Summary of PICO/PPICO criteria to define the question(s ...



RATIFIED PICOApplication 1614:Magnetic resonance-guided focused ultrasound for the treatment of medically refractory essential tremor Summary of PICO/PPICO criteria to define the question(s) to be addressed in an Assessment Report to the Medical Services Advisory Committee (MSAC)ComponentDescriptionPatientsAdults with medically refractorya essential tremor [under the care of a neurologist] and symptoms causing severe [functional or social] disabilityInterventionUnilateral Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomyComparatorDeep brain stimulation (DBS), unilateral or bilateralbBest supportive medical care (BSC)c, OutcomesSafety:Adverse Events:Numbness, paraesthesiaes, ataxia, dysarthria, dysphagia, in short and long term (> 12 months)Intraprocedural harms (due to helmet or other events as noted in RCT and observational studiesFailed procedure rate (skull thickness, claustrophobia/anxiety, other)Efficacy / effectiveness including, but not limited to, patient-relevant outcomes:Number of patients with benefit (number reaching minimum clinically important difference (MCID) threshold of tremor scale (if validated)Median (not mean) benefit in tremor, using MCID of CRSTDuration of adequate benefit (using MCID)Need for retreatment with DBSAbility to cease medicationsQoL outcomes- standardised (SF36) and disease specific (QUEST)Return to employment/productivityChange in social disabilityHealthcare resources.Costs to deliver the intervention, including cost of the treatment kitdRe-intervention costsCost-effectiveness.Total Australian Government healthcare costs.Total cost to the Medicare Benefits Schedule (MBS)Total cost to the Pharmaceutical Benefits Scheme (PBS)Total cost to other healthcare servicesa Patients who fail to derive adequate benefit from pharmacological treatment (first-line treatment: propranolol or primidone; gapapentin, alprazoloam and topiramate available where first-line drugs are contraindicated or not tolerated)b Patients might also be receiving concurrent medical therapy (i.e. BSC)c In those unwilling to accept the risks associated with DBS or are contra-indicated for the procedured The applicant advised that the helmet is reused compared with the treatment kit which is disposablePICO or PPICO rationale for therapeutic and investigative medical services onlyPOPULATIONEssential tremor (ET) is one of the most common movement disorders, affecting approximately 1% of the population worldwide ADDIN EN.CITE <EndNote><Cite><Author>Louis</Author><Year>2010</Year><RecNum>19</RecNum><DisplayText>(Louis and Ferreira 2010)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="p5z2edva7sfr05e2de7xf0012vtddstz5ae9" timestamp="1582766000">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Louis, E. D.</author><author>Ferreira, J. J.</author></authors></contributors><auth-address>GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. EDL2@columbia.edu</auth-address><titles><title>How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor</title><secondary-title>Mov Disord</secondary-title><alt-title>Movement disorders : official journal of the Movement Disorder Society</alt-title></titles><periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></periodical><alt-periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></alt-periodical><pages>534-41</pages><volume>25</volume><number>5</number><edition>2010/02/23</edition><keywords><keyword>Age Factors</keyword><keyword>Community Health Planning</keyword><keyword>Essential Tremor/diagnosis/*epidemiology</keyword><keyword>Ethnic Groups</keyword><keyword>Europe/epidemiology</keyword><keyword>*Global Health</keyword><keyword>Humans</keyword><keyword>Prevalence</keyword><keyword>Quality of Life</keyword><keyword>Sex Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>0885-3185</isbn><accession-num>20175185</accession-num><urls></urls><electronic-resource-num>10.1002/mds.22838</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Louis and Ferreira 2010). It is a chronic, progressive neurologic disease whose identifying feature is a kinetic tremor, i.e. an involuntary rhythmic oscillatory movement of one or both arms that occurs during voluntary movements (writing, eating). The tremor cannot be attributed to another cause (e.g. Parkinson’s disease). There is a slow progression of tremor intensity with age and the tremor may also spread to involve other body regions, most commonly the head, larynx (voice tremor), and lower limbs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ2xhcmsgYW5kIExvdWlzIDIwMTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRlN3hmMDAxMnZ0ZGRzdHo1YWU5

IiB0aW1lc3RhbXA9IjE1ODI3NjYwNTIiPjIzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5DbGFyaywgTC4gTi48L2F1dGhvcj48YXV0aG9yPkxvdWlzLCBFLiBELjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2Yg

UGF0aG9sb2d5IGFuZCBDZWxsIEJpb2xvZ3ksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyBhbmQgU3Vy

Z2VvbnMsIGFuZCBUYXViIEluc3RpdHV0ZSBmb3IgUmVzZWFyY2ggb24gQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlIGFuZCB0aGUgQWdpbmcgQnJhaW4sIENvbHVtYmlhIFVuaXZlcnNpdHksIE5ldyBZ

b3JrLCBOWSwgVW5pdGVkIFN0YXRlcy4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBSZXNlYXJjaCBv

biBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwgQ29sdW1iaWEg

VW5pdmVyc2l0eSwgTmV3IFlvcms7IGFuZCBEZXBhcnRtZW50cyBvZiBOZXVyb2xvZ3kgYW5kIG9m

IENocm9uaWMgRGlzZWFzZSBFcGlkZW1pb2xvZ3kgYW5kIENlbnRlciBmb3IgTmV1cm9lcGlkZW1p

b2xvZ3kgYW5kIENsaW5pY2FsIE5ldXJvbG9naWNhbCBSZXNlYXJjaCwgWWFsZSBTY2hvb2wgb2Yg

TWVkaWNpbmUsIE5ldyBIYXZlbiwgQ1QsIFVuaXRlZCBTdGF0ZXMuIEVsZWN0cm9uaWMgYWRkcmVz

czogZWxhbi5sb3Vpc0B5YWxlLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Fc3Nl

bnRpYWwgdHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkhhbmRiIENsaW4gTmV1cm9sPC9z

ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5IYW5kYm9vayBvZiBjbGluaWNhbCBuZXVyb2xvZ3k8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IYW5kYiBDbGluIE5l

dXJvbDwvZnVsbC10aXRsZT48YWJici0xPkhhbmRib29rIG9mIGNsaW5pY2FsIG5ldXJvbG9neTwv

YWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SGFuZGIgQ2xp

biBOZXVyb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5IYW5kYm9vayBvZiBjbGluaWNhbCBuZXVyb2xv

Z3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4yMjktMjM5PC9wYWdlcz48dm9sdW1l

PjE0Nzwvdm9sdW1lPjxlZGl0aW9uPjIwMTgvMDEvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkVzc2VudGlhbCBUcmVtb3IvZXBpZGVtaW9sb2d5LypnZW5ldGljcy8qcGh5c2lvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUtRW52aXJvbm1lbnQgSW50ZXJhY3Rpb248L2tleXdv

cmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlLypnZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+UGhlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPmVzc2VudGlhbCB0cmVtb3I8

