Focused Ultrasound Ablation for Neurological Disorders




Abstract


Focused ultrasound ablation is an emerging treatment for neurologic and psychiatric disorders. The ability to perform subthreshold sonications to evoke reversible clinical effects makes it suitable for functional neurosurgery. The integration of magnetic resonance imaging guidance allows for lesion shape and location monitoring with thermography and anatomical imaging. Thalamotomy for the surgical treatment of essential tremor is the first US Food and Drug Administration–approved indication for focused ultrasound ablation. Active research is under way to explore its application in other movement disorders (Parkinson disease, dystonia), epilepsy (lesional and nonlesional epilepsy), neuropathic pain, and obsessive-compulsive disorder. Combined with microbubbles to pass through the blood–brain barrier, this technology is also an attractive option for targeted drug delivery for chemical (e.g., chemotherapy) or biological (e.g., growth factors) agents.




Keywords

Essential tremor, Focused ultrasound ablation, High-intensity focused ultrasound, Noninvasive functional neurosurgery, Thalamotomy

 






  • Outline



  • Introduction 443



  • Initial Applications of Focused Ultrasound Ablation for Neurosurgery 444



  • Transcranial Focused Ultrasound Ablation for Neurosurgery 445




    • Essential Tremor 445



    • Parkinson Disease 445



    • Obsessive-Compulsive Disorder 445



    • Epilepsy 446



    • Oncology 446



    • Future Developments 447




  • Summary 447



  • References 447




Introduction


High-intensity focused ultrasound is a transformative technology for noninvasive therapeutic thermal ablation using ultrasonic waves. The response of the tissue varies depending on the energy delivery to the treatment area, ranging from transient inhibition to therapeutic ablation. In recent years, several technological advances have positioned focused ultrasound ablation (FUSA) as an emerging modality for transcranial surgery, particularly in the area of functional neurosurgery ( ). Initial investigations into the medical applications of ultrasounds began in the early 1940s ( ). In , Lynn et al. described the biological use of ultrasonic waves in animal tissue samples and in living animals. Initially, they recorded effects of low-, medium-, and high-intensity sound waves with varying exposure durations. Eventually, they transitioned testing to ex vivo tissue blocks and in vivo canine brains ( ). The authors successfully created microscopic lesions in different cortical regions. The clinical effects of FUSA persisted after reversal of anesthesia and were specific to location of ablation (e.g., paralysis, muscular coordination disturbance, and blindness). However, scalp necrosis remained a challenge in these experiments, underscoring the need of craniotomy for a potential human application.


Almost a decade later, performed a histologic analysis of nerve tissue exposed to focused ultrasound. Eventually, the Fry brothers were the first to create lesions using focused ultrasound in humans. Their experiments highlighted the different effects of focused ultrasound on gray and white matter; for example, nerve cell bodies were more susceptible to ultrasonic exposure than were nerve fibers. Those studies also showed that gray matter ablation required higher ultrasonic energy compared with white matter, theoretically due to higher blood flow in gray matter acting as a “heat sink.” By late 1950s, despite the successful application of focused ultrasound for movement disorders ( ), the procedure was largely abandoned due to the need for a craniotomy to allow ultrasound waves to reach the target. This limited the adoption of FUSA until the early 1990s, when advances in phase correction algorithms ( ) and implementation of magnetic resonance (MR) imaging (MRI) thermometry ( ) made transcranial procedures a reality. Today, MR-guided FUSA is an emerging noninvasive approach for the treatment of a variety of neurologic diseases (e.g., essential tremor [ET] and Parkinson disease [PD]) ( ) ( Fig. 31.1 ). It is an exciting technology for functional neurosurgery, especially with its precision, immediacy of clinical effects, and reversibility of effects at low sonication energy (presonication). The results of the first multicenter trials are encouraging ( ) and provide high expectations for its use in a variety of other neurologic disorders ( ). In this chapter, we briefly review the history of neurosurgical applications of ultrasound therapy, current clinical applications, and the emerging indications for FUSA. We also review the future advances in ultrasound technology for a wider application in neurologic disorders, including neuromodulation and blood–brain barrier (BBB) opening.




