Hi, my name is Abdul. I'm a second year resident at the University of Maryland Neurosurgery Program. Today for the Young Neurosurgeons Research Forum, I want to talk about a trial we are running here at the University of Maryland. MRI-guided focused ultrasound thalamotomy of the central lateral nucleus for neuropathic pain. This is our early phase one trial. I've had many mentors and colleagues in this project. I especially want to thank Dr. Eisenberg and Dr. Gandhi for their indispensable mentorship. I have no disclosures. Today I want to talk about neuropathic pain, both what it is, what it means for patients, and the different medical and surgical treatment options available to them. I also want to talk about the central lateral nucleus and what it means in terms of chronic neuropathic pain, and why performing a thalamotomy is valuable for these patients. Then I want to talk about MRI-guided focused ultrasound, which has shown to be able to produce thalamotomy for essential tremor before, and which we are using to perform a thalamotomy in the central lateral nucleus. I want to talk about the trial design, and then the safety and pain. So neuropathic pain, this includes conditions like diabetic neuropathy, chemotherapy-induced neuropathy, radiculopathy. It results from a lesion or disease of any part of the somatosensory nervous system as you can see on the right side. Seven to eight percent of individuals will experience neuropathic pain in their lifetime. It accounts for up to 25 percent of patients with chronic pain. Chronic pain itself results in $560 billion in annual indirect and direct costs. Of course, as you can imagine, it leads to a significant loss of quality of life. There are many medication options for these patients. Unfortunately, a lot of these patients do end up taking opioid medications and those are difficult sometimes as they have high addiction potential. Most cases of neuropathic pain are medication refractory. So any method of treating this pain or alleviating these symptoms without using these medications would be very helpful to these patients. So what are the treatment options in terms of interventions or surgeries? I love this image here on the right by Pereira. It depicts the entire neural matrix or the neural systems underlying pain. As you can see, this involves neurosurgery at almost every level. One intervention in particular I wanted to talk about is deep brain stimulation. So deep brain stimulation has a track record with treating movement disorders. Unfortunately, it has inconsistent results with neuropathic pain patients. The targets in deep brain stimulation for this are the periventricular and periaqueductal gray and the adjacent midline thalamic nuclei. The VPL and VPM are also targets as is the anterior cingulate cortex. The outcomes are unproven in Portugal and the United Kingdom did report a good three-year outcomes though. There can be complications like hemorrhagic infection and neurologic deficits, though they are small in frequency. The stimulation frequency use is not standardized. So given all this, it remains off-label. So if we're going to talk about treatment for neuropathic pain, we should talk about the pathophysiology, which is thought to be thalamic cortical dysrhythmia. This is in particular for chronic neuropathic pain. When the peripheral nervous system is damaged, this leads to a loss of excitatory input to the thalamus, which results in hyperpolarization of the membrane. This leads to de-inactivation of T-type calcium channels, which results in low threshold spikes, which occur with a theta rhythmicity. This results in thalamocortical dysfunction as the thalamus and cortex communicate with each other in a loop. This theta rhythmicity remains between the two, which can cause disruptions in other higher functions in the brain. It is thought that the medial thalamus, as it was historically called, is the nidus of where low threshold spikes occur. This has been recorded in previous studies. This is actually now called the central lateral neoplasm. This thalamus segment transfers no susceptive information from the spinal thalamic tract to higher centers within the brain. It is actually a very interesting and optimal surgical target for us. Speaking of surgical target, we can use a different modality than has been previously used. I'm talking about magnetic resonance guided focused ultrasound. This is a method in which a patient sits on an MR scanner and 1,024 ultrasound elements shoot sound to a single point within the brain to create a lesion, with the accuracy of a millimeter. The patient sits on the scanner and has a water-cooled helmet on. It does require a skull density ratio of at least 0.4, so the sound can better travel through the skull to the brain. There is different software available to allow this system to create accurate lesions within the brain. Patients are awake, so you can get real-time feedback from them on their symptoms, and also perform thermometry to make sure that you are lesioning appropriately. There has been a prior study on this exactly. The Gene Monod Group, and he has been critical in a lot of this