L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZmFtaWx5IHN0dWRp

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Z2Vub21ld2lk

ZSBhc3NvY2lhdGlvbiBzdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPnBoZW5vdHlwaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPndob2xlLWdlbm9tZSBzZXF1ZW5jaW5nPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PC9kYXRlcz48aXNibj4wMDcyLTk3NTIgKFByaW50KSYj

eEQ7MDA3Mi05NzUyPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzI1NjEzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1ODk4NjE2PC9jdXN0b20yPjxjdXN0b202Pk5JSE1T

OTU2NzM1PC9jdXN0b202PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2I5NzgtMC00

NDQtNjMyMzMtMy4wMDAxNS00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFi

YXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8

L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl

Y051bT4yMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oQ2xhcmsgYW5kIExvdWlzIDIwMTgpPC9EaXNw

bGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+

PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRlN3hmMDAxMnZ0ZGRzdHo1YWU5

IiB0aW1lc3RhbXA9IjE1ODI3NjYwNTIiPjIzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5DbGFyaywgTC4gTi48L2F1dGhvcj48YXV0aG9yPkxvdWlzLCBFLiBELjwvYXV0

aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2Yg

UGF0aG9sb2d5IGFuZCBDZWxsIEJpb2xvZ3ksIENvbGxlZ2Ugb2YgUGh5c2ljaWFucyBhbmQgU3Vy

Z2VvbnMsIGFuZCBUYXViIEluc3RpdHV0ZSBmb3IgUmVzZWFyY2ggb24gQWx6aGVpbWVyJmFwb3M7

cyBEaXNlYXNlIGFuZCB0aGUgQWdpbmcgQnJhaW4sIENvbHVtYmlhIFVuaXZlcnNpdHksIE5ldyBZ

b3JrLCBOWSwgVW5pdGVkIFN0YXRlcy4mI3hEO1RhdWIgSW5zdGl0dXRlIGZvciBSZXNlYXJjaCBv

biBBbHpoZWltZXImYXBvcztzIERpc2Vhc2UgYW5kIHRoZSBBZ2luZyBCcmFpbiwgQ29sdW1iaWEg

VW5pdmVyc2l0eSwgTmV3IFlvcms7IGFuZCBEZXBhcnRtZW50cyBvZiBOZXVyb2xvZ3kgYW5kIG9m

IENocm9uaWMgRGlzZWFzZSBFcGlkZW1pb2xvZ3kgYW5kIENlbnRlciBmb3IgTmV1cm9lcGlkZW1p

b2xvZ3kgYW5kIENsaW5pY2FsIE5ldXJvbG9naWNhbCBSZXNlYXJjaCwgWWFsZSBTY2hvb2wgb2Yg

TWVkaWNpbmUsIE5ldyBIYXZlbiwgQ1QsIFVuaXRlZCBTdGF0ZXMuIEVsZWN0cm9uaWMgYWRkcmVz

czogZWxhbi5sb3Vpc0B5YWxlLmVkdS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Fc3Nl

bnRpYWwgdHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkhhbmRiIENsaW4gTmV1cm9sPC9z

ZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5IYW5kYm9vayBvZiBjbGluaWNhbCBuZXVyb2xvZ3k8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5IYW5kYiBDbGluIE5l

dXJvbDwvZnVsbC10aXRsZT48YWJici0xPkhhbmRib29rIG9mIGNsaW5pY2FsIG5ldXJvbG9neTwv

YWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SGFuZGIgQ2xp

biBOZXVyb2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5IYW5kYm9vayBvZiBjbGluaWNhbCBuZXVyb2xv

Z3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4yMjktMjM5PC9wYWdlcz48dm9sdW1l

PjE0Nzwvdm9sdW1lPjxlZGl0aW9uPjIwMTgvMDEvMTM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkVzc2VudGlhbCBUcmVtb3IvZXBpZGVtaW9sb2d5LypnZW5ldGljcy8qcGh5c2lvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUtRW52aXJvbm1lbnQgSW50ZXJhY3Rpb248L2tleXdv

cmQ+PGtleXdvcmQ+R2VuZXRpYyBQcmVkaXNwb3NpdGlvbiB0byBEaXNlYXNlLypnZW5ldGljczwv

a2V5d29yZD48a2V5d29yZD5HZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+UGhlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPmVzc2VudGlhbCB0cmVtb3I8

L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZmFtaWx5IHN0dWRp

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Z2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Z2Vub21ld2lk

ZSBhc3NvY2lhdGlvbiBzdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPnBoZW5vdHlwaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPndob2xlLWdlbm9tZSBzZXF1ZW5jaW5nPC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PC9kYXRlcz48aXNibj4wMDcyLTk3NTIgKFByaW50KSYj

eEQ7MDA3Mi05NzUyPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5MzI1NjEzPC9hY2Nlc3Npb24tbnVt

Pjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM1ODk4NjE2PC9jdXN0b20yPjxjdXN0b202Pk5JSE1T

OTU2NzM1PC9jdXN0b202PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2I5NzgtMC00

NDQtNjMyMzMtMy4wMDAxNS00PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFi

YXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8

L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA (Clark and Louis 2018). The cause of ET is unknown.ET is heterogeneous in its clinical presentation, pharmacological response and disease progression, and is therefore increasingly considered as a syndrome of different clinical features rather than a single entity. The International Parkinson and Movement Disorder Society set the following criteria for diagnosis of ET PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0aWE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+MjA8L1JlY051bT48RGlzcGxheVRleHQ+KEJoYXRpYSwgQmFpbiBldCBhbC4gMjAxOCk8

L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRkZHN0

ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjAxOCI+MjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm

LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48

YXV0aG9ycz48YXV0aG9yPkJoYXRpYSwgSy4gUC48L2F1dGhvcj48YXV0aG9yPkJhaW4sIFAuPC9h

dXRob3I+PGF1dGhvcj5CYWphaiwgTi48L2F1dGhvcj48YXV0aG9yPkVsYmxlLCBSLiBKLjwvYXV0

aG9yPjxhdXRob3I+SGFsbGV0dCwgTS48L2F1dGhvcj48YXV0aG9yPkxvdWlzLCBFLiBELjwvYXV0

aG9yPjxhdXRob3I+UmFldGhqZW4sIEouPC9hdXRob3I+PGF1dGhvcj5TdGFtZWxvdSwgTS48L2F1

dGhvcj48YXV0aG9yPlRlc3RhLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+RGV1c2NobCwgRy48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Tb2JlbGwgRGVwYXJ0

bWVudCBvZiBNb3RvciBOZXVyb3NjaWVuY2UgYW5kIE1vdmVtZW50IERpc29yZGVycywgVW5pdmVy

c2l0eSBDb2xsZWdlIExvbmRvbiAoVUNMKSBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBMb25kb24s

