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Gamma knife radiosurgery as a lesioning technique in movement disorder surgery

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  • Prostate Cancer Center Seattle

Abstract and Figures

To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results. Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.
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Gamma knife radiosurgery as a lesioning technique in movement
disorder surgery
Ronald F. Young, M.D., Anne Shumway-Cook, Ph.D., Sandra S. Vermeulen, M.D., Peter Grimm,
D.O., John Blasko, M.D., and Allen Posewitz, M.S.
Northwest Neuroscience Institute and Gamma Knife Center, Northwest Hospital, Seattle, Washington
Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or
globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and
postoperatively by a team of observers skilled in the assessment of gait and movement disorders who
were blinded to the procedure performed. They were not associated with the surgical team and
concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did
not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit
using the 4-mm secondary collimator helmet and a single isocenter with dose maximums from 120 to
160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy
became tremor free or nearly tremor free. Statistically significant improvements in performance were
noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the
patients undergoing thalamotomy. Eighty-five and seven-tenths percent of patients undergoing
pallidotomy who had exhibited levodopa-induced dyskinesias had total or near-total relief of that
symptom. Clinical assessment indicated improvement of bradykinesia and rigidity in 64.3% of patients
who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant
improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed
improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral
score (58%), and contralateral motor scores (47%). Ipsilateral total UPDRS and ipsilateral motor scores
were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous
hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of
any kind were seen. Follow-up neuroimaging confirmed correct lesion location in all patients, with a
mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions
at regular interals on postoperative magnetic resonance images demonstrated considerable variability in
lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be
similar to those made with the assistance of electrophysiological guidance with open functional
stereotactic procedures.
Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The
efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with
electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use
of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older
patients and those with major systemic diseases or coagulopathies; its use in the general movement
disorder population seems reasonable as well.
Key Words * gamma knife * thalamotomy * pallidotomy * Parkinson's disease * radiosurgery
Stereotactic lesioning in the thalamus and basal ganglia to treat movement disorders was one of the
earliest functional stereotactic procedures to be performed. The advent first of computerized tomography
(CT) and then magnetic resonance (MR) imaging improved the surgeon's ability to identify the desired
target anatomically. The use of microelectrode stimulation and recording also provided the surgeon with
the ability to identify the intended target for lesioning electrophysiologically.[1] In spite of these
advances, functional stereotactic surgery for the treatment of movement disorders still requires the use of
invasive techniques to provide a skull opening and to pass electrodes or probes through the brain to the
proposed target. Some authors continue to use positive-contrast ventriculography for target
localization.[4,5] These invasive techniques put the patient at risk of intracerebral or extracerebral
hemorrhage, infection, seizures, brain displacement, tension pneumocephalus, and direct injury from
probe placement, among others. Lars Leksell developed the concept of radiosurgery so that functional
neurosurgery could be performed with less risk.[38,39] Leksell and colleagues used the gamma knife
(Elekta Instruments, Atlanta, GA) to perform thalamotomies to treat chronic pain and psychiatric
disorders and focused it on the trigeminal ganglion in attempts to treat trigeminal
neuralgia.[14,38,40-42,58] More recently, others have reported on the use of the gamma knife to treat
trigeminal neuralgia, psychiatric disorders, and epilepsy.[9,16,27,29,46,53,55,66,67] Some limited
reports on the use of the gamma knife to treat movement disorders have also
appeared.[12,18,20,31,43,47-49,52] In this report, we describe our experience in treating movement
disorders using the gamma knife. Both thalamotomy and pallidotomy have been used to treat a variety of
movement disorders, including those related to Parkinson's disease (PD), as well as essential tremor,
tremor following stroke, and tremor following cerebral infection. Particular strengths of this report
include independent assessment by observers not involved in the treatment of PD patients and the use of
Hoehn and Yahr scores and Unified Parkinson's Disease Rating Scale (UPDRS) for comparison with a
control group of PD patients who did not receive surgical treatment.
CLINICAL MATERIAL AND METHODS
Patient Selection
Fifty-five patients with movement disorders underwent thalamotomy (27 patients) or pallidotomy (28
patients) using the Leksell gamma unit. All patients who underwent pallidotomy were treated for
bradykinesia, rigidity, or levodopa-induced dyskinesias related to PD. Thalamotomy was performed for
treatment of tremor in 16 patients with PD, eight with essential tremor, two with tremor following
cerebral infarctions, and one with tremor following a bout of encephalitis. Table 1 shows demographic
data obtained in those patients who were evaluated independently by a movement disorder team. The
team was blind to the patients' condition and were not involved in the selection of patients or the surgical
procedures. There were no significant differences in the demographics of this subgroup compared with
the entire treated population.
All surgically treated patients described in this report had previously been under the care of a neurologist
and had exhausted pharmacological therapy or had experienced undesirable side effects of medical
therapy that prevented effective treatment.
The minimum baseline, preoperative evaluation included physical and neurological examinations and
videotaping of abnormal movements. Patients with PD were also assessed by an independent team
composed of a Ph.D. specialist in movement disorders (A.S.) and specially trained physical therapists
who determined Hoehn and Yahr stage ratings as well as UPDRS scores.[37] Psychological assessment
was performed by a psychologist using both standardized psychological tests and an interview. These
results will be reported separately. Follow-up evaluation was performed at 6 and 12 months following the
procedure. In some cases, follow-up clinical data were obtained by a trained nurse via telephone because
distance or other factors prevented a return visit by the patient.