Initial Applications of Focused Ultrasound Ablation for Neurosurgery


Although initial medical use of focused ultrasound therapy ncluded improving wound healing and selective tissue destruction ( ), the Fry brothers were the front runners in testing FUSA in neurosurgery ( ). Their work led to advances in an ultrasound B-mode image-guided focused ultrasound system ( ), also called the “candy machine,” used specifically to treat brain tumors in the early 1970s. Meanwhile, Padmaker Lele was independently making significant advances toward clinical applications of focused ultrasound during the 1950s ( ). He used thermocouplers with focused ultrasound to deliver energy at the target and create more precise lesioning ( ). investigations, along with those of Dr. H Thomas Ballantine, led to other new discoveries and breakthroughs. Of importance, Ballantine et al. also envisioned opening of the BBB and attenuation of pain responses with FUSA ( ). Around the same time, in Sweden, Petter Lindstrom also pioneered the use of FUSA for neurosurgery ( ). He studied FUSA for pain, psychoneuroses, anxiety, depression, and epilepsy. He later introduced the idea to Lars Leksell ( ). Leksell was especially interested in focused ultrasound use in psychiatric disorders. His investigations for transcranial therapy met with technological challenges, leading him to redirect his focus to radiosurgery.


Hynynen et al. developed ultrasound transducers with phased arrays in an attempt to resolve the distortion issues of the ultrasound fields during transcranial treatments ( ). The phased arrays corrected for the phase deviations induced by the varied pathway lengths, permitting more-efficient focusing of the ultrasound beams. Later, focused ultrasound technology integration with MRI launched the modern era of FUSA for clinical neurosurgical applications. In the next section, we discuss the current clinical and research indications of FUSA.




Transcranial Focused Ultrasound Ablation for Neurosurgery


Essential Tremor


ET, the most common movement disorder in adults, is characterized by postural or kinetic tremor typically involving the hands and forearms ( ). ET is considered a pure movement disorder with a benign course, but it can be severely debilitating for patients ( ). Although the precise etiology of ET remains elusive, there is emerging evidence of genetic susceptibility linked to a distinct polymorphism ( ). The medical therapy for ET is limited and a majority of patients eventually become medication refractory. Patients with disabling and refractory treatment are considered candidates for surgical therapy with either includes deep brain stimulation (DBS) or gamma knife radiosurgery; most recently, FUSA of the ventral intermediate (VIM) thalamic nucleus. Although considered the gold standard, only a minority of patients choose to undergo DBS. FUSA offers a treatment avenue for these patients due to its noninvasive approach. The initial phase 1 studies established the safety and efficacy of this procedure ( ). A large multicenter randomized controlled trial recently reported significant reduction in tremor immediately after treatment, although some patients experienced a rebound of tremor 1 year after surgery ( ). Reduction in tremor was associated with overall improvement in quality of life and disability, and adverse effects were mostly classified as mild to moderate. Further advances in image-based targeting may further improve the efficacy and reduce side effects ( ). Technological advances in the design of the transducer may allow us to overcome the barriers associated with heterogeneous skulls and include a larger number of patients ( ).


Parkinson Disease


PD, a progressive neurodegenerative disorder ( ), is clinically characterized by bradykinesia, rigidity, and tremor. Degeneration of dopaminergic neurons in the substantia nigra is responsible for motor and nonmotor symptoms observed in the disease (e.g., sleep disturbance, visual hallucinations, mood problems). PD also has a familial component, with 10–15% of patients having at least one first-degree relative with the disease ( ). First-line treatment for PD is pharmacologic therapy using l -dopa and dopamine agonists ( ). The pharmacological therapy is very effective for most patients; however, over time, some patients develop motor fluctuations and medication failures. In addition, medication-associated dyskinesia can become prominent in patients with advanced PD. These patients are considered candidates for surgical interventions with DBS or lesioning procedures.


The target of choice for FUSA in PD is the globus pallidus internus (GPi) ( ), although the subthalamic zone has also been recently targeted ( ). Magara et al. performed unilateral pallidotomy on 13 patients with chronic and therapy-resistant PD. The patients were separated into two groups; the first four patients received a single ablation at peak temperature (56.2°C) and remaining nine patients received repetitive (4–5 times) peak energy ablations. There were no reported neurologic side effects or any clinically relevant cognitive impairment. The Unified Parkinson Disease Rating Scale (UPDRS) decreased postoperatively and remained low at 3-month follow-up, except in one patient. The first group (single peak temperature sonication group) at 3 months had recurrence of symptoms, indicating that the initial strategy for single ablation was insufficient. More recently, reported outcomes after FUSA in a 55-year-old woman with a 12-year history of PD. The authors reported successful control of levodopa-induced dyskinesia and cardinal motor symptoms. After the procedure, patient showed a greater than 61% reduction in UPDRS score within the first week and beneficially maintained until 6-month follow-up. Currently, larger feasibility studies are under way to study the effects of GPi FUSA in patients with advanced PD.


