Horizon Scanning Centre

March 2013

ExAblate Neuro MR guided focused ultrasound for Parkinsons disease, essential tremor and neuropathic pain
SUMMARY Lay summary click here
The ExAblate Neuro system has been developed for the non-invasive treatment of neurological disorders such as Parkinsons disease, essential tremor and neuropathic pain. The system includes a helmet like device that allows the safe delivery of focused ultrasound to thermally ablate (destroy) brain tissue under magnetic resonance imaging (MRI) guidance, with the aim of reducing patients symptoms. Research into its effectiveness for a range of neurological disorders is at an early stage.
InSightec Ltd

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

BACKGROUND
Parkinson's disease (PD) is a progressive neurodegenerative condition resulting from the death of the dopamine-containing cells of the substantia nigra. PD predominantly leads to problems with movement, such as tremor, muscle stiffness or rigidity and slow physical movements (called bradykinesia). As the disease progresses, non-motor symptoms such as depression, apathy, pain and cognitive impairment increasingly affect quality of life. About 1 in 500 people have PD and there are currently 127,000 people in the UK with the condition1,2. The average age for the symptoms to start is around 60; around 1 in 20 cases develop in people aged under 501,2. Essential tremor (ET) is the most common cause of disabling tremor and is distinct from PD. ET typically affects the arms and hands, although it may also involve the head, jaw, tongue and legs. ET affects men and women equally. The prevalence of ET is about 300 per 100,000 population. Most people who develop ET are aged over 35, but it can occur in younger people 3,4 . The cause is unknown, but many describe a family history suggesting an autosomal dominant pattern of inheritance.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health. NIHR Horizon Scanning Centre, University of Birmingham Email: nihrhsc@contacts.bham.ac.uk Web: www.hsc.nihr.ac.uk

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Neuropathic pain develops as a result of damage to, or dysfunction of, the nervous system. Common causes include diabetic neuropathy, post-herpetic neuralgia (after shingles) and trigeminal neuralgia. People with neuropathic pain may experience altered pain sensation, areas of numbness or burning, and continuous or spontaneous pain. Neuropathic pain is very unpleasant and can have a significant impact on a person's quality of life. It is often difficult to treat, because it is resistant to many medications and/or because of the adverse effects associated with effective medications. It is estimated that about 1 in 100 people in the UK has persistent (chronic) neuropathic pain and it is much more common in older people5,6.

CURRENT PRACTICE
In a small number of patients affected with the neurological conditions described above, medical therapy (mainly drugs) may be insufficient to control symptoms and surgery on the brain has been used as an alternative. In the past, surgery was used to destroy specific targets within the central nervous system, but technical developments have led to the evolution of deep brain stimulation (DBS) as the preferred surgical method. DBS involves implanting one or more electrodes in certain areas of the brain. The electrodes are placed in the brain by inserting fine needles through small holes in the skull under a general anaesthetic. Thin wires run from the electrodes to a pulse generator (a device that is similar to a pacemaker), which is implanted under the skin in the chest. The generator produces an electric current that overstimulates the target, thus switching off that part of the brain, which can lead to improvements in tremor. DBS is a recognised treatment for PD and ET7,8. ET can also be treated using a procedure called a thalamotomy, which involves ablating (destroying) brain tissue within the thalamus using radiofrequency energy. Although this procedure has been shown to be effective, DBS is preferred to the invasive thalamotomy because it is associated with fewer complications and greater control3. Neuropathic pain may be treated using electrical stimulation such as transcutaneous electrical stimulation (TENS). In more severe cases, spinal cord stimulation may be considered and NICE recommends consideration of this in patients who have had chronic pain for six months9. As with all surgical procedures, there are potential risks to stimulation therapy, which include pain, bleeding and infection. Specific risks of DBS include stroke, balance disturbances, speech and visual problems7. Expert opinion has suggested risk of serious harm to patients to be less than 5%.

NEW TECHNOLOGY
The ExAblate Neuro MR guided focused ultrasound (MRgFUS) system has been developed by InSightec Ltd. The ExAblate is a novel device that combines therapeutic acoustic ultrasound waves with continuous MRI guidance for thermal ablation of tissue. Currently ExAblate is intended for use in PD, ET and neuropathic pain. The company intends for this technology to be used as an alternative to surgical procedures. ExAblate is a helmet-like device made up of thousands of individual ultrasound elements. MRgFUS is undertaken with the patient lying inside an MRI scanner (like a large ring-shaped magnet). The patient is awake and is able to communicate with the operator to assess 2

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neurological improvement during treatment and to report on adverse symptoms, if they occur, such as burning sensations or pain. Low power ultrasound is used to identify the target, followed by high power pulses to ablate tissue. Chilled water is circulated around the skull during the treatment to prevent thermal damage to the brain caused by an increase in bone temperature due to high ultrasound absorption in bone. The procedure takes approximately 3 hours and symptom relief should be immediate. Exablate Neuro was CE marked in December 2012 and is commercially available in the UK. The cost was not available for this briefing.