work, published their results in 2012 of 11 patients that they treated. Nine of them were adequately lesioned and eight of those had a adequate one-year post-procedure follow-up. They experienced a 40.7 percent improvement in pain on the visual analog scale, and a lot of them either took the same medications as they had prior or took no pain medications at all at their one-year follow-up. Our trial is an early trial design. We intend to enroll 20 patients to perform bilateral central lateral nucleus thalmatomy. Bilateral because studies have shown that there is that low threshold spike activity on both sides, even in unilateral pain patients. This is a single-arm non-randomized unblinded study. The primary aim of this trial was to determine the safety and feasibility of performing central lateral thalamotomy with MR-guided focus ultrasound, in treating this syndrome of medication refractory neuropathic pain. A second aim, although smaller, was to see how efficacious this intervention is, both by using the pain inventory scale, the brief pain inventory scale and the pain disability index, which are both validated indices to determine how much pain is interfering with life. Mainly, we wanted to enroll patients with radiculopathy or radicular pain, spinal cord injury, or phantom limb pain. Our inclusion and exclusion criteria are numerous, the main of which include they had to be between 21 and 75 years old, had to have a skull density ratio greater than 0.4, so they would be eligible for focus ultrasound treatment. Their pain had to have lasted greater than six months, as confirmed by a pain doctor or neurologist. They should have failed standard of care and at least three pain medications, and also failed an intervention like a spinal cord stimulator or nerve injection. The important exclusion criteria include prior deep brain stimulation, a history of central nervous system disease, inability to tolerate the procedure, and severe comorbidities. These are our patients. As you can see, they tend to be in their 40s and 50s. One was 69. They all had eligible skull density ratios. They had symptoms consistent with phantom limb pain, failed back syndrome, either some peripheral nerve injury from a crush injury or an avulsion injury, one with a spinal cord injury from a arachnoid cyst. And as you can see, they underwent many interventions that had also failed them. And this is how those treatments went. On average, they were in the scanner for four hours. They were receiving sonication or sound to their brain for an average of two hours, and an average of 55 degrees Celsius was the maximum average temperature reached. For safety outcomes, we have four patients that had followed up to one year and one pending their one-year follow-up. There were no serious adverse events. The only adverse events were mild, including head pain or pin site pain or headache from the stereotactic frame we used for the focus ultrasound, all of which resolved within one week. At one-year follow-up, they had an average of 57% decrease in their brief pain inventory scores. Similarly, in pain disability index, there was a 48% average decrease over one-year follow-up in the four patients that did follow-up for a year. This is a post-treatment MRI on the left, a T2-weighted sequence, and a one-year follow-up MRI. You can see the lesion created as the T2 hyperintense signal in the central lateral nucleus. This patient was only able to tolerate unilateral treatment because of the stereotactic frame. And here is an example of similar MRI sequences for a bilateral central lateral thalamotomy treatment. You can see the T2-weighted signal signifying perilesional edema, which decreases, and you can see at one-year follow-up, those lesions persist. Some patients experienced changes in pain medications they were taking to manage their pain. One reduced their tramadol, bupropion, and hydrocodone intake. One decreased their morphine sulfate intake, and another decreased some medications but increased others. So our conclusions are that this is an early phase one study. Further enrollment is necessary. This treatment is a feasible and safe way to treat neuropathic pain. And patients with the indications we were selecting for did have a decrease in their pain as seen on validated scales. A future study is needed with a control arm to determine how efficacious this is exactly. And it is possible that this method can reduce the use of pain medications. Some lessons we've learned is that patients with radicular pain tend to do well. Selection of patients is vital. And that pain medications are difficult to track. Patients may decrease their pain medication intake before their procedure, or have difficulty leaving their medications for other reasons regardless of what their pain level is. And these are my conclusions. And I want to thank everyone that helped with this project, Dr. Gandhi and Dr. Eisenberg in particular. I want to thank you for listening, and I want to thank the AANS for this opportunity.

Abdul

University of Maryland Neurosurgery Program

MRI-guided focused ultrasound thalamotomy

neuropathic pain

central lateral nucleus