's disease: Blunted reactivity 
to aversive stimuli. Brain, 129(Pt 12), 3356-3365]. In the present study, we
tested the hypothesis that this hyporeactivity was primarily driven by diminished
reactivity to fear-eliciting stimuli as opposed to other types of aversive
pictures. This hypothesis was based on previous evidence suggesting amygdalar
abnormalities in PD patients, coupled with the known role of the amygdala in fear
processing. To test this hypothesis, 24 patients with Parkinson's disease and 24 
controls viewed standardized sets of emotional pictures that depicted fear,
disgust (mutilations, contaminations), pleasant, and neutral contents. Startle
eyeblinks were elicited while subjects viewed these emotional pictures. Results
did not support the hypothesis of a specific emotional reactivity deficit to fear
pictures. Instead, the PD patients showed reduced reactivity to mutilation
pictures relative to other types of negative pictures in the context of normal
subjective ratings. Further analyses revealed that controls displayed a pattern
of increased startle eyeblink magnitude for "high arousal" versus "low arousal"
negative pictures, regardless of picture category, whereas startle eyeblink
magnitude in the PD group did not vary by arousal level. These results suggest
that previous findings of decreased aversion-modulated startle is driven by
reduced reactivity to highly arousing negative stimuli rather than to a specific 
category (i.e., fear or disgust) of emotion stimuli.

PMCID: 2709833
PMID: 19428424 [PubMed - indexed for MEDLINE]


6. Mov Disord. 2009 Jul 15;24(9):1352-8.

The relationship between quality of life and swallowing in Parkinson's disease.

Plowman-Prine EK, Sapienza CM, Okun MS, Pollock SL, Jacobson C, Wu SS, Rosenbek
JC.

Department of Neurology, University of Florida, USA.
emily.prine@neurology.ufl.edu

Few studies exist in the literature investigating the impact of idiopathic
Parkinson's Disease (IPD) on swallow-related quality of life. We therefore aimed 
in this project to: (1) evaluate swallow-specific quality of life in IPD; (2)
delineate potential relationships between IPD duration and severity with
swallow-specific quality of life; (3) investigate relationships between
swallow-specific quality of life and general health-related quality of life; and 
(4) investigate relationships between swallow-specific quality of life and
depression. Thirty-six patients diagnosed with IPD with and without dysphagia
filled out self-report assessments of the SWAL-QOL, Parkinson's Disease
Questionnaire-39 (PDQ-39), and Beck Depression Inventory (BDI). A series of Mann 
Whitney U tests were performed between non-dysphagic and dysphagic groups for the
total SWAL-QOL score and the 10 SWAL-QOL domains. Spearman's Rho correlation
analyses were performed between the SWAL-QOL and (1) PDQ-39; (2) Hoehn and Yahr
stage; (3) PD disease duration; (4) UPDRS "on" score; and (5) the BDI. The
dysphagia swallowing group reported significant reductions compared to the
non-dysphagic group for the total SWAL-QOL score (P = 0.02), mental health domain
score (P = 0.002) and social domain score (P = 0.002). No relationships existed
between swallow-specific quality of life and disease duration or severity.
Significant relationships existed between swallow-specific quality of life and
general health-related quality of life (r(s) =-0.56, P = 0.000) and depression
(r(s) = -0.48, P = 0.003). These exploratory data highlight the psychosocial
sequelae that swallowing impairment can have in those with IPD and suggest a
possible association between swallowing, social function, and depression. 2009
Movement Disorder     Society.

PMID: 19425089 [PubMed - indexed for MEDLINE]


7. J Neurol. 2009 Aug;256(8):1321-9. Epub 2009 Apr 12.

Greater improvement in quality of life following unilateral deep brain
stimulation surgery in the globus pallidus as compared to the subthalamic
nucleus.

Zahodne LB, Okun MS, Foote KD, Fernandez HH, Rodriguez RL, Wu SS, Kirsch-Darrow
L, Jacobson CE 4th, Rosado C, Bowers D.

Department of Clinical and Health Psychology, University of Florida, PO Box
100165, Gainesville, FL 32610-0165, USA. lzahodne@phhp.ufl.edu

While deep brain stimulation (DBS) surgery is a well-accepted treatment for
Parkinson disease (PD) that improves overall quality of life (QoL), its effects
across different domains of QoL are unclear. The study reported here directly
compared the effects of unilateral DBS in subthalamic nucleus (STN) or globus
pallidus (GPi) on QoL in 42 non-demented patients with medication-refractory PD. 
Patients were enrolled in the COMPARE trial, a randomized clinical trial of
cognitive and mood effects of STN versus GPi DBS conducted at the University of
Florida Movement Disorders Center. Patients underwent motor, mood, verbal fluency
and QoL (Parkinson disease questionnaire: PDQ-39) measures before and 6 months
following surgery. Groups experienced motor and mood improvements that did not
differ by target. Patients with STN DBS evidenced a slight decrement on letter
fluency. On average, all patients endorsed better overall QoL after surgery.
However, despite similar motor and mood improvements, GPi patients improved more 
than STN patients (38 vs. 14%, respectively; P = 0.03). Patients reported better 
QoL on subscales of mobility, activities of daily living (ADLs), emotional
well-being, stigma, cognition and discomfort, but not on those of social support 
and communication. Improvements on the mobility, ADLs, stigma and social support 
subscales were greater amongst GPi patients. In regression analyses, only
depression changes independently predicted changes in overall QoL as well as
emotional well-being and social support changes. Within the STN group only,
declining category fluency scores correlated with poorer QoL on the communication
subscale. Unilateral DBS in both STN and GPi improved QoL overall and in
disparate domains 6 months after surgery. Patients receiving GPi DBS reported
greater improvements that cannot be explained by differential mood or motor
effects; however, verbal fluency changes may have partially contributed to lesser
QoL improvements amongst STN patients.

PMID: 19363633 [PubMed - in process]


8. Neuroimage. 2009 Aug;47 Suppl 2:T44-52. Epub 2009 Apr 10.

A high resolution and high contrast MRI for differentiation of subcortical
structures for DBS targeting: the Fast Gray Matter Acquisition T1 Inversion
Recovery (FGATIR).

Sudhyadhom A, Haq IU, Foote KD, Okun MS, Bova FJ.

Department of Neurosurgery, University of Florida, Gainesville, FL, USA.
atchars@neurosurgery.ufl.edu

DBS depends on precise placement of the stimulating electrode into an appropriate
target region. Image-based (direct) targeting has been limited by the ability of 
current technology to visualize DBS targets. We have recently developed and
employed a Fast Gray Matter Acquisition T1 Inversion Recovery (FGATIR) 3T MRI
sequence to more reliably visualize these structures. The FGATIR provides
significantly better high resolution thin (1 mm) slice visualization of DBS
targets than does either standard 3T T1 or T2-weighted imaging. The T1
subcortical image revealed relatively poor contrast among the targets for DBS,
though the sequence did allow localization of striatum and thalamus. T2 FLAIR
scans demonstrated better contrast between the STN, SNr, red nucleus (RN), and
pallidum (GPe/GPi). The FGATIR scans allowed for localization of the thalamus,
striatum, GPe/GPi, RN, and SNr and displayed sharper delineation of these
structures. The FGATIR also revealed features not visible on other scan types:
the internal lamina of the GPi, fiber bundles from the internal capsule piercing 
the striatum, and the boundaries of the STN. We hope that use of the FGATIR to
aid initial targeting will translate in future studies to faster and more
accurate procedures with consequent improvements in clinical outcomes.

PMID: 19362595 [PubMed - indexed for MEDLINE]


9. NeuroRehabilitation. 2009;24(2):131-44.

Perceptual characteristics of Parkinsonian speech: a comparison of the
pharmacological effects of levodopa across speech and non-speech motor systems.

Plowman-Prine EK, Okun MS, Sapienza CM, Shrivastav R, Fernandez HH, Foote KD,
Ellis C, Rodriguez AD, Burkhead LM, Rosenbek JC.

Department of Neurology, University of Florida, Gainesville, FL 32610, USA.
emily.prine@neurology.ufl.edu

The purpose of this study was to: (1) define perceptual speech characteristics of
idiopathic Parkinson disease (IPD) across 35 speech dimensions adapted from
Darley et al. [19] and grouped under six speech-sign clusters (respiration,
phonation, resonance, articulation, prosody and rate); (2) examine the effects of
levodopa on the 35 perceptual speech dimensions and speech-sign clusters; and (3)
to compare the relative effectiveness of levodopa on global motor functioning vs.
speech production. Sixteen patients with IPD read the 'Grandfather Passage' both 
'on' and 'off' levodopa. Three blinded speech-language pathologists performed
perceptual speech analyses using a seven-point scale. The diagnosis of IPD was
made by a movement disorders fellowship trained neurologist who applied UK Brain 
bank criteria and administered the Unified Parkinson Disease Rating Scale.
Concordant with previous studies, the results of this experiment indicated that
IPD disrupted multiple speech production subsystems, with prosody being the most 
severely affected domain. The perceptual dimensions that were most severely
affected included: (1) sound imprecision; (2) mono-loudness; (3) mono-pitch; (4) 
reduced stress and (5) harsh voice. No significant differences were obtained
between medicated states ('on'/'off') for any of the 35 individual speech
dimensions and speech-sign clusters. Global motor function significantly improved
following dopaminergic medications.

PMID: 19339752 [PubMed - indexed for MEDLINE]


10. J Neurol Sci. 2009 Jun 15;281(1-2):116-21. Epub 2009 Mar 29.

Turning off artistic ability: the influence of left DBS in art production.

Drago V, Foster PS, Okun MS, Cosentino FI, Conigliaro R, Haq I, Sudhyadhom A,
Skidmore FM, Heilman KM.

Department of Neurology, University of Florida, College of Medicine, PO BOX
100236, Gainesville, FL 32610-0236, USA. valeria.drago@neurology.ufl.edu

BACKGROUND: The influence of Parkinson's disease (PD) as well as deep brain
stimulation (DBS) on visual-artistic production of people who have been artists
is unclear. We systematically assessed the artistic-creative productions of a
patient with PD who was referred to us for management of a left subthalamic
region (STN) DBS. The patient was an artist before her disease started,
permitting us to analyze changes in her artistic-creative production over the
course of the illness and during her treatment with DBS. METHODS: We collected
her paintings from four time periods: Time 1 (Early Pre-Presymptomatic), Time 2
(Later Presymptomatic), Time 3 (Symptomatic), and Time 4 (DBS Symptomatic). A
total of 59 paintings were submitted to a panel of judges, who rated the
paintings on 6 different artistic qualities including: aesthetics, closure,
evocative impact, novelty, representation, technique. RESULTS: Aesthetics and
evocative impact significantly declined from Time 2 to Time 4. Representation and
technique indicated a curvilinear relationship, with initial improvement from
Time 1 to Time 2 followed by a decline from Time 2 to Time 4. CONCLUSIONS: These 
results suggest that left STN/SNR-DBS impacted artistic performances in our
patient. The reason for these alterations is not known, but it might be that
alterations of left hemisphere functions induce a hemispheric bias reducing the
influence the right hemisphere which is important for artistic creativity. The
left hemisphere itself plays a critical role in artistic creativity and DBS might
have altered left hemisphere functions or altered the mesolimbic system which
might have also influenced creativity. Future studies will be required to learn
how PD and DBS influence creativity.

PMID: 19329128 [PubMed - indexed for MEDLINE]


11. Ann Neurol. 2009 May;65(5):586-95.

Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus
pallidus interna deep brain stimulation: the COMPARE trial.

Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M,
Jacobson CE 4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward H,
Rodriguez RL, Foote KD.

Movement Disorders Center, University of Florida, McKnight Brain Institute,
College of Medicine, Department of Neurology, Gainesville, FL 32611, USA.
okun@neurology.ufl.edu

OBJECTIVE: Our aim was to compare in a prospective blinded study the cognitive
and mood effects of subthalamic nucleus (STN) vs. globus pallidus interna (GPi)
deep brain stimulation (DBS) in Parkinson disease. METHODS: Fifty-two subjects
were randomized to unilateral STN or GPi DBS. The co-primary outcome measures
were the Visual Analog Mood Scale, and verbal fluency (semantic and letter) at 7 
months post-DBS in the optimal setting compared to pre-DBS. At 7 months post-DBS,
subjects were tested in four randomized/counterbalanced conditions (optimal,
ventral, dorsal, and off DBS). RESULTS: Forty-five subjects (23 GPi, 22 STN)
completed the protocol. The study revealed no difference between STN and GPi DBS 
in the change of co-primary mood and cognitive outcomes pre- to post-DBS in the
optimal setting (Hotelling's T(2) test: p = 0.16 and 0.08 respectively). Subjects
in both targets were less "happy", less "energetic" and more "confused" when
stimulated ventrally. Comparison of the other 3 DBS conditions to pre-DBS showed 
a larger deterioration of letter verbal fluency in STN, especially when off DBS. 
There was no difference in UPDRS motor improvement between targets.
INTERPRETATION: There were no significant differences in the co-primary outcome
measures (mood and cognition) between STN and GPi in the optimal DBS state.
Adverse mood effects occurred ventrally in both targets. A worsening of letter
verbal fluency was seen in STN. The persistence of deterioration in verbal
fluency in the off STN DBS state was suggestive of a surgical rather than a
stimulation-induced effect. Similar motor improvement were observed with both STN
and GPi DBS.

PMCID: 2692580
PMID: 19288469 [PubMed - indexed for MEDLINE]


12. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):794-7. Epub 2009 Feb 22.

Brain penetration effects of microelectrodes and DBS leads in STN or GPi.

Mann JM, Foote KD, Garvan CW, Fernandez HH, Jacobson CE 4th, Rodriguez RL, Haq
IU, Siddiqui MS, Malaty IA, Morishita T, Hass CJ, Okun MS.

Department of Neurology, University of Florida College of Medicine/Shands
Hospital, Movement Disorders Center, McKnight Brain Institute, Gainesville,
Florida 32610, USA.

OBJECTIVE: To determine how intraoperative microelectrode recordings (MER) and
intraoperative lead placement acutely influence tremor, rigidity, and
bradykinesia. Secondarily, to evaluate whether the longevity of the MER and lead 
placement effects were influenced by target location (subthalamic nucleus (STN)
or globus pallidus interna (GPi)). BACKGROUND: Currently most groups who perform 
deep brain stimulation (DBS) for Parkinson disease (PD) use MER, as well as
macrostimulation (test stimulation), to refine DBS lead position. Following MER
and/or test stimulation, however, there may be a resultant
"collision/implantation" or "microlesion" effect, thought to result from
disruption of cells and/or fibres within the penetrated region. These effects
have not been carefully quantified. METHODS: 47 consecutive patients with PD
undergoing unilateral DBS for PD (STN or GPi DBS) were evaluated. Motor function 
was measured at six time points with a modified motor Unified Parkinson Disease
Rating Scale (UPDRS): (1) preoperatively, (2) immediately after MER, (3)
immediately after lead implantation/collision, (4) 4 months following surgery-off
medications, on DBS (12 h medication washout), (5) 6 months postoperatively-off
medication and off DBS (12 h washout) and (6) 6 months-on medication and off DBS 
(12 h washout). RESULTS: Significant improvements in motor scores (p<0.05)
(tremor, rigidity, bradykinesia) were observed as a result of MER and lead
placement. The improvements were similar in magnitude to what was observed at 4
and 6 months post-DBS following programming and medication optimisation. When
washed out (medications and DBS) for 12 h, UPDRS motor scores were still improved
compared with preoperative testing. There was a larger improvement in STN
compared with GPi following MER (p<0.05) and a trend for significance following
lead placement (p<0.08) but long term outcome was similar. CONCLUSION: This study
demonstrated significant acute intraoperative penetration effects resulting from 
MER and lead placement/collision in PD. Clinicians rating patients in the
operating suite should be aware of these effects, and should consider pre- and
post-lead placement rating scales prior to activating DBS. The
collision/implantation effects were greater intraoperatively with STN compared
with GPi, and with greater disease duration there was a larger effect.

PMID: 19237386 [PubMed - indexed for MEDLINE]


13. Neurocase. 2008;15(1):66-9.

Tardive parkinsonism in a bipolar patient: post-mortem examination supports a
physiological rather than pathological dysfunction.

Won MS, Mikos A, Hurd M, Fernandez H, Eskin T, Romrell J, Okun MS.

Department of Neurology, Movement Disorders Center, McKnight Brain Institute,
University of Florida, Gainesville, FL 32610, USA.

We describe a case of tardive parkinsonism in the setting of bipolar syndrome,
and we offer pathological confirmation that idiopathic Parkinson disease was not 
the underlying etiology. A 74-year-old Hispanic woman with a history of bipolar
disease was noted to have oro-buccal-lingual chorea and parkinsonian symptoms
such as resting tremor, rigidity, bradykinesia, and gait disorder persisting
several months after neuroleptic discontinuation. She had minor improvement in
ambulation with levodopa treatment, and she significantly improved in ambulation 
only during her manic states. Examination of the subject's post-mortem brain
revealed no explicit evidence of degeneration in substantia nigra or other
brainstem centers, and no nigral or cortical Lewy bodies were present. Glial
cytoplasmic inclusions (characteristic of multiple systems atrophy) and globose
neurofibrillary tangles (seen in progressive supranuclear palsy) were not seen
either. This patient's presentation was most consistent with neuroleptic-induced 
parkinsonism and tardive dyskinesia; the etiology was likely related to previous 
neuroleptic exposure.

PMID: 19235627 [PubMed - indexed for MEDLINE]


14. Mov Disord. 2009 Apr 15;24(5):684-8.

How cautious should we be when assessing apathy with the Unified Parkinson's
Disease Rating Scale?

Kirsch-Darrow L, Zahodne LB, Hass C, Mikos A, Okun MS, Fernandez HH, Bowers D.

Department of Clinical and Health Psychology, College of Public Health and Health
Professions, University of Florida, Gainesville, Florida 32610-0165, USA.
lkirsch@phhp.ufl.edu

Current practice often assesses apathy with a single item from the Unified
Parkinson's Disease Rating Scale (UPDRS, item 4). Yet, the relationship between
the UPDRS item 4 and the validated Apathy Scale (AS) is unknown. The purpose of
this study was to evaluate the operating characteristics of UPDRS item 4 in
relation to the AS. Three hundred and one patients with PD were administered the 
AS and the UPDRS. We compared the UPDRS item 4 to the standard AS classification 
of > or =14 as apathetic. A receiver operating characteristics (ROC) curve was
obtained, and sensitivity, specificity, positive, and negative predictive power
were calculated. The ROC curve showed area under the curve as 0.75. A cut-off of 
1 had good sensitivity (81%) but poor specificity (53%; high false positive
rate). A cut-off point of 2 had acceptable specificity (87%) but poor sensitivity
(52%, high false negative rate). Continuing to increasing the cut-off point
(e.g., 3, 4) continues to increase specificity at the expense of dramatically
reducing sensitivity. These findings suggest the use of caution when screening
for apathy with item 4 due to its poor sensitivity in relation to the AS.

PMID: 19185011 [PubMed - indexed for MEDLINE]


15. Clin Neuropsychol. 2009 Jul;23(5):805-17. Epub 2009 Jan 26.

Awareness of expressivity deficits in non-demented Parkinson disease.

Mikos AE, Springer US, Nisenzon AN, Kellison IL, Fernandez HH, Okun MS, Bowers D.

Department of Clinical and Health Psychology, University of Florida, Gainesville,
FL 32601, USA. mikos@phhp.ufl.edu

A masked facial expression, one of the hallmark features of Parkinson disease
(PD), can form the basis for misattributions by others about a patient's mood or 
interest levels. Reports of preserved intensity of internal emotional experience 
in PD participants raise the question of whether patients are aware of their
outward expressivity levels. The aim of the present study was to determine
whether PD participants exhibit deficits in overall emotional expressivity, and
if so, whether they are aware of these deficits. We evaluated 37 non-demented PD 
participants and 21 comparison participants using the Berkeley Expressivity
Questionnaire (BEQ). To examine awareness of emotional expressivity, we compared 
participant self-ratings of their own expressivity to ratings made by family
members or close friends. Participants also completed questionnaires regarding
depression and apathy and underwent motor examination and cognitive screening. PD
participants' self-ratings of emotional expressivity were significantly lower
than comparison participants' self-ratings. Even so, the PD participants viewed
themselves as experiencing equivalent levels of emotional intensity to comparison
participants, based on analysis of the BEQ subscales. Informant and PD
participant self-ratings did not differ, indicating that PD participants
accurately appraise the extent of their reduced expressivity. These findings
suggest that anosognosia for emotional expressivity is not a prominent feature of
nondemented Parkinson disease. Importantly, PD participants are aware of their
reduced expressivity and report experiencing emotions as intensely as comparison 
participants. These findings highlight the view that diminished emotional
expressivity in PD should not be mistaken for decreased subjective emotional
experience.

PMID: 19169938 [PubMed - indexed for MEDLINE]


16. Mov Disord. 2009 Apr 15;24(5):677-83.

Examination of the Lille Apathy Rating Scale in Parkinson disease.

Zahodne LB, Young S, Kirsch-Darrow L, Nisenzon A, Fernandez HH, Okun MS, Bowers
D.

Department of Clinical & Health Psychology, University of Florida, Gainesville,
Florida 32610-0165, USA. lzahodne@phhp.ufl.edu

Apathy is a unique, multidimensional syndrome commonly encountered in patients
with Parkinson disease (PD). Recently, the Lille Apathy Rating Scale (LARS), a
semistructured interview yielding a global score, and composite subscores for
different domains of apathy (i.e., cognitive, behavioral, affective, self
awareness), was developed and given to a sample of patients with PD in France.
This study is the first outside of its original developers to examine the English
language version of the LARS in PD. We found the LARS to be a coherent instrument
demonstrating both convergent and divergent validity, as compared to the Apathy
Scale (AS) and Beck Depression Inventory (BDI-II). Using a receiver operating
characteristic (ROC) analysis comparing the LARS to the AS, a validated and
widely-used measure, we identified a cut-off score (sensitivity = 64%,
specificity = 92%, PPV = 88%, NPV = 75%) that was higher than that proposed by
the original authors, who derived their cut-off by comparing LARS global scores
to clinical judgments of apathy. Although the present study does not compare the 
LARS to a diagnostic gold standard or promote its utility for diagnosing apathy, 
it provides further support for the LARS as a promising instrument to examine
apathy in PD.

PMID: 19133658 [PubMed - indexed for MEDLINE]


17. Epilepsy Behav. 2009 Mar;14(3):459-64. Epub 2009 Jan 6.

Subjective perception of cognition is related to mood and not performance.

Marino SE, Meador KJ, Loring DW, Okun MS, Fernandez HH, Fessler AJ, Kustra RP,
Miller JM, Ray PG, Roy A, Schoenberg MR, Vahle VJ, Werz MA.

Experimental and Clinical Pharmacology, University of Minnesota, 717 Delaware
Street SE, Room 517, Minneapolis, MN 55414, USA. marin007@umn.edu

OBJECTIVE: Clinicians monitor cognitive effects of drugs primarily by asking
patients to describe their side effects. We examined the relationship of
subjective perception of cognition to mood and objective cognitive performance in
healthy volunteers and neurological patients. METHODS: Three separate experiments
used healthy adults treated with lamotrigine (LTG) and topiramate (TPM), adults
with epilepsy on LTG or TPM, and patients with idiopathic Parkinson's disease.
Correlations were calculated for change scores on and off drugs in the first two 
experiments and for the single assessment in Experiment 3. RESULTS: Across all
three experiments, significant correlations were more frequent (chi(2)=259, P <
or = 0.000) for mood versus subjective cognitive perception (59%) compared with
subjective versus objective cognition (2%) and mood versus objective cognitive
performance (2%). CONCLUSIONS: Subjective perception of cognitive effects is
related more to mood than objective performance. Clinicians should be aware of
this relationship when assessing patients' cognitive complaints.

PMCID: 2688662
PMID: 19130899 [PubMed - indexed for MEDLINE]


18. Stereotact Funct Neurosurg. 2009;87(1):25-30. Epub 2008 Nov 27.

Venous air embolism in deep brain stimulation.

Hooper AK, Okun MS, Foote KD, Haq IU, Fernandez HH, Hegland D, Robicsek SA.

University of Florida Movement Disorders Center, Gainesville, Fla. 32601, USA.
akhooper@ufl.edu

BACKGROUND/AIMS: During the placement of electrodes for deep brain stimulation
(DBS), patients are commonly in a seated position, awake, and spontaneously
breathing. Air may be entrained through bone or dural veins causing venous air
emboli (VAE) and this phenomenon can result in significant hemodynamic changes.
Although VAEs have been described in many types of neurosurgical procedures,
their incidence during DBS surgery is unknown. METHODS: Following approval from
the Institutional Review Board, the University of Florida Movement Disorders
Center database comprising 286 DBS leads placed since 2002 was reviewed.
Intraoperative cough, which has been associated with VAE, as well as hemodynamic 
instability were the focus of the review. Additionally, a prospective evaluation 
of the incidence of VAE using precordial Doppler ultrasound was undertaken over a
3-month period (June 2007-August 2007). RESULTS: The retrospective review
revealed a 3.2% incidence of cough per lead. Prospective monitoring in 21
consecutive patients with 22 leads yielded the detection of 1 VAE, and an
incidence of 4.5% per lead. CONCLUSION: VAEs are rare but potentially serious
complications of DBS surgery unless recognized. Patient positioning and the
occurrence of cough are two important predictors to consider in VAE. Precordial
Doppler is a safe, non-invasive monitor that can be used in the early detection
of VAE in these procedures.

PMID: 19039260 [PubMed - indexed for MEDLINE]


19. Chest. 2009 May;135(5):1301-8. Epub 2008 Nov 24.

Impact of expiratory muscle strength training on voluntary cough and swallow
function in Parkinson disease.

Pitts T, Bolser D, Rosenbek J, Troche M, Okun MS, Sapienza C.

Departments of Communication Sciences and Disorders, University of Florida,
Gainesville, FL 32611, USA. tepitts@csd.ufl.edu

BACKGROUND: Cough provides high expiratory airflows to aerosolize and remove
material that cannot be adequately removed by ciliary action. Cough is
particularly important for clearing foreign particles from the airway in those
with dysphagia who may be at risk for penetration/aspiration (P/A). Expiratory
muscle strength training (EMST) was tested to improve cough and swallow function.
METHODS: Ten male participants, diagnosed with Parkinson disease (PD), with
videofluorographic evidence of penetration or with evidence for aspiration of
material during swallow of a thin 30-mL bolus, completed 4 weeks of an EMST
program to test the hypothesis that EMST would improve cough and/or swallow
function. Measured parameters from an airflow waveform produced during voluntary 
cough, pre-EMST and post-EMST, included inspiration phase duration, compression
phase duration (CPD), expiratory phase peak flow (EPPF), expiratory phase rise
time (EPRT), and cough volume acceleration (VA) [ie, the EPPF/EPRT ratio]. The
swallow outcome measure was the degree of P/A during the swallow task. RESULTS:
There was a significant decrease in the duration of the CPD and EPRT; the
decrease in EPRT resulted in a significant increase in cough VA. Significant
decreases in the P/A scores were found posttraining. CONCLUSIONS: The results
demonstrate that EMST is a viable treatment modality for a population of
participants with PD at risk of aspiration.

PMID: 19029430 [PubMed - indexed for MEDLINE]


20. Neurosurgery. 2008 Oct;63(4):754-60; discussion 760-1.

Reoperation for suboptimal outcomes after deep brain stimulation surgery.

Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, Jacobson
CE 4th, Okun MS.

Department of Neurology, Movement Disorders Center, University of Florida,
McKnight Brain Institute, Gainesville, Florida, USA.

OBJECTIVE: To examine a case series of reoperations for deep brain stimulation
(DBS) leads in which clinical scenarios revealed suboptimal outcome from a
previous operation. Suboptimally placed DBS leads are one potential reason for
unsatisfactory results after surgery for Parkinson's disease (PD), essential
tremor (ET), or dystonia. In a previous study of patients who experienced
suboptimal results, 19 of 41 patients had misplaced leads. Similarly, another
report commented that lead placement beyond a 2- to 3-mm window resulted in
inadequate clinical benefit, and, in 1 patient, revision improved outcome. The
goal of the current study was to perform an unblinded retrospective chart review 
of DBS patients with unsatisfactory outcomes who presented for reoperation.
METHODS: Patients who had DBS lead replacements after reoperation were assessed
with the use of a retrospective review of an institutional review board-approved 
movement disorders database. Cases of reoperation for suboptimal clinical benefit
were included, and cases of replacement of DBS leads caused by infection or
hardware malfunction were excluded. Data points studied included age, disease
duration, diagnosis, motor outcomes (the Unified Parkinson Disease Rating Scale
III in PD, the Tremor Rating Scale in ET, and the Unified Dystonia Rating Scale
in dystonia), quality of life (Parkinson's Disease Questionnaire-39 in PD), and
the Clinician Global Impression scale. The data from before and after reoperation
were examined to determine the estimated impact of repeat surgery. RESULTS: There
were 11 patients with PD, 7 with ET, and 4 with dystonia. The average age of the 
PD group was 52 years, the disease duration was 10 years, and the average vector 
distance of the location of the active DBS contact was adjusted 5.5 mm. Six
patients (54%) with PD had preoperative off medication on DBS Unified Parkinson
Disease Rating Scale scores that could be compared with postoperative off
medication on DBS scores. The average improvement across this group of patients
was 24.4%. The Parkinson's Disease Questionnaire-39 improved in the areas of
mobility (28.18), activities of daily living (14.77), emotion (14.72), stigma
(17.61), and discomfort (17.42). The average age of the ET group was 66 years,
the disease duration was 29 years, and the average adjusted distance was 6.1 mm. 
Five ET patients (83.3%) in the cohort had a prereplacement on DBS Tremor Rating 
Scale and a postreplacement on DBS Tremor Rating Scale with the average
improvement of 60.4%. The average age of the dystonia group was 39 years, the
average disease duration was 7 years, and the average adjusted lead distance was 
6.7 mm. Three patients (75%) with dystonia had prereplacement on DBS Unified
Dystonia Rating Scale and postreplacement on DBS Unified Dystonia Rating Scale
scores. Across these 3 dystonia patients, the improvement was 12.8%. Clinician
Global Impression scale scores (1, very much improved; 2, much improved; 3,
minimally improved; 4, no change; 5, minimally worse; 6, much worse; 7, very much
worse) after replacement revealed the following results in patients with PD: 1, 7
patients; 2, 3 patients; 3, 1 patient); with ET (1, 4 patients; 2, 3 patients);
and with dystonia (1, 1 patient; 2, 2 patients; 3, 1 patient). The latency from
original lead placement to reoperation (repositioning/revision) overall was 28.9 
months (range, 2-104 mo); however, in leads referred from outside institutions (n
= 11 patients), this latency was 48 months (range, 12-104 mo) compared with leads
implanted by surgeons from the University of Florida (n = 11 patients), which was
9.7 months (range, 2-19 mo). The most common clinical history was failure to
achieve a perceived outcome; however, history of an asymmetric benefit was
present in 4 (18.2%) of 22 patients, and lead migration was present in 3 (13.6%) 
of 22 patients. CONCLUSION: There are many potential causes of suboptimal benefit
after DBS. Timely identification of suboptimal lead placements followed by
reoperation and repositioning/replacement in a subset of patients may improve
outcomes.

PMID: 18981887 [PubMed - indexed for MEDLINE]


21. J Neurol Sci. 2009 Jan 15;276(1-2):138-42. Epub 2008 Oct 21.

Artistic creativity and DBS: a case report.

Drago V, Foster PS, Okun MS, Haq I, Sudhyadhom A, Skidmore FM, Heilman KM.

Department of Neurology, University of Florida, College of Medicine, Gainesville,
FL 32610-0236, USA. valeria.drago@neurology.ufl.edu

BACKGROUND: Deep brain stimulation (DBS) is a treatment for patients with
Parkinson's disease (PD) who are not adequately controlled with medications. An
artist reported changes in her artistic creativity and art appreciation when
treated with left DBS. We sought to study her artistic productions and her
appreciation of art while both "on" and "off" left DBS. METHODS: A 69-year-old
right-handed woman with an approximate 20-year history of PD was referred to us
for management of a left subthalamic region nucleus (STN) DBS placed at another
institution 4 years prior. In Experiment 1 we had her rate several dimensions
(Evocative Impact, Aesthetics, Novelty, Technique, Closure and Representation) of
another artist's paintings. In Experiment 2, we tested her with the Abbreviated
Torrance Test (of creativity) for Adults (ATTA). During testing the patient
remained on her dopaminergic medication, but was tested on and off left DBS.
RESULTS: On the judgment task while "on" left DBS, versus "off" DBS, there were
significant reductions in her appreciation of artistic Closure and Technique.
When "off" DBS her ATTA creativity index was above average, but when switched
"on" her creativity index was below average. CONCLUSIONS: These results suggest
the possibility that left ventral STN/SNR DBS reduces creativity as well as
appreciation of art. The reason for these alterations is not known, but might be 
related to enhanced activation of the left hemisphere and reciprocal deactivation
of the right hemisphere which mediates both visuospatial skills and global
attention, both of which are important in artistic creativity and appreciation.

PMID: 18945449 [PubMed - indexed for MEDLINE]


22. Clin Neuropsychol. 2009 Apr;23(3):385-405. Epub 2008 Sep 23.

Cognitive declines one year after unilateral deep brain stimulation surgery in
Parkinson's disease: a controlled study using reliable change.

Zahodne LB, Okun MS, Foote KD, Fernandez HH, Rodriguez RL, Kirsch-Darrow L,
Bowers D.

Clinical and Health Psychology, University of Florida, Gainesville, FL
32610-0165, USA. lzahodne@phhp.ufl.edu

Conflicting research suggests that deep brain stimulation surgery, an effective
treatment for medication-refractory Parkinson's disease (PD), may lead to
selective cognitive declines. We compared cognitive performance of 22 PD patients
who underwent unilateral DBS to the GPi or STN to that of 19 PD controls at
baseline and 12 months. We hypothesized that compared to PD controls, DBS
patients would decline on tasks involving dorsolateral prefrontal cortex
circuitry (letter fluency, semantic fluency, and Digit Span Backward) but not on 
other tasks (Vocabulary, Boston Naming Test), and that a greater proportion of
DBS patients would fall below Reliable Change Indexes (RCIs). Compared to
controls, DBS patients declined only on the fluency tasks. Analyses classified
50% of DBS patients as decliners, compared to 11% of controls. Decliners
experienced less motor improvement than non-decliners. The present study adds to 
the literature through its hypothesis-driven method of task selection, inclusion 
of a disease control group, longer-term follow-up and use of Reliable Change. Our
findings provide evidence that unilateral DBS surgery is associated with verbal
fluency declines and indicate that while these changes may not be systematically 
related to age, cognitive or depression status at baseline, semantic fluency
declines may be more common after left-sided surgery. Finally, use of Reliable
Change highlights the impact of individual variability and indicates that fluency
declines likely reflect significant changes in a subset of patients who
demonstrate a poorer surgical outcome overall.

PMID: 18821180 [PubMed - indexed for MEDLINE]


23. Parkinsonism Relat Disord. 2009 May;15(4):315-7. Epub 2008 Sep 14.

Does laterality of motor impairment tell us something about cognition in
Parkinson disease?

Cooper CA, Mikos AE, Wood MF, Kirsch-Darrow L, Jacobson CE, Okun MS, Rodriguez
RL, Bowers D, Fernandez HH.

Department of Neurology, University of Florida, PO Box 100236, Gainesville, FL
32610, USA.

This cross-sectional study investigates the relationship between severity of
right- and left-sided motor symptoms and deficits in global cognitive function as
well as individual cognitive domains in 117 Parkinson disease patients. Items of 
the Unified Parkinson Disease Rating Scale Part III were divided into right- and 
left-sided total scores. Composite scores in verbal fluency, verbal memory,
executive function, and visuoperceptual skills were obtained from a full
neuropsychological battery. We observed a significant association between
right-sided motor impairment and verbal memory, visuoperceptual skills, and
verbal fluency, but not executive function. The relationship between right
symptoms and verbal fluency was fully mediated by cognitive status, while the
relationship between right symptoms and verbal memory as well as visuoperceptual 
skills was not. Left-sided motor symptoms were not significantly related to any
composite cognitive domain. When patients were divided into groups based on the
side of predominant symptoms, no group differences were found in performance on
the specific cognitive domains. This suggests that the degree of right-sided
symptoms is more correlated to specific cognitive domains than is group
classification of laterality.

PMID: 18793864 [PubMed - indexed for MEDLINE]


24. World J Biol Psychiatry. 2008 Mar 10:1-7. [Epub ahead of print]

Inappropriate crying and laughing in Parkinson disease and movement disorders.

Siddiqui MS, Fernandez HH, Garvan CW, Kirsch-Darrow L, Bowers D, Rodriguez RL,
Jacobson CE 4th, Rosado C, Vaidyanathan S, Foote KD, Okun MS.

Department of Neurology, Wake Forest University School of Medicine,
Winston-Salem, NC, USA.

Objective. To examine in a pilot study inappropriate crying and laughing (also
termed pseudobulbar affect (PBA)) and underlying mood disturbances in a large
clinic based population of Parkinson's disease and movement disorder patients.
Background. PBA is characterized by uncontrollable laughter without mirth, or
alternatively crying without the feeling of sadness. It is a common condition
affecting more than one million people with neurological diseases. While PBA has 
been studied in many neurological diseases, little is known about its prevalence 
in movement disorders, or its relationship to more chronic mood disturbances. We 
carried out this pilot study to examine this relationship. Methods. Seven hundred
and nineteen out of 860 consecutive patients who visited our Movement Disorders
Center met inclusion criteria (i.e. >/=18 years of age, formal diagnosis by a
movement disorder specialist, completion of PBA questionnaire, and absence of
brain surgery including deep brain stimulation). All subjects were interviewed
for symptoms of PBA during their visit. In addition, 661 of these patients
completed both the Visual Analog Mood Scale (VAMS) and Beck Depression Inventory 
I (BDI-I). Results. Thirty-seven of the 719 reported PBA symptoms; 75.7% (28/37) 
had pathological 'crying', 13.5% (5/37) had pathological 'laughing' and 10.8%
(4/37) had both. The prevalence of PBA in individual diagnostic categories was:
4.7% (18/387) of idiopathic Parkinson's disease (PD), 2.7% (2/74) of primary
dystonia, 3.1% (2/65) of essential tremor (ET), 7.8% (8/108) of patients with
other forms of Parkinsonism, 21.7% (5/23) of psychogenic movement disorders, 0%
(0/18) of patients with combined PD and ET, and 4.5% (2/44) of other movement
disorders. Patients with PBA had a higher total BDI score (P=0.0278) and VAMS
'tiredness' score (P=0.0109). In patients on antidepressant therapy the
prevalence of PBA was 7.1% compared to 2.7% in the group not on therapy
(P=0.0094). Conclusion. PBA was present in most movement disorders, but
especially prevalent in parkinsonism. PBA patients in this cohort had more
chronic depressive symptoms and tiredness.

PMID: 18609421 [PubMed - as supplied by publisher]


25. Clin Neuropsychol. 2009 Jan;23(1):100-17. Epub 2008 Mar 12.

Neuropsychological profile of a Filipino gentleman with X-linked
dystonia-parkinsonism: a case report of Lubag disease.

Howe LL, Kellison IL, Fernandez HH, Okun MS, Bowers D.

Clinical and Health Psychology, McKnight Brain Institute, University of Florida, 
Gainesville, FL, USA. lauralshowe@yahoo.com

X-Linked Dystonia-Parkinsonism (XDP or "Lubag") is a progressive
neurodegenerative disorder unique to the Island of Panay in the Philippines.
Imaging and autopsy studies have suggested involvement of the caudate and putamen
in late stages. Because the clinical presentation of patients with XDP resembles 
that of patients with Parkinson disease or dystonia, it is reasonable to predict 
the neuropsychological profile might be similar; however, the neuropsychological 
profile of a XDP patient has not previously been published. We present the
neuropsychological findings of a 67-year-old gentleman with a 10-year history of 
XDP who presented with parkinsonian and dystonic symptoms. He was evaluated for
suitability for deep brain stimulation surgery. Neuropsychological findings
demonstrated diffuse impairment involving memory, visuospatial, language, and
executive functioning.

PMID: 18609312 [PubMed - indexed for MEDLINE]


26. Mov Disord. 2008 Jul 30;23(10):1466-8.

Distribution of motor impairment influences quality of life in Parkinson's
disease.

Stewart KC, Fernandez HH, Okun MS, Jacobson CE, Hass CJ.

Department of Applied Physiology and Kinesiology, University of Florida,
Gainesville, Florida 32611, USA.

We evaluated the relationship between upper extremity (UE) and lower extremity
(LE) motor impairments in Parkinson's disease (PD) to overall disability and
quality of life (QoL) measures. A total of 639 patients who were diagnosed with
idiopathic PD were administered the Unified Parkinson's Disease Rating Scale
(UPDRS), QoL, activities of daily living (ADL), and behavioral scales. Composite 
UE and LE scores from the motor section of the UPDRS were correlated with ADL,
QoL, and behavioral measurement scores while controlling for disease duration.
Patients with greater UE and LE motor impairments had lower QoL scores. However, 
LE impairments had a greater influence than UE impairments across all QoL
measures. Copyright 2008 Movement Disorder     Society.

PMID: 18546324 [PubMed - indexed for MEDLINE]


27. Parkinsonism Relat Disord. 2008 Aug;14(6):481-8. Epub 2008 Mar 14.

The persistent effects of unilateral pallidal and subthalamic deep brain
stimulation on force control in advanced Parkinson's patients.

Alberts JL, Okun MS, Vitek JL.

Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA.
albertj@ccf.org

The persistent effects of unilateral deep brain stimulation (DBS) of the globus
pallidus interna (GPi) or subthalamic nucleus (STN) on specific movement
parameters produced by Parkinson's disease (PD) patients are poorly understood.
The aim of this study was to determine the effects of unilateral GPi and STN DBS 
on the force-producing capabilities of PD patients during maximal efforts and
functional bimanual dexterity. Clinical and biomechanical data were collected
from 14 unilaterally implanted patients (GPi=7; STN=7), at least 13 months
post-DBS surgery, during On and Off stimulation in the absence of medication.
Unilateral DBS of either location produced a 33% improvement in UPDRS motor
scores. Significant gains in maximum force production were present in both limbs 
during unimanual efforts. The greatest increase in maximum force, for both limbs,
was under bimanual conditions. Force in the contralateral limb increased more
than 30% during bimanual efforts while ipsilateral force increased by 25%.
Unilateral DBS improved grasping force control and consistency of digit placement
during the performance of a bimanual dexterity task. The clinical and
biomechanical data indicate that unilateral DBS of GPi or STN results in
persistent improvements in the control and coordination of grasping forces during
maximal efforts and functional dexterous actions. Unilateral DBS implantation of 
either site should be considered an option for those patients in which bilateral 
procedures are contraindicated.

PMCID: 2605295
PMID: 18342565 [PubMed - indexed for MEDLINE]


28. Stereotact Funct Neurosurg. 2008;86(3):147-52. Epub 2008 Mar 12.

Clinical cases where lesion therapy was chosen over deep brain stimulation.

Hooper AK, Okun MS, Foote KD, Fernandez HH, Jacobson C, Zeilman P, Romrell J,
Rodriguez RL.

University of Florida, Movement Disorders Center, Gainesville, FL 32601, USA.
akhooper@ufl.edu

Deep brain stimulation (DBS) surgery has become the gold standard for treatment
of select refractory cases of Parkinson disease and essential tremor. Despite the
usefulness of DBS surgery in many cases, there remain situations where lesion
therapy (subthalamotomy, pallidotomy or thalamotomy) may provide a reasonable
alternative to DBS. We reviewed the University of Florida Institutional Review
Board-approved database for movement disorders surgery and identified 286 DBS
leads placed in 189 patients as well as 4 additional patients who had lesion
therapy. In these 4 cases we reviewed the clinical presentations that resulted in
a multidisciplinary team opting for lesion therapy over DBS. Lesion therapy
represents a viable alternative and has several important advantages, including a
decreased need for access to specialists and clinical follow-up, improved
affordability, and a lower infection risk. 2008 S. Karger AG, Basel.

PMID: 18334856 [PubMed - indexed for MEDLINE]


29. Neuropsychiatr Dis Treat. 2007 Dec;3(6):955-8.

Cognitive decline tracks motor progression and not disease duration in Parkinson 
patients.

Riggeal B, Crucian G, Seignourel P, Jacobson C, Okun M, Rodriguez R, Fernandez
HH.

Department of Neurology;

We performed an analysis of prospectively-acquired cross sectional data on 106
Parkinson disease (PD) patients who underwent comprehensive neuropsychological
testing and the Unified Parkinson Disease Rating Scale (UPDRS) motor scale. A
significant correlation between the UPDRS motor and neuropsychological tests in
all cognitive domains except for general intelligence and visuo-spatial function 
was seen. In this study, cognitive decline within this PD cohort correlated with 
motor impairment but not disease duration. Our findings suggest that overall
cognitive impairment (except visuospatial dysfunction) may track motor
progression in PD more than duration of disease. Longitudinal studies are needed 
to confirm our results.

PMCID: 2656340
PMID: 19300633 [PubMed - in process]


30. Neurologist. 2007 Sep;13(5):253-60.

Pearls in patient selection for deep brain stimulation.

Rodriguez RL, Fernandez HH, Haq I, Okun MS.

Department of Neurology, University of Florida Movement Disorders Center,
McKnight Brain Institute, Gainesville, Florida, USA.
ramon.rodriguez@neurology.ufl.edu

BACKGROUND: Deep brain stimulation (DBS) has emerged as an important treatment
for medication refractory movement and neuropsychiatric disorders. General
neurologists and even general practitioners may be called upon to screen
potential candidates for DBS. The patient selection process plays an important
role in this procedure. REVIEW SUMMARY: In this article, we discuss "pearls" for 
the clinician who may be called upon to identify appropriate candidates for DBS. 
Additionally, we will discuss the important points that should be considered when
referring patients for surgical intervention. CONCLUSION: Diagnosis, response to 
levodopa, cognitive status, psychiatric status, access to care, and patient
expectations are all essential elements of the patient selection process for DBS.
These areas must be adequately addressed prior to any surgical procedure.

PMID: 17848865 [PubMed - indexed for MEDLINE]


31. Neurocase. 2007 Jun;13(3):158-64.

The crossed response inhibition task in Parkinson's disease: disinhibition
hyperkinesia.

Crucian GP, Heilman K, Junco E, Maraist M, Owens WE, Foote KD, Okun MS.

Department of Neurology, University of Florida, Gainesville, FL, USA.
greg.crucian@cantebury.ac.nz

Patients with Parkinson's disease (PD) have dysfunction in frontal-basal ganglia 
networks. Many of these patients have difficulties with mental processing speed, 
response inhibition, and shifting between different conceptual sets, suggesting
frontal-executive dysfunction. Since frontal lobe dysfunction is associated with 
disengagement deficits such as perseveration and echopraxia we wanted to learn if
patients with PD demonstrated defective response inhibition. Using a brief
clinical test called the crossed response inhibition (CRI) task we assessed
patients with PD (n = 17), and a group of age matched controls (n = 30). In
addition to the CRI, subjects were asked to perform two tests of frontal lobe
function: verbal word fluency, anti-saccade test. In the CRI task, patients are
instructed to lift the hand opposite to the one the examiner touches. An error is
scored whenever the patient makes any movement of the touched (ipsilateral)
extremity after stimulation (from shoulder to fingers). The task is performed
with the patient's eyes closed. Whereas no differences were found between PD and 
control subjects on the verbal fluency or anti-saccade tasks, PD patients made
significantly more errors on the CRI than did controls. Subsequent analyses found
no difference in performance associated with the laterality (asymmetry) of PD
symptoms or signs. In addition, there was no difference between PD patients' CRI 
performance when they were "on" their dopaminergic medications versus when they
were "off" these medicines. Based on these findings, it appears that PD is
associated with a disengagement-inhibition defect that is not induced by a
dopaminergic deficit. In addition, the CRI task might be a brief sensitive
bedside task for evaluating frontal dysfunction in PD.

PMID: 17786774 [PubMed - indexed for MEDLINE]


32. Neurodegener Dis. 2007;4(5):386-91. Epub 2007 Jul 6.

Comprehensive screening of a North American Parkinson's disease cohort for LRRK2 
mutation.

Johnson J, Paisán-Ruíz C, Lopez G, Crews C, Britton A, Malkani R, Evans EW,
McInerney-Leo A, Jain S, Nussbaum RL, Foote KD, Mandel RJ, Crawley A, Reimsnider 
S, Fernandez HH, Okun MS, Gwinn-Hardy K, Singleton AB.

Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience
Research Center, National Institutes of Health, Bethesda, MD 20892, USA.

BACKGROUND: Recently, mutations in LRRK2 encoding the protein dardarin have been 
linked to an autosomal dominant form of parkinsonism. OBJECTIVE: To identify
mutations causing Parkinson's disease (PD) in a cohort of North Americans with
familial PD. METHODS: We sequenced exons 1-51 of LRRK2 in 79 unrelated North
American PD patients reporting a family history of the disease. RESULTS: One
patient had a missense mutation (Thr2356Ile) while two others had the common
Gly2019Ser mutation. In addition, 1 patient had a 4-bp deletion in close
proximity to the exon 19 splice donor (IVS20+4delGTAA) that in vitro abrogates
normal splicing. CONCLUSIONS: Our observations in the 79 North American patients 
indicate that mutations in LRRK2 are associated with approximately 5% of PD cases
with a positive family history. The results also show that G2019S represents
approximately half of the LRRK2 mutations in United States PD cases with a family
history of the disease. We have identified two novel mutations in LRRK2.
Copyright (c) 2007 S. Karger AG, Basel.

PMID: 17622782 [PubMed - indexed for MEDLINE]


33. Curr Neurol Neurosci Rep. 2007 Jul;7(4):278-89.

Limbic, associative, and motor territories within the targets for deep brain
stimulation: potential clinical implications.

Sudhyadhom A, Bova FJ, Foote KD, Rosado CA, Kirsch-Darrow L, Okun MS.

Department of Neurology, McKnight Brain Institute, 100 South Newell Drive,
Gainesville, FL 32610, USA. okun@neurology.ufl.edu

The use of deep brain stimulation (DBS) has recently been expanding for the
treatment of many neurologic disorders such as Parkinson disease, dystonia,
essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression,
and obsessive compulsive disorder. The target structures for DBS include specific
segregated territories within limbic, associative, or motor regions of very small
subnuclei. In this review, we summarize current clinical techniques for DBS, the 
cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to
functional territories within specific brain targets. Future development of new
techniques and technology that may include a more direct visualization of "motor"
territories within target structures may prove useful for avoiding side effects
that may result from stimulation of associative and limbic regions.
Alternatively, newer procedures may choose and specifically target non-motor
territories for chronic electrical stimulation.

PMID: 17618533 [PubMed - indexed for MEDLINE]


34. Geriatrics. 2007 May;62(5):18-24.

Identifying candidates for deep brain stimulation in Parkinson's disease: the
role of the primary care physician.

Okun MS, Fernandez HH, Rodriguez RL, Foote KD.

Department of Neurology, University of Florida Movement Disorders Center,
McKnight Brain Institute, Gainesville, USA.

Deep brain stimulation (DBS) can improve symptoms in well-selected patients with 
Parkinson's disease. Primary care physicians must take into account many
important issues when considering referral for DBS. The Florida Surgical
Questionnaire for PD (FLASQ-PD), a 5-section screening tool that can help primary
care providers identify appropriate DBS candidates, can be filled out and scored 
by a general practitioner, advanced clinical nurse practitioner, physician
assistant, or trained nurse. Potential candidates who score well on this
questionnaire can be referred for presurgical multidisciplinary evaluation at an 
experienced DBS implanting center.

PMID: 17489644 [PubMed - indexed for MEDLINE]


35. Clin Neuropsychol. 2007 Jan;21(1):162-89.

Deep brain stimulation and the role of the neuropsychologist.

Okun MS, Rodriguez RL, Mikos A, Miller K, Kellison I, Kirsch-Darrow L, Wint DP,
Springer U, Fernandez HH, Foote KD, Crucian G, Bowers D.

Department of Neurology, Movement Disorders Center, University of Florida,
Gainesville, FL 32610, USA. okun@neurology.ufl.edu

Deep brain stimulation (DBS) now plays an important role in the treatment of
Parkinson's disease, tremor, and dystonia. DBS may also have a role in the
treatment of other disorders such as obsessive-compulsive disorder, Tourette's
syndrome, and depression. The neuropsychologist plays a crucial role in patient
selection, follow-up, and management of intra-operative and post-operative
effects (Pillon, 2002; Saint-Cyr & Trepanier, 2000). There is now emerging
evidence that DBS can induce mood, cognitive, and behavioral changes. These
changes can have dramatic effects on patient outcome. There have been
methodological problems with many of the studies of DBS on mood, cognition, and
behavior. The neuropsychologist needs to be aware of these issues when following 
up patients, and constructing future studies. Additionally, this article will
review all aspects of the DBS procedure that can result in mood, cognitive, and
behavioral effects and what role(s) the neuropsychologist should play in
screening and follow-up.

PMID: 17366283 [PubMed - indexed for MEDLINE]


36. Stroke. 2007 Apr;38(4):1390-2. Epub 2007 Mar 1.

Punding as a complication of brain stem stroke?: report of a case.

Nguyen FN, Pauly RR, Okun MS, Fernandez HH.

Department of Neurology, University of Florida College of Medicine, Gainesville, 
FL 32610, USA.

BACKGROUND AND PURPOSE: Stereotyped motor behaviors, known as "punding,"
originally described among amphetamine abusers have only recently been reported
in Parkinson disease associated with both pro-(eg, levodopa) or anti-(eg,
quetiapine) dopaminergic therapy. We describe a non-Parkinson disease case of
nonpharmacologically induced punding as a complication of a brain stem
cardiovascular accident. SUMMARY OF CASE: A 54-year-old man, after an episode of 
brain stem cardiovascular accident secondary to basilar artery thrombosis, was
noted to endlessly purchase and hoard food items and to write, copy and organize 
recipes. His activity was excessive, disruptive and affected his interaction with
family members. The patient's punding behaviors significantly improved with an
increased dose of sertraline from 100 mg to 150 mg per day. CONCLUSIONS: Our
patient's presentation was most consistent with punding, but interestingly was
not a result of dopaminergic therapy. Moreover, improvement of his behavior was
noted with a selective serotonin reuptake inhibitor, further questioning the
dopaminergic hypothesis of punding.

PMID: 17332454 [PubMed - indexed for MEDLINE]


37. Mov Disord. 2007 Apr 15;22(5):666-72.

Depression symptoms in movement disorders: comparing Parkinson's disease,
dystonia, and essential tremor.

Miller KM, Okun MS, Fernandez HF, Jacobson CE 4th, Rodriguez RL, Bowers D.

Department of Clinical and Health Psychology, College of Public Health and Health
Professions, University of Florida, Gainesville, FL 32608, USA.
kmmiller@phhp.ufl.edu

Depression is common in Parkinson's disease (PD) and affects 30 to 50% of all
patients. In contrast to the wealth of research on depression in PD, little is
known about the occurrence of depression in other movement disorders. The primary
objective of the current study was to determine whether the high prevalence of
depression symptoms seen in PD is also found in other movement disorders, by
directly comparing rates of specific depression symptoms and depression severity 
across PD, dystonia, and essential tremor (ET). Three hundred and fifty-four
patients with PD, 83 patients with dystonia, and 53 patients with ET completed
the Beck Depression Inventory (BDI). We found no significant between-groups
differences for depression severity, frequency, or endorsement of specific
depression symptoms. Forty-eight percent of PD patients, 37.3% of dystonia
patients, and 34% of ET patients were found to be at least mildly depressed (BDI 
score of 10 or higher). The most commonly endorsed symptoms were fatigability,
difficulty with work, anhedonia, and sleep disturbance. Clinicians should be
aware that depression is a frequent problem in dystonia and ET, in addition to
PD, and inquire about depression symptoms in these patients so that they can be
appropriately treated.

PMID: 17266084 [PubMed - indexed for MEDLINE]


38. Neuropsychiatr Dis Treat. 2007 Feb;3(1):161-7.

The four As associated with pathological Parkinson disease gamblers: anxiety,
anger, age, and agonists.

Shapiro MA, Chang YL, Munson SK, Jacobson CE, Rodriguez RL, Skidmore FM, Okun MS,
Fernandez HH.

Department of Neurology, Movement Disorders Center, McKnight Brain Institute,
University of Florida College of Medicine, Gainesville, FL, USA;

Several studies have related pathological gambling in PD to dopamine agonist
therapy. A mail-in survey was sent to PD patients seen at the University of
Florida Movement Disorders Center to determine gambling frequency and behavior,
and any lifestyle or environmental factors associated with compulsive gambling in
PD. 462 surveys were sent and 127 completed surveys were returned, of which ten
were from patients who met criteria for compulsive gambling. All ten were taking 
dopamine agonists coincident with the compulsive gambling. Compulsive gamblers
were younger, and psychological distress measures revealed that compulsive
gamblers exhibited higher levels of anxiety, anger, and confusion. Thus in this
cohort, we have uncovered the several characteristics of the most likely PD
compulsive gambler, namely: (young) age, "angry", "anxious", and using a
(dopamine) agonist.

PMCID: 2654528
PMID: 19300546 [PubMed - in process]


39. Neurosci Lett. 2007 Mar 19;415(1):59-63. Epub 2006 Dec 30.

BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease
in diverse ethnic groups.

Xiromerisiou G, Hadjigeorgiou GM, Eerola J, Fernandez HH, Tsimourtou V, Mandel R,
Hellström O, Gwinn-Hardy K, Okun MS, Tienari PJ, Singleton AB.

Neurogenetics Unit, Department of Neurology, University of Thessaly, Medical
School, Papakyriazi 22 Street, Larissa 41222, Greece, and Helsinki University
Centeral Hospital, Finland.

Experimental and clinical data suggest that genetic variations in brain-derived
neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We 
performed a case-control association analysis of BDNF in three independent
Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging 
SNPs and five constructed haplotypes. No statistically significant differences in
genotype and allele frequencies were found between cases and controls in all
series. A relatively rare BDNF haplotype showed a trend towards association in
the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not
detected in the North American series). However, given the large number of
comparisons these associations are considered non-significant. In conclusion, our
results do not provide statistically significant evidence that common genetic
variability in BDNF would associate with the risk for PD in the Caucasian
populations studied here.

PMID: 17229524 [PubMed - indexed for MEDLINE]


40. Neurology. 2007 Jan 9;68(2):150-1. Epub 2006 Dec 6.

Limb-kinetic apraxia in Parkinson disease.

Quencer K, Okun MS, Crucian G, Fernandez HH, Skidmore F, Heilman KM.

Department of Neurology, University of Florida College of Medicine, Center for
Neuropsychological Studies, Gainesville, FL 32610, USA.

Comment in:
    Neurology. 2007 Aug 21;69(8):810-1; author reply 811.    Neurology. 2007 Jan 9;68(2):90-1.

To learn if limb-kinetic apraxia (LKA) is associated with Parkinson disease (PD),
participants with PD (on medications) and control subjects performed finger
tapping (FT), measuring movement speed, and performed coin rotation (CR),
measuring precise coordinated but independent finger movements and speed. There
were no group differences in FT, a measure of bradykinesia-rigidity, but CR
rotation was impaired in PD. Thus, LKA, not related to bradykinesia-rigidity, is 
associated with PD.

PMID: 17151340 [PubMed - indexed for MEDLINE]


41. Eur J Neurol. 2006 Dec;13(12):1298-301.

LRRK2 mutations in a clinic-based cohort of Parkinson's disease.

Scholz S, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Barton E, Munson S,
Singleton A, Okun MS.

Molecular Genetics Unit, National Institute on Aging, National Institutes of
Health, Bethsda, MD, USA.

In the last decade, major breakthroughs in the understanding of genetic
contributions to Parkinson's disease (PD) have been achieved. Recently, mutations
in LRRK2, encoding dardarin, have been found to be responsible for an autosomal
dominant parkinsonism (OMIM 607060). We screened 311 subjects (cases: n = 202,
controls: n = 109) for the three previously reported LRRK2 mutations. Our
investigation revealed a sporadic case of PD with a heterozygous mutation G2019S 
(c.6055G>A). Here, we present the clinical phenotype of this patient and discuss 
the implications of genetic testing for the G2019S mutation in patients with
sporadic PD.

PMID: 17116211 [PubMed - indexed for MEDLINE]


42. Mov Disord. 2007 Jan;22(1):141-5.

Laterality, region, and type of motor dysfunction correlate with cognitive
impairment in Parkinson's disease.

Williams LN, Seignourel P, Crucian GP, Okun MS, Rodriguez RL, Skidmore FM, Foster
PS, Jacobson CE 4th, Romrell J, Bowers D, Fernandez HH.

Department of Neurology, University of Florida College of Medicine, Gainesville, 
Florida 32610, USA.

We studied the relationship between two screening cognitive measures and off
motor Unified Parkinson's Disease Rating Scale (UPDRS) scores in 108 Parkinson's 
disease patients. Multiple regressions were conducted to examine the UPDRS
subscores' unique contributions to cognitive function. When including
bradykinesia, rigidity, and postural/gait instability subscores, only
bradykinesia predicted Mini Mental Status Examination (MMSE), normalized beta =
-0.57, t(104) = -3.31, P < 0.01, and Dementia Rating Scale-2 (DRS-2), normalized 
beta = -0.45, t(104) = -2.55, P < 0.05. Tremor was not included in the regression
analyses because it did not correlate with cognitive function. When including
axial and appendicular subscores, only the axial subscore predicted MMSE,
normalized beta = -0.39, t(105) = -3.19, P < 0.01, and DRS-2 scores, normalized
beta = -0.40, t(106) = -3.28, P < 0.01. When including left-sided and right-sided
subscores, only the right-sided symptoms predicted DRS-2 scores, normalized beta 
= -0.28, t(105) = -2.45, P < 0.05, and showed a trend toward predicting MMSE
scores, normalized beta = -0.22, t(105) = -1.95, P = 0.054. We therefore found
that right-sided symptoms (for laterality), axial symptoms (for region), and
bradykinesia (for type of symptoms) were the best predictors of cognitive
function. Copyright 2006 Movement Disorder     Society.

PMID: 17089386 [PubMed - indexed for MEDLINE]


43. Lancet Neurol. 2006 Nov;5(11):911-6.

Genome-wide genotyping in Parkinson's disease and neurologically normal controls:
first stage analysis and public release of data.

Fung HC, Scholz S, Matarin M, Simón-Sánchez J, Hernandez D, Britton A, Gibbs JR, 
Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD,
Rodríguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of 
Health, Bethesda, MD 20892, USA.

Comment in:
    Lancet Neurol. 2006 Nov;5(11):896-7.

BACKGROUND: Several genes underlying rare monogenic forms of Parkinson's disease 
have been identified over the past decade. Despite evidence for a role for
genetics in sporadic Parkinson's disease, few common genetic variants have been
unequivocally linked to this disorder. We sought to identify any common genetic
variability exerting a large effect in risk for Parkinson's disease in a
population cohort and to produce publicly available genome-wide genotype data
that can be openly mined by interested researchers and readily augmented by
genotyping of additional repository subjects. METHODS: We did genome-wide,
single-nucleotide-polymorphism (SNP) genotyping of publicly available samples
from a cohort of Parkinson's disease patients (n=267) and neurologically normal
controls (n=270). More than 408,000 unique SNPs were used from the Illumina
Infinium I and HumanHap300 assays. FINDINGS: We have produced around 220 million 
genotypes in 537 participants. This raw genotype data has been and as such is the
first publicly accessible high-density SNP data outside of the International
HapMap Project. We also provide here the results of genotype and allele
association tests. INTERPRETATION: We generated publicly available genotype data 
for Parkinson's disease patients and controls so that these data can be mined and
augmented by other researchers to identify common genetic variability that
results in minor and moderate risk for disease.

PMID: 17052657 [PubMed - indexed for MEDLINE]


44. Arch Neurol. 2006 Aug;63(8):1181-4.

Deep brain stimulation of the internal segment of the globus pallidus in delayed 
runaway dyskinesia.

Graff-Radford J, Foote KD, Rodriguez RL, Fernandez HH, Hauser RA, Sudhyadhom A,
Rosado CA, Sanchez JC, Okun MS.

Department of Neurology, University of Florida Movement Disorders Center,
University of Florida, Gainesville, FL, USA.

BACKGROUND: Dyskinesias that occur during a period without medication after
embryonic cell transplantation have been commonly reported in double-blind
trials; however, to date, they have not been reported in the few patients who
participated in open-label pilot studies. DESIGN: Single case observation with
preoperative and postoperative data, and intraoperative single-cell physiology.
PATIENT: A patient who underwent embryonic cell transplantation in 1993 as part
of the University of South Florida open-label study was referred for evaluation
of intractable dyskinesia of the right arm. The dyskinesia was present during
evaluation of the patient after a 12-hour period without medication and was
clinically disabling. It was manifested as a severe groping movement of the hand.
Intraoperative physiologic evaluation revealed decreased firing rates in the
internal segment of the globus pallidus. RESULTS: Deep brain stimulation of the
internal segment of the globus pallidus resulted in resolution of the dyskinesia.
CONCLUSION: This case highlights the delayed development of runaway dyskinesia
after a period without medication as an important potential long-term adverse
effect of embryonic cell transplantation in patients with Parkinson disease.

PMID: 16908749 [PubMed - indexed for MEDLINE]


45. Neurology. 2006 Jul 11;67(1):33-8.

Dissociating apathy and depression in Parkinson disease.

Kirsch-Darrow L, Fernandez HH, Marsiske M, Okun MS, Bowers D.

Department of Clinical and Health Psychology, College of Public Health and Health
Professions, University of Florida, Gainesville 32608, USA. lkirsch@phhp.ufl.edu

Erratum in:
    Neurology. 2006 Oct 10;67(7):1315. Fernandez, H F [corrected to Fernandez, HH].

Comment in:
    Neurology. 2006 Jul 11;67(1):10-1.

OBJECTIVE: To examine the hypothesis that apathy is a core feature of Parkinson
disease (PD) and that apathy can be dissociated from depression. METHODS: Eighty 
patients with PD and 20 patients with dystonia completed depression and apathy
measures including the Marin Apathy Evaluation Scale (AES), Beck Depression
Inventory (BDI), and Centers for Epidemiologic Studies-Depression Scale (CES-D). 
RESULTS: There was a significantly higher severity and frequency of apathy in PD 
(frequency = 51%, 41/80) than in dystonia (frequency = 20%, 4/20). Apathy in the 
absence of depression was frequent in PD and did not occur in dystonia (PD =
28.8%, dystonia = 0%). CONCLUSIONS: Patients with Parkinson disease (PD)
experienced significantly higher frequency and severity of apathy when compared
with patients with dystonia. Apathy may be a "core" feature of PD and occurs in
the absence of depression.

PMID: 16832074 [PubMed - indexed for MEDLINE]


46. CNS Spectr. 2006 Jul;11(7):521-36.

Lessons learned in deep brain stimulation for movement and neuropsychiatric
disorders.

Skidmore FM, Rodriguez RL, Fernandez HH, Goodman WK, Foote KD, Okun MS.

Department of Neurology, McKnight Brain Institute, University of Florida College 
of Medicine in Gainesville, 32610, USA.

The introduction of deep brain stimulation (DBS) as a treatment for
medication-refractory essential tremor in the late 1980s revealed, for the first 
time, that "chronically" implanted brain hardware had the potential to modulate
neurologic function with surprisingly low morbidity. Over time, the therapeutic
promise of DBS has become evident in Parkinson's disease and dystonia. In some
experienced centers, complex tremor disorders, such as posttraumatic Holmes
tremor and the tremor of multiple sclerosis, are being increasingly targeted.
More recently, other indications, including obsessive-compulsive disorder,
Tourette's syndrome, major depression, and chronic pain, have been proposed. As
the field has expanded, our knowledge about potential cognitive side effects of
DBS has also expanded. This article reviews the current knowledge regarding the
impact of stimulation of the subthalamic nucleus, globus pallidus internus, and
ventralis intermedius nucleus of the thalamus on symptoms in essential tremor,
Parkinson's disease, and dystonia. Also discussed are the emerging targets, what 
is known about the cognitive sequelae of DBS, and what has been learned about the
complications and therapeutic failures.

PMID: 16816792 [PubMed - indexed for MEDLINE]


47. Parkinsonism Relat Disord. 2006 Sep;12(6):392-5. Epub 2006 May 26.

Hypersexuality and paraphilia induced by selegiline in Parkinson's disease:
report of 2 cases.

Shapiro MA, Chang YL, Munson SK, Okun MS, Fernandez HH.

Department of Neurology, McKnight Brain Institute, University of Florida College 
of Medicine, P.O. Box 100236, Gainesville, FL 32610, USA.

While hypersexuality and paraphilia are known side effects of anti-Parkinson
medications, it is seldom reported. Furthermore, selegiline is rarely implicated 
in such behaviors. We report two cases of early onset PD who experienced
paraphilia and hypersexuality when selegiline was initiated, and later developing
obsessive-compulsive and punding behavior with the addition of dopamine agonists.
Social repercussions may prohibit patients and/or their families from
volunteering such information.

PMID: 16730214 [PubMed - indexed for MEDLINE]


48. NeuroRehabilitation. 2006;21(1):71-9.

Tutorial on maximum inspiratory and expiratory mouth pressures in individuals
with idiopathic Parkinson disease (IPD) and the preliminary results of an
expiratory muscle strength training program.

Silverman EP, Sapienza CM, Saleem A, Carmichael C, Davenport PW, Hoffman-Ruddy B,
Okun MS.

University of Florida, Gainesville, FL 32611, USA. epearson@ufl.edu

Respiratory symptoms are recognized as sequelae of motor dysfunction in
idiopathic Parkinson's disease (IPD) and these symptoms have the potential to
cause problems with swallow, cough, voice and speech. Specifically, maneuvers
that require rapid activation and coordination of upper airway and chest wall
musculature become progressively impaired as motor dysfunction progresses during 
the natural course of the disease. This study reports on the maximum inspiratory 
and expiratory pressures produced by 28 participants (average age 64) diagnosed
with moderate to severe IPD (average stage 2.5 with a range of 2.0-3.0). All
measures were collected during the "medication on" state. Outcomes of a specific 
respiratory muscle strength training technique for improving maximum expiratory
pressure are reported for three of the patients in this study. Techniques that
focus on strengthening the respiratory muscles in patients with IPD (other than
with low load breathing exercises), have not been previously reported. The
results of this pilot study demonstrate that respiratory muscle weakness may be
an important factor in the respiratory complications in IPD and that respiratory 
muscle strength training has the potential to improve expiratory muscle strength 
for this population. This improvement has the potential to positively impact high
forced respiratory activities, such as forced breathing maneuvers, swallow, cough
and speech functions that require greater magnitude and duration of expiration.

PMID: 16720940 [PubMed - indexed for MEDLINE]


49. Arch Neurol. 2006 May;63(5):729-35.

Testosterone therapy in men with Parkinson disease: results of the TEST-PD Study.

Okun MS, Fernandez HH, Rodriguez RL, Romrell J, Suelter M, Munson S, Louis ED,
Mulligan T, Foster PS, Shenal BV, Armaghani SJ, Jacobson C, Wu S, Crucian G.

Department of Neurology, University of Florida Movement Disorders Center,
McKnight Brain Institute, Gainesville, FL 32610, USA. okun@neurology.ufl.edu

BACKGROUND: Testosterone deficiency has been reported in patients with Parkinson 
disease (PD), Alzheimer disease, and Huntington disease. It is not known whether 
testosterone therapy (TT) in men with borderline hypogonadism and
neurodegenerative diseases will be of substantial benefit. Previously, we
reported that testosterone deficiency is more common in patients with PD compared
with age-matched control subjects, and we also reported in 2 small open-label
studies that some nonmotor symptoms responded favorably to TT. OBJECTIVE: To
define the effects of TT on nonmotor and motor symptoms in men with PD and
probable testosterone deficiency. DESIGN: Double-masked, placebo-controlled,
parallel-group, single-center trial. PATIENTS: Two experimental groups: patients 
with PD who were receiving either TT or placebo. INTERVENTIONS: Participants
received either the study drug by intramuscular injection (200 mg/mL of
testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium
chloride solution injections). In patients in each group, the testosterone serum 
concentration was obtained at each study visit. During 2 study visits,
testosterone levels were blindly evaluated and the intramuscular testosterone
dose was increased by 200 mg/mL if the free testosterone value failed to double
from the baseline value. MAIN OUTCOME MEASURES: The primary outcome variable was 
the St Louis Testosterone Deficiency Questionnaire, and secondary outcome
measures included measures of mood, cognition, fatigue, motor function, and
frequency of adverse events. At the end of the double-blind phase, all patients
were offered open-label TT and were followed up after 3 and 6 months. RESULTS:
Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean
total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone
level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7
years), receiving an average total levodopa equivalent dose of 734 mg/d, who had 
a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally
well tolerated. More subjects in the TT group experienced lower extremity edema
(40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels
were elevated from baseline. The improvement in the TT group compared with the
placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not 
statistically significant. In addition, there were no significant differences in 
motor and nonmotor features of PD between the 2 groups, although a few subscales 
showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual
Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but
sustained improvement in subjects in the TT group who continued to receive
treatment (n = 6) compared with subjects in the placebo group who elected not to 
receive TT (n = 3). CONCLUSIONS: Testosterone therapy was generally well
tolerated in elderly men with PD and probable testosterone deficiency. While
there was no significant difference in the motor and nonmotor scales between the 
TT and placebo groups at the end of 8 weeks compared with baseline, this may be
due to several study limitations, including small sample size, a strong placebo
effect with intramuscular therapy, and short follow-up that did not allow
measurement of delayed effects of TT in some subjects. Until more definitive
studies are reported, practitioners should be particularly cautious in treatment 
of low testosterone concentrations in men with PD and borderline testosterone
deficiency, and careful consideration should be given to the risks vs the
benefits of TT.

PMID: 16682542 [PubMed - indexed for MEDLINE]


50. NeuroRehabilitation. 2005;20(4):323-33.

Respiratory muscle strength training: treatment and response duration in a
patient with early idiopathic Parkinson's disease.

Saleem AF, Sapienza CM, Okun MS.

University of Florida Movement Disorders Center, Gainesville, FL, USA.
asaleem@ammanu.edu.jo

The outcome of a 20 week expiratory muscle strength training program (EMST) is
documented in a patient with early idiopathic Parkinson's disease. A pressure
threshold device was utilized and training occurred in the home setting. The
training was intensive with a physiologically challenging load specific to the
expiratory muscles, adjusted weekly based on the participant's performance.
Results indicated that strength, as indexed by the generation of maximum
expiratory pressure (MEP), increased by 50% in the first 4 weeks of training,
consistent with the average strength increase obtained in previous research.
Strength increases continued beyond the traditional 4 weeks of training with a
final improvement in MEP of 158% from baseline over the 20 weeks. When the EMST
was discontinued for a period of 4 weeks, the participant's MEP decreased by 16% 
from the 20 week endpoint measurement. The strength training pattern of the
expiratory muscles observed in this study was similar to the pattern previously
reported for limb muscles.

PMID: 16403998 [PubMed - indexed for MEDLINE]


51. Neurosci Lett. 2006 Mar 13;395(3):227-9. Epub 2005 Nov 18.

The human prion gene M129V polymorphism is not associated with idiopathic
Parkinson's disease in three distinct populations.

Scholz SW, Xiromerisiou G, Fung HC, Eerola J, Hellström O, Papadimitriou A,
Hadjigeorgiou GM, Tienari PJ, Fernandez HH, Mandel R, Okun MS, Gwinn-Hardy K,
Singleton AB.

Molecular Genetics Unit, National Institute on Aging, National Institutes of
Health, Building 35, Room 1A-1012, Bethesda, MD 20892, USA. scholzs@mail.nih.gov

Coexistence of prion disease and idiopathic Parkinson's disease (IPD) has been
previously described. It remains unclear whether this relationship may reflect
the high incidence of IPD or whether both prion and IPD share common pathogenetic
mechanisms. For this reason, we investigated the genotype distribution of the
M129V polymorphism of the human prion gene for association with IPD (controls: n 
= 398, IPD cases: n = 400). No association between genotypes in codon 129 and IPD
was detected in three distinct populations, suggesting that this PRNP
polymorphism has no direct influence on the susceptibility to IPD.

PMID: 16298483 [PubMed - indexed for MEDLINE]


52. Arch Neurol. 2005 Aug;62(8):1250-5. Epub 2005 Jun 13.

Management of referred deep brain stimulation failures: a retrospective analysis 
from 2 movement disorders centers.

Okun MS, Tagliati M, Pourfar M, Fernandez HH, Rodriguez RL, Alterman RL, Foote
KD.

Department of Neurology, University of Florida, Movement Disorders Center,
McKnight Brain Institute, Gainesville, FL 32610, USA. okun@neurology.ufl.edu

Comment in:
    Arch Neurol. 2005 Dec;62(12):1938; author reply 1938-9.

BACKGROUND: Since the Food and Drug Administration approved DBS, there has been a
surge in the number of centers providing the procedure. There is currently no
consensus regarding appropriate screening procedures, necessary training of
individuals providing the therapy, the need for an interdisciplinary team, or
guidelines for the management of complications. An increasing number of patients 
come to experienced DBS centers after unsatisfactory results from DBS surgery. An
attempt is made herein to evaluate the reasons for DBS failure in a series of
such patients and to make recommendations to improve overall DBS outcomes.
OBJECTIVE: To improve outcomes of deep brain stimulation (DBS) surgery by
analyzing a series of patients who had suboptimal results from DBS. METHODS:
Forty-one consecutive patients complaining of suboptimal results from DBS surgery
came to the University of Florida Movement Disorders Center, or to Beth Israel
Movement Disorders Center, over a 24-month period. All patients had undergone
implantation of DBS devices at outside medical centers. Each patient was
evaluated by a movement disorders neurologist, and the complete medical record
was reviewed. The DBS device for each patient was interrogated for adverse
effects and programmed for maximal benefit. Postoperative imaging studies were
evaluated whenever possible. RESULTS: The average age of patients was 63.4 years 
(range, 49-84 years). The indication for surgery (by record review) included 9
patients with essential tremor, 31 with Parkinson disease, and 1 with dystonia.
The diagnoses after referral examination included 5 with essential tremor, 26
with Parkinson disease, 3 with Parkinson disease and dementia, 1 with Parkinson
disease and essential tremor, 1 with corticobasal degeneration, 1 with dystonia, 
2 with multiple system atrophy, 1 with progressive supranuclear palsy, and 1 with
myoclonus. Issues related to inadequate preoperative screening: Thirty (73%) of
41 patients saw a movement disorders specialist prior to DBS implantation.
Fourteen (34%) patients had neuropsychological testing, 4 (10%) did not have
testing, and in 23 cases (56%), it could not be determined whether or not they
were tested. Five (12%) of 41 patients had an inadequate medication trial, and 5 
patients (12%) had significant cognitive dysfunction prior to their DBS
implantation. Surgical and device-related complications: Nineteen (46%) of 41
patients had suboptimally placed electrodes. Seven electrodes (17%) were replaced
with improvement. Three patients' devices had failed due to end of battery life, 
2 had infections, and 1 had a fractured lead. Programming and medication
adjustments: Seven (17%) of 41 patients had no or poor access to programming. Two
patients (5%) moved, and 2 physicians (5%) moved, creating issues with access to 
care. Eight patients (20%) required local follow-up (they flew to remote centers 
to have the surgery performed). Fifteen patients (37%) were inadequately
programmed and improved significantly with reprogramming. Six patients (15%)
experienced partial improvement with reprogramming, and 21 patients (51%) failed 
to improve despite extensive reprogramming. Thirty patients (73%) benefited from 
medication changes, 4 (10%) had antidepressants added to their regimens, and 1
(2%) had donepezil hydrochloride added. One patient's carbidopa/levodopa (2%) was
restarted after complete discontinuation. Outcomes: With the various
postoperative interventions described, 21 (51%) of 41 patients had good outcomes,
6 (15%) had modest clinical improvement, and 14 (34%) did not improve.
CONCLUSIONS: With appropriate intervention, 51% of patients who complained of
"failed" DBS procedures ultimately had good outcomes. Thirty-four percent of
these patients had persistently poor outcomes despite maximal intervention. This 
case series provides important insights into reasons for "DBS failure" and
proposes strategies to manage patients with DBS more effectively.

PMID: 15956104 [PubMed - indexed for MEDLINE]


53. Arch Neurol. 2005 Jan;62(1):141-3.

Stimulation of the subthalamic nucleus in a patient with Parkinson disease and
essential tremor.

Stover NP, Okun MS, Evatt ML, Raju DV, Bakay RA, Vitek JL.

Department of Neurology, University of Alabama at Birmingham, Birmingham, AL,
USA.

BACKGROUND: The preferred surgical target for the treatment of Parkinson disease 
(PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the
target for treatment of essential tremor (ET) is the thalamic subnucleus
ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the
identification of a single surgical target to treat both parkinsonian motor
symptoms and ET would be of practical importance. OBJECTIVE: To describe the use 
of the STN target in deep brain stimulator (DBS) surgery to treat PD motor
symptoms and the action-postural tremor of ET. DESIGN: Case report. PATIENT: A
62-year-old man had a greater than 30-year history of action-postural tremor in
both hands, well controlled with beta-blockers for more than 20 years. He
developed resting tremor, bradykinesia, and rigidity on his right side that
progressed to his left side during the past 10 years. Dopaminergic medication
improved his rigidity and bradykinesia, with only mild improvement of his resting
tremor and no effect on his action-postural tremor. INTERVENTIONS: Left
pallidotomy followed by placement of a left DBS in the Vim and subsequent
placement of a right STN DBS. MAIN OUTCOME MEASURES: Control of symptoms of PD
and ET. RESULTS: The left pallidotomy controlled the patient's parkinsonian motor
symptoms on the right side of his body, but did not affect the action-postural
component of his tremor. The symptoms on the left side of the body, including
both an action-postural and a resting tremor (as well as the rigidity and
bradykinesia), improved after placement of a single right STN DBS. CONCLUSION:
Placement of an STN DBS should be considered as the procedure of choice for
surgical treatment of patients with a combination of PD and ET.

PMID: 15642861 [PubMed - indexed for MEDLINE]


54. Arch Neurol. 2004 Dec;61(12):1898-904.

Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.

Rogaeva E, Johnson J, Lang AE, Gulick C, Gwinn-Hardy K, Kawarai T, Sato C, Morgan
A, Werner J, Nussbaum R, Petit A, Okun MS, McInerney A, Mandel R, Groen JL,
Fernandez HH, Postuma R, Foote KD, Salehi-Rad S, Liang Y, Reimsnider S, Tandon A,
Hardy J, St George-Hyslop P, Singleton AB.

Centre for Research in Neurodegenerative Diseases and Division of Neurology,
Department of Medicine, Toronto Western Hospital, University of Toronto, Ontario,
Canada.

BACKGROUND: Mutations in the PTEN-induced kinase (PINK1) gene located within the 
PARK6 locus on chromosome 1p35-p36 have recently been identified in patients with
recessive early-onset Parkinson disease. OBJECTIVE: To assess the prevalence of
PINK1 mutations within a series of early- and late-onset Parkinson disease
patients living in North America. DESIGN: All coding exons of the PINK1 gene were
sequenced in a series of 289 Parkinson disease patients and 80 neurologically
normal control subjects; the mutation frequencies were evaluated in additional
controls (100 white and 50 Filipino subjects). RESULTS: We identified 27
variants, including the first reported compound heterozygous mutation (Glu240Lys 
and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset
Parkinson disease patients. CONCLUSION: Autosomal recessive mutations in PINK1
are a rare cause of young-onset Parkinson disease.

PMID: 15596610 [PubMed - indexed for MEDLINE]


55. Motor Control. 2004 Oct;8(4):484-99.

Comparison of pallidal and subthalamic stimulation on force control in patient's 
with Parkinson's disease.

Alberts JL, Elder CM, Okun MS, Vitek JL.

School of applied Physiology, Georgia Institute of Technology, Atlanta, GA 30332,
USA.

The aim of this study was to determine the effects of unilateral deep brain
stimulation (DBS) on the control and coordination of grasping forces produced by 
Parkinson's disease (PD) patients. Ten advanced PD patients with unilateral DBS
in the globus pallidus (GPi) or the subthalamic nucleus (STN) (5 patients in each
group) performed a functional bimanual dexterous manipulation task. Experiments
were performed in the "Off" medication state with DBS "On" and "Off. " DBS
resulted in (a) significant clinical improvements, (b) greater maximum grip force
for both limbs, (c) reduced movement time, and (d) bilateral coupling of grasping
forces. There were no significant differences between the GPi and STN groups for 
any clinical or kinematic measures. DBS of the GPi and STN leads to an
improvement in the motor functioning of advanced PD patients. Improvement in
force-timing specification during DBS might allow PD patients to employ a
feedforward method of force control.

PMID: 15585903 [PubMed - indexed for MEDLINE]


56. Stereotact Funct Neurosurg. 2004;82(4):186-90. Epub 2004 Nov 18.

Aphasia and thalamotomy: important issues.

Bruce BB, Foote KD, Rosenbek J, Sapienza C, Romrell J, Crucian G, Okun MS.

Department of Neurology, McKnight Brain Institute, Movement Disorders Center,
University of Florida, Gainesville, FL 32610, USA.

Patients may present with classical symptoms suggesting aphasia following
thalamotomy (repetition, comprehension, fluency and naming abnormalities). They
may also present with 'freezing of speech', and this symptom should not be
considered as a speech disorder or a symptom of Parkinson's disease progression, 
without careful testing to rule out language deficits, particularly dysfluency.
There are important issues related to all language complications of thalamotomy, 
including (1) the time course of problems following surgery, (2) the impact of
preexistingspeech problems, (3) the importance of the size and location of
lesions, (4) the potential circuits important in the pathogenesis of a thalamic
language disturbance and (5) whether laterality makes a difference (left- versus 
right-sided thalamic lesions). As more centers switch from thalamotomy to deep
brain stimulation, the issues regarding aphasia will need to be addressed. 2004
S. Karger AG, Basel.

PMID: 15557767 [PubMed - indexed for MEDLINE]


57. Mov Disord. 2005 Jan;20(1):104-5.

Rebound psychosis: effect of discontinuation of antipsychotics in Parkinson's
disease.

Fernandez HH, Trieschmann ME, Okun MS.

Department of Neurology, University of Florida/McKnight Brain Institute, Movement
Disorders Program, Gainesville, Florida 32610, USA. fernandez@neurology.ufl.edu

Comment in:
    Mov Disord. 2005 Apr;20(4):515; author reply 515.

To determine whether psychiatrically stable patients with a history of
drug-induced psychosis could be successfully weaned off their antipsychotic drug,
we offered consecutive Parkinson disease (PD) patients on quetiapine or
clozapine, who were free of any on-going psychosis, to be slowly weaned off their
antipsychotic drug. Before the study was aborted 6 PD patients (mean age, 78
years) with an average antipsychotic exposure of 20 months (5 on quetiapine, 1 on
clozapine) were enrolled. After the antipsychotic agent was discontinued,
psychosis recurred in 5 of 6 patients. In 3 patients the "rebound psychosis" was 
worse than the original psychotic episode and required subsequent higher
antipsychotic medication doses. (c) 2004 Movement Disorder     Society.

PMID: 15390047 [PubMed - indexed for MEDLINE]


58. Neurologist. 2004 Sep;10(5):290.

A mnemonic for Parkinson disease patients considering DBS: a tool to improve
perceived outcome of surgery.

Okun MS, Foote KD.

Department of Neurology, Movement Disorders Center, University of Florida
McKnight Brain Institute, Gainesville, Florida 32610, USA. okun@neurology.ufl.edu

Patients considering deep brain stimulation (DBS) for Parkinson disease (PD) may 
be exposed to videotapes, media coverage, or literature which show dramatic
improvements in PD symptoms after surgical intervention. Based on this
information, patients may seek a medical center with expertise in DBS for an
evaluation and assessment of their candidacy for surgery. If patients receive a
device, they may be disappointed or despondent following surgery because of a
failure to achieve a preconceived and unrealistic outcome. In order to address
the important issue of patient misconception of potential outcome, we have
introduced a simple mnemonic device. The device may be taught and then reviewed
with patients and families both before and after surgery. Use of this mnemonic
device may allow the patient and family the time necessary to alter the
perception of perceived benefit. This education can help to ensure that outcome
meets or exceeds expectation, and as a result they become a more satisfied and
easy-to-manage DBS patient.

PMID: 15335446 [PubMed - indexed for MEDLINE]


59. J Geriatr Psychiatry Neurol. 2004 Sep;17(3):127-36.

Psychosis in Parkinson's disease.

Wint DP, Okun MS, Fernandez HH.

Department of Psychiatry, McKnight Brain Institute/University of Florida,
Gainesville 32610, USA.

Psychosis in Parkinson's disease (PD) is a fairly common and vexing problem.
Although it can occur at any stage of the illness, it is a particularly important
issue for patients who are in the later stages of PD and have been chronically
treated with anti-PD medications. The exact pathophysiology of PD-related
psychosis remains a mystery. Neurochemical imbalances, sleep disturbances, and
visual processing abnormalities in PD have been implicated in its pathogenesis.
Treatment of psychotic symptoms should occur only after potential medical and
environmental causes of delirium have been eliminated or addressed. Initial
pharmacologic changes should include limiting the patient's anti-PD medications
to those that are necessary to preserve motor function. Should that fail, an
atypical antipsychotic agent is presently the treatment of choice. An emerging
treatment option is the use of acetylcholinesterase inhibitors. This article
reviews what is known about the epidemiology, risk factors, pathophysiology, and 
treatment of PD-related psychosis.

PMID: 15312276 [PubMed - indexed for MEDLINE]


60. Neurology. 2004 Jul 13;63(1):161-3.

Development and initial validation of a screening tool for Parkinson disease
surgical candidates.

Okun MS, Fernandez HH, Pedraza O, Misra M, Lyons KE, Pahwa R, Tarsy D, Scollins
L, Corapi K, Friehs GM, Grace J, Romrell J, Foote KD.

Department of Neurology, University of Florida McKnight Brain Institute, 100 S.
Newell Dr., 3rd fl., rm. L3-100, PO Box 100236, Gainesville, FL 32610, USA.
okun@neurology.ufl.edu

As there is currently no standardized assessment tool for evaluating Parkinson
disease (PD) patients for deep brain stimulation (DBS), the authors developed the
Florida Surgical Questionnaire for Parkinson Disease (FLASQ-PD). Part I of the
study was a retrospective analysis of 174 patients presenting for a surgical
screening. Part II was a multicenter study to assess the correlation of FLASQ-PD 
scores. The results of this study suggest that the FLASQ-PD may be a useful
triage tool for screening PD patients for DBS surgery.

PMID: 15249630 [PubMed - indexed for MEDLINE]


61. J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):921-3.

Pseudobulbar crying induced by stimulation in the region of the subthalamic
nucleus.

Okun MS, Raju DV, Walter BL, Juncos JL, DeLong MR, Heilman K, McDonald WM, Vitek 
JL.

Department of Neurology, University of Florida McKnight Brain Institute,
Gainesville, FL 32610, USA. okun@neurology.ufl.edu

We describe a case of pseudobulbar crying associated with deep brain stimulation 
(DBS) in the region of the subthalamic nucleus (STN). Patients with pseudobulbar 
crying show no other evidence of subjective feelings of depression such as
dysphoria, anhedonia, or vegetative signs. This may be accompanied by other
symptoms of pseudobulbar palsy and has been reported to occur with ischaemic or
structural lesions in both cortical and subcortical regions of the brain.
Although depression has been observed to result from DBS in the region of the
STN, pseudobulbar crying has not been reported. A single patient who reported the
symptoms of pseudobulbar crying after placement of an STN DBS was tested in the
off DBS and on DBS conditions. The patient was tested using all four DBS lead
contacts and the observations and results of the examiners were recorded. The
Geriatric Depression Scale was used to evaluate for depression in all of the
conditions. The patient exhibited pseudobulbar crying when on monopolar
stimulation at all four lead contacts. The pseudobulbar crying resolved off
stimulation. This case describes another type of affective change that may be
associated with stimulation in the region of or within the STN. Clinicians should
be aware of this potential complication, the importance of differentiating it
from stimulation induced depression, and its response to a serotonin reuptake
inhibitor, such as sertraline.

PMCID: 1739063
PMID: 15146017 [PubMed - indexed for MEDLINE]


62. Mov Disord. 2004 Apr;19(4):375-89.

Lesion therapy for Parkinson's disease and other movement disorders: update and
controversies.

Okun MS, Vitek JL.

Department of Neurology, University of Florida, Gainesville, Florida, USA.
okun@neurology.ufl.edu

An analysis of the international literature on lesioning for movement disorders
was undertaken to review lesion therapy for Parkinson's disease (PD) and other
movement disorders and to highlight important controversies surrounding this
surgical technique. Lesions have been placed throughout the neuraxis with varying
approaches and success. Our understanding of the pathophysiological basis
underlying the development of PD and other movement disorders has led to a better
understanding of why lesioning certain portions of the nervous system should
improve motor function. Advances in imaging technology and electrophysiological
techniques used for localization of brain structures, such as microelectrode
mapping, have improved the ability to accurately identify and lesion target
structures deep in the brain. This improvement has led to an increase in the
degree and consistency of clinical benefit. The major controversies in lesion
therapy include: (1) which target for which disorder; (2) determination of the
optimal lesion site and whether the external globus pallidus (GPe) should be
included in the pallidotomy lesion for PD; (3) determination of the size of the
lesion; (4) whether bilateral lesions can be placed without the high incidence of
side effects reported by some investigators; (5) whether microelectrodes aid in
the ability to improve clinical outcomes or increase the risk of side effects by 
making multiple microelectrode penetrations; (6) whether the subthalamic nucleus 
(STN) should be explored further as a lesioning target; and (7) whether lesioning
should be abandoned entirely in favor of deep brain stimulation (DBS). Many
important questions and controversies regarding lesion therapy remain unanswered.
It is unlikely given the pro-DBS environment that these questions will be
answered in the near future. We should, however, be careful not to abandon an
effective therapy before fully exploring through randomized trials the relative
effect of different surgical approaches for the treatment of patients with
movement disorders. Copyright 2004 Movement Disorder     Society

PMID: 15077235 [PubMed - indexed for MEDLINE]


63. Neurology. 2004 Feb 10;62(3):411-3.

Plasma testosterone levels in Alzheimer and Parkinson diseases.

Okun MS, DeLong MR, Hanfelt J, Gearing M, Levey A.

Department of Neurology, University of Florida, McKnight Brain Institute,
Gainesville 32610, USA. okun@neurology.ufl.edu

BACKGROUND: Testosterone deficiency, a treatable condition commonly seen in aging
men, has been linked to Parkinson disease (PD) and Alzheimer disease (AD). In
normal subjects, low testosterone levels are associated with cognitive and
neuropsychiatric symptoms, yet the relationship between testosterone levels and
cognitive function in PD and AD remains unclear. OBJECTIVE: To examine the
relationship of testosterone levels to age and cognitive function in PD and AD.
METHODS: Plasma testosterone levels were determined in men enrolled in a clinical
registry of subjects with PD and AD, and neuropsychological testing was performed
on subjects who consented. Testosterone levels in men with PD were compared with 
those in men with AD. In both groups, the relationship between testosterone
levels and neuropsychological test scores was analyzed, adjusting for age and
education. RESULTS: Linear regression analysis revealed that testosterone levels 
decreased with age in male PD patients (p < 0.03) and male AD patients (p <
0.07). The rate of decline was similar for the two groups. In PD patients, lower 
testosterone levels were associated with poorer performance on Trails B Seconds
(p < 0.02). CONCLUSIONS: There is a similar age-related decline in plasma
testosterone levels in men with either PD or AD. Previously described
associations between low testosterone levels and frontal lobe dysfunction in
normal aged men, together with these results, suggest that the hormonal
deficiency may act as a "second hit" to impair cognitive function in
neurodegenerative disease.

PMID: 14872022 [PubMed - indexed for MEDLINE]


64. J Neurol Neurosurg Psychiatry. 2003 Nov;74(11):1584-6.

Mood changes with deep brain stimulation of STN and GPi: results of a pilot
study.

Okun MS, Green J, Saben R, Gross R, Foote KD, Vitek JL.

University of Florida McKnight Brain Institute, Gainesville, Florida 32610, USA. 
okun@neurology.ufl.edu

The results of this study suggest that there are mood changes associated with
deep brain stimulation of the subthalamic nucleus (STN) and the globus pallidus
interna (GPi). Further, optimal placement of electrodes in both STN and GPi seems
to result in overall improvement in mood and is associated with a lower incidence
of adverse mood effects than stimulation outside the optimal site. Preliminary
data from this study, however, suggest that slight movement dorsal or ventral to 
the site of optimal motor performance may be associated with more adverse changes
in mood with STN stimulation than with GPi stimulation.

PMCID: 1738229
PMID: 14617726 [PubMed - indexed for MEDLINE]


65. Expert Opin Pharmacother. 2003 Oct;4(10):1747-61.

Rationale for current therapies in Parkinson's disease.

Romrell J, Fernandez HH, Okun MS.

University of Florida, Department of Neurology, McKnight Brain Institute, PO Box 
100236, Gainesville, FL 32610, USA.

Parkinson's disease (PD) is a neurodegenerative disorder that affects an
estimated 1 million people in the US and tens of millions worldwide. Medication
therapy has made significant advances and improvements especially over the last
10 years. A number of new treatments and new strategies have emerged and the
quality of life for the average sufferer has improved. This review will describe 
the rationale and strategies for current medical therapies in PD, with special
emphasis on the use of antipsychotic agents. Levodopa remains the most
efficacious medication for the management of PD. Long-term use of levodopa,
however, is associated with the development of motor fluctuations including
dyskinesia. Trials with dopamine agonists have demonstrated a delay in the onset 
of dyskinesia with the use of this therapy. There is also active, ongoing
investigation to determine whether a neuroprotective effect may be present with
agonist therapy. Anticholinergics have been successfully used to treat tremor as 
well as sialorrhoea and urinary urgency. Catechol-O-methyltransferase inhibitors 
increase 'on time', decrease 'off time,' and improve motor scores. Continuous
stimulation of dopamine receptors may decrease the fluctations observed with
pulsatile delivery of anti-Parkinsonian medications, but this will require more
study. Monoamine oxidase-B inhibitors, specifically selegiline, may provide
symptomatic improvement; the question as to whether a neuroprotective benefit is 
present remains unanswered. Amantadine has demonstrated both symptomatic benefit 
and dyskinesia benefit in some patients. Selective dopamine blockers such as
clozaril and quetiapine, have been shown to be effective in the treatment of
psychosis. This class of medications is particularly useful as an adjunctive to
levodopa and dopamine agonists. Doses of dopaminergic drugs can be escalated to
treat Parkinsonian symptoms, whereas selective dopamine blockers can be added to 
block psychosis. Old management strategies required a reduction in dopaminergic
therapy and therefore worsened Parkinsonian symptoms. Even though there have been
great advances in the medical options for symptomatic management of PD, there are
still many unmet needs for this patient population.

PMID: 14521485 [PubMed - indexed for MEDLINE]


66. Front Biosci. 2003 Sep 1;8:s992-7.

Visual-spatial ability in Parkinson's disease.

Crucian GP, Okun MS.

University of Florida Department of Neurology, P.O. Box 100236, Gainesville, FL
32610-0236, USA. crucigp@neurology.ufl.edu

Parkinson's Disease (PD) has traditionally been viewed as primarily a disturbance
of motor functioning, typically involving tremor, rigidity, hypokinesia, gait
disturbance, and postural instability. More recently, decline in cognitive
function has been recognized as a feature of PD. One prominent cognitive symptom 
of PD involves deficits on tasks of spatial ability. However, findings of
visual-spatial deficits in individuals with PD have been inconsistent. There are 
several methodological issues in this area of research that potentially confound 
the interpretation of data and need to be taken into consideration, including
subject characteristics (e.g., age, sex and education), duration of illness, the 
current level of disability, the presence of emotional depression, the current
level of medications, and the presence of dementia. Further, the tests that have 
shown visual-spatial deficits in PD are often complex, showing sensitivity to
other cognitive processes as well. Another problem in this area of research is
the lack of a clear understanding of the brain mechanisms that underlie
visual-spatial deficits in PD. One theory of cognitive dysfunction in PD suggests
that these cognitive deficits are in some way related to disruption of
frontal-basal ganglia neural circuits important in executive functions. However, 
frontal-basal ganglionic dysfunction does not appear to account entirely for the 
visual-spatial cognitive deficits seen in PD. Subtle differences in performance
on executive function measures appear to dissociate individuals with frontal lobe
damage from individuals with PD. Findings from two recent studies indicate that
PD is indeed associated with deficits in visual-spatial ability. These findings
also indicate that the relationship between visual-spatial ability and
frontal-executive function in PD is likely complex, and that the visual-spatial
deficits in PD may be sensitive to the sex of the individual with PD.

PMID: 12957858 [PubMed - indexed for MEDLINE]


67. Brain Cogn. 2003 Jul;52(2):281-3.

Transient manic behavior after pallidotomy.

Okun MS, Bakay RA, DeLong MR, Vitek JL.

Department of Neurology, University of Florida, Gainesville, FL, USA.

We report two cases of transient hypomanic behavior following pallidotomy. Both
of the reported patients had lesions involving non-motor portions of the globus
pallidus. Patient 1 had a lesion in the left anteromedial portion of GPi, while
patient 2 had one lesion involving the anteromedial portion of GPi on the right
and a second lesion involving the postero-ventral most portion of the putamen on 
the left. These cases emphasize the importance of placing lesions within the
sensori-motor portion of GPi without infringing on adjacent non-motor portions.
Cases involving transient manic behavior after pallidotomy have not been
previously reported. Centers performing pallidotomy or DBS should be aware that
lesions or stimulation too anterior in the GPi might lead to manic behavior.

PMID: 12821111 [PubMed - indexed for MEDLINE]


68. Arch Neurol. 2002 Nov;59(11):1750-3.

Beneficial effects of testosterone replacement for the nonmotor symptoms of
Parkinson disease.

Okun MS, Walter BL, McDonald WM, Tenover JL, Green J, Juncos JL, DeLong MR.

Department of Neurology, Emory University, Atlanta, Ga., USA.
okun@neurology.ufl.edu

OBJECTIVE: To investigate whether a single daily dose of testosterone replacement
gel has beneficial effects on testosterone deficiency symptoms, cognitive
function, nonmotor symptoms of Parkinson disease (PD), and motor symptoms of PD. 
BACKGROUND: Recently it has been observed that testosterone replacement therapy
improves refractory nonmotor symptoms in testosterone-deficient men with PD. Many
of the symptoms of testosterone deficiency are nonspecific and overlap with the
nonmotor symptoms of PD, such as decreased enjoyment of life, lack of energy,
sexual dysfunction, and depression. Replacement therapy for men with PD and
comorbid testosterone deficiency may be an important addition to antiparkinsonian
management strategies. METHODS: A prospective open-labeled pilot study of
testosterone topical gel (5 g of AndroGel; Unimed Pharmaceutical Inc, Deerfield, 
Ill) administered daily to testosterone-deficient (free testosterone <80 pg/mL)
men with PD. All 10 patients were followed up for 1 month and 6 patients were
followed up for a total of 3 months. Patients were administered a battery of
testosterone deficiency questionnaires, cognitive studies, and scales of PD
nonmotor and motor function at baseline, 1, and 3 months. RESULTS: With the daily
transdermal testosterone gel, patients had an average increase in levels of free 
testosterone from baseline (53 pg/mL) to a 1-month follow-up visit (131 pg/mL; P 
=.06) and to a 3-month follow-up visit (98 pg/mL; P =.04). Testosterone
deficiency symptoms improved in these patients (St Louis Testosterone Deficiency 
Questionnaire) from baseline (7.9 deficiency symptoms) to 1 month (5.6 deficiency
symptoms, P =.04) and 3 months (5.8 deficiency symptoms, P =.08). The Unified
Parkinson's Disease Rating Scale IV showed improvement at 1 month (P =.008).
Additionally, there were trends toward improvement in the following scales:
Unified Parkinson's Disease Rating Scale I at the 3-month follow-up (P =.09),
Letter Fluency at the 3-month follow-up (P =.08), and the Hamilton Anxiety Scale 
at the 1-month follow-up (P =.09). CONCLUSIONS: A daily dose of transdermal
testosterone gel improved testosterone deficiency symptoms in men with PD.
Although there were trends in improvement in other nonmotor and motor symptoms of
PD, future placebo control studies will need to be powered to answer these
important questions. Whether testosterone deficiency is simply a comorbidity in
PD or whether it plays a role in the pathogenesis of disease also remains for
future study.

PMID: 12433262 [PubMed - indexed for MEDLINE]


69. Mov Disord. 2002 May;17(3):622-4.

Treatment of pseudobulbar laughter after gamma knife thalamotomy.

Okun MS, Heilman KM, Vitek JL.

Emory University, Department of Neurology, Atlanta, Georgia, USA.
msokun@dnamail.com

We describe a case of pathological laughter after gamma knife thalamotomy which
resolved after treatment with sertraline. It is important to identify this
potentially treatable complication of surgical therapy. Copyright 2002 Movement
Disorder Society

PMID: 12112225 [PubMed - indexed for MEDLINE]


70. Arch Neurol. 2002 May;59(5):807-11.

Refractory nonmotor symptoms in male patients with Parkinson disease due to
testosterone deficiency: a common unrecognized comorbidity.

Okun MS, McDonald WM, DeLong MR.

Department of Neurology, Emory University, 1639 Pierce Dr, Suite 6000, Atlanta,
GA 30322, USA. msokun@dnamail.com

BACKGROUND: Many patients with Parkinson disease (PD) suffer from nonmotor
symptoms including depression, anxiety, sexual dysfunction, decreased energy
level, and an overall decline in quality of life. Comorbid depression,
hypothyroidism, and sleep disorders may account for some, but not all, of these
problems. Testosterone deficiency affects 20% to 25% of males over the age of 60 
years in the general population and may cause signs and symptoms of the nonmotor 
symptoms seen in PD. We observed numerous patients with PD whose nonmotor
symptoms were refractory to treatment. OBJECTIVE: To determine whether treatment 
of comorbid testosterone deficiency in male patients with PD can lead to
improvements in refractory nonmotor symptoms. METHODS: Case studies were reviewed
of the first 5 male patients who had PD with symptoms of testosterone deficiency 
who were treated in our clinic. All patients had low serum testosterone levels.
Screening for testosterone deficiency symptoms using the St Louis Testosterone
Deficiency Questionnaire was performed for 4 of the 5 patients. Additionally, to 
assess the prevalence of PD, total testosterone levels in 68 patients in our PD
registry were sent for evaluation. RESULTS: Following testosterone replacement
therapy, all 5 patients experienced significant improvements in their refractory 
nonmotor symptoms. Of 68 male patients with PD enrolled in our PD registry, 24
(35%) had plasma evidence of testosterone deficiency. We also noted that the risk
of testosterone deficiency per decade was found to increase 2.8-fold per decade
(P<.001), paralleling that which is found in the general elderly male population.
CONCLUSIONS: The findings from this study reveal the heretofore unrecognized high
prevalence of testosterone deficiency in elderly male patients with PD similar to
that found in the general population. These symptoms, which may be refractory to 
antidepressants, anxiolytics, and antiparkinsonian medications, may respond to
treatment with testosterone. More rigorous controlled studies will need to be
undertaken to examine the treatment of this common comorbidity in male patients
with PD.

PMID: 12020264 [PubMed - indexed for MEDLINE]


71. Neurology. 2002 Feb 26;58(4 Suppl 1):S63-70.

Depression associated with Parkinson's disease: clinical features and treatment.

Okun MS, Watts RL.

Department of Neurology, Emory University School of Medicine & Wesley Woods
Geriatric Center, Atlanta, GA 30322, USA.

Depression associated with Parkinson's disease (PD) is common and affects 25 to
40% of patients. Recognition of the signs and symptoms of depression associated
with PD is essential for clinical practitioners. Treatment of depression in this 
subset of patients can have a direct and dramatic impact on functional disability
and quality of life. A review of the literature concerning depression and
depression associated with PD was undertaken, with specific attention given to
disease mechanisms, clinical presentation, association with thyroid disease, and 
the principles of management and treatment. Specific signs and symptoms of
depression can be easily identified in patients with PD. Practitioners should be 
aware of these signs and symptoms when diagnosing and treating depression
associated with PD. Practitioners should also be aware of the pros and cons of
each treatment option and should choose a therapy appropriate for each individual
patient's needs. It is important to identify the features of depression
associated with PD in order to render early diagnosis and institute practical and
efficacious therapy.

PMID: 11909987 [PubMed - indexed for MEDLINE]


72. Arch Neurol. 2001 Dec;58(12):1995-2002.

Complications of gamma knife surgery for Parkinson disease.

Okun MS, Stover NP, Subramanian T, Gearing M, Wainer BH, Holder CA, Watts RL,
Juncos JL, Freeman A, Evatt ML, Schuele SU, Vitek JL, DeLong MR.

Emory University, Wesley Wood Health Center Building, Third Floor Neurology, 1841
Clifton Rd NE, Atlanta, GA 30329, USA. msokun@pol.net

Comment in:
    Arch Neurol. 2001 Dec;58(12):1970-2.    Arch Neurol. 2002 Aug;59(8):1334-5; author reply 1335.    Arch Neurol. 2002 Oct;59(10):1660-2; author reply 1662-4.    Arch Neurol. 2002 Oct;59(10):1660; author reply 1662-4.    Arch Neurol. 2003 Oct;60(10):1494-6; author reply 1496.

BACKGROUND: Many medical centers throughout the world offer radiosurgery with the
gamma knife (GK) for pallidotomy and thalamotomy as a safe and effective
alternative to radiofrequency ablative surgery and deep brain stimulation for
Parkinson disease (PD). The reported incidence of significant complications
varies considerably, and the long-term complication rate remains unknown. DESIGN:
We describe 8 patients seen during an 8-month period referred for complications
of GK surgery for PD. RESULTS: Of the 8 patients, 1 died as a result of
complications, including dysphagia and aspiration pneumonia. Other complications 
included hemiplegia, homonymous visual field deficit, hand weakness, dysarthria, 
hypophonia, aphasia, arm and face numbness, and pseudobulbar laughter. In all
patients, lesions were significantly off target. CONCLUSIONS: The 8 patients with
PD seen in referral at our center for complications of GK surgery highlight a
spectrum of potential problems associated with this procedure. These include
lesion accuracy and size and the delayed development of neurological
complications secondary to radiation necrosis. Gamma knife surgery may have a
higher complication rate than has been previously appreciated due to delayed
onset and underreporting. We believe that the risk-benefit ratio of the GK will
require further scrutiny when considering pallidotomy or thalamotomy in patients 
with PD. Physicians using this technique should carefully follow up patients
postoperatively for delayed complications, and fully inform patients of these
potential risks.

PMID: 11735773 [PubMed - indexed for MEDLINE]







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