CLINICAL STUDIES AND RESEARCH QUESTIONS

There are no published trials which assess the effectiveness of ExAblate Neuro MRgFUS treatment compared to currently available treatments. There is one published noncomparative study (in neuropathic pain). There is one completed but unpublished noncomparative study (in ET), one ongoing non-comparative study (in neuropathic pain) and one ongoing non-comparative study (in movement disorders including PD and ET). Some details of these studies are given here. In a published study, 11 patients with chronic therapy-resistant neuropathic pain, underwent a central lateral thalamotomy (CLT) using ExAblate transcranial MRgFUS system10. The treated neuropathic pain syndromes had peripheral (five patients) or central (six patients) origins and involved different body regions. Patients experienced mean pain relief of 49% at the three month follow-up (nine patients) and 57% at the one year follow-up (eight patients). Mean improvement according to the visual analogue scale amounted to 42% at 3 months and 41% at one year. Six patients experienced immediate and persisting symptomatic improvements. There was one serious complication; a haemorrhagic stroke. The company have stated that in an unpublished study 13 patients with chronic therapyresistant neuropathic pain underwent the procedure. Patients experienced mean pain relief of 47% (13 patients) at three month follow-up and 75% at one year follow-up (10 patients). Mean improvement according to the visual analogue scale amounted to 33% at 3 months and 63% at one year. In a completed unpublished non-comparative feasibility (phase I) study, 15 patients with ET underwent a unilateral thalamotomy using the ExAblate transcranial MRgFUS system11. The company states that this study for essential tremor reported suppression of tremor and a resolved average of 85% relief of tremor disability as measured in the Disability subsection of the Clinical Rating Scale for Tremor (CRST) after one year follow-up. In an ongoing non-comparative study, 30 patients with neuropathic pain and movement disorders will receive treatment with ExAblate transcranial MRgFUS targetting the thalamus, subthalamus or pallidum12. The primary outcome is improvement in pain scores on the visual analogue scale, Unified Parkinson's Disease Rating Scale (UPDRS) and CRST scores following the intervention and at follow-up. The study is expected to complete in December 2013. A randomised controlled trial for tremor dominant PD is ongoing in the US (study will enroll 30 patients and is expected to complete December 2014) and a separate pivotal randomised controlled trial for essential tremor is expected to start in 2014. Randomised controlled trials where patients receive treatment using the ExAblate Neuro MRgFUS system or a standard treatment option would provide the strongest evidence as to 3

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whether treatment with ExAblate brings clinical benefits. Such trials would need to include long term effects and the potential need for repeated treatments.

POTENTIAL IMPACT
The ExAblate Neuro MRgFUS system is less invasive than the current surgical options for the treatment of PD, ET and neuropathic pain, such as DBS, potentially reducing the risk of complications10,11,12. A further clinical benefit is that no ionizing radiation is used and this enables repeated treatments with no long term risk of radiation damage for the patient. An added potential benefit of this technology is that the intraoperative image guidance allows for high level of accuracy. However there is currently insufficient evidence to demonstrate that it is at least as safe and at least as effective as currently established techniques.

Lay summary The Exablate Neuro is a new device to help treat patients with Parkinsons disease, tremor and neuropathic pain. Some patients may not respond very well to medicines and may need a kind of surgery. This new device may give another choice of treatment. It is a helmet like piece of equipment that sends ultrasound energy deep into the brain and it hopes to reduce the patients unpleasant symptoms. Studies are going on to see how well it works and if it is safe.

REFERENCES
National Institute of Health and Clinical Excellence. Parkinsons disease: diagnosis in primary and secondary care. Clinical guideline CG35. London: NICE; June 2006. 2 NHS Choices. Parkinsons disease. http://www.nhs.uk/conditions/Parkinsonsdisease/Pages/Introduction.aspxx Accessed 16 January 2013. 3 Patient.co.uk. Essential tremor. http://www.patient.co.uk/health/Essential-Tremor.htm Accessed 16 January 2013. 4 NHS Choices. Tremor (essential). http://www.nhs.uk/conditions/Tremor(essential)/Pages/Introduction.aspx Accessed 16 January 2013. 5 Patient.co.uk. Neuropathic pain. http://www.patient.co.uk/health/neuropathic-pain Accessed 16 January 2013. 6 National Institute for Health and Clinical Excellence. Neuropathic pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. Clinical Guideline CG 96. London: NICE; March 2010. 7 National Institute for Health and Clinical Excellence. Deep brain stimulation for Parkinson's disease. Interventional Procedure Guidance IPG19. London: NICE; November 2003. 8 National Institute for Health and Clinical Excellence. Deep brain stimulation for tremor and dystonia (excluding Parkinson's disease). Interventional Procedure Guidance IPG188. London: NICE; August 2006. 9 National Institute for Health and Clinical Excellence. Pain (chronic neuropathic or ischaemic) spinal cord stimulation. Technology Appraisal TA 159. London: NICE; October 2008. 10 Jeanmonod D, Werner B, Morel A, et al. Transcranial magnetic resonance imaging-guided focused ultrasound: noninvasive central lateral thalamotomy for chronic neuropathic pain. Neurosurgical Focus. 2012 Jan;32(1):E1. 11 ClinicalTrials.gov. ExAblate Transcranial MR Guided Focused Ultrasound in the treatment of essential tremor. 1

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http://www.clinicaltrials.gov/ct2/show/NCT01304758?term=exablate+neuro&rank=1 Accessed rd 23 January 2013. 12 ClinicalTrials.gov. Safety study using Transcranial MR Guided Focused Ultrasound in the treatment of neuropathic pain (FUS-CLT). http://www.clinicaltrials.gov/ct2/ rd show/NCT01699477?term=exablate+neuro&rank=4 Accessed 23 January 2013.