This report is relatively unique in that it incorporates a control group of 11 patients with PD who did not
undergo surgery but were treated medically by their referring neurologists and studied using the same
quantitative assessment methods. Demographic data for this group are also shown in Table 1.
Fig. 1. Upper: Preoperative stereotactic MR
image demonstrating the planned thalamic
target. Lower: Postoperative MR image
demonstrating the thalamotomy lesion. The
patient experienced complete resolution of
tremor by 6 months postoperatively.
Lesioning Technique
Targets were localized by stereotactic MR imaging.
Strict quality assurance was used to minimize MR
image distortion.[71,72] A 1-tesla magnet (Magnetom;
Siemens, Erlangen, Germany) was used that
incorporated a specially tuned head coil with a field
gradient of 15 mtesla/m. Alignment of the main
magnet was verified before each imaging session. The
Leksell model G stereotactic frame (Elekta
Instruments) was applied to the patient's head so as to
position the intended target as close to the center of the
stereotactic space as possible. A preliminary image
was made to assure correct placement of the
stereotactic frame, and measurements of the distances
between the end fiducials were determined from the
display monitor and compared to the known distances
between the fiducial markers on the frame. Distances
between the right and left intermediate fiducials and
the end fiducials were also compared to assure that the
frame was correctly aligned and that there was no
distortion of the image from one side to the other.
Both T1-weighted and short tau inversion recovery, as
well as magnetization prepared rapid gradient echo
images were used to maximize quality and to
differentiate gray matter nuclei from white matter
tracts. Finally, the phase and frequency encoding
directions were reversed for identical images to take advantage of the reduced distortion of the phase
encoded direction for all stereotactic measurements. The images were transported by fiberoptic link to
the computer dose planning system (GammaPlan; Elekta Instruments) for the Leksell gamma unit.
Targets were calculated by reference to the Schaltenbrand and Wahren Stereotactic Atlas[57] adjusted
for the intercommissural (IC) distance, third ventricular width, and thalamic and basal ganglion
anatomy.[53] For thalamotomy lesions, the intent was to place the lesions in the nucleus ventralis
intermedius (VIM) and the posterior portion of the ventralis oralis posterior ventrolateral nucleus,
contralateral to the side of the patient's more severe tremor.[15,19,23,47-49] The anteroposterior or y
coordinate was calculated from the atlas and adjusted as just described. The x or lateral coordinate was
determined from coronal images such that the lateral border of the lesion was calculated to coincide with
the lateral thalamic border, that is, the junction between the thalamus and internal capsule (Fig. 1). The z
or vertical coordinate was calculated from coronal images such that the inferior edge of the lesion
coincided with the inferior border of the thalamus (Fig. 1). The axial MR images were used to confirm
the coordinates as well. Twenty-seven thalamotomy lesions were created in 27 patients. The general
targeting coordinates reported by Laitinen were used for pallidotomy lesions.[29-32] The y coordinate
was again calculated by reference to the atlas, approximately 2 to 3 mm anterior to the IC point. The x
and z coordinates were calculated by reference to coronal images so as to place the lesion in the medial
globus pallidus just superior to the optic tract and just inferomedial to the internal capsule (Fig. 2). Both
of the structures could be identified directly on the images. Axial images were also used to verify the
targets.
Fig. 2. Upper: Preoperative stereotactic MR
image demonstrating a planned pallidotomy
target. Lower: Postoperative MR image
demonstrating the pallidotomy lesion. The patient
experienced complete cessation of contralateral
dyskinesias, marked reduction in ipsilateral
dyskinesias, and significant improvements in
bradykinesia and rigidity.
A total of 32 pallidotomy lesions were made in 28
patients. Three patients with severe akinesia received
bilateral simultaneous lesioning and one patient
underwent staged bilateral lesions 15 months apart. All
other patients underwent unilateral lesioning, usually
placed contralateral to the dominant hand, which in
most patients exhibited the maximum functional
disability due to bradykinesia and levodopa-induced
dyskinesias.
All lesions were made using the 201-source 60Co
Leksell gamma unit and the 4-mm secondary collimator
helmet. The dose maximum varied between 120 and
160 Gy. Previous experience indicated that such doses
would produce a spherical lesion that could be
identified on follow-up contrast-enhanced MR images
and that measured approximately 6 to 8 mm in
diameter, that is, to approximately the 40 to 50%
isodose line. Exposure times varied from 55 to 75
minutes and were dependent on the date on which the
lesion was made, based on the radioactive half-life
decay of the 60Co sources.
Patients were hospitalized overnight and discharged the following morning. Follow-up MR images were
obtained every 3 months for the 1st year after treatment and then at intervals of 6 and 12 months.
RESULTS
The minimum follow-up time for patients reported here is 3 months (range 3-41 months) and the mean
follow-up time is 14.1 months. Thirty-three patients have been followed for at least 1 year.
Control Group
Table 1 shows a comparison of the relevant demographic variables in the control, pallidotomy, and
thalamotomy groups for those who were assessed by the independent team for determination of Hoehn
and Yahr and UPDRS scores. There was no statistically significant difference between the groups on the
basis of age or gender. The surgically treated patients, however, had a longer duration of illness (p <
0.05) and higher Hoehn and Yahr scores (p < 0.05) than the control patients. Follow-up testing 6 months
after the initial evaluations showed no statistically significant overall changes in Hoehn and Yahr scores
or UPDRS scores for the control group.
