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HIFU & LITT.pptx

  1. Dr. Shahnawaz Alam Resident; MCh-Neurosurgery Moderated by: Dr. V. C. Jha HOD, Dept. of Neurosurgery HIGH-INTENSITY FOCUSED ULTRASOUND AND MR THERMAL ABLATION: APPLICATION IN NEUROSURGERY
  2. INTRODUCTION • Ultrasonic waves are sound waves that propagate through matter, and their frequencies are above the hearing range of human ears (> 20,000 Hz). Typical US frequencies from therapeutic equipment are between 1 to 3 MHz. • Sonic intensity (SI) can be defined as a average rate of sonic energy-flow through a unit area (SI unit: W/cm2). • High-intensity US generally refers to US with an intensity higher than 5 W/cm2. This type of US can transfer enough energy to cause coagulation necrosis of tissue and is usually used for ultrasonic surgery. • Low-intensity US (0.125-3 W/cm2) causes non-destructive heating, therefore, it stimulates or accelerates normal physiological responses to an injury. This range of US is usually used for physiotherapy.
  3. • In the modern era of minimal invasiveness, high-intensity focused ultrasound (HIFU) promises therapeutic utility for multiple neurosurgical pathologies. • The use of focused ultrasound (FUS) waves for intracerebral ablation was first described by Lynn et al. in 1942. • Later, the Fry brothers designed a complex device with 4 piezoelectric transducers that had the ability to focus pinpoint lesions and used HIFU for safe ablation of intracranial tumors by performing craniectomy to create a window for the transmission of acoustic waves. • With intraoperative MRI, the magnetic resonance-guided focused ultrasound (MRgFUS) is more precise than ultrasound or a surgeon’s direct visualization.
  4. PRINCIPLES AND MECHANISMS OF ACTION OF HIFU • In the MRgFUS procedure, a small target is heated with ultrasound rays, a technique called sonication. • The pre-sonication volume target is identified by MRI, post-sonication temperature is measured by proton resonance frequency shift by means of fast GRE sequences, and the ablated volume is identified by means of T2-weighted fast spin-echo sequences. • Primary goal: to maximize energy accumulation at the target area to induce significant biological reactions (coagulation necrosis) without instigating harm to surrounding tissues. • The “focal zone” can be defined as the area where the ultrasound intensity (energy/unit area) is high enough to create a lesion. These lesions are ellipsoidal, 8–15 mm in length, and have a diameter of 1–2 mm. • In HIFU treatment, FUS is applied for local ablation therapy of various types of tumors in the body using an intensity of 100-10,000 W/cm2 .
  5. • HIFU exposure can be either constant (thermal) or pulsed (acoustic cavitation).  Thermal Mechanisms of Action • Ultrasound produces frictional heat by causing vibration of molecules in tissue; a temperature of > 56°C maintained for 2 seconds or more leads to coagulative necrosis. The thermal damage leads to unplanned cell death. • The targeted cells retain their outline, their proteins coagulate, and their metabolic activity halts.
  6. HIFU transducer with focused beam on a tumor. HIFU produces a focused ultrasound beam that passes through the overlying skin and tissues to necrose a localized region (tumor), which may lie deep within the tissues. The affected area at the focal point of the beam leads to lesion coagulative necrosis and is shown in red.
  7.  Nonthermal (Mechanical) Mechanisms of Action • The pulsed method of HIFU exposure can cause fast changes in the targeted tissue pressure, known as the peak rarefaction pressure amplitude (PRPA). • There is a threshold for PRPA for each tissue at which acoustic cavitation (formation of gas- or liquid-filled cavities) occurs, generally at points of “weakness,” such as the interfaces between different layers of tissue or fluid- filled structures. • These acoustic cavitation bubbles oscillate at large displacement amplitudes and exert shear stresses on the surrounding tissue, causing mechanical tearing; k/a histotripsy.
  8.  ACOUSTIC STREAMING is described as a small scale eddying of fluids near a vibrating structure such as the surface of stable cavitation gas bubble. This phenomenon is known to affect diffusion rates & membrane permeability.  Sodium ion permeability is altered resulting in changes in the cell membrane potential. Calcium ion transport is modified which in turn leads to an alteration in the enzyme control mechanisms of various metabolic processes, especially concerning protein synthesis & cellular secretions.
  9.  There are 2 types of cavitation: 1. STABLE CAVITATION does seem to occur at therapeutic doses of US. This is the formation & growth of gas bubbles by accumulation of dissolved gas in the medium. They take approx. 1000 cycles to reach their maximum size. The `cavity' acts to enhance the acoustic streaming phenomena & as such would appear to be beneficial. 2. UNSTABLE (TRANSIENT) CAVITATION is the formation of bubbles at the low pressure part of the US cycle. These bubbles then collapse very quickly releasing a large amount of energy which is detrimental to tissue viability. Forms of stable and inertial cavitation
  10. Schematic of tcMRgHIFU setup MRgHIFU setup consists of a positioning system, a transducer, and a stereotactic head frame, which is placed for patient immobilization during the procedure.
  11. A: Noninvasive setup of HIFU transducer with transducer tracker, head-motion tracker, and degassed water. B: HIFU transducer converging noninvasive transcranial ultrasonic energy at the ellipsoidal focal zone to produce tissue lesions at depth.
  12. INITIAL CHALLENGES WITH TRANSCRANIAL MRgHIFU  Bone: relatively high attenuation coefficient, absorbs and reflects ultrasound energy; Also its acoustic impedance higher than that of the soft tissues, inferior efficacy of energy transfer and unwanted heating of the skull in transcranial HIFU therapy.  To overcome this, transducers with a large number of high-energy sources; An external cooling system that circulates chilled water around the scalp.  To distribute the heat as widely as possible, the active area has been maximized through a hemispheric design, known as a piezoelectric component arrangement.  Severe aberration of FUS waves d/t Irregularity in skull thickness, result in the defocusing of ultrasound beams.  A computerized multichannel hemispheric phased-array transducer (ExAblate Neuro, InSightec Ltd.).
  13. An ExAblate Neuro MRgFUS transducer helmet on an MRI table
  14. CURRENT APPLICATIONS IN NEUROSURGERY • A silicone diaphragm is fitted to the scalp, and the transducer is filled with degassed water (dissolved oxygen below 1.2 ppm). The cooled degassed water (between 15°- 20°C) is circulated between sonications to prevent unwarranted heating and lower the skull temperature. • GBM is MC & most aggrassive; the center of attention for multiple HIFU trials.  According to Medel et al. HGG are not an ideal pathology for HIFU, and the technique might be more effective for well-circumscribed lesions, such as metastases or benign tumors, inaccessible to surgery.
  15. Functional Neurosurgery Transcranial MRgHIFU • Precise ablation of the focused targets in the thalamus, subthalamus, or basal ganglia; These locations are centers to many pathological conditions, namely neuropathic pain, Parkinson’s disease (PD), and essential tremor (ET).  In 2009, Martin et al. reported the first successful application of tcMRgHIFU for functional neurosurgery. They treated 9 patients with chronic neuropathic pain with medial thalamotomies. The ablations were precisely located within a diameter of 4 mm according to MRI. There were no neurological deficits on follow-up.  Jung et al. were the first to describe the use of MRgFUS for the treatment of medically refractory obsessive-compulsive disorder (OCD). They performed bilateral thermal anterior limb capsulotomy in 4 patients and reported favorable results. Similarly, a clinical trial of 10 patients evaluated the feasibility, safety, and initial efficacy of MRgFUS in the treatment of major depressive disorder.
  16.  Enhancing Drug Delivery Across the Blood-Brain Barrier: Several studies have demonstrated the potential of FUS to deliver chemotherapeutic agents, antibodies, growth factors, or genes to the desired area of the brain.  By modifying the sonication parameters from those used for ablation, a controlled, reversible, and reproducible opening of the BBB can be achieved, allowing for the delivery of targeted drugs, such as liposomal doxorubicin; nanoparticles; fluorophores; and naked DNA injected systemically to locally sonicated tissue in vivo.  Targeting ligands can also be conjugated to microbubbles, enabling the microbubble complex to accumulate selectively in areas of interest. When these microbubbles are destroyed with low-frequency, high-power ultrasound, the microvessel walls become permeable, allowing for the drugs or genes contained within microbubbles to be released into the bloodstream and then delivered to tissue by convective forces.
  17. Schematic illustration of transient BBB opening. MRgFUS in conjunction with microbubbles leads to open the BBB by separating the endothelial tight junction, allowing enhanced delivery of therapeutic agents.
  18. • Several preclinical studies have also demonstrated the successful delivery of anti- amyloid antibodies and other disease-modifying drugs across the BBB using FUS therapy for the treatment of Alzheimer’s disease (AD).  Sonothrombolysis in Ischemic Stroke: As evident from several preclinical studies, HIFU based thrombolysis has recently emerged as a promising drug-free treatment option. FUS causes microbubble oscillation, leading to mechanical disruption of the ischemic clot and improving rates of recanalization.  The Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and the Transcranial Low-Frequency Ultrasound-Mediated Thrombolysis in Brain Ischemia (TRUMBI) trial with unfocused, low-frequency (300 kHz) ultrasound have shown some promise, but with complications such as increased hemorrhage rates.
  19. HIFU-Induced Immunomodulation and Antitumor Immunity • The release of tumor antigens from necrotic cells and a diverse array of endogenous signals from HIFU-damaged tumor cells can enhance an antitumor immune response. • A HIFU-induced strong antitumor immune response could help to combat residual tumor cells at the primary lesion site and suppress metastasis. • Future Applications of tcMRgFUS: Trigeminal Neuralgia and Refractory seizure.