IFVuaXRlZCBLaW5nZG9tLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBDaGFyaW5n

IENyb3NzIEhvc3BpdGFsLCBJbXBlcmlhbCBDb2xsZWdlIExvbmRvbiwgVW5pdGVkIEtpbmdkb20u

JiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIE5vdHRpbmdoYW0gVW5pdmVyc2l0eSBIb3NwaXRh

bCwgTm90dGluZ2hhbSwgVW5pdGVkIEtpbmdkb20uJiN4RDtTb3V0aGVybiBJbGxpbm9pcyBVbml2

ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU3ByaW5nZmllbGQsIElsbGlub2lzLCBVU0EuJiN4

RDtIdW1hbiBNb3RvciBDb250cm9sIFNlY3Rpb24sIE5hdGlvbmFsIEluc3RpdHV0ZSBvZiBOZXVy

b2xvZ2ljYWwgRGlzb3JkZXJzIGFuZCBTdHJva2UsIE5JSCwgQmV0aGVzZGEsIE1hcnlsYW5kLCBV

U0EuJiN4RDtEaXZpc2lvbiBvZiBNb3ZlbWVudCBEaXNvcmRlcnMsIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBZYWxlIFNjaG9vbCBvZiBNZWRpY2luZSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2

ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGFuZCBEZXBhcnRtZW50IG9mIENocm9uaWMgRGlzZWFzZSBF

cGlkZW1pb2xvZ3ksIFlhbGUgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIFlhbGUgVW5pdmVyc2l0

eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIFVuaXZlcnNpdGF0c2tsaW5pa3VtIFNjaGxlc3dpZy1Ib2xzdGVpbiwgS2llbCBDYW1wdXMs

IENocmlzdGlhbiBBbGJyZWNodHMgVW5pdmVyc2l0eSBLaWVsLCBLaWVsLCBHZXJtYW55LiYjeEQ7

RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFBoaWxpcHBzIFVuaXZlcnNpdHksIE1hcmJ1cmcsIEdl

cm1hbnk7IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBBdHRpa29uIEhvc3BpdGFsLCBVbml2ZXJz

aXR5IG9mIEF0aGVucywgQXRoZW5zLCBHcmVlY2UuJiN4RDtWaXJnaW5pYSBDb21tb253ZWFsdGgg

VW5pdmVyc2l0eSwgUmljaG1vbmQsIFZpcmdpbmlhLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+Q29uc2Vuc3VzIFN0YXRlbWVudCBvbiB0aGUgY2xhc3NpZmljYXRpb24gb2YgdHJl

bW9ycy4gZnJvbSB0aGUgdGFzayBmb3JjZSBvbiB0cmVtb3Igb2YgdGhlIEludGVybmF0aW9uYWwg

UGFya2luc29uIGFuZCBNb3ZlbWVudCBEaXNvcmRlciBTb2NpZXR5PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk1vdiBEaXNvcmQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk1vdmVtZW50IGRp

c29yZGVycyA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIE1vdmVtZW50IERpc29yZGVyIFNvY2ll

dHk8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Nb3YgRGlzb3Jk

PC9mdWxsLXRpdGxlPjxhYmJyLTE+TW92ZW1lbnQgZGlzb3JkZXJzIDogb2ZmaWNpYWwgam91cm5h

bCBvZiB0aGUgTW92ZW1lbnQgRGlzb3JkZXIgU29jaWV0eTwvYWJici0xPjwvcGVyaW9kaWNhbD48

YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TW92IERpc29yZDwvZnVsbC10aXRsZT48YWJici0x

Pk1vdmVtZW50IGRpc29yZGVycyA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIE1vdmVtZW50IERp

c29yZGVyIFNvY2lldHk8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43NS04NzwvcGFn

ZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTcvMTIv

MDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPipDb25zZW5zdXM8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbnRlcm5hdGlvbmFsIENvb3BlcmF0aW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FRExJTkUvc3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwv

a2V5d29yZD48a2V5d29yZD5Tb2NpZXRpZXMsIE1lZGljYWwvKnN0YW5kYXJkczwva2V5d29yZD48

a2V5d29yZD5UcmVtb3IvKmNsYXNzaWZpY2F0aW9uLypkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+KmNsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipkaWFnbm9zdGljIGF4ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+KmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPip0cmVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+KnRyZW1vciBzeW5kcm9tZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjA4ODUtMzE4NTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTE5MzM1OTwvYWNj

ZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTI+UE1DNjUzMDU1MjwvY3VzdG9tMj48Y3Vz

dG9tNj5OSUhNUzEwMjkzMjI8L2N1c3RvbTY+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEw

MDIvbWRzLjI3MTIxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXBy

b3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1

YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0aWE8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS

ZWNOdW0+MjA8L1JlY051bT48RGlzcGxheVRleHQ+KEJoYXRpYSwgQmFpbiBldCBhbC4gMjAxOCk8

L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjA8L3JlYy1udW1iZXI+PGZvcmVpZ24t

a2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRkZHN0

ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjAxOCI+MjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVm

LXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48

YXV0aG9ycz48YXV0aG9yPkJoYXRpYSwgSy4gUC48L2F1dGhvcj48YXV0aG9yPkJhaW4sIFAuPC9h

dXRob3I+PGF1dGhvcj5CYWphaiwgTi48L2F1dGhvcj48YXV0aG9yPkVsYmxlLCBSLiBKLjwvYXV0

aG9yPjxhdXRob3I+SGFsbGV0dCwgTS48L2F1dGhvcj48YXV0aG9yPkxvdWlzLCBFLiBELjwvYXV0

aG9yPjxhdXRob3I+UmFldGhqZW4sIEouPC9hdXRob3I+PGF1dGhvcj5TdGFtZWxvdSwgTS48L2F1

dGhvcj48YXV0aG9yPlRlc3RhLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+RGV1c2NobCwgRy48L2F1

dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Tb2JlbGwgRGVwYXJ0

bWVudCBvZiBNb3RvciBOZXVyb3NjaWVuY2UgYW5kIE1vdmVtZW50IERpc29yZGVycywgVW5pdmVy

c2l0eSBDb2xsZWdlIExvbmRvbiAoVUNMKSBJbnN0aXR1dGUgb2YgTmV1cm9sb2d5LCBMb25kb24s

IFVuaXRlZCBLaW5nZG9tLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb3NjaWVuY2VzLCBDaGFyaW5n