Obsessive-Compulsive Disorder


Obsessive-compulsive disorder (OCD) is a common psychiatric disorder involving recurrent distressing thoughts (obsessions) and repetitive behaviors (compulsions) performed to reduce anxiety. It is postulated that hyperactivity in the orbitofrontal cortex, the cingulate cortex, and the head of the caudate nucleus are central to the pathophysiology of OCD ( ). OCD is often very debilitating, and some patients become refractory to medical therapy with selective serotonin reuptake inhibitors. This disorder has a substantial impact on the quality of life of patients ( ); often aggressive management is key to satisfactory long-term outcomes for them ( ). For patients refractory to pharmacologic and behavioral therapy, surgery may be an option. Cingulotomy ( ) or stereotactic lesions ( ) within the anterior limb of the internal capsule have been shown to provide symptomatic relief in refractory cases. More recently, the FDA has approved the use of bilateral nucleus accumbens DBS in these patients ( ). Lesioning is still under consideration in selected cases because it does not require permanent hardware implantation. reported the results of the first series of treatments using FUSA of the anterior limb of internal capsule of four patients with refractory OCD. Capsulotomy was performed bilaterally by using a formulaic method approximately 7 mm in front of the anterior commissure at the intercommissural plane. All patients had a reduction in OCD symptoms, as measured by the Yale-Brown Obsessive Compulsive Scale, with two patients showing a greater than 35% improvement at 6 months. No complications were reported. More studies are needed to further refine sonication target and long-term clinical outcomes for patients with OCD. Further, randomized comparisons of FUSA to DBS outcomes are needed to establish the relative long-term efficacy of the procedure.


Epilepsy


Partial-onset epilepsy is the most common epilepsy syndrome among adults ( ), with approximately one-third of patients eventually becoming refractory to medications ( ). Neuromodulation procedures are available in these cases to help decrease seizure burdens. Current neuromodulation treatments for epilepsy include DBS of the anterior thalamic nucleus (AN), as well as responsive neuromodulation and cranial nerve stimulation (vagus nerve and trigeminal nerve stimulation) ( ). AN DBS has a long track record ( ) of investigational application, and the long-term results from a large randomized studies are encouraging ( ). However, there is still ambiguity surrounding duty cycle, choice of stimulation parameters, and the problems associated with implanted hardware in patients with epilepsy. In the past, some groups reported efficacy of AN lesioning ( ); however, the interest waned after publication of reports using thalamic DBS in the early 1980s. High-intensity focused ultrasound has the potential to address some of the challenges associated with AN DBS. A clinical trial to evaluate the safety and efficacy of AN thalamotomy in prevention of secondary generalizations is currently under way. Another line of investigation aims to assess the safety and efficacy of FUSA in lesional epilepsy. Independently, there are two other trials under way investigating the safety of lesioning using MR-guided focused ultrasound in patients with hypothalamic hamartomas ( ) and other dysplastic subcortical lesions.


There is preclinical evidence suggesting the use of low-frequency focused ultrasound for transiently inactivating the cortical seizure foci ( ) in experimental animal models. Although effective, the safety considerations of this approach are essentially linked to the potential of creating cavitations ( ). Recently, advocated for the safety of low-intensity focused ultrasound applications on the basis of evidence from preclinical studies. A human trial is currently ongoing to evaluate the safety of this approach ( ).


Oncology


The deep-seated malignancies can potentially be treated with focused ultrasound thermal ablation ( ). This method is particularly of interest because high-intensity ultrasound can be sharply delivered with minimal manipulation of the surrounding tissue. Another advantage is that treatment can be monitored with real-time MR thermometry. Tissue heterogeneity poses a major challenge for this focused ultrasound application. The differences in perfusion rates inside the tumor may result in variations in local tissue temperature elevation with constant sonication parameters ( ). Additionally, for larger tumors some anatomical locations may be outside the focused ultrasound treatment envelope. reported the first application of high-intensity focused ultrasound in three patients with histologically confirmed recurrence of glioblastoma multiform. In this phase 1 trial, Exablate 2000 (Insightech, Inc., Haifa, Israel) was used to deliver sonications through a craniectomy centered on the lesion . Target temperatures up to 90°C were achieved through this approach. More recently, published their experience of transcranial sonications in three patients with high-grade brain tumors. The authors used the Exablate 3000 (Insightech, Inc.) transducer with a goal to reach 55°C peak at the target locations. Target temperatures (>55°C) could not be reached in two patients despite the lesions being within the treatment envelop (deep and midline). It is noteworthy that in this study, extensive involvement of the skull from disease or previous surgery was an exclusion criterion. Further advancements in transducer technology may allow researchers to overcome some of these limitations. Expanding the indications of FUSA to treat meningiomas or low-grade malignancies could potentially affect a larger cohort of patients that may not be surgical candidates due to risks associated with invasive interventions.


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Sep 9, 2018 | Posted by in NEUROLOGY | Comments Off on Focused Ultrasound Ablation for Neurological Disorders

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