  20. MRgHIFU parameters in various intracranial disease applications
  21. • MRI-guided laser interstitial thermal therapy (LITT) is the selective ablation of a lesion or a structure using heat liberated from a laser. • The laser is selectively applied to the region of the tumor using optical fibers. LITT uses an Nd:YAG laser with a wavelength of 1064 nm. The tissue penetration ranges from 2 to 10 mm. • During 1976-1979, Asher and Heppner performed more than 250 central nervous system (CNS) lesion ablations after modifying the CO2 laser. In addition, they coupled the laser to an operating microscope to increase precision. • A neodymium-doped yttrium aluminum garnet (Nd: YAG) laser was also used but lacked the precision required for most neurosurgical procedures owing to poor absorption by CNS tissue, leading to extensive collateral damage.
  22. • Because the Nd:YAG laser is selectively absorbed by blood and blood vessels, it can be used to occlude small blood vessels. • The Nd:YAG laser penetrated deeper than the CO2 laser; the depth of penetration is predictable, and its effect on vascularized tissues is greater than that of the CO2 laser. • Recent advances in MRI equipment, thermal imaging sequences, software, and laser delivery techniques and equipment enabled the prediction and accurate control of tissue temperatures which renewed the use of the Nd:YAG laser.
  23. • When the laser hits the tumor, the tumor tissue interacts by absorbing the laser photons, which are then transformed into thermal energy insider the tumor tissue. When the temperature of the tissue is between 43-45 °C for more than 10 min, the cancer cells are sensitized to chemotherapy and radiation therapy. • When the temperatures ranges between 50-80 °C for a shorter amount of time, tumor necrosis occurs through protein denaturation. • The damage can be quantified using the Arrhenius thermal dose model; Using this model, MRI software can generate thermal maps to visualize thermal changes and monitor tumor necrosis.
  24. • The LITT system comprises a laser system, workstation, and MRI. There are two clinically U.S.FDA approved LITT systems: Visualase (Visualase, Inc.) and NeuroBlate (Monteris Medical, Inc.). • The main differences between the two systems are the laser wavelength, cooling method, heat production, and distribution pattern. 1. The NeuroBlate system, approved by FDA in 2009, has a 1064nm diode pulsed laser with a CO2 cooled side firing probe or diffusing tip probe. 2. The Visualase system, approved by the FDA in 2007, has a 980nm diode continuous laser with a saline cooled diffusing applicator tip. Laser The laser system comprises a laser light source, laser fibers, applicator, sheath and diffusion tip.
  25. • MRI images obtained before and during the LITT procedure are sent from the MRI scanner to a linked workstation. • It provides real-time thermal maps for monitoring the procedure and estimates tissue necrosis (c/a magnetic resonance thermometry). • It also identify the lesion and plan the trajectory for the laser probe. Navigation software is used for registration and trajectory planning. • The laser shuts off automatically if the valid temperature range at the tip is exceeded.
  26. MRI of laser-ablated lesion: Immediate and early stage (0 to 3 months post procedures) MRI of laser-ablated lesion: Delayed stage (2 weeks to 6 months post procedure)
  27. Immediately after and in the early stages after LITT (0 to 3 months post procedure). The treated lesion shows a distinct central zone and peripheral zone surrounded by vasogenic edema.
  28. Summary of studies reporting clinical application of LITT in neurosurgery
  29. Summary of common complications of LITT and recommendation to avoid
  30. Conclusions  MRgFUS is an emerging technique allowing non-invasive, incision-free transcranial treatment for a variety of intracranial diseases via thermal and non-thermal mechanisms.  Despite improvements that have overcome the initial technical challenges, only very few clinical trials have thus far been carried out.  Accurate thermal ablation via MRgHIFU-mediated stereotactic lesioning can be confirmed with real-time visualization of the target volume with MRI thermometry.  Emerging preclinical evidence suggests that MRgFUS-mediated BBB opening has potential to revolutionize the targeted treatment of selected brain diseases, including brain tumors and neurogenerative disease.
  31.  The principle of LITT is selective ablation of tumor cells by heat and is monitored by real-time MRI thermometry.  LITT has a range of applications, such as treatment of glioma, metastases, radiation necrosis, chronic pain, and epilepsy.  LITT is used for selected lesions and in selected patients as a safer alternative treatment option for patients in whom the lesion is not accessible by surgery, in patients who are not surgical candidates, or in those in whom other standard treatment options have failed.  Complications of LITT include hemorrhage, brain edema, thermal injury of adjacent structures, and treatment failure.
  32. References: • Rhoton's Cranial Anatomy and Surgical Approaches • Schmidek and Sweet: Operative Neurosurgical Techniques 6th edition • Youmans and Winn neurological surgery 8th edition • Ramamurthi & Tandon's textbook of neurosurgery 3rd edition • Internet THANK YOU