IENyb3NzIEhvc3BpdGFsLCBJbXBlcmlhbCBDb2xsZWdlIExvbmRvbiwgVW5pdGVkIEtpbmdkb20u

JiN4RDtEaXZpc2lvbiBvZiBOZXVyb2xvZ3ksIE5vdHRpbmdoYW0gVW5pdmVyc2l0eSBIb3NwaXRh

bCwgTm90dGluZ2hhbSwgVW5pdGVkIEtpbmdkb20uJiN4RDtTb3V0aGVybiBJbGxpbm9pcyBVbml2

ZXJzaXR5IFNjaG9vbCBvZiBNZWRpY2luZSwgU3ByaW5nZmllbGQsIElsbGlub2lzLCBVU0EuJiN4

RDtIdW1hbiBNb3RvciBDb250cm9sIFNlY3Rpb24sIE5hdGlvbmFsIEluc3RpdHV0ZSBvZiBOZXVy

b2xvZ2ljYWwgRGlzb3JkZXJzIGFuZCBTdHJva2UsIE5JSCwgQmV0aGVzZGEsIE1hcnlsYW5kLCBV

U0EuJiN4RDtEaXZpc2lvbiBvZiBNb3ZlbWVudCBEaXNvcmRlcnMsIERlcGFydG1lbnQgb2YgTmV1

cm9sb2d5LCBZYWxlIFNjaG9vbCBvZiBNZWRpY2luZSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2

ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGFuZCBEZXBhcnRtZW50IG9mIENocm9uaWMgRGlzZWFzZSBF

cGlkZW1pb2xvZ3ksIFlhbGUgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIFlhbGUgVW5pdmVyc2l0

eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIFVuaXZlcnNpdGF0c2tsaW5pa3VtIFNjaGxlc3dpZy1Ib2xzdGVpbiwgS2llbCBDYW1wdXMs

IENocmlzdGlhbiBBbGJyZWNodHMgVW5pdmVyc2l0eSBLaWVsLCBLaWVsLCBHZXJtYW55LiYjeEQ7

RGVwYXJ0bWVudCBvZiBOZXVyb2xvZ3ksIFBoaWxpcHBzIFVuaXZlcnNpdHksIE1hcmJ1cmcsIEdl

cm1hbnk7IERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBBdHRpa29uIEhvc3BpdGFsLCBVbml2ZXJz

aXR5IG9mIEF0aGVucywgQXRoZW5zLCBHcmVlY2UuJiN4RDtWaXJnaW5pYSBDb21tb253ZWFsdGgg

VW5pdmVyc2l0eSwgUmljaG1vbmQsIFZpcmdpbmlhLCBVU0EuPC9hdXRoLWFkZHJlc3M+PHRpdGxl

cz48dGl0bGU+Q29uc2Vuc3VzIFN0YXRlbWVudCBvbiB0aGUgY2xhc3NpZmljYXRpb24gb2YgdHJl

bW9ycy4gZnJvbSB0aGUgdGFzayBmb3JjZSBvbiB0cmVtb3Igb2YgdGhlIEludGVybmF0aW9uYWwg

UGFya2luc29uIGFuZCBNb3ZlbWVudCBEaXNvcmRlciBTb2NpZXR5PC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPk1vdiBEaXNvcmQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk1vdmVtZW50IGRp

c29yZGVycyA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIE1vdmVtZW50IERpc29yZGVyIFNvY2ll

dHk8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Nb3YgRGlzb3Jk

PC9mdWxsLXRpdGxlPjxhYmJyLTE+TW92ZW1lbnQgZGlzb3JkZXJzIDogb2ZmaWNpYWwgam91cm5h

bCBvZiB0aGUgTW92ZW1lbnQgRGlzb3JkZXIgU29jaWV0eTwvYWJici0xPjwvcGVyaW9kaWNhbD48

YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TW92IERpc29yZDwvZnVsbC10aXRsZT48YWJici0x

Pk1vdmVtZW50IGRpc29yZGVycyA6IG9mZmljaWFsIGpvdXJuYWwgb2YgdGhlIE1vdmVtZW50IERp

c29yZGVyIFNvY2lldHk8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43NS04NzwvcGFn

ZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0aW9uPjIwMTcvMTIv

MDI8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPipDb25zZW5zdXM8L2tleXdvcmQ+PGtleXdv

cmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPipJbnRlcm5hdGlvbmFsIENvb3BlcmF0aW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FRExJTkUvc3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwv

a2V5d29yZD48a2V5d29yZD5Tb2NpZXRpZXMsIE1lZGljYWwvKnN0YW5kYXJkczwva2V5d29yZD48

a2V5d29yZD5UcmVtb3IvKmNsYXNzaWZpY2F0aW9uLypkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+KmNsYXNzaWZpY2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipkaWFnbm9zdGljIGF4ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+KmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPip0cmVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+KnRyZW1vciBzeW5kcm9tZXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxODwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjA4ODUtMzE4NTwvaXNibj48YWNjZXNzaW9uLW51bT4yOTE5MzM1OTwvYWNj

ZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTI+UE1DNjUzMDU1MjwvY3VzdG9tMj48Y3Vz

dG9tNj5OSUhNUzEwMjkzMjI8L2N1c3RvbTY+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEw

MDIvbWRzLjI3MTIxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXBy

b3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1

YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Bhatia, Bain et al. 2018):Isolated tremor syndrome characterised by bilateral upper-limb action tremorDuration of at least 3 yearsWith or without tremor in other locations (e.g., head, voice, or lower limbs)Absence of other neurologic signs, such as dystonia, ataxia, and parkinsonism.Depending on the symptom severity, persons living with ET may experience significant functional and psychological disability. The symptoms may interfere with the ability to perform activities of daily living (ADL) such as drinking, dressing, writing and drawing, and shaving. Patients may be forced to retire prematurely.ET may also be associated with other neurological signs, such as cognitive and sensory impairments, mild ataxia, or impaired memory PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXViZW5iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFs

bGV0dCAyMDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4

ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MDYzIj4yNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGF1YmVuYmVyZ2VyLCBELjwvYXV0aG9yPjxhdXRo

b3I+SGFsbGV0dCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5Gcm9tIHRoZSBDbGluaWNhbCBUcmlhbHMgVW5pdCwgT2ZmaWNlIG9mIHRoZSBDbGluaWNh

bCBEaXJlY3RvciAoRC5ILiksIGFuZCB0aGUgSHVtYW4gTW90b3IgQ29udHJvbCBTZWN0aW9uLCBN

ZWRpY2FsIE5ldXJvbG9neSBCcmFuY2ggKE0uSC4pLCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1

cm9sb2dpY2FsIERpc29yZGVycyBhbmQgU3Ryb2tlIEludHJhbXVyYWwgUmVzZWFyY2ggUHJvZ3Jh

bSwgTmF0aW9uYWwgSW5zdGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRC48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5Fc3NlbnRpYWwgVHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmds

YW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5UaGUgTmV3IEVuZ2xh

bmQgam91cm5hbCBvZiBtZWRpY2luZTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl

cz4xODAyLTE4MTA8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xOTwvbnVtYmVy

PjxlZGl0aW9uPjIwMTgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFibGF0aW9u

IFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWRyZW5lcmdpYyBiZXRhLUFudGFnb25pc3Rz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRpY29udnVsc2FudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNvbnRyYWluZGljYXRpb25zLCBEcnVnPC9rZXl3

b3JkPjxrZXl3b3JkPkRlZXAgQnJhaW4gU3RpbXVsYXRpb24vYWR2ZXJzZSBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVz

c2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzL2RydWcgdGhlcmFweS8qdGhlcmFweTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJh

Y3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmltaWRvbmUvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByb3ByYW5vbG9sL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5UaGFsYW11cy9zdXJnZXJ5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTA8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk3

NDIzNzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDU2L05FSk1jcDE3MDc5Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdl

PmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXViZW5iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFs

bGV0dCAyMDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4

ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MDYzIj4yNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGF1YmVuYmVyZ2VyLCBELjwvYXV0aG9yPjxhdXRo

b3I+SGFsbGV0dCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5Gcm9tIHRoZSBDbGluaWNhbCBUcmlhbHMgVW5pdCwgT2ZmaWNlIG9mIHRoZSBDbGluaWNh

bCBEaXJlY3RvciAoRC5ILiksIGFuZCB0aGUgSHVtYW4gTW90b3IgQ29udHJvbCBTZWN0aW9uLCBN

ZWRpY2FsIE5ldXJvbG9neSBCcmFuY2ggKE0uSC4pLCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1

cm9sb2dpY2FsIERpc29yZGVycyBhbmQgU3Ryb2tlIEludHJhbXVyYWwgUmVzZWFyY2ggUHJvZ3Jh

bSwgTmF0aW9uYWwgSW5zdGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRC48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5Fc3NlbnRpYWwgVHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmds

YW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5UaGUgTmV3IEVuZ2xh

bmQgam91cm5hbCBvZiBtZWRpY2luZTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl

cz4xODAyLTE4MTA8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xOTwvbnVtYmVy

PjxlZGl0aW9uPjIwMTgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFibGF0aW9u

IFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWRyZW5lcmdpYyBiZXRhLUFudGFnb25pc3Rz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRpY29udnVsc2FudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNvbnRyYWluZGljYXRpb25zLCBEcnVnPC9rZXl3

b3JkPjxrZXl3b3JkPkRlZXAgQnJhaW4gU3RpbXVsYXRpb24vYWR2ZXJzZSBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVz

c2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzL2RydWcgdGhlcmFweS8qdGhlcmFweTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJh

Y3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmltaWRvbmUvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByb3ByYW5vbG9sL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5UaGFsYW11cy9zdXJnZXJ5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTA8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk3

NDIzNzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDU2L05FSk1jcDE3MDc5Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdl

PmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Haubenberger and Hallett 2018). Patients may also develop sleep disturbances, depressive symptoms, and dementia. The gradually worsening tremor together with these co-morbidities result in a functional decline, as well as increased frailty. ET is among the most prevalent movement disorders ADDIN EN.CITE <EndNote><Cite><Author>Louis</Author><Year>2010</Year><RecNum>19</RecNum><DisplayText>(Louis and Ferreira 2010)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="p5z2edva7sfr05e2de7xf0012vtddstz5ae9" timestamp="1582766000">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Louis, E. D.</author><author>Ferreira, J. J.</author></authors></contributors><auth-address>GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. EDL2@columbia.edu</auth-address><titles><title>How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor</title><secondary-title>Mov Disord</secondary-title><alt-title>Movement disorders : official journal of the Movement Disorder Society</alt-title></titles><periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></periodical><alt-periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></alt-periodical><pages>534-41</pages><volume>25</volume><number>5</number><edition>2010/02/23</edition><keywords><keyword>Age Factors</keyword><keyword>Community Health Planning</keyword><keyword>Essential Tremor/diagnosis/*epidemiology</keyword><keyword>Ethnic Groups</keyword><keyword>Europe/epidemiology</keyword><keyword>*Global Health</keyword><keyword>Humans</keyword><keyword>Prevalence</keyword><keyword>Quality of Life</keyword><keyword>Sex Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>0885-3185</isbn><accession-num>20175185</accession-num><urls></urls><electronic-resource-num>10.1002/mds.22838</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Louis and Ferreira 2010), and increases markedly with age, and exponentially with advanced age PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3VpczwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl

Y051bT40MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTG91aXMgMjAxOSk8L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+NDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRkZHN0ejVhZTkiIHRpbWVzdGFt

cD0iMTU4NDkyOTM4MSI+NDE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkxvdWlzLCBFLiBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkRpdmlzaW9uIG9mIE1vdmVtZW50IERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIFlhbGUgU2Nob29sIG9mIE1lZGljaW5lLCBZYWxlIFVuaXZlcnNpdHksIE5ldyBIYXZlbiwg

Q29ubmVjdGljdXQsIFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVkdS4mI3hEO0RlcGFydG1lbnQgb2Yg

Q2hyb25pYyBEaXNlYXNlIEVwaWRlbWlvbG9neSwgWWFsZSBTY2hvb2wgb2YgUHVibGljIEhlYWx0

aCwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGVsYW4ubG91

aXNAeWFsZS5lZHUuJiN4RDtDZW50ZXIgZm9yIE5ldXJvZXBpZGVtaW9sb2d5IGFuZCBDbGluaWNh

bCBOZXVyb2xvZ2ljYWwgUmVzZWFyY2gsIFlhbGUgU2Nob29sIG9mIE1lZGljaW5lLCBZYWxlIFVu

aXZlcnNpdHksIE5ldyBIYXZlbiwgQ29ubmVjdGljdXQsIFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVk

dS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgUm9sZXMgb2YgQWdlIGFuZCBBZ2lu

ZyBpbiBFc3NlbnRpYWwgVHJlbW9yOiBBbiBFcGlkZW1pb2xvZ2ljYWwgUGVyc3BlY3RpdmU8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48

YWx0LXRpdGxlPk5ldXJvZXBpZGVtaW9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVy

b2VwaWRlbWlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb2VwaWRlbWlv

bG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjExMS0xMTg8L3BhZ2VzPjx2b2x1

bWU+NTI8L3ZvbHVtZT48bnVtYmVyPjEtMjwvbnVtYmVyPjxlZGl0aW9uPjIwMTkvMDEvMTA8L2Vk

aXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBGYWN0

b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBvZiBPbnNldDwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFn

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzLyplcGlkZW1p

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5j

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QcmV2YWxl

bmNlPC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+

PGtleXdvcmQ+KkFkdmFuY2VkIGFnZTwva2V5d29yZD48a2V5d29yZD4qQWdlPC9rZXl3b3JkPjxr

ZXl3b3JkPipBZ2Ugb2Ygb25zZXQ8L2tleXdvcmQ+PGtleXdvcmQ+KkFnaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPipFcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkVzc2VudGlhbCB0cmVtb3I8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxOTwveWVhcj48L2RhdGVzPjxpc2Ju

PjAyNTEtNTM1MDwvaXNibj48YWNjZXNzaW9uLW51bT4zMDYyNTQ3MjwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAwNDkyODMxPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkxvdWlzPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVjTnVt

PjQxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1r

ZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2dGRkc3R6

NWFlOSIgdGltZXN0YW1wPSIxNTg0OTI5MzgxIj40MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+TG91aXMsIEUuIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgTW92ZW1lbnQgRGlzb3JkZXJzLCBEZXBhcnRt

ZW50IG9mIE5ldXJvbG9neSwgWWFsZSBTY2hvb2wgb2YgTWVkaWNpbmUsIFlhbGUgVW5pdmVyc2l0

eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLCBlbGFuLmxvdWlzQHlhbGUuZWR1LiYjeEQ7

RGVwYXJ0bWVudCBvZiBDaHJvbmljIERpc2Vhc2UgRXBpZGVtaW9sb2d5LCBZYWxlIFNjaG9vbCBv

ZiBQdWJsaWMgSGVhbHRoLCBZYWxlIFVuaXZlcnNpdHksIE5ldyBIYXZlbiwgQ29ubmVjdGljdXQs

IFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVkdS4mI3hEO0NlbnRlciBmb3IgTmV1cm9lcGlkZW1pb2xv

Z3kgYW5kIENsaW5pY2FsIE5ldXJvbG9naWNhbCBSZXNlYXJjaCwgWWFsZSBTY2hvb2wgb2YgTWVk

aWNpbmUsIFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLCBlbGFu

LmxvdWlzQHlhbGUuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBSb2xlcyBv

ZiBBZ2UgYW5kIEFnaW5nIGluIEVzc2VudGlhbCBUcmVtb3I6IEFuIEVwaWRlbWlvbG9naWNhbCBQ

ZXJzcGVjdGl2ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvZnVsbC10aXRs

ZT48YWJici0xPk5ldXJvZXBpZGVtaW9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvZnVsbC10aXRsZT48YWJici0x

Pk5ldXJvZXBpZGVtaW9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MTExLTEx

ODwvcGFnZXM+PHZvbHVtZT41Mjwvdm9sdW1lPjxudW1iZXI+MS0yPC9udW1iZXI+PGVkaXRpb24+

MjAxOS8wMS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdv

cmQ+PGtleXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+RXNzZW50aWFsIFRyZW1vci9kaWFn

bm9zaXMvKmVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJ

bmRleDwva2V5d29yZD48a2V5d29yZD4qQWR2YW5jZWQgYWdlPC9rZXl3b3JkPjxrZXl3b3JkPipB

Z2U8L2tleXdvcmQ+PGtleXdvcmQ+KkFnZSBvZiBvbnNldDwva2V5d29yZD48a2V5d29yZD4qQWdp

bmc8L2tleXdvcmQ+PGtleXdvcmQ+KkVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD4qRXNz

ZW50aWFsIHRyZW1vcjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE5PC95ZWFy

PjwvZGF0ZXM+PGlzYm4+MDI1MS01MzUwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjMwNjI1NDcyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE1

OS8wMDA0OTI4MzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TG91aXM8L0F1dGhvcj48WWVhcj4yMDE5

PC9ZZWFyPjxSZWNOdW0+NDE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQxPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRl

N3hmMDAxMnZ0ZGRzdHo1YWU5IiB0aW1lc3RhbXA9IjE1ODQ5MjkzODEiPjQxPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3VpcywgRS4gRC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBNb3ZlbWVudCBEaXNv

cmRlcnMsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBZYWxlIFNjaG9vbCBvZiBNZWRpY2luZSwg

WWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGVsYW4ubG91aXNA

eWFsZS5lZHUuJiN4RDtEZXBhcnRtZW50IG9mIENocm9uaWMgRGlzZWFzZSBFcGlkZW1pb2xvZ3ks

IFlhbGUgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVu

LCBDb25uZWN0aWN1dCwgVVNBLCBlbGFuLmxvdWlzQHlhbGUuZWR1LiYjeEQ7Q2VudGVyIGZvciBO

ZXVyb2VwaWRlbWlvbG9neSBhbmQgQ2xpbmljYWwgTmV1cm9sb2dpY2FsIFJlc2VhcmNoLCBZYWxl

IFNjaG9vbCBvZiBNZWRpY2luZSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3Rp

Y3V0LCBVU0EsIGVsYW4ubG91aXNAeWFsZS5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIFJvbGVzIG9mIEFnZSBhbmQgQWdpbmcgaW4gRXNzZW50aWFsIFRyZW1vcjogQW4gRXBp

ZGVtaW9sb2dpY2FsIFBlcnNwZWN0aXZlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvZXBp

ZGVtaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvZXBpZGVtaW9s

b2d5PC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9lcGlkZW1pb2xvZ3k8L2FiYnItMT48L3Blcmlv

ZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvZXBpZGVtaW9sb2d5PC9mdWxs

LXRpdGxlPjxhYmJyLTE+TmV1cm9lcGlkZW1pb2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2Fs

PjxwYWdlcz4xMTEtMTE4PC9wYWdlcz48dm9sdW1lPjUyPC92b2x1bWU+PG51bWJlcj4xLTI8L251

bWJlcj48ZWRpdGlvbj4yMDE5LzAxLzEwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVs

dDwva2V5d29yZD48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BZ2Ugb2Yg

T25zZXQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBh

bmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5Fc3NlbnRp

YWwgVHJlbW9yL2RpYWdub3Npcy8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5JbmNpZGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0

eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPipBZHZhbmNlZCBhZ2U8L2tleXdv

cmQ+PGtleXdvcmQ+KkFnZTwva2V5d29yZD48a2V5d29yZD4qQWdlIG9mIG9uc2V0PC9rZXl3b3Jk

PjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48a2V5d29yZD4qRXBpZGVtaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPipFc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTk8L3llYXI+PC9kYXRlcz48aXNibj4wMjUxLTUzNTA8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MzA2MjU0NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTU5LzAwMDQ5MjgzMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90

ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3Vh

Z2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3VpczwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl

Y051bT40MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTG91aXMgMjAxOSk8L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+NDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRkZHN0ejVhZTkiIHRpbWVzdGFt

cD0iMTU4NDkyOTM4MSI+NDE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkxvdWlzLCBFLiBELjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy

ZXNzPkRpdmlzaW9uIG9mIE1vdmVtZW50IERpc29yZGVycywgRGVwYXJ0bWVudCBvZiBOZXVyb2xv

Z3ksIFlhbGUgU2Nob29sIG9mIE1lZGljaW5lLCBZYWxlIFVuaXZlcnNpdHksIE5ldyBIYXZlbiwg

Q29ubmVjdGljdXQsIFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVkdS4mI3hEO0RlcGFydG1lbnQgb2Yg

Q2hyb25pYyBEaXNlYXNlIEVwaWRlbWlvbG9neSwgWWFsZSBTY2hvb2wgb2YgUHVibGljIEhlYWx0

aCwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGVsYW4ubG91

aXNAeWFsZS5lZHUuJiN4RDtDZW50ZXIgZm9yIE5ldXJvZXBpZGVtaW9sb2d5IGFuZCBDbGluaWNh

bCBOZXVyb2xvZ2ljYWwgUmVzZWFyY2gsIFlhbGUgU2Nob29sIG9mIE1lZGljaW5lLCBZYWxlIFVu

aXZlcnNpdHksIE5ldyBIYXZlbiwgQ29ubmVjdGljdXQsIFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVk

dS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgUm9sZXMgb2YgQWdlIGFuZCBBZ2lu

ZyBpbiBFc3NlbnRpYWwgVHJlbW9yOiBBbiBFcGlkZW1pb2xvZ2ljYWwgUGVyc3BlY3RpdmU8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L3NlY29uZGFyeS10aXRsZT48

YWx0LXRpdGxlPk5ldXJvZXBpZGVtaW9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVy

b2VwaWRlbWlvbG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb2VwaWRlbWlv

bG9neTwvYWJici0xPjwvYWx0LXBlcmlvZGljYWw+PHBhZ2VzPjExMS0xMTg8L3BhZ2VzPjx2b2x1

bWU+NTI8L3ZvbHVtZT48bnVtYmVyPjEtMjwvbnVtYmVyPjxlZGl0aW9uPjIwMTkvMDEvMTA8L2Vk

aXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBGYWN0

b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZSBvZiBPbnNldDwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3JkPkFn

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzLyplcGlkZW1p

b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lkZW5j

ZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QcmV2YWxl

bmNlPC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+

PGtleXdvcmQ+KkFkdmFuY2VkIGFnZTwva2V5d29yZD48a2V5d29yZD4qQWdlPC9rZXl3b3JkPjxr

ZXl3b3JkPipBZ2Ugb2Ygb25zZXQ8L2tleXdvcmQ+PGtleXdvcmQ+KkFnaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPipFcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KkVzc2VudGlhbCB0cmVtb3I8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxOTwveWVhcj48L2RhdGVzPjxpc2Ju

PjAyNTEtNTM1MDwvaXNibj48YWNjZXNzaW9uLW51bT4zMDYyNTQ3MjwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAwNDkyODMxPC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPkxvdWlzPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVjTnVt

PjQxPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj40MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1r

ZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2dGRkc3R6

NWFlOSIgdGltZXN0YW1wPSIxNTg0OTI5MzgxIj40MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYt

dHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxh

dXRob3JzPjxhdXRob3I+TG91aXMsIEUuIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjxhdXRoLWFkZHJlc3M+RGl2aXNpb24gb2YgTW92ZW1lbnQgRGlzb3JkZXJzLCBEZXBhcnRt

ZW50IG9mIE5ldXJvbG9neSwgWWFsZSBTY2hvb2wgb2YgTWVkaWNpbmUsIFlhbGUgVW5pdmVyc2l0

eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLCBlbGFuLmxvdWlzQHlhbGUuZWR1LiYjeEQ7

RGVwYXJ0bWVudCBvZiBDaHJvbmljIERpc2Vhc2UgRXBpZGVtaW9sb2d5LCBZYWxlIFNjaG9vbCBv

ZiBQdWJsaWMgSGVhbHRoLCBZYWxlIFVuaXZlcnNpdHksIE5ldyBIYXZlbiwgQ29ubmVjdGljdXQs

IFVTQSwgZWxhbi5sb3Vpc0B5YWxlLmVkdS4mI3hEO0NlbnRlciBmb3IgTmV1cm9lcGlkZW1pb2xv

Z3kgYW5kIENsaW5pY2FsIE5ldXJvbG9naWNhbCBSZXNlYXJjaCwgWWFsZSBTY2hvb2wgb2YgTWVk

aWNpbmUsIFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVuLCBDb25uZWN0aWN1dCwgVVNBLCBlbGFu

LmxvdWlzQHlhbGUuZWR1LjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRoZSBSb2xlcyBv

ZiBBZ2UgYW5kIEFnaW5nIGluIEVzc2VudGlhbCBUcmVtb3I6IEFuIEVwaWRlbWlvbG9naWNhbCBQ

ZXJzcGVjdGl2ZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvc2Vj

b25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TmV1cm9lcGlkZW1pb2xvZ3k8L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvZnVsbC10aXRs

ZT48YWJici0xPk5ldXJvZXBpZGVtaW9sb2d5PC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwvZnVsbC10aXRsZT48YWJici0x

Pk5ldXJvZXBpZGVtaW9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MTExLTEx

ODwvcGFnZXM+PHZvbHVtZT41Mjwvdm9sdW1lPjxudW1iZXI+MS0yPC9udW1iZXI+PGVkaXRpb24+

MjAxOS8wMS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtl

eXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIG9mIE9uc2V0PC9rZXl3b3Jk

PjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdv

cmQ+PGtleXdvcmQ+QWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+RXNzZW50aWFsIFRyZW1vci9kaWFn

bm9zaXMvKmVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl

eXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPlByZXZhbGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJ

bmRleDwva2V5d29yZD48a2V5d29yZD4qQWR2YW5jZWQgYWdlPC9rZXl3b3JkPjxrZXl3b3JkPipB

Z2U8L2tleXdvcmQ+PGtleXdvcmQ+KkFnZSBvZiBvbnNldDwva2V5d29yZD48a2V5d29yZD4qQWdp

bmc8L2tleXdvcmQ+PGtleXdvcmQ+KkVwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD4qRXNz

ZW50aWFsIHRyZW1vcjwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE5PC95ZWFy

