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J. Stancanello
Politecnico di Milano, Bioengineering Department and NEARlab, Milano, Italy 20133and Siemens AG, Research and Clinical Collaborations, Erlangen, Germany 91052
P. Romanelli
Functional Neurosurgery Deptartment, Neuromed IRCCS, Pozzilli, Italy 86077
E. Pantelis
CyberKnife Center, Iatropolis, Athens, Greece 15231
F. Sebastiano and N. Modugno
Functional Neurosurgery Deptartment, Neuromed IRCCS, Pozzilli, Italy 86077
Received 16 July 2008; revised 7 November 2008; accepted for publication 4 December 2008;published 14 January 2009
Functional disorders of the brain, such as dystonia and neuropathic pain, may respond poorly tomedical therapy. Deep brain stimulation
DBS
of the globus pallidus pars interna
GPi
and thecentromedian nucleus of the thalamus
CMN
may alleviate dystonia and neuropathic pain, respec-tively. A noninvasive alternative to DBS is radiosurgical ablation
internal pallidotomy
IP
andmedial thalamotomy
MT
. The main technical limitation of radiosurgery is that targets are se-lected only on the basis of MRI anatomy, without electrophysiological confirmation. This meansthat, to be feasible, image-based targeting must be highly accurate and reproducible. Here, wereport on the feasibility of an atlas-based approach to targeting for functional radiosurgery. In thismethod, masks of the GPi, CMN, and medio-dorsal nucleus were nonrigidly registered to patients’T1-weighted MRI
T1w-MRI
and superimposed on patients’ T2-weighted MRI
T2w-MRI
. Ra-diosurgical targets were identified on the T2w-MRI registered to the planning CT by an expertfunctional neurosurgeon. To assess its feasibility, two patients were treated with the CyberKnifeusing this method of targeting; a patient with dystonia received an IP
120 Gy prescribed to the65% isodose
and a patient with neuropathic pain received a MT
120 Gy to the 77% isodose
. Sixmonths after treatment, T2w-MRIs and contrast-enhanced T1w-MRIs showed edematous regionsaround the lesions; target placements were reevaluated by DW-MRIs. At 12 months post-treatmentsteroids for radiation-induced edema and medications for dystonia and neuropathic pain were sup-pressed. Both patients experienced significant relief from pain and dystonia-related problems. Fif-teen months after treatment edema had disappeared. Thus, this work shows promising feasibility of atlas-based functional radiosurgery to improve patient condition. Further investigations are indi-cated for optimizing treatment dose. ©
2009 American Association of Physicists in Medicine
.
Key words: functional radiosurgery, internal pallidotomy, medial thalamotomy
I. INTRODUCTION
Lesioning or neuroprostethic stimulation
of selected targetsin the thalamus and basal ganglia are widely accepted pro-cedures aimed towards the symptomatic improvement of avariety of neurodegenerative brain disorders. The subtha-lamicnucleus
STN
is the region most commonly targetedtoday.
Deep brain stimulation
DBS
of the STN is a proce-dure commonly offered to patients with advanced Parkin-son’s disease
PD
who have developed motor complicationsrelated to dopaminergic replacement
on-off phenomena,dyskinesias, freezing, etc.
. DBS is a safe procedure that canproduce substantial motor benefit in patients undergoingchronic stimulation.
The main advantages of STN DBS in-clude a remarkable improvement of off-medication motorfunctioning scores, substantial reduction in the need fordopaminergic drugs, and abolition of drug-related side ef-fects such as dyskinesias. On the other hand, several sideeffects havebeen observed after STN DBS, includingcogni-
tive decline,
apathy and other affective disorders,
andhypophonia.
While DBS rarely induces permanent braindamage, lesioning of the STN induces a permanent ablationof brain tissue. Nevertheless, the results of STN lesioning byradiofrequency thermal ablation or by radiosurgery appear tobe equivalent to those induced by DBS.
In addition, le-sioning techniques are less expensive than DBS, and theiruse is spreading in countries where the costof DBS is pro-hibitive. Gene therapy targeting the STN,
which is func-tionally modified to produce a gabergic
instead thanglutamatergic
The globus pallidus is anothercommon stereotactic target in the basal ganglia. The targetlies inthepostero-ventro-lateral part of the internal globuspallidus
GPi
where the sensorimotor region is located.GPi DBS induces motor improvements in patients affectedby PD which are grossly equivalent to those associated with
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STN DBS, but to date has not resulted in substantial reduc-tion of dopaminergic drugs.
On the other hand, GPi DBShas a safer profile in terms of cognitive and psychiatric com-plications associated with chronic stimulation.
GPi DBS isalso used to treat dystonias, with remarkable improvementseen in primary dystonias such as those characterized by thepresence of the gene DyT1.
GPi lesioning has been widelyused until recently,providing good symptomatic improve-ment in PD patients.
The lesioning technique most widelyused is microelectrode-guided postero-ventro-lateral palli-dotomy,and reports of radiosurgical pallidotomy are alsoavailable.
Another less common basal ganglia target is theputamen,where stem cells producing dopamine have beenimplanted.
Other important stereotactic targets are lo-cated in the thalamus. The lateral region of the thalamus ispart of the sensorimotor circuit which returns to the cortexthe inputs originated from the sensorimotor cortex and trans-mitted to the thalamus by the basal ganglia. The nucleusventralisintermedius
VIM
is an excellent target to controltremor,
while the nucleus ventralis oralis pars anterior andpars posterior areeffective to control focal dystonias such aswriter’scramp.
Again, there is wide experience lesioningthe VIM,
DBS implantation of the nucleusventralis posterolateralisof the thalamus has been used totreat neuropathic pain.
CMN
, whichis part of the intralaminar complex.
A recent report sug-gests a promising effect of DBS implantation of the CMNand the anterior nucleus of the thalamus to treat selectedcases of medically refractory epilepsy.
Correct target identification is crucial for the success of each of these procedures. Image guidance is essential andincludes modalities such as MRI, CT, and ventriculography.MRI allows direct localization of several structures; STNand GPi can be easily identified on T2 FSE imaging.
3 TMRI offers enhanced visualization of basal ganglia and tha-lamic targets, allowing identification of targets
such as theVIM
Ventriculography is a long-practiced invasivetechnique that permits the targeting of specific nuclei on thebasis of a fairly fixed relation with a line passingthrough theanterior and posterior commissure
AC-PC line
.
For DBSimplantation, microelectrode recording is frequently used toobtain final confirmation that a specific target is reached, atechnique that is effective because the targetnuclei have acharacteristic electrophysiologic activity.
Nevertheless,volumetric reconstruction of basal ganglia and thalamic tar-gets has been recently described as an additional tool to im-prove target localization.
Our recent efforts have been devoted to the developmentand validation of an accurate technique for three-dimensionally mapping a few nuclei relevant in functionalneurosurgery and radiosurgery, such as the STN, the GPi andglobuspallidus pars externa
GPe
, the CMN, and the rednucleus.
we believe three-dimensional atlas-based identification of such nuclei could significantly im-prove the accuracy of radiosurgery treatment. Until now,however, it had not been applied to real cases. The aim of this work was to demonstrate the clinical feasibility of func-tional radiosurgery using atlas-based target identification.
II. MATERIALS AND METHODS
Two patients affected by functional brain disorders wereselected for functional radiosurgery. The first patient,53 years old, suffered from facial neuropathic pain. He hadundergone several surgeries to drain an infected right on theright maxillary sinus developing over time a lancinantingpain over the distribution of the second and third branch of the trigeminal nerve. This pain proved to be refractory tomedical therapy and to several procedures including partialsection of the right trigeminal nerve
which elicited a severeconstant burning overlapping the original shooting pain
. Heunderwent CyberKnife
Accuray Incorporated, Sunnyvale,CA
radiosurgery targeting the cisternal segment of the nerve
57 Gy prescribed to the 70% isodose volume
and left mo-tor cortex stimulation. The second patient, 41 years old, de-veloped post-anoxic focal dystonia secondary to prolongedcerebral hypoxia experienced during heart valve surgery. Thepatient was in an anoxic coma for about 72 hours after sur-gery and then in a barbiturate coma for about 15 days. Hesubsequently developed dysarthria, bilateral blepharospasmand severe and painful dystonia of the right arm and leg.Eventually, according to the pathologies, the two patientsunderwent medial thalamotomy
MT
and internal palli-dotomy
IP
, respectively, delivered by CyberKnife radiosur-gery. Radiosurgical MT was offered due to the severity of pain, lack of response to any other non-destructive procedureand to CT-PET findings indicating bilateral hypermetabolismof the medial thalamus. Radiosurgical IP was offered to re-lieve dystonia because he was on anticoagulant therapy.Targets were selected and spatially defined on the pa-tients’ MRIs by an expert functional neurosurgeon, aided byatlas-based computerized identification providing volumetricreconstruction of selected targets. For the neuropathic painpatient,
18
F-FDG-PET
ECAT PET, Siemens Medical Solu-tions, Malvern, PA
, using reconstructed transversal spatialresolution and slice thickness equal to 2 and 2.4 mm, respec-tively, was also considered as a primary source of informa-tion for target delineation in the nonselective MT, a lesioningtechnique involving many thalamic nuclei: this exam showedincreased metabolism in the medial thalamus and intralami-nar complex, including the CMN and centrolateral nucleus.The accuracy of target localization was aided by reference toTalairach and Tournoux and Montreal Neurological Institute
MNI
atlases. Medio-dorsal
MD
and CMN nuclei wereconferred onto the images of the neuropathic pain patient,and GPi and GPe were conferred onto the dystonia patient’simages. Both patients were scanned using T1-weighted-MRI
T1w-MRI
and T2-weighted-MRI
T2w-MRI
, acquiredwith standard MRI at 1.5 T with a Genesis Signa
GE Medi-cal Systems, Waukesha, WI
for the IP patient and at 3 Twith a TrioTim
Siemens Medical Solutions, Malvern, PA
for the MT patient. Acquisition and reconstruction param-
458 Stancanello
et al.
