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Neurology 2000 Jun 13;54(11):2182-4

Ineffective subthalamic nucleus stimulation in levodopa-resistant postischemic
parkinsonism.

Krack P, Dowsey PL, Benabid AL, Acarin N, Benazzouz A, Kunig G, Leenders KL,
Obeso JA, Pollak P

Department of Clinical and Biological Neurosciences, Joseph Fourier University,
Grenoble, France. p.krack@neurologie.uni-kiel.de

The authors report a patient with postischemic parkinsonism who responded
neither to levodopa nor to bilateral subthalamic nucleus (STN) stimulation. MRI
revealed bilateral lesions of the substantia nigra, the striatum, the external
pallidum, and part of the internal pallidum. PET showed reduced striatal
dopa-decarboxylase activity, D2 receptor binding, and glucose metabolism.
Perioperative microrecording showed low-frequency activity of STN cells. This
case suggests that parkinsonian patients who do not have a good response to
levodopa or in whom a postsynaptic dopaminergic lesion can be shown may not be
good candidates for STN surgery.

PMID: 10851392, UI: 20311594

2: Brain 2000 Jun;123 ( Pt 6):1142-54

The impact of deep brain stimulation on executive function in Parkinson's
disease.

Jahanshahi M, Ardouin CM, Brown RG, Rothwell JC, Obeso J, Albanese A,
Rodriguez-Oroz MC, Moro E, Benabid AL, Pollak P, Limousin-Dowsey P

Department of Clinical Neurology, Institute of Neruology, The National Hospital
for Neurology and Neurosurgery, London, UK. m.jahanshahi@ion.ucl.ac.uk

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal
segment of the globus pallidus (GPi) improves Parkinson's disease and increases
frontal blood flow. We assessed the effects of bilateral DBS on executive
function in Parkinson's disease patients, seven with electrodes implanted in the
STN and six in the GPi. Patients were assessed off medication with stimulators
off, on and off again. The groups showed differential change with stimulation on
the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of
random number generation and Wisconsin Card Sorting (STN improved, GPi worse
with stimulation). Across the groups, stimulation speeded up responding (Stroop
control trial, TMT A) and improved performance on paced serial addition and
missing digit tests. Conversely, conditional associative learning became more
errorful with stimulation across the two groups. In general, change in
performance with stimulation was significant for the STN but not the GPi group.
These results support two opposite predictions. In support of current models of
Parkinson's disease, 'releasing the brake' on frontal function with DBS improved
aspects of executive function. Conversely, disruption of basal ganglia outflow
during DBS impaired performance on tests requiring changing behaviour in novel
contexts as predicted by Marsden and Obeso in 1994.

PMID: 10825353, UI: 20340249

3: Cell Transplant 2000 Mar-Apr;9(2):215-21

Implication of the subthalamic nucleus in the pathophysiology and pathogenesis
of Parkinson's disease.

Benazzouz A, Piallat B, Ni ZG, Koudsie A, Pollak P, Benabid AL

Laboratoire de Neurobiologie Preclinique, INSERM U.318, Grenoble, France.
Abdelhamid.Benazzouz@ujf-grenoble.fr

[Medline record in process]

The subthalamic nucleus (STN) has been shown to play an important role in the
control of movement and has been considered as a key structure in the functional
organization of the basal ganglia. Several studies postulated that the STN plays
a critical role in the pathophysiology of Parkinson's disease and that its
inhibition or its lesioning can reverse the cardinal motor symptoms.
Nevertheless, the beneficial effect was accompanied by dyskinetic abnormal
movements. In order to avoid unpleasant and irreversible side effects we used
high-frequency stimulation (HFS) of the STN instead of lesions. We have shown
that parkinsonian motor symptoms, akinesia, rigidity, and tremor can be
alleviated by HFS of the STN in the nonhuman primate model. Side effects were
controllable and appeared only at intensities higher than that inducing the
improvement of motor symptoms. In severe parkinsonian patients, bilateral
STN-HFS greatly improved parkinsonian motor symptoms. Motor fluctuations were
attenuated and patients became independent in most activities of daily living.
It appears that STN-HFS mimics the effects of lesions by inhibiting its neuronal
activity. In a rat model of parkinsonism, we studied the implication of the STN
in the excitotoxicity of nigral dopamine cells. We showed that kainic acid
lesioning of the STN can protect nigral dopaminergic cells against
6-hydroxydopamine-induced toxicity. The evidence reviewed in the present article
clearly demonstrates that the STN is implicated in the pathophysiology and
pathogenesis of Parkinson's disease.

PMID: 10811394, UI: 20269531

4: Neurol Res 2000 Apr;22(3):237-46

Future prospects of brain stimulation.

Benabid AL, Koudsie A, Pollak P, Kahane P, Chabardes S, Hirsch E, Marescaux C,
Benazzouz A

Inserm U 318, CHU of Grenoble, France.

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has
replaced thalamotomy as a treatment of tremor of various origins and was
extended to two other targets (Subthalamic nucleus (STN) and the medial pallidus
(GPi)), since 1993 based on recent experimental data in rats and monkeys. STN
appears to be a target of major interest, able to control the three cardinal
symptoms and to allow the decrease or suppression of levodopa treatment, which
then suppresses also levodopa induced dyskinesias. The mechanisms of action of
HFS are not fully understood, but are definitely related to high frequency and
are probably different depending on the target. Inhibition of cellular activity
or of network functions could be induced, by jamming of a retroactive loop for
tremor, or by shutdown of neurotransmitter release in STN. All cardinal symptoms
are alleviated from tremor to akinesia and rigidity. The effects remain stable
over more than five years chronic HFS of STN, as the method of choice when a
surgical procedure is indicated for the treatment of Parkinson's disease and
even more when a bilateral procedure is necessary. Recent data show that STN
stimulation could be useful in the treatment of dystonia as well as some forms
of epilepsies. It is therefore possible that DAS in STN as well as in other
targets could become a potent therapeutic tool in the future for neurological
disorders. The future of brain stimulation will depend on new technologies (new
circuits, electrodes, web based programmers), waveforms (alternatives to square
waves, random distribution), targets (hypothalamic nuclei, locus coeruleus) and
indications (dystonia, epilepsy, eating disorders.

Publication Types:
Review
Review, academic

PMID: 10769816, UI: 20232649

5: Ann Neurol 2000 Apr;47(4 Suppl 1):S189-92

Dyskinesias and the subthalamic nucleus.

Benabid AL, Benazzouz A, Limousin P, Koudsie A, Krack P, Piallat B, Pollak P

Department of Clinical and Biological Neurosciences, INSERM Preclinical
Neurobiology U-318, Joseph Fourier University of Grenoble, Hopital A. Michallon,
France.

Severe dyskinesias or ballism can occur following hemorrhagic events in the
subthalamic nucleus (STN), and it has recently been established that the STN
plays a major role in the pathophysiology of the motor dysfunction of
Parkinson's disease (PD) and that STN inhibition improves parkinsonian
dysfunction. Deep brain stimulation of the STN in PD patients is therefore
currently being evaluated as a therapy. High-frequency stimulation of the STN in
PD patients can induce intense dyskinesias that are similar to those induced by
levodopa. These may occur with a variable latency and resemble all types of
levodopa-induced dyskinesias (LIDs). They can be decreased by reducing the
levodopa dosage, which is permitted by the antiparkinsonian effect of
stimulating the STN. STN stimulation has been shown to improve all types of
LIDs, with the most dramatic effect being that on off-period dystonia. The
improvement in LIDs may relate to the decrease in drug dosage, while the
off-period dystonia is likely improved by the simultaneous administration of
levodopa and STN stimulation. It is thought that the STN is an important node in
a network, which can produce dyskinesias when disturbed by a lesion, and is
particularly sensitive for the induction of these abnormal movements.

Publication Types:
Review
Review, tutorial

PMID: 10762147, UI: 20222801

6: Eur Neurol 1999;42(3):136-40

Effect of bilateral subthalamic nucleus stimulation and dopatherapy on oral
control in Parkinson's disease.

Gentil M, Tournier CL, Pollak P, Benabid AL

INSERM, U 318, Centre Hospitalier Universitaire, Grenoble, France.

This study focuses on the speech organs of a parkinsonian patient who initially
had been treated with levodopa for 13 years, and had become severely disabled by
motor fluctuations. This patient has been treated with bilateral chronic
stimulation of the subthalamic nucleus (STN) for the last 2 years. Upper lip,
lower lip and tongue force production were examined before surgery under off and
on medication conditions, and 2 years after surgery under off and on stimulation
conditions. We compared the effect of stimulation and dopatherapy on the speech
organs. L-Dopa had a poor effect whereas bilateral stimulation improved oral
control and speech intelligibility. These results suggest that STN stimulation
influences speech organs in a different way from the dopaminergic system and
similarly affects oral and limb motor systems.

PMID: 10529538, UI: 20002492

7: J Neurol 1999 Sep;246 Suppl 2:II42-5

Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's
disease.

Limousin-Dowsey P, Pollak P, Van Blercom N, Krack P, Benazzouz A, Benabid A

MRC Human Movement and Balance Unit, Institute of Neurology, 23 Queen Square,
London WC1N3BG, email: P.Limousin@ion.ucl.ac.uk.

The limits of drug therapy in severe forms of Parkinson's disease have lead to a
renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep
brain stimulation (DBS) of these structures was developed with the aims of
reducing the morbidity of surgery and of offering an adaptative treatment. DBS
was first applied to the thalamus in patients with severe tremor. Tremor of the
hemibody is greatly reduced by stimulation of the contralateral electrode in 85%
of the cases. There is little change in other symptoms. However, motor
fluctuations and dyskinesias are a more frequent problem than severe tremor; in
attempt to treat these symptoms, DBS has recently been applied to the
subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation
greatly decreases off motor symptoms and motor fluctuations, which allows a
reduction of drug dosage and consequently of dyskinesias. GPi stimulation
decreases dyskinesias in most patients, but the effect on off motor symptoms is
more variable from one series to another, from very good to nil. The severe
morbidity of DBS applied to these 3 targets is low. Comparative studies of the
cost and the efficacy of DBS and lesions applied to these different targets are
now required.

Publication Types:
Review
Review, tutorial

PMID: 10526001, UI: 20002771

8: Rev Neurol (Paris) 1999 Sep;155(8):543-50

[The effect of thalamic stimulation on levodopa induced dyskinesias--evaluation
of a new target: the center parafascicular median].

[Article in French]

Caparros-Lefebvre D, Pollak P, Feltin MP, Blond S, Benabid AL

Service de Neurologie, CHU des Antilles et de la Guyane.

After 10 years of clinical practice (1987-1997), chronic thalamic deep brain
stimulation (DBS) is considered to be effective in the treatment of
drug-resistant parkinsonian tremor. DBS has produced few side-effects, which are
usually reversible. More recently, DBS has been applied to other movement
disorders (akinesia and rigidity, dyskinesias, dystonia), using new targets:
internal pallidum, subthalamic nucleus. These targets have been selected on the
basis of neurophysiological or anatomo-clinical data suggesting they could be
effective. Control of L-Dopa peak-dose dyskinesias by thalamic ventralis
intermedius nucleus (V.im.) stimulation has been reported by the Lille team, but
not by the Grenoble team. We therefore re-examined all teleradioanatomical data
of both teams, and compared them with the therapeutic effects. Location of 99
monopolar electrodes of thalamic stimulation, applied to treat parkinsonian
tremor, has been retrospectively measured. The Lille team included 21 patients
(22 electrodes); the Grenoble team included 52 patients (74 electrodes). L-Dopa
dyskinesias were suppressed in all 9 patients in Lille, and improved clearly in
only 8 out of 32 patients in Grenoble. The mean center of electrodes was
significantly different between both teams, being deeper, more posterior and
medial in Lille. This did not correspond to the coordinates of the V.im., but
seems to be closer to those of the centromedian and parafascicular complex
(CM-Pf), according to stereotactic atlases. Considering only the dyskinetic
patients, the therapeutic effects on L-Dopa dyskinesias were related to the
differences observed in the electrode position, but not to the team membership.
Improvement of L-Dopa dyskinesias was significantly associated with deeper and
more medial placement of electrodes. Retrospective analysis of ventriculographic
data confirmed that the electrode position and therapeutic effects of DBS are
strongly related. Our study suggested that CM-Pf stimulation could control both
tremor and L-Dopa dyskinesias. This hypothesis is consistent with
neuro-anatomical data showing that CM-Pf is connected to internal pallidum, the
stimulation of which controls specifically L-Dopa dyskinesias.

Publication Types:
Clinical trial

PMID: 10486844, UI: 99416312

9: J Neurol Neurosurg Psychiatry 1999 Sep;67(3):329-33

Effect of stimulation of the subthalamic nucleus on oral control of patients
with parkinsonism.

Gentil M, Garcia-Ruiz P, Pollak P, Benabid AL

INSERM, Unit 318, CHU Grenoble, France. michele.Gentil@ujf-grenoble.fr

OBJECTIVES: To assess the oral system of parkinsonian patients treated with
chronic stimulation of the bilateral subthalamic nucleus (STN) to evaluate
precisely the effectiveness of this procedure on the articulatory organs.
METHODS: Load sensitive cantilevers were used to sample ramp and hold force
contractions generated by the upper lip, lower lip, and tongue. The subject was
given the instruction to produce forces as rapidly and as accurately as possible
in response to the target signal (ranging from 0.25 to 2 N), which appeared on a
screen. Maximal force of each effector organ was also measured. Fourteen healthy
control subjects and 10 patients participated in this study. After an overnight
fast the patients were evaluated in the morning under two conditions: during
bilateral stimulation and 1 hour after stopping STN stimulation. RESULTS: During
STN stimulation, dynamic and static control of the articulatory organs were
improved: the maximal strength of the articulatory organs, their accuracy to
reach the target, and the precision of the hold phase increased. In addition,
the reaction time and the rise time of the ramp phase decreased. Patients'
speech as assessed by the item 18 of the unified Parkinson's disease rating
scale (UPDRS) was greatly improved by electrical stimulation of the STN
CONCLUSIONS: Improvement of oral control of the stimulated patients suggests
that STN stimulation modulates neuronal structures involved in speech. However,
more patients have to be evaluated for a fuller understanding of the effect of
this surgical procedure on speech.

PMID: 10449555, UI: 99380428

10: J Neurol Neurosurg Psychiatry 1999 Sep;67(3):308-14

Improvement of levodopa induced dyskinesias by thalamic deep brain stimulation
is related to slight variation in electrode placement: possible involvement of
the centre median and parafascicularis complex.

Caparros-Lefebvre D, Blond S, Feltin MP, Pollak P, Benabid AL

Department of Neurology, Pointe a Pitre University Hospital, French West Indies.

OBJECTIVE: To define the reason why two teams using the same procedure and the
same target for deep brain stimulation (DBS) obtained different results on
levodopa induced dyskinesias, whereas in both, parkinsonian tremor was improved
or totally suppressed. 

METHODS: Deep brain stimulation can replace lesions in
the surgical treatment of abnormal movements. After 10 years of experience with
DBS in Parkinson's disease, a comparison of results between the teams of Lille
(A) and Grenoble (B) was carried out, for as long as they used intraoperative
ventriculography. Both teams aimed at the same target, the ventralis intermedius
nucleus of the thalamus (VIM), but team A found a clear improvement of choreic
peak dose dyskinesias, whereas team B did not consistently. Therefore all
teleradioanatomical data of both teams were re-examined and compared with the
therapeutic effects. Location of 99 monopolar electrodes of thalamic stimulation
applied to treat parkinsonian tremor has been retrospectively measured (team A
included 21 patients, 22 electrodes; team B included 52 patients, 74
electrodes). Peak dose levodopa dyskinesias were suppressed by DBS in all nine
patients of team A, four of which were severely disabling. Only eight out of 32
patients from team B experienced a moderate (four) or clear (four) improvement
of dyskinesias, whereas in the remaining 24 patients, dyskinesias were unchanged
with stimulation. 

RESULTS: The mean centre of team A's electrodes was on average
2.9 mm deeper, more posterior and medial than team B's (t=8.05; p<0.0001). This
does not correspond to the coordinates of the VIM, but seems to be closer to
those of the centre median and parafascicularis complex (CM-Pf), according to
stereotaxic atlases. Considering only the dyskinetic patients, significant
differences were found in the electrode position according to the therapeutic
effects on levodopa dyskinesias, but they were not related to the team
membership. Improvement in levodopa dyskinesias was significantly associated
with deeper and more medial placement of electrodes. 

CONCLUSION: The retrospective analysis of patients treated with DBS using comparable
methodologies provides important information concerning electrode position and
therapeutic outcome. The position of the electrode is related to the therapeutic
effects of DBS. The results support the hypothesis that patients experiencing an
improvement of dyskinesias under DBS are actually stimulated in a structure
which is more posterior, more internal, and deeper than the VIM, very close to
the CM-Pf. These results are consistent with neuroanatomical and
neurophysiological data showing that the CM-Pf is included in the motor circuits
of the basal ganglia system and receives an important input from the internal
pallidum. This suggests that the CM-Pf could be involved specifically in the
pathophysiology of levodopa peak dose dyskinesias.

PMID: 10449551, UI: 99380424

11: Ann Neurol 1999 Aug;46(2):217-23

Bilateral subthalamic or pallidal stimulation for Parkinson's disease affects
neither memory nor executive functions: a consecutive series of 62 patients.

Ardouin C, Pillon B, Peiffer E, Bejjani P, Limousin P, Damier P, Arnulf I,
Benabid AL, Agid Y, Pollak P

Department of Clinical and Biological Neurosciences, Centre Hospitalier,
Grenoble, France.

There is a renewal of interest in surgical approaches including lesions and deep
brain stimulation directed at motor subcorticofrontal loops. Bilateral lesioning
presents a far greater risk of adverse effects, especially cognitive impairment.
Furthermore, the main advantages of the stimulation procedure over lesioning are
adaptability and reversibility of effects. The aim of this study was to assess
the influence of bilateral stimulation of the subthalamic nucleus or internal
globus pallidus on memory and executive functions in Parkinson's disease.
Sixty-two patients were assessed before and after 3 to 6 months of chronic
bilateral stimulation of the subthalamic nucleus (n = 49) or internal globus
pallidus (n = 13). The neuropsychological tests used were the Mattis Dementia
Rating Scale, the Grober and Buschke Verbal Learning Test, the Wisconsin Card
Sorting Test, category and literal fluency, graphic and motor series, the Stroop
Test, and the Trail Making Test. Mood was evaluated by the Beck Depression
Inventory. Only 4 of 25 cognitive variables were affected by deep brain
stimulation. Under stimulation, performance improved for Parts A and B of the
Trail Making Test, but there was a deterioration in literal and total lexical
fluency. There was also a mild but significant improvement in mood. It may
therefore be concluded that stimulation of the subthalamic nucleus or internal
globus pallidus does not change the overall cognitive performance in Parkinson's
disease and does not greatly affect the functioning of subcorticofrontal loops
involved in cognition in humans. This relative absence of cognitive impairment
in bilateral deep brain stimulation is likely because of the accurate
positioning of the electrodes, allowing the effects of stimulation to be
confined to sensorimotor circuits.

PMID: 10443887, UI: 99371487


13: Brain 1999 Jun;122 ( Pt 6):1133-46

From off-period dystonia to peak-dose chorea. The clinical spectrum of varying
subthalamic nucleus activity.

Krack P, Pollak P, Limousin P, Benazzouz A, Deuschl G, Benabid AL

Department of Clinical and Biological Neurosciences, Joseph Fourier University,
Grenoble, France.

The effect of chronic bilateral high-frequency stimulation of the subthalamic
nucleus (STN) on levodopa-induced dyskinaesias was investigated in eight
patients with fluctuating Parkinson's disease complicated by functionally
disabling off-period dystonia. All of the patients also had severe diphasic and
peak-dose chorea, so that it was possible to study the effect of high-frequency
stimulation on the different types of levodopa-induced dyskinaesias. Off-period
fixed dystonia was reduced by 90% and off-period pain by 66%. After acute
levodopa challenge, high-frequency stimulation of the STN reduced diphasic
mobile dystonia by 50% and peak-dose choreic dyskinaesias by 30%. The effect of
bilateral high-frequency stimulation of the STN on the Unified Parkinson's
Disease Rating Scale motor score had the same magnitude as the preoperative
effect of levodopa. This allowed the levodopa dose to be reduced by 47%. The
combination of reduced medication and continuous high-frequency stimulation of
the STN reduced the duration of on-period diphasic and peak-dose dyskinaesias by
52% and the intensity by 68%. Acute high-frequency stimulation of the STN mimics
an acute levodopa challenge, concerning both parkinsonism and dyskinaesias, and
suppresses off-period dystonia. Increasing the voltage can induce repetitive
dystonic dyskinaesias, mimicking diphasic levodopa-induced dyskinaesias. A
further increase in voltage leads to a shift from a diphasic-pattern dystonia to
a peak-dose pattern choreodystonia. Chronic high-frequency stimulation of the
STN also mimics the benefit of levodopa on parkinsonism and improves all kinds
of levodopa-induced dyskinaesias to varying degrees. Off-period dystonia,
associated with neuronal hyperactivity in the STN is directly affected by
stimulation and disappears immediately. The effect of chronic high-frequency
stimulation of the STN on diphasic and peak-dose dyskinaesias is more complex
and is related directly to the functional inhibition of the STN and indirectly
to the replacement of the pulsatile dopaminergic stimulation by continuous
functional inhibition of the STN. Chronic high-frequency stimulation of the STN
allows a very gradual increase in stimulation parameters with increasing
beneficial effect on parkinsonism while reducing the threshold for the
elicitation of stimulation-induced dyskinaesias. In parallel with improvement of
parkinsonism, the levodopa dose can be gradually decreased. As diphasic dystonic
dyskinaesias are improved to a greater degree than peak-dose dyskinaesias, both
direct and indirect mechanisms may be involved. Peak-dose choreatic
dyskinaesias, associated with little evidence of parkinsonism and thus with low
neuronal activity in the STN, are improved, mostly indirectly. Fixed off-period
dystonia, mobile diphasic dystonia and peak-dose choreodystonia seem to
represent a continuous clinical spectrum reflecting a continuous spectrum of
underlying activity patterns of STN neurons.

PMID: 10356065, UI: 99284548

14: Ann Neurol 1999 Apr;45(4):473-88

Impact of deep brain stimulation on upper limb akinesia in Parkinson's disease.

Brown RG, Dowsey PL, Brown P, Jahanshahi M, Pollak P, Benabid AL, Rodriguez-Oroz
MC, Obeso J, Rothwell JC

MRC Human Movement and Balance Unit, Institute of Neurology, London, UK.

Recent pathophysiological models of Parkinson's disease have led to new surgical
approaches to treatment including deep brain stimulation (DBS) and lesioning of
basal ganglia structures. Various measures of upper limb akinesia were assessed
in 6 patients with bilateral DBS of the internal pallidum and 6 with DBS of the
subthalamic nucleus. Stimulation improved a number of aspects of motor function,
and particularly movement time, and force production. Time to initiate
movements, and to perform repetitive movements also improved but less
dramatically. Processes indicating preparatory motor processes showed no
significant change. Few significant differences were found between the internal
pallidum and subthalamic nucleus groups. In general, the effects of DBS closely
parallel previous reports of the effects of dopaminergic medication. It is
suggested that disrupted pallidal output in Parkinson's disease interferes with
the rate, level, and coordination of force production but has little effect on
preparatory processes. The similarity of the effects of subthalamic nucleus and
internal pallidum stimulation suggests this disrupted outflow is the most
important determinant of upper limb akinesia in Parkinson's disease. The effects
of DBS were similar to the effects of unilateral pallidal lesions reported
elsewhere.

PMID: 10211472, UI: 99226454

15: Mov Disord 1998 Nov;13(6):907-14

Treatment of tremor in Parkinson's disease by subthalamic nucleus stimulation.

Krack P, Benazzouz A, Pollak P, Limousin P, Piallat B, Hoffmann D, Xie J,
Benabid AL

Department of Clinical and Biological Neurosciences, Centre Hospitalier
Universitaire, Grenoble, France.

The recent resurgent interest in functional surgery for the treatment of
Parkinson's disease (PD) has focused on the effects on akinesia and
levodopa-induced dyskinesia. Stimulation of the subthalamic nucleus (STN)
improves akinesia and rigidity but its effects on tremor have not been studied.
The objective of this study was to assess the efficacy of STN stimulation on
tremor in patients with the complete parkinsonian triad with motor fluctuations.
Of 27 consecutive patients with STN stimulation (26 bilateral), 15 exhibited
tremor rated at least 2/4 according to item 20 (rest tremor) of the Unified
Parkinson's Disease Rating Scale (UPDRS) in at least one limb. The mean
preoperative tremor score was 11.3+/-5.6 in off-drug and 1.2+/-2.4 in on-drug
conditions. The postoperative tremor scores at the last follow up (from 1-12
months) were 2.2+/-2.2 off-drug/on-stimulation and 0.2+/-0.4
on-drug/on-stimulation. Both rest and action tremors were improved in all
patients. The UPDRS tremor score was reduced by 80%, rigidity score by 65%, and
akinesia score by 51% on average. For the three symptoms, the stimulation effect
was close to that induced before surgery by a suprathreshold dose of levodopa
given in the morning. STN stimulation can be considered an interesting
alternative to thalamic or internal pallidal surgery even in PD patients with
severe high-amplitude tremor. In keeping with electrophysiological data in
monkeys rendered parkinsonian by MPTP injections, our results emphasize the
importance of the oscillation of a neuronal loop involving the STN in the
pathophysiology of parkinsonian tremor.

PMID: 9827614, UI: 99043316

16: Mov Disord 1998;13 Suppl 3:119-25

Long-term electrical inhibition of deep brain targets in movement disorders.

Benabid AL, Benazzouz A, Hoffmann D, Limousin P, Krack P, Pollak P

Department of Clinical and Biological Neurosciences, INSERM Preclinical
Neurobiology, Joseph Fourier University of Grenoble, Hopital A. Michallon,
France.

Stimulation of the thalamic nucleus ventralis intermedius (Vim) at high (130-Hz)
frequency has been used over the last 8 years as a treatment in 134 patients
with movement disorders (91 Parkinson's disease [PD], 23 essential tremor [ET],
21 various dyskinesias and dystonias, including four multiple sclerosis [MS]),
implanted with long-term electrodes connected to a programmable stimulator. In
PD patients, tremor was selectively suppressed for < or = 11 years. In ET
patients, results were satisfactory, but in 35% of the cases deteriorated with
time, when tremor had an action component. Other types of dyskinesias were much
less influenced. Sixty-eight patients were bilaterally implanted, and 14 were
implanted contralateral to a previous thalamotomy. Side effects were often
minor, well tolerated, and immediately reversible. Three secondary scalp
infections led to temporary removal of implanted material. There was no
permanent morbidity. Long-term Vim stimulation, which is reversible, adaptable,
and well tolerated, even by bilaterally operated-on (68 of 134) and by elderly
patients, should replace thalamotomy in the regular surgical treatment of
parkinsonian and essential tremors. More recently, we stimulated the subthalamic
nucleus (STN) in 51 patients (44 bilateral) and the globus pallidus internus
(GPi) in 12 patients (seven bilateral). STN stimulation has a spectacular effect
on akinesia and rigidity and may improve the patients so as to maintain them all
day at a level similar to their best "on" periods. A 30-50% reduction in drug
dosage was possible in most of the patients. GPi stimulation has indications and
effects similar to those of pallidectomy: abnormal involuntary movements are
totally suppressed, whereas effects on akinesia and rigidity are not so
important as they are with STN stimulation. For all three targets, morbidity is
low and reversible, even when bilateral implantations are performed. The
deep-brain stimulation method has now proved its safety as compared with
ablative surgery and is able to provide a significant improvement to these
severely disabled patients. Long-term follow up is establishing the security of
the method, which should be considered in earlier stages of the disease actively
to participate to rehabilitation.

Publication Types:
Review
Review, tutorial

PMID: 9827607, UI: 99043309

17: N Engl J Med 1998 Oct 15;339(16):1105-11

Electrical stimulation of the subthalamic nucleus in advanced Parkinson's
disease.

Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL

Department of Clinical and Biologic Neurosciences, Joseph Fourier University,
Grenoble, France.

BACKGROUND: In many patients with idiopathic Parkinson's disease, treatment with
levodopa is complicated by fluctuations between an "off" period, when the
medication is not working and the motor symptoms of parkinsonism are present,
and an "on" period, when the medication is causing improved mobility, often
accompanied by debilitating dyskinesias. In animal models of Parkinson's
disease, there is overactivity in the subthalamic nucleus, and electrical
stimulation of the subthalamic nucleus improves parkinsonism. We therefore
sought to determine the efficacy and safety of electrical stimulation of the
subthalamic nucleus in patients with Parkinson's disease. 

METHODS: We studied 24 patients with idiopathic Parkinson's disease in whom 
electrodes were implanted
bilaterally in the subthalamic nucleus under stereotactic guidance with imaging
and electrophysiologic testing of the location. Twenty were followed for at
least 12 months. Clinical evaluations included the Unified Parkinson's Disease
Rating Scale, a dyskinesia scale, and timed tests conducted before and after
surgery, when patients were off and on medications. RESULTS: After one year of
electrical stimulation of the subthalamic nucleus, the patients' scores for
activities of daily living and motor examination scores (Unified Parkinson's
Disease Rating Scale parts II and III, respectively) off medication improved by
60 percent (P<0.001). The subscores improved for limb akinesia, rigidity,
tremor, and gait. In the testing done on medication, the scores on part III
improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was
reduced by half. The cognitive-performance scores remained unchanged, but one
patient had paralysis and aphasia after an intracerebral hematoma during the
implantation procedure. CONCLUSIONS: Electrical stimulation of the subthalamic
nucleus is an effective treatment for advanced Parkinson's disease. The severity
of symptoms off medication decreases, and the dose of levodopa can be reduced
with consequent reduction in dyskinesias.

PMID: 9770557, UI: 98432450

18: Mov Disord 1998 Jul;13(4):648-52

Inhibition of levodopa effects by internal pallidal stimulation.

Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, Benabid AL

Department of Clinical and Biological Neurosciences and INSERM U318, Joseph
Fourier University of Grenoble, France.

We report three patients with bilateral GPi stimulation for stage 4 Parkinson's
disease (PD) with severe levodopa-induced dyskinesias (LID). In all three it was
possible to completely inhibit LID using high-stimulation parameters. Parallel
to complete inhibition of LID, an inhibition of the anti-akinetic effect of
levodopa was observed, whereas, at the same time, rigidity was markedly
improved. GPi stimulation is adaptable over time, and stimulation parameters
have to be programmed according to off- and on-period motor symptoms. The main
interest of stimulation is the possibility of finding a compromise between LID
alleviation in on-phase without loss of the beneficial motor effects and
improvement in parkinsonism in off-phase. In some patients, residual dyskinesias
have to be accepted so as not to aggravate on-period motor symptoms by a
presumed overinhibition of basal ganglia outflow.

Comments:
 Comment in: Mov Disord 1999 May;14(3):536-40

PMID: 9686769, UI: 98349558

19: Brain 1998 Mar;121 ( Pt 3):451-7

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's
disease.

Krack P, Pollak P, Limousin P, Hoffmann D, Xie J, Benazzouz A, Benabid AL

Department of Clinical and Biological Neurosciences, Joseph Fourier University
of Grenoble, France.

The aim of this study was to compare, retrospectively, the value of chronic
bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic
nucleus (STN) in patients with young onset Parkinson's disease. We selected 13
consecutive patients with similar characteristics at the time of surgery: age at
onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in
off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were
operated on in the STN and five in the GPi. The Unified Parkinson's Disease
Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and
off-drug conditions before surgery and 6 months after surgery on stimulation
using the chronic electrical parameters found to improve best the motor state of
the individual patient, without adverse effects. In off-drug phases, the motor
score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi
stimulation on average. This difference was statistically significant (P <
0.05). Whereas rigidity and tremor showed good improvement in both groups, the
decrease in the akinesia score was more pronounced in the STN group. In the STN
group, the improvement of all motor symptoms was very close, or equal, to the
best levodopa response. Thus the levodopa test was predictive of outcome. The
improvement in off-drug period motor handicap allowed a decrease in the
levodopa-equivalent dose only in the STN group (-56%). The voltage, frequency
and pulse width used for chronic stimulation were lower in the STN group. In the
on-drug phases there was a marked improvement in LID in the GPi group, as
measured by the dyskinesias score during an acute levodopa test, whereas there
was only a small decrease in the STN group (P < 0.05). However, in the long
term, the reduction of levodopa dosage in the STN group led to an indirect
reduction of LID similar to that in the GPi group during activities of everyday
life. In conclusion, the overall results favour the neurosurgical treatment of
Parkinson's disease by stimulating the STN rather than the GPi.

PMID: 9549521, UI: 98210689

20: Ann Neurol 1998 Feb;43(2):180-92

Opposite motor effects of pallidal stimulation in Parkinson's disease.

Krack P, Pollak P, Limousin P, Hoffmann D, Benazzouz A, Le Bas JF, Koudsie A,
Benabid AL

Department of Clinical and Biological Neurosciences, and INSERM U318, Joseph
Fourier University of Grenoble, France.

We studied the effects--on parkinsonian signs, on levodopa-induced dyskinesias,
and on levodopa response--of acute experimental high-frequency stimulation of
the internal pallidum (GPi) during off-drug and on-drug phases. Thirteen
quadripolar electrodes were evaluated in 8 patients with Parkinson's disease
(PD). Stimulation of the most ventral contacts, lying at the ventral margin of
or just below the GPi, led to pronounced improvement in rigidity and a complete
arrest of levodopa-induced dyskinesias. The antiakinetic effect of levodopa was
also blocked and the patients became severely akinetic. Stimulation of the most
dorsal contacts, lying at the dorsal border of the GPi or inside the external
pallidum, usually led to moderate improvement of off-drug akinesia and could
also induce dyskinesias in some patients. When using an intermediate contact for
chronic stimulation, a good compromise between these opposite effects was
usually obtained, mimicking the effect of pallidotomy. We conclude that there
are at least two different functional zones within the globus pallidus, at the
basis of a different pathophysiology of the cardinal symptoms of PD. The
opposite effects may explain the variable results of pallidal surgery reported
in the literature and may also largely explain the paradox of PD surgery. A
possible anatomical basis for these differential functional effects could be a
functional somatotopy within the GPi, with the segregation of the pallidofugal
fibers from the outer portion of the GPi, on one hand, forming the ventral ansa
lenticularis and from the inner portion of the GPi, on the other hand, forming
the dorsal lenticular fasciculus.

Publication Types:
Clinical trial

PMID: 9485059, UI: 98143593

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