PjwvZGF0ZXM+PGlzYm4+MDI1MS01MzUwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjMwNjI1NDcyPC9h

Y2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE1

OS8wMDA0OTI4MzE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TG91aXM8L0F1dGhvcj48WWVhcj4yMDE5

PC9ZZWFyPjxSZWNOdW0+NDE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjQxPC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRl

N3hmMDAxMnZ0ZGRzdHo1YWU5IiB0aW1lc3RhbXA9IjE1ODQ5MjkzODEiPjQxPC9rZXk+PC9mb3Jl

aWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxj

b250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Mb3VpcywgRS4gRC48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBNb3ZlbWVudCBEaXNv

cmRlcnMsIERlcGFydG1lbnQgb2YgTmV1cm9sb2d5LCBZYWxlIFNjaG9vbCBvZiBNZWRpY2luZSwg

WWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3RpY3V0LCBVU0EsIGVsYW4ubG91aXNA

eWFsZS5lZHUuJiN4RDtEZXBhcnRtZW50IG9mIENocm9uaWMgRGlzZWFzZSBFcGlkZW1pb2xvZ3ks

IFlhbGUgU2Nob29sIG9mIFB1YmxpYyBIZWFsdGgsIFlhbGUgVW5pdmVyc2l0eSwgTmV3IEhhdmVu

LCBDb25uZWN0aWN1dCwgVVNBLCBlbGFuLmxvdWlzQHlhbGUuZWR1LiYjeEQ7Q2VudGVyIGZvciBO

ZXVyb2VwaWRlbWlvbG9neSBhbmQgQ2xpbmljYWwgTmV1cm9sb2dpY2FsIFJlc2VhcmNoLCBZYWxl

IFNjaG9vbCBvZiBNZWRpY2luZSwgWWFsZSBVbml2ZXJzaXR5LCBOZXcgSGF2ZW4sIENvbm5lY3Rp

Y3V0LCBVU0EsIGVsYW4ubG91aXNAeWFsZS5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIFJvbGVzIG9mIEFnZSBhbmQgQWdpbmcgaW4gRXNzZW50aWFsIFRyZW1vcjogQW4gRXBp

ZGVtaW9sb2dpY2FsIFBlcnNwZWN0aXZlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5ldXJvZXBp

ZGVtaW9sb2d5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5OZXVyb2VwaWRlbWlvbG9neTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvZXBpZGVtaW9s

b2d5PC9mdWxsLXRpdGxlPjxhYmJyLTE+TmV1cm9lcGlkZW1pb2xvZ3k8L2FiYnItMT48L3Blcmlv

ZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5ldXJvZXBpZGVtaW9sb2d5PC9mdWxs

LXRpdGxlPjxhYmJyLTE+TmV1cm9lcGlkZW1pb2xvZ3k8L2FiYnItMT48L2FsdC1wZXJpb2RpY2Fs

PjxwYWdlcz4xMTEtMTE4PC9wYWdlcz48dm9sdW1lPjUyPC92b2x1bWU+PG51bWJlcj4xLTI8L251

bWJlcj48ZWRpdGlvbj4yMDE5LzAxLzEwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVs

dDwva2V5d29yZD48a2V5d29yZD5BZ2UgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5BZ2Ugb2Yg

T25zZXQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLCA4MCBh

bmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BZ2luZzwva2V5d29yZD48a2V5d29yZD5Fc3NlbnRp

YWwgVHJlbW9yL2RpYWdub3Npcy8qZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFu

czwva2V5d29yZD48a2V5d29yZD5JbmNpZGVuY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJldmFsZW5jZTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0

eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPipBZHZhbmNlZCBhZ2U8L2tleXdv

cmQ+PGtleXdvcmQ+KkFnZTwva2V5d29yZD48a2V5d29yZD4qQWdlIG9mIG9uc2V0PC9rZXl3b3Jk

PjxrZXl3b3JkPipBZ2luZzwva2V5d29yZD48a2V5d29yZD4qRXBpZGVtaW9sb2d5PC9rZXl3b3Jk

PjxrZXl3b3JkPipFc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTk8L3llYXI+PC9kYXRlcz48aXNibj4wMjUxLTUzNTA8L2lzYm4+PGFjY2Vzc2lvbi1u

dW0+MzA2MjU0NzI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTU5LzAwMDQ5MjgzMTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90

ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3Vh

Z2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA (Louis 2019). A 2010 meta-analysis of population-based prevalence studies found worldwide prevalence to be 4.6% for ages ≥65 years, increasing to be as high as 22% for ages ≥95 years ADDIN EN.CITE <EndNote><Cite><Author>Louis</Author><Year>2010</Year><RecNum>19</RecNum><DisplayText>(Louis and Ferreira 2010)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="p5z2edva7sfr05e2de7xf0012vtddstz5ae9" timestamp="1582766000">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Louis, E. D.</author><author>Ferreira, J. J.</author></authors></contributors><auth-address>GH Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA. EDL2@columbia.edu</auth-address><titles><title>How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor</title><secondary-title>Mov Disord</secondary-title><alt-title>Movement disorders : official journal of the Movement Disorder Society</alt-title></titles><periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></periodical><alt-periodical><full-title>Mov Disord</full-title><abbr-1>Movement disorders : official journal of the Movement Disorder Society</abbr-1></alt-periodical><pages>534-41</pages><volume>25</volume><number>5</number><edition>2010/02/23</edition><keywords><keyword>Age Factors</keyword><keyword>Community Health Planning</keyword><keyword>Essential Tremor/diagnosis/*epidemiology</keyword><keyword>Ethnic Groups</keyword><keyword>Europe/epidemiology</keyword><keyword>*Global Health</keyword><keyword>Humans</keyword><keyword>Prevalence</keyword><keyword>Quality of Life</keyword><keyword>Sex Factors</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr 15</date></pub-dates></dates><isbn>0885-3185</isbn><accession-num>20175185</accession-num><urls></urls><electronic-resource-num>10.1002/mds.22838</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Louis and Ferreira 2010). Despite this high prevalence, the precise number of cases of ET is difficult to determine, since the variable clinical presentation often leads to misdiagnosis. The application form provided prevalence estimates from the literature in REF _Ref35341434 \h Table 1. To date, no estimates are available for Australia.Expert opinion provided in the application form estimated that of the Deep Brain Stimulation (DBS) procedures performed in Australia within a private hospital setting ( REF _Ref35342198 \h Table 3) approximately 25% are used to treat severe disabling ET (N=65), with the remainder performed for Parkinson’s disease or dystonia.Table SEQ Table \* ARABIC 1Prevalence estimates of ETAuthorYearCountryStudy designAgesPrevalence estimateEliasen2019DenmarkPopulation-based screening followed by clinical examination in randomly selