Lesioning Methods for Movement Disorders

5 Lesioning Methods for Movement Disorders

Shayan Moosa, Travis S. Tierney, Fred A. Lenz, William S. Anderson, W. Jeffrey Elias

Abstract

Lesioning techniques, the primary surgical procedures for the treatment of movement disorders, continue to remain important therapeutic procedures for neurosurgeons in the era of neuromodulation. The technology for creating high-precision brain lesions has evolved from the original stereotactic radio-frequency thalamotomies and pallidotomies and now includes minimally invasive laser interstitial therapy with magnetic resonance (MR) thermography and transcranial MRI-guided focused ultrasound lesioning.

Keywords: therapeutic brain lesion, radiofrequency thermocoagulation, laser interstitial therapy, MRI-guided focused ultrasound

5.1 Introduction

Prior to the widespread use of deep brain stimulation (DBS) techniques (beginning in mid-late 1990s) for the treatment of movement disorders, stereotactic radiofrequency (RF) thermocoagulation techniques were the most widely used surgical procedures, with a proven track record of efficacy and safety. The use of these techniques dwindled considerably over time with advances in neuromodulation, but lesioning still has an important role in cases of patients traveling from the developing world with poor local follow-up, patients who had prior neuromodulation systems implanted but later had them removed due to infections, or patients with very thin skin or poor wound healing or nutritional issues. In such cases, RF lesioning is still occasionally utilized. In addition, with the advent of magnetic resonance (MR) thermography imaging, it is now also possible to offer transcranial methods of brain lesioning via MR-guided focused ultrasound techniques (MRgFUS). Similarly, minimally invasive lesioning procedures are being performed using stereotactically applied laser interstitial thermal therapy (LITT), again with concurrent MR thermography. In this chapter, we provide a brief historical review of RF lesioning as practiced for movement disorders and describe the new less invasive MRgFUS and LITT procedures.

Prior to the reduction in use of lesioning techniques, with the advent of dopaminergic medications and subsequently DBS, reports of tissue disruption for abnormal movements date into the early 1900s. For instance, Victor Horsely was performing cortical resections for chorea in 1906,1 and Russell Meyers began reporting transventricular fiber disruptions in the region of the basal ganglia in the 1930s.² Spiegel and Wycis introduced the stereotactic frame to neurosurgical procedures in the late 1940s,³ and other authors developed stereotactic techniques for pallidotomy in Parkinson’s disease (Leksell)⁴ and thalamotomy for tremor (Hassler).⁵ After it became clear that even with dopaminergic therapies there are considerable side effects (dyskinesias) and continued progression of Parkinson’s disease (PD) with tightening therapeutic windows,⁶ the pallidotomy again grew in importance clinically for treating rigidity and bradykinesia.⁷ These surgical efforts then grew further with the introduction of DBS⁸ and the minimally invasive lesioning techniques described below.

5.2 Pallidotomy

In the early 1990s, the posteroventral pallidotomy in a clinical series was described by Laitinen et al.7 In this, 38 PD patients underwent stereotactic pallidotomy with a mean follow-up of 28 months. The primary indication for the surgery was bradykinesia/akinesia. Formal motor testing was performed postoperatively and significant improvements in rigidity and bradykinesia were observed in 92% of the subjects. There was also meaningful improvement in patients with tremor (81%), and reductions in drug-induced dyskinesias were also observed. The most common significant complication was a visual field defect (central homonymous) from injury to the optic tract ventrally (6 subjects).

Several subsequent studies of pallidotomy for PD were reported,^{9,10,11,12,13} some of which included blinded postoperative outcomes rating via video documentation.^9,10,12 The two widely used clinical rating scales for PD (the Hoehn and Yahr Staging Scale¹⁴ and the Unified Parkinson’s Disease Rating Scale, UPDRS)¹⁵ began to be incorporated with surgical series at this time. Patients in these series were typically those who were in Hoehn and Yahr stage III or worse, and postoperative UPDRS improvements ranged from 14 to 70% (with ranges of follow-up from 3 months to 1 year). Specific symptomatic improvements were observed in dyskinesias, on/off fluctuations, and the cardinal features of PD, including bradykinesia, cogwheel rigidity, tremor, and gait imbalance.

A later series by the Toronto group was published, presenting 11 patients undergoing pallidotomy for PD with a 2-year follow-up period.¹⁶ UPDRS motor improvement at the end of this time period was a stable 28%, with continuing improvements in the cardinal features of PD. The first report of the use of DBS for PD was in 1994,¹⁷ in which Siegfried and Lippitz described three subjects undergoing placement in the globus pallidus interna (GPi). These three patients had advanced PD and all three showed significant improvements in on/off fluctuations and dyskinesias.

Stereotactic pallidotomies do have an inherent risk profile. In a small series of 15 patients undergoing the procedure,¹¹ 2 suffered asymptomatic hemorrhages, 1 exhibited dysarthria that was transient, 1 experienced worsening of preexisting dysarthria, and 1 had a superior quadrant visual field defect that did not improve over time. There were also reports of transient likely edema-related confusion and facial weakness in this small series. In the series of 34 patients undergoing pallidotomy described by Ondo et al, 5 patients experienced transient side effects, which included aphasia and cognitive changes.¹²

Another series of 26 patients undergoing stereotactic pallidotomy reported 1 fatal hemorrhage, 3 nonfatal hemorrhages, 3 declines in cognitive function or behavioral issues postoperatively, 1 case of aphasia, 1 case of a mild but persistent hemiparesis, and 1 case of worsening dysarthria. There were other patients having neurological changes that were not persistent, such as altered mental status, facial weakness, and dysarthria. A series of 18 patients published by Dogali et al demonstrated no significant complications after a pallidotomy procedure.9 In 1998, the Pittsburgh group published a series of 120 stereotactic pallidotomies and reported a 5% risk of postoperative dysarthria that was always transient. This series had no significant hemorrhages.¹⁸ A large series of 126 pallidotomies was published by Iacono et al, with 68 of them being bilateral procedures.¹⁹ These authors reported a hemorrhage frequency of 3.2% per pallidotomy.

A large series of 334 unilateral pallidotomies was described by de Bie et al covering 8 years.²⁰ These authors found a risk of 13.8% for permanent significant complications, including behavioral problems, dysarthria, visual field defects, and dysphagia. Significant symptomatic hemorrhages occurred in 3.9% of the patients, and there was a 1.2% mortality rate. In general, patients undergoing microelectrode recording (MER) prior to placement of the pallidotomy lesion appear to have a higher frequency of complications.^18,20

5.3 Ventral Thalamotomy

The ventral thalamotomy, or lesioning of the cerebellar receiving nucleus of the thalamus (nucleus ventral intermediate, Vim), has been described as a treatment for tremor-predominant PD and essential tremor (ET).21,22 For instance, Fox et al described a series of stereotactic thalamotomies performed for tremor-predominant PD involving 36 patients with preoperative mean Hoehn and Yahr Stage 2 to 4.²³ Of these, 31 patients reported complete relief of their tremors, with 2 of them suffering recurrent tremor during the follow-up period of 14 to 68 months. Diederich et al performed an interesting blinded study, comparing tremor on the contralateral side to the thalamotomy with the ipsilateral tremor in a group of 17 patients with fairly symmetric preoperative tremor. Ratings were performed from videotape assessments at a mean follow-up time of 11 years. Tremor severity was significantly less on the contralateral side.²⁴ MERs have also been used to identify the area to be lesioned, and the area posterior to the nucleus ventralis oralis posterior (Vop), which was identified as the cerebellar receiving zone (Vim), was later found to have rhythmic bursting activity close to the frequency of tremor.²⁵

In 1995, Jankovic et al published a retrospective review of 60 patients with a variety of tremor etiologies including PD (42 patients), ET (6 patients), cerebellar tremor (6 patients), and tremor after traumatic brain injury (TBI) (6 patients).²¹ After unilateral Vim thalamotomy (2 of the PD patients had bilateral procedures) and a mean follow-up of > 50 months, the PD patients demonstrated significant improvement in tremor in 86% of cases. ET patients demonstrated significant improvement in 83% of cases, with positive but less significant results for cerebellar and post-TBI tremors. A small series from Johns Hopkins in 1999 showed similar results for ET after Vim thalamotomy with significant tremor improvement in 72% of cases.²² Two series have described specific complications associated with thalamotomy procedures^21,23 (ranging from 58–70% of patients), including contralateral weakness, dysarthria or dysphasia, sensory changes, transient confusion, and the induction of dystonic movements. Permanent complications described in these two series were rarer, in the range of 14 to 23%, including weakness and coordination difficulties, and dysarthria. Bilateral thalamotomies are in general not recommended due to high incidences of speech problems and dysphagia in this context. In the era of neuromodulation, many authors would now implant a DBS lead contralateral to a prior lesion.^21,24,26

5.4 Stereotactic Surgical Technique

Both preoperative MRI and/or CT imaging as well as MERs may be used to localize ablation targets for movement disorders.10,22 The well-known atlas-based targeting procedures may be performed by identifying the anterior and posterior commissures as described elsewhere in this text, with subsequent lesion targets defined relative to the midcommissural point or the midpoint of the posterior commissure itself. MERs may then be used with single to multiple MER passes to further refine the lesioning target.²⁷ Other described approaches include a variety of CT/MR fusion techniques,²⁸ ventriculography-guided lesioning, and semi-MERs with macrostimulation to estimate lesioning effects.²⁹ No systematic comparison of these techniques has ever been undertaken.

RF thermocoagulation may be performed through a variety of commercially available systems, which unfortunately are becoming rarer to find as use of this technology dwindles. One popular existing electrode has a 1.1 mm outer diameter with a 3-mm exposed tip (Integra Radionics, Burlington, MA). These electrodes often house a thermistor at the tip for temperature measurements. During lesioning, enough RF power is applied to maintain a constant tip temperature of 60 °C for typically 1 minute. Stepped increases in temperature to 80 °C have also been described for an additional 1 minute of energy application.²⁶ These procedures are often performed on awake interactive patients so that neurological testing can be performed during the lesioning process.

5.5 Radiosurgical Lesioning Procedures

A few centers have described the use of stereotactic radiosurgery as a means of lesioning tissue to treat movement disorders.30,31,32 This technique (similar to the use of MRgFUS) has some advantages for patients with a history of prior stimulation hardware infections, or with health conditions or skin thickness incompatible with implanted DBS systems. The therapeutic benefit appears to be similar to studies of RF thermocoagulation. The Pittsburgh group has shown that Gamma Knife thalamotomy for ET has an approximate 69% rate of meaningful tremor amplitude reduction.³⁰ Of note, radiosurgical lesioning does not utilize MER for target refining as it is a completely incisionless technique, although there could be higher rates of lesioning complications due to this lack of mapping ability.³³

The specific complications that can occur with radiosurgical lesioning procedures have been delineated by Okun et al.³¹ This study reported 8 cases of complications in a series of 118 patients undergoing radiosurgical lesioning. Listed complications include weakness (3 patients), visual field cut (1 patient), dysarthria (3 patients), and 1 case of aspiration with pneumonia associated with dysphagia. As described in these studies, radiosurgical lesioning is probably best used in patients whose preoperative comorbidities would preclude safe implantation of stimulation hardware or MER-guided RF thermocoagulation.

5.6 Laser Interstitial Thermal Therapy with MR Thermography

LITT (with concurrent MRI-based thermography) has been primarily used intracranially to treat epilepsy, various grade brain tumors, and other delimited lesions including hypothalamic hamartomas and radiation necrosis.34,35 Because of the additional benefits of concurrent MRI-based thermography (including the ability to monitor the thermal lesioning temperature as well as temperature changes in surrounding and sometimes eloquent structures), and because of the relatively minimally invasive characteristics of placing the laser applicator in the brain, a few groups have begun exploring the use of LITT for treating movement disorders. For example, Gross and Stern recently described two patients with dystonia undergoing MRI-guided LITT to perform pallidotomy lesions.³⁶ One subject (12-year-old male) had a primary DYT1 dystonia and underwent bilateral LITT pallidotomy. This patient demonstrated right-sided improvements in dystonia symptoms, but also suffered worsening left upper extremity hypertonicity and a jaw-opening dystonia component. The second case was a 32-yearold male with generalized dystonia who underwent a right LITT pallidotomy, and demonstrated substantial improvements in his axial symptoms and speech. Efforts for treating movement disorders with LITT are in their infancy, but the adjunctive MR thermography techniques (which cannot be performed with RF lesioning) may prove useful for increases in safety.

5.7 MR-guided Focused Ultrasound

The practice of using acoustic energy to create intracranial lesions dates back to the 1950s.37 Recent advances in transcranial acoustic energy delivery, phase correction technology, and MR thermography have allowed for the incisionless and precise ablative procedure known as MRgFUS.³⁸ This procedure begins with extensive planning prior to patient arrival using a head CT scan to calculate the skull density ratio (SDR), a measure of skull favorability for the procedure, and delineate regions that would impede the transmission of the acoustic wave. The CT is later fused to a volumetric MRI for accurate targeting. When the patient arrives, the hair is clipped and then head is shaved carefully prior to administration of a stereotactic frame and silicone membrane over the scalp, which is attached to the ultrasound transducer (NeuroAblate 4000; Insightec) ( Fig. 5.1). Chilled, degassed water is filled into the space between the scalp and ultrasound transducer. After additional T2-weighted images are obtained to reference the patient in MR space, the transducer is positioned so that its focus precisely matches the intended target. Test lesions are first created using low-energy sonications with a goal temperature of 40 to 45 °C, followed by initial treatment lesions that can produce clinical effects at 50 to 55 °C. Adjustments are made based on clinical feedback, similar to DBS and RF localization techniques. Finally, the energy is increased to achieve temperatures of 55 to 60 °C for permanent effect. This final temperature goal yields roughly 51 °C temperature thresholds at the margins, which most closely correlates with the final lesion size of 5 mm.³⁹ In the treatment of ET using focused ultrasound (FUS) thalamotomy, the lesion is then enlarged dorsally by focusing an additional sonication 2 mm superiorly.⁴⁰ A postablation MRI can be performed to confirm accurate lesioning, but a higher-quality MRI is typically obtained the next day as lesion sizes are similar one day and one month postoperatively ( Fig. 5.2).⁴¹

Three uncontrolled pilot studies^42,43,44 set the stage for a multicenter, randomized, sham-controlled trial⁴⁵ demonstrating the effectiveness of MRgFUS in the treatment of medication-refractory ET. In this trial, Elias et al analyzed hand tremor and disability scores for 76 patients with medically-refractory ET who underwent either unilateral FUS thalamotomy or a sham procedure. From blinded videotape assessment at 3 months, it was observed that mean tremor and disability scores improved 47% and 59%, respectively in the thalamotomy group, with improvement sustained to 12 months. A 2-year follow-up study of 67 of these patients demonstrated clinical durability with 56% improvement in mean tremor score and 60% improvement in disability score in the thalamotomy group.⁴⁶

Trials that have demonstrated the feasibility of using MRgFUS for the treatment of Parkinsonian tremor have targeted the Vim⁴⁷ and pallidothalamic tract.⁴⁸ In a recent clinical trial of 27 patients with medication-refractory, tremor-dominant PD randomized to unilateral FUS thalamotomy or a sham procedure, Bond et al demonstrated 62% improvement in on-medication median tremor scores in the FUS thalamotomy group, which was significantly different from the 22% improvement observed in the group controlled by sham procedures.⁴⁹ Obeso et al published a pilot study of 10 patients who underwent unilateral FUS subthalamotomy with improvement in their motor symptoms of PD, although 1 patient developed mild hemiballism that later resolved.⁵⁰ Unilateral FUS pallidotomy has also been performed for levodopa-induced dyskinesia,⁵¹ and there is a multicenter randomized control trial currently underway to evaluate the safety and efficacy of unilateral FUS thalamotomy to manage dyskinesia symptoms in advanced PD (ClinicalTrials.gov identifier: NCT03319485). Of note, MRgFUS thalamotomy is now approved by the Food and Drug Administration for the treatment of ET and tremor-dominant PD.

There have been no reports of intracranial hemorrhage or mortality from MRgFUS procedures for movement disorders.⁵² Cavitation, i.e., the formation of microbubbles from acoustic pressure, can cause unintended tissue destruction; however, cavitation monitoring is used to automatically halt sonication in this event. Patient movement is also automatically detected, and the system stops further sonication to unintended areas. The most common side effect is paresthesia, which is typically transient but has been reported to be permanent in a small number of patients. In addition, cerebellar symptoms such as disequilibrium or ataxia have been observed but often resolve within a month.⁴³ Treatment effect may decrease over time like other lesioning modalities, but salvage therapy can be performed with DBS⁵³ or repeat ablation. The risk of serious adverse event with MRgFUS is reported to be 1.6%,⁵² making it a safe and well-tolerated procedure that can be performed on an outpatient basis. There are a few challenges with this new procedure that need to be tackled, such as optimizing lesioning parameters in patients with low SDRs, improving the durability of lesions, safely treating bilateral tremors, eliminating the need for head shaving, and reducing the overall time of the procedure for patient comfort.