Clinical Evaluation of Surgical Patients
Clinical evaluations were performed by two independent, trained nurses as well as the senior author
(R.F.Y.). Tremor was evaluated by patient self-assessment, direct observation, performance tests (such as
finger tapping), writing samples, and videotaped analysis. Tremor was classified as completely absent
(excellent result), nearly completely absent (good result), or not significantly changed (failed). Notation
was made of the patient's usual medication usage and of the most recent dosing to determine if patients
were in the "on" or "off" states at the time of assessment. Every effort was made to perform the
preoperative and follow-up assessments at the same time point in reference to medication usage.
Levodopa-induced dyskinesias were evaluated in a similar way to tremor, as were bradykinesia, rigidity,
and gait.
The clinical results of thalamotomy are presented in Table 2. Twenty-four (88.9%) of 27 patients who
underwent thalamotomy experienced complete (19 patients) or nearly complete (five) resolution of
tremor. These results were confirmed by direct observation and handwriting samples obtained by the
senior author and by patient self-assessments obtained by the independent nursing team. Videotaped
analyses were reviewed independently by both the senior author and the nursing team and there was
uniform agreement on the effect of the procedures on tremor. Finger tapping speed was tested by the
senior author and improved from 15 to 95% in the 24 patients who showed other evidence of
improvement in tremor. There was no improvement in finger tapping in the three patients judged by
other criteria to have no improvement in tremor. Usually within 2 to 3 months of the procedure the
patients noted a gradual, progressive decrease in tremor that continued to decrease over the ensuing 3 to
6 months. A single patient showed little or no effect within 6 to 12 months of the procedure, but then
over the next several months experienced progressive reduction in tremor. In three patients, follow-up
MR imaging showed the development of well-placed lesions of the expected sizes; however, there was
little or no reduction in tremor. These patients have been followed for 12, 18, and 36 months,
respectively.
The clinical results following pallidotomy are shown in Table 3. Fourteen patients in this group
originally demonstrated levodopa-induced dyskinesias and 12 (85.7%) experienced either complete or
nearly complete resolution of this symptom as judged by the senior author and independently
corroborated by the nursing team. Two other patients experienced significant improvements in
dyskinesias. The effects were nearly always contralateral to the side of the lesion. Four patients showed
ipsilateral reduction in dyskinesias; however, these ipsilateral effects were much less dramatic than the
contralateral effects. As in the thalamotomy group, the reduction in dyskinesias usually began 2 to 3
months after the procedure with continued improvement noted over the next 3 to 6 months. All 28
patients who underwent pallidotomy experienced bradykinesia to varying degrees and 18 (64.3%) of 28
were thought to have significant clinical improvement following the procedures. Finger tapping speed
was increased from 15 to 70% in the 18 patients who showed improvements in bradykinesia. There were
no significant changes in the other 10 patients. The time course of improvement was similar to the time
course for tremors and dyskinesias and again was strictly contralateral to the lesioned side.
Three severely akinetic patients who underwent bilateral simultaneous pallidotomies were not
significantly improved after the procedures. One patient underwent staged bilateral pallidotomy with 15
months between procedures. This patient had undergone three prior radiofrequency thalamotomies for
tremor at another institution without sustained relief. At the last follow-up review 41 months after the
first procedure, he had complete relief of all tremor. Although he remains independently ambulatory, a
progressive gait disturbance and reduced voice volume have developed over the past 12 to 18 months.
Patients with severe gait disturbances and balance problems (Hoehn and Yahr stage IV) showed little or
no improvement in gait, as judged clinically, although improvements in bradykinesia and
levodopa-induced dyskinesias were noted in some of them.
Quantitative Testing
Thalamotomy. Eight of 16 patients with PD who underwent thalamotomy were evaluated preoperatively
and again 6 months after lesioning. There was no overall change in Hoehn and Yahr scores. Evaluations
of UPDRS scores (Table 4) showed statistically significant improvements in the activities of daily living
(ADL) (p = 0.008), contralateral motor subscore (p = 0.03) and total UPDRS scores, both contralateral (p
= 0.05) and ipsilateral (p = 0.02) to the side of the lesion when compared to the control group.
Comparisons of UPDRS scores at the time of initial evaluations and 6 months after lesioning showed
statistically significant improvements in the ADL subscores (p = 0.02) and in the total UPDRS scores (p
= 0.02) contralateral to the lesions (Table 5). Total UPDRS scores ipsilateral to the lesions also showed
improvement but the changes did not quite reach statistical significance (p = 0.06).
Pallidotomy. Seventeen of 28 patients who underwent pallidotomy were evaluated preoperatively and
again 6 months after lesioning. There were no significant changes in the overall population in any of the
comparisons for Hoehn and Yahr or UPDRS scores whether the UPDRS scores were compared to the
control group or compared pre- and postoperatively for the same patients (Tables 4 and 5). Examination
of the individual UPDRS scores indicated that 10 (58.8%) of 17 patients demonstrated improved scores
for ADL (mean improvement 19.4%) and for total scores contralateral to the lesions (mean improvement
23.2%). Eight patients (47%) showed improvements in contralateral motor scores (mean improvement
32.2%). Interestingly, 10 patients (58.8%) also showed improvements in ipsilateral total UPDRS scores
(mean 27.8%) and 10 (58.8%) showed improvements in ipsilateral motor scores (mean 37.7%). Overall,
11 (64.7%) of 17 patients showed improvement in at least one UPDRS score.
Complication Rate
Only one patient (1.8%) experienced any complication due to a procedure. This 65-year-old man
developed a complete left homonymous hemianopsia 9 months after a right pallidotomy performed at
120 Gy. Follow-up MR images at 3 and 6 months showed a normally developing lesion, but at 9 months
the lesion was substantially larger than expected (volume 950 mm3) and included the optic tract.
Additional follow-up imaging showed a gradual decrease in the size of the lesion but there had been no
clinical improvement as of 22 months after the procedure.
Follow-Up MR Imaging
At least one follow-up image was available in each of the 44 patients. Lesion volumes were measured to
the outer edge of the contrast-enhanced ring. A total of 95 lesions were measured in 44 patients. For a
variety of reasons, images were not available in 11 patients. Mean lesion volumes are shown in Table 6
at 3, 6, 9, and 12 months postoperatively. There were too few images obtained at 18 and 24 months from
which to make meaningful calculations. The range of lesion volumes is also shown in Table 6. The small
number of lesions available for measurement at 9 months (seven lesions) and 1 year (14 lesions) resulted
in the mean values being skewed by two patients with relatively large lesions at those time intervals.
Excluding those two patients, the mean volumes at 9 and 12 months were smaller than those at 3 and 6
months postoperatively (Table 6). In addition, the accuracy of lesion placement was estimated on
follow-up images. Measurements of the stereotactic coordinates of lesions were obtained postoperatively.
If possible, images were obtained at our institution by placing the patient's head within the stereotactic
fiducial system but without skull fixation. The image data were then entered into the computer dose
planning system for coordinate determination. Images obtained at other institutions were measured by
hand to determine the stereotactic coordinates of the lesions. In addition to stereotactic coordinate
determination, lesions were observed for their relationships to adjacent structures such as the internal
capsule and optic tract. Repeated measurements on the same image indicated that the error in the
measurement technique alone, because of differences in estimates of lesion's centers, location of
commissures, and other anatomical structures, averaged approximately 1 to 1.5 mm. Details of these
measurements will be published later.
The maximum deviation from the calculated target in any of the coordinates (x, y, z) was 2.1 mm and the
mean deviation was 0.5 mm for x, 0.8 mm for y, and 1 mm for z. No lesion unintentionally encroached
on an adjacent structure except the one that resulted in a homonymous hemianopsia. In that case the
lesion eventually became much larger than expected, but the lesion center was initially at the intended
target coordinates.
DISCUSSION
Several controversies exist in the field of functional stereotactic neurosurgery for movement disorders.
These include the accuracy of stereotactic planning using MR imaging, the role of microelectrode
recording in target localization, and the efficacy of pallidotomy and thalamotomy, among others.
The current report addresses these and other controversial issues. Our prior reports show that MR
imaging alone is sufficiently accurate to provide localization for stereotactic lesioning.[68-72] A number
of authors have addressed the issue of magnetic field inhomogeneity resulting in distortion in MR
imaging.[2,3,59] Alexander and colleagues[2] described a method to correct MR image distortion using a
formula based on CT scanning. We replied then and we reiterate now, that with a meticulous quality
assurance program, MR image distortion can be minimized so that the test is sufficiently accurate for
stereotactic coordinate determination.[72] The important elements of MR image quality assurance
include regular alignment of the main magnet, use of a high magnetic field gradient, placement of the
stereotactic frame to locate the intended target close to the center of the stereotactic space where
distortion is at a minimum, and use of the minimal distortion in the phase encoded direction of the
imager.[59,72] With such measures, accuracy in the 1-mm range can be achieved.
The value of electrophysiological localization to refine the targets for stereotactic lesioning for
movement disorders has been generally accepted.[1,6-8,10,15,22,23,26,33-36,45,50,61-63] Yet in 1985,
Laitinen[32] reported that 12 different, well-respected, stereotactic neurosurgeons throughout the world
identified a variety of thalamic lesion sites as their ideal target for treatment of the movement disorders
of PD. The same is true of pallidotomy.[6,8,21,25,28,33,35,44] These observations belie the idea that
there is some magical tiny cluster of cells within the basal ganglia that can only be identified by
electrophysiological localization and that, when lesioned, produces the best results in movement disorder
surgery. A recent survey of practice techniques indicated that only approximately 50% of neurosurgeons
performing pallidotomy used microelectrode recording for target localization, although another 25%
were considering adding that capability to their procedures.[13] Although there are strong advocates for
the microelectrode approach, there is in reality no documentation that such methods improve either the
efficacy or safety of functional stereotactic procedures.[6-8,15,21,24-26,28,44,62] Our own experience
with microelectrode techniques for clinical and research purposes indicates that procedures performed
with such guidance are probably no more effective and may be associated with more complications than
those that are not.[56] In fact, Ohye, et al.,[47] a group with extensive experience in
microelectrode-guided functional stereotactic procedures for movement disorders, have recently
described their experience with gamma knife thalamotomy using methods similar to those described in
our report.
The use of an open surgical technique may account for the apparent need for electrophysiological
localization because of brain shifts that may result from loss of cerebrospinal fluid or because even
microelectrodes may displace rather than penetrate brain tissue.[23] Certainly if techniques such as
ventriculography or CT scanning are used for stereotactic localization, electrophysiological corroboration
is needed to identify functional targets accurately. The ability of MR imaging to demonstrate the actual
target for lesioning as well as anatomical reference points such as the commissures makes the need for
electrophysiological target localization questionable.[72] In fact, Dogali, et al.,[11] reported that the
electrophysiologically identified target for pallidotomy varied by a maximum of 1 mm from the
anatomically determined target using MR imaging.
More important than these theoretical considerations, however, is the safety and efficacy of the
procedures. Our success rates based on clinical evaluations for thalamotomy for tremor control and
pallidotomy for control of bradykinesia, rigidity, and levodopa-induced dyskinesias are very similar to
those reported for open stereotactic procedures of a similar type. Our success rate of 88.9% in controlling
tremor by gamma knife thalamotomy compares favorably with the 91% reported by Fox, et al.,[15] and
90% reported by Jankovic, et al.,[23] for open thalamotomy. Quantitative, blinded assessment of Hoehn
and Yahr and UPDRS scores produced some different results from those of the the clinical evaluations.
For thalamotomy the efficacy of the procedure as assessed clinically was confirmed by the UPDRS
scores without a change in Hoehn and Yahr scores. These improvements were verified in comparisons
made of the same patients before and at 6 months after surgery and in comparisons made with a control
group of PD patients who did not receive surgical treatment. The efficacy rates for pallidotomy remain
controversial, with some authors reporting very good results and others reporting little overall
effectiveness.[11,16,22,33-36,44,60] Using clinical assessment, gamma knife pallidotomy controlled
levodopa-induced dyskinesias in 85.7% of patients with PD who exhibited this symptom, and there were
significant reductions in dyskinesias in the other 14.3%. Thus, all patients with dyskinesias experienced
improvement after pallidotomy. Bradykinesia and rigidity were improved in 64.3%.
Quantitative, blinded assessment gave different results depending on the evaluation method and such
differences have been discussed previously by Pernat, et al.[51] Considering the pallidotomy population
as a whole, neither Hoehn and Yahr nor UPDRS scores confirmed the clinical improvements. When
examined individually, however, nearly 60% of patients showed improvements in ADL scores and in
total scores contralateral to the lesions. In addition, nearly half (47%) showed improvements in
contralateral motor scores, whereas ipsilateral total UPDRS scores and ipsilateral motor scores were
improved in 59%. The greater improvement in ipsilateral than in contralateral scores is puzzling but may
be accounted for, at least in part, by the relatively small number (17) of patients assessed and the large
impact of changes in only a few patients. The results do point out, however, that ipsilateral as well as
contralateral benefit may be obtained by unilateral pallidotomy. Overall, 11 (64.7%) of 17 patients
showed improvement in one or more of the UPDRS scores. Thus, we confirm that pallidotomy can
improve performance in approximately two-thirds of patients. Currently we are seeking to determine
what factors may precipitate favorable outcomes to refine our selection process. It appears that our
overall clinical assessments and the blinded UPDRS evaluations correlate reasonably well and indicate
that although useful, at least in our hands, pallidotomy is not a cure-all for PD. The reason for the
differences in the pooled UPDRS scores for the thalamotomy group versus the pallidotomy group is
unclear. The significant improvements in pooled UPDRS scores for thalamotomy patients confirmed the
clinical results, whereas for pallidotomy patients the pooled data did not show any overall change. The
follow-up images confirmed the accuracy of lesion placement for both groups; this tends to reduce the
likelihood that targeting errors accounted for the less favorable results in the pallidotomy group. The
pallidotomy group had higher beginning Hoehn and Yahr scores, perhaps indicating that patients with
more advanced stages of the disease do not fare as well as with surgical intervention. Another possible
interpretation is that pallidotomy is a less effective procedure than thalamotomy. It does not appear to
ameliorate all symptoms and the factors that predict a favorable outcome have not been fully determined.
Only one complication, a homonymous hemianopsia following pallidotomy, has been observed in 55
patients in our experience. Jankovic, et al.,[23] recently reported a 58% immediate complication rate
following stereotactic radiofrequency thalamotomy and a 23% persistent complication rate. Additionally,
Jankovic, et al., reported that an initial thalamotomy failed to give lasting relief of tremor in nine of 60
patients and these lesions were enlarged during second procedures performed an average of 2 months
after the initial procedures. Thus the failure rate for the first procedure was 15%, virtually identical to our
failure rate of 11.1%.[23] Laitinen, et al.,[34] reported a 15% incidence of visual field defects after
radiofrequency pallidotomy, but in more recent reports such field defects are rare.[11,22,33,35,36,44]
Lozano, et al.,[44] reported an intracerebral hemorrhage that required craniotomy for evacuation
following a microelectrode-guided pallidotomy.
The primary problem with functional stereotactic procedures using the gamma knife has been accuracy in
identifying or attaining appropriate targets. The primary problem has been variability in lesion volumes
using identical radiosurgical parameters.[17,27,72] Leksell and colleagues have described medial
thalamic lesions made using the gamma knife with dose maximums of 180 to 200 Gy.[14,38,40,58]
These lesions were made to control cancer-related pain. Only a few autopsy descriptions of such lesions
were obtained, usually after patient survival times of just a few months.[65] Imaging techniques to study
such lesions were not available at that time. Although the lesions in the early reports were made with a
single isocenter, the secondary collimator helmet used at that time is not currently available. We and
others have reported the variability in volumes of lesions made with the gamma knife.[17,27,72]
Tomlinson, et al.,[64] also described MR imaging following radiofrequency thalamotomy for tremor
control. We have gradually decreased the dose maximums we used to make functional lesions with the
gamma knife.[72] In addition, we no longer make multiisocenter lesions with the gamma knife because
this technique appears to result in even more variability in lesion size.[72] Using dose maximums in the
120- to 140-Gy range and the 4-mm collimator helmet, lesion volumes are relatively reproducible. Dose
maximums below 120 Gy may not produce lesions identifiable on follow-up MR images. Whether
changes in brain function may be induced by gamma knife radiosurgery without an identifiable lesion is
unproven. There is some evidence, however, that such functional changes may indeed occur.[54]
Interestingly, our single complication occurred with a lesion made using only 120 Gy, which may
indicate the unpredictable nature of functional radiolesions even at lower dosage levels. It is clear from
our earlier work, however, that lower dosage and single isocenter lesions are more predictable in size
than are lesions made at higher doses with multiple isocenters.[72] Even with this variability, however,
we found only one clinical complication in 55 patients (1.8%). This compares very favorably to the
complication rate for radiofrequency lesioning procedures.
We believe that radiosurgical lesions made with the gamma knife may be used successfully and safely to
treat movement disorders. The efficacy and safety of the procedure compares favorably to that of open,
electrophysiologically controlled, radiofrequency lesioning procedures and is a viable alternative
technique that may be particularly suitable for older patients, those with significant systemic diseases
other than their movement disorders, and those with coagulopathies caused by disease or the use of
anticoagulant agents. Its use in the general movement disorder population also appears reasonable.
Acknowledgments
The authors thank Lisa Kesler and Diane Johnson who participated in the independent patient
assessments and Beverly Rhode, R.N., and James Rogers, R.N., who assisted with the clinical
evaluations. We also thank Janis Rose, Wanda McKinney, and Julie Hancock for assistance with patient
management and data collection and Gary Lai who performed statistical analysis.
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Manuscript received January 27, 1997.
Accepted in final form February 24, 1997.
Address reprint requests to: Ronald F. Young, M.D., Northwest Hospital Gamma Knife Center, 1560
North 115th Street, Suite G-5, Seattle, Washington 98133. email: ryoung@nwhsea.org
... Other authors have encountered more serious complications with GK-T, including hemiplegia and death. 20,31,45 This draws attention to the importance of improving the procedure by taking advantage of modern imaging. The acceptance of modification of established techniques meets resistance from traditional medicine, especially in surgical specialties in which a surgeon's adventures with new methods can be catastrophic for patients. ...
... 18 Radiation dose used in GK-T varies among previous reports from 120 to 180 Gy. 8,20,30,45 Adjusting the position of the target more medially and cranially proved to be the most effective strategy to avoid high doses to the IC. This leads to compromise of the location of the higher dose to the target, as shown in this study. ...
... Additionally, it was necessary to shape the dose distribution. Subtle changes in the VIM when GK-T is performed were already suggested by the pioneering authors of the technique, 8,30,45 who had to progressively decrease the dose used to achieve acceptable results. 30 Plugging techniques, 22,40 before a laborious strategy, have become automatic since the Gamma Knife Perfexion (Elekta, Inc.) was introduced. ...
Article
OBJECTIVE The role of tractography in Gamma Knife thalamotomy (GK-T) planning is still unclear. Pyramidal tractography might reduce the risk of radiation injury to the pyramidal tract and reduce motor complications. METHODS In this study, the ventralis intermedius nucleus (VIM) targets of 20 patients were bilaterally defined using Iplannet Stereotaxy Software, according to the anterior commissure–posterior commissure ( AC-PC) line and considering the localization of the pyramidal tract. The 40 targets and tractography were transferred as objects to the GammaPlan Treatment Planning System (GP-TPS). New targets were defined, according to the AC-PC line in the functional targets section of the GP-TPS. The target offsets required to maintain the internal capsule (IC) constraint of < 15 Gy were evaluated. In addition, the strategies available in GP-TPS to maintain the minimum conventional VIM target dose at > 100 Gy were determined. RESULTS A difference was observed between the positions of both targets and the doses to the IC. The lateral (x) and the vertical (z) coordinates were adjusted 1.9 mm medially and 1.3 mm cranially, respectively. The targets defined considering the position of the pyramidal tract were more medial and superior, based on the constraint of 15 Gy touching the object representing the IC in the GP-TPS. The best strategy to meet the set constraints was 90° Gamma angle (GA) with automatic shaping of dose distribution; this was followed by 110° GA. The worst GA was 70°. Treatment time was substantially increased by the shaping strategy, approximately doubling delivery time. CONCLUSIONS Routine use of DTI pyramidal tractography might be important to fine-tune GK-T planning. DTI tractography, as well as anisotropy showing the VIM, promises to improve Gamma Knife functional procedures. They allow for a more objective definition of dose constraints to the IC and targeting. DTI pyramidal tractography introduced into the treatment planning may reduce the incidence of motor complications and improve efficacy. This needs to be validated in a large clinical series.
Chapter
Functional radiosurgery for severe limb tremor was introduced by Leksell in 1951. Since then, several studies described the effectiveness of radiosurgical thalamotomy for intractable tremors, mostly using a frame-based technique. Indeed, lesioning invisible targets residing in the thalamus and basal ganglia to treat movement disorders is still a domain of frame-based procedures, because of the need for a solid reference system registered to the anterior commissure-posterior commissure (AC-PC) line to allow the use of stereotactic atlases for the precise localization of targets that are invisible in MR. CyberKnife (CK) radiosurgery system appears to be a less invasive procedure with potentially equivalent accuracy. Here, we summarize the principles of radiosurgical thalamotomy and describe the technique to obtain tremor control with the CK. We also describe our preliminary clinical experience and discuss the method for determining the 3D coordinates of a known functional target to be treated with frameless radiosurgery. Based on our initial experiences, frameless radiosurgery appears to be a safe alternative treatment for essential tremor, but further studies are necessary to set the minimum dose.
Chapter
The treatment of medication-refractory tremor with cerebral lesioning has significantly evolved since its inception in the 1930s. While originally a highly morbid procedure, innovations in stereotactic localization and image guidance have led to several safe and efficacious methods for the surgical treatment of essential tremor. Current targets include the ventral intermediate nucleus of the thalamus and posterior subthalamic area. Radiofrequency ablation, Gamma Knife radiosurgery, and magnetic resonance-guided focused ultrasound are modern lesioning modalities in the treatment of essential tremor, and individual patient characteristics and expectations are taken into account when choosing a particular technique. The irreversibility of cerebral lesioning in the setting of current neuromodulation technology has reduced its enthusiasm; but recent advancements in transcranial procedures, patient-specific targeting, and image guidance are reinvigorating lesioning as a surgical option for tremor.
Article
Full-text available
Background: Ablative therapies have been used for the treatment of neurological disorders for many years. They have been used both for creating therapeutic lesions within dysfunctional brain circuits and to destroy intracranial tumors and space-occupying masses. Despite the introduction of new effective drugs and neuromodulative techniques, which became more popular and subsequently caused brain ablation techniques to fall out favor, recent technological advances have led to the resurgence of lesioning with an improved safety profile. Currently, the four main ablative techniques that are used for ablative brain surgery are radiofrequency thermoablation, stereotactic radiosurgery, laser interstitial thermal therapy and magnetic resonance-guided focused ultrasound thermal ablation. Object: To review the physical principles underlying brain ablative therapies and to describe their use for neurological disorders. Methods: The literature regarding the neurosurgical applications of brain ablative therapies has been reviewed. Results: Ablative treatments have been used for several neurological disorders, including movement disorders, psychiatric disorders, chronic pain, drug-resistant epilepsy and brain tumors. Conclusions: There are several ongoing efforts to use novel ablative therapies directed towards the brain. The recent development of techniques that allow for precise targeting, accurate delivery of thermal doses and real-time visualization of induced tissue damage during the procedure have resulted in novel techniques for cerebral ablation such as magnetic resonance-guided focused ultrasound or laser interstitial thermal therapy. However, older techniques such as radiofrequency thermal ablation or stereotactic radiosurgery still have a pivotal role in the management of a variety of neurological disorders.
Chapter
Introduction: There is an urgent need to develop improved treatments for Parkinson’s disease (PD), and frustration has mounted over recent years due to difficulties translating promising preclinical and early-phase clinical data into approved therapies. This has in turn prompted examination of the likely roadblocks, including limitations in clinical trial outcome measures. Measurement of response to intervention in the short term or in changes in PD over time currently relies on observation of signs and/or patients’ perceptions of symptoms. These are typically recorded using clinical rating scales that incorporate information provided by the patient and/or caregiver, and by the investigator. A number of valuable validated rating scales exist that address motor and nonmotor symptoms, as well as quality-of-life measures (as detailed in Chapter 22, this volume). In terms of determining the impact of PD on a person’s function and well-being, such scales are critically important. However, this approach has many disadvantages. First, sensitivity may be limited and large phase 3 clinical trials that are costly and time-consuming are required to demonstrate efficacy. Secondly, clinical rating scales do not distinguish short-term symptomatic benefits from neuroprotective effects, again resulting in the need for large trials over extended time periods. Thirdly, clinical findings do not determine whether a given treatment engages its predicted target - this is important information in terms of go/no go decisions during early phases of drug development, and also in understanding negative trial results. Fourthly, clinical measures do not determine whether there are changes in function that might be predicted to have long-term advantages or disadvantages, for example whether antibodies develop to a given treatment. In 2001, a Biomarkers Working Definition Working Group was convened by the National Institutes of Health and defined a biomarker as a “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. The hope is that development of validated biomarkers will provide sensitive and reliable measures of treatment effects to rationally inform go/no go decisions, to improve the pace of bringing new drugs to the clinic, and to decrease the cost of drug development. One specific need is a biomarker incorporated as a primary outcome measure in clinical trials designed to track progression of PD and test an intervention’s potential for neuroprotection, a so-called “surrogate marker.”.
Chapter
Introduction: On the contrary, there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least, the progress of the disease may be stopped. James Parkinson, Royal College of Surgeons, An Essay on the Shaking Palsy, 1817. Levodopa (3,4-dihydroxyphenyl-l-alanine or l-DOPA) has been the mainstay of treatment of Parkinson’s disease (PD) for almost 5 decades, now in combination with a peripherally acting DOPA decarboxylase inhibitor such as benserazide or carbidopa. Levodopa typically produces a robust clinical response with reduction of classic motor symptoms of PD but over time is associated with motor fluctuations and drug-induced dyskinesias, both of which may be quite debilitating. Several drug classes, such as catechol-O-methyl transferase (COMT) inhibitors, monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists (DAs) are used as adjuncts to prolong the effects of levodopa. When MAO-B inhibitors or DAs are used as initial monotherapy for PD, studies have demonstrated a delay in the development of both dyskinesias and motor fluctuations, but these drugs alone are insufficient to provide adequate clinical benefit without the addition of levodopa over a period of more than a few years. While strategies exist for managing long-term complications of levodopa therapy, only amantadine has demonstrated definitive clinical efficacy in suppressing dyskinesias without worsening PD symptoms. The future of PD management using agents that bypass the dopaminergic system holds the hope of helping to optimize clinical benefits while avoiding the development of motor complications [1]. The ideal therapy would treat motor and nonmotor symptoms of PD without serious side effects and would also slow or stop the disease progression. While deep-brain stimulation (DBS) provides a powerful tool in the treatment of motor symptoms in PD, it is nevertheless not a cure, nor does it remove the need for pharmacological therapy in the vast majority of cases. In addition, DBS introduces other limitations, including surgical risk. The indications, use and outcome of DBS are covered in Chapters 18-20 (this volume). Finally, it should be noted that the actual benefits of DBS are frequently compared with the clinical benefits of levodopa therapy. In other words, the use of “electrical levodopa” can help supplant the need for increasing and/or repetitive doses of levodopa containing drugs, allowing an absolute reduction in the total daily dose of levodopa while concomitantly decreasing motor symptoms and complications.
Book
Parkinson’s disease is no longer considered only a motor disorder. It has become evident that the pathological changes are broad, the progression seems to follow a pattern suggesting transynaptic transmission via templation of proteins in a prion-like fashion, and that these pathological changes usually antedate the motor symptoms by decades. This book emphasizes treatment options for Parkinson’s disease, critically assessing pharmacologic and surgical interventions for all aspects of the disease. Evidence from randomized controlled clinical trials is highlighted to develop practical recommendations for clinical practice. Lessons learnt from clinical trials - and controversies and future challenges - are all addressed. Readers will find the necessary clinical and scientific foundations for the understanding of the disease, the underpinnings of the pathological processes, the identification of disease biomarkers, and the basis for solid therapeutics. Chapters are authored by an international team of specialists who bring their expertise to improving the management of this disease.
Chapter
The “shaking palsy” was first recognized by James Parkinson in 1817 when he described a condition characterized by “involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace [here he was referring to festination or more accurately referred to in that era as scelotyrbe festinans]: the sense and intellects being uninjured.” In his writings, James Parkinson credits Galen as first noticing shaking of the limbs belonging to this disease and calling them “by an appropriate term: tremor.” Parkinson further and correctly stated that “tremor can indeed only be considered as a symptom” and not a disease in itself. Since then, others have laid the foundations for the study and understanding of this condition. Freidrich Lewy described the body that now bears his name and the central focus of the science behind Parkinson’s disease (PD). Froscher Tretiakoff localized the disease to the substantia nigra. Greenfield confirmed the scattered cellular changes in the locus coeruleus of the pontine tegmentum and substantia nigra. In his 1962 monograph on the Basal ganglia, Derek Denny-Brown described his clinical and pathological experience of PD patients, calling attention to the presence of the preponderance of thinning of the myelin sheaths as a consequence of nigral cell loss and pallor of the outer pallidum and ansa lenticularis. Arvid Carlsson, a Nobel Prize winner, recognized that the sole function of dopamine was not limited to the synthesis of norepinephrine, and, together with the work by Walter Birkmayer and Oleh Hornykiewicz, demonstrated that dopamine was decreased in the striatum in PD. George Cotzias successfully treated PD patients with levodopa (3,4-dihydroxyphenyl-l-alanine or l-DOPA), initiating the modern era of neurotherapeutics based on solid scientific data. Long gone are the days of blood letting and other treatment options that Parkinson himself recommended as the treatment of choice to “release the humors causing the condition.” Recent advances in our understudying of the pathological distribution and progression in PD along with progress in genomics are constantly challenging our understanding and are providing hope for the future of the PD patient. Since the first description and recognition of PD, many other movement disorders have been recognized. Oppenheimer first described dystonia muscular deformans in 1912, and tremor has been recognized since Galen times, and chorea was already recognized by the Romans.
Article
IN THE COMPUTED tomography/magnetic resonance imaging (CT/MRI) era, the need for ventriculography to perform ventrolateral thalamotomy accurately has been debated. We retrospectively compared CT/MRI-derived coordinates for ventrolateral thalamotomy with the final lesion coordinates that were determined by ventriculography and microelectrode recording in 74 thalamotomies performed from 1984 to 1994. The median three-dimensional distance between the CT/MRI-derived loci and the ventriculography/microelectrode loci was 4.7 mm (range, 1.0–11.7 mm). The techniques correlated least along the Y axis (median, −0.3 mm; range, −8.2 to 8.0 mm). Correlation along the X axis was most consistent (median, 0.5 mm; range, −4.2 to 5.0 mm). Since 1990, the CT/MRI-derived coordinates have been generated by a multimodality correlative imaging technique (MCIT). A comparison of thalamotomies performed with and without the MCIT revealed a significant improvement in the correlation of CT/MRI- and ventriculography/microelectrode-derived coordinates when the MCIT was employed. The greatest improvement was noted along the Y axis where the median absolute difference was reduced from 4.0 to 1.8 mm (P = 0.0001). The result was a statistically significant reduction in the median three-dimensional distance from 5.6 to 3.7 mm (P = 0.0007). The authors conclude that thalamotomies can be safely and effectively performed without ventriculography when the MCIT is employed and supported by neurophysiological monitoring.
Article
RADIOSURGICAL STEREOTACTIC THALAMOTOMY was performed in a patient with parkinsonian tremor with a computerized stereotactic brain atlas, which was transformed to fit the patient's thin-sliced magnetic resonance image to select an optimal target in the nucleus ventralis intermedius of the thalamus. The patient's tremor and rigidity disappeared and have not appeared again for more than 1 year since the eighth postoperative month. A method for converting the presurgically planned stereotactic coordinates in the atlas coordinate system to the coordinates in the frame coordinate system is described.