: Atlas-based functional radiosurgery: Early results 458Medical Physics, Vol. 36, No. 2, February 2009
eters for T1w- and T2w-MRIs were the same as in Ref.34.T1w-MRIs were used for automatic local non-rigid registra-tions of the MNI electronic atlas onto patient volumes, ac-cording to the method described in Ref.33.T2w-MRIs were
acquired for manual identification of the target nuclei by anexpert functional neurosurgeon, whose delineation was aidedby automatic atlas-based identification.MD, CMN, GPi, andGPe masks were nonrigidly registered
to the patient T2w-MRI
see Fig.1
and integrated into the planning CT.The target delineation for the MT was based on the hy-permetabolic zone identifiable in the
18
F-FDG-PET, whichwas registered to the patient CT. The CMN was superim-posed on the
18
F-FDG-PET-based target, to be sure it wasentirely enclosed within the target limits. Additionally, theMD nucleus mask was superimposed on the
18
F-FDG-PET-based target to determine that extent to whichit was actually involved. In this case no modification wasapplied to the
18
F-FDG-PET-based target because the CMNand MD were judged by the functional neurosurgeon to beadequately within the
18
F-FDG-PET-based target.The coarse target delineation for the IP was initially basedon anatomical landmarks. The GPi and GPe masks were thensuperimposed on the anatomical-landmark-based target,which was substantially refined using the three-dimensionalinformation from the two masks in order to target thepostero-ventro-lateral part of the GPi.The MultiPlan™ treatment planning system was used todelineate the multimodality-imaging-based targets and createconformal treatment plans for the IP and MT
see Fig.2
. Forthe IP, the critical structure of the optic tract was delineated;it was much farther from the target than the reported error of the atlas-based identification method.
During the optimiza-tion of the treatment plan, the dose delivered to the optictract was kept as low as possible. Additional artificial criticalstructures were delineated to limit the spread of the low per-centage isodose curves, which given the high doses used infunctional radiosurgery may still be associated with a highabsolute dose. A strategy to minimize radiation delivery timefor the dystonic patient was investigated due to severe dys-tonia and generally poor clinical condition. After comparingconformality and treatment time for IP treatment plans gen-erated using the 5- and 7.5-mm collimators with the trigemi-nal path, we chose to accept the slightly lower plan confor-mality associated with the 7.5-mm collimator to reduce theamount of time the patient was under anesthesia during treat-ment delivery. Therefore, the plan using the trigeminal pathwith 7.5-mm collimator
i.e., 6.1 mm field size at 650 mmsource-to-axis distance
was selected.Six- and twelve-month follow-up exams consisted of contrast-enhanced
CE-
T1w- and T2w-MRIs
T1w-MRIand T2w-MRI reconstructed transversal spatial resolutionand slice thickness equal to 0.47 and 1.33 mm, respectively;both of them acquired by the same 1.5 T scanner used forplanning the IP
. Additionally, MR diffusion-weighted im-ages
DWIs
were acquired to distinguish the lesion from
F
IG
. 1. Superposition of the atlas-based identification of the GPi and CMNon the T1w-MRIs of the IP
upper panel
and MT
lower panel
patients, inaxial, coronal, and sagittal views.F
IG
. 2. 3D beam distribution
upper-left
, axial
upper-right
, sagittal
lower-left
, and coronal
lower-right
views of the IP
a
and MT
b
treatment plansvisualized on the patients’ T2w-MRIs.
459 Stancanello
et al.
: Atlas-based functional radiosurgery: Early results 459Medical Physics, Vol. 36, No. 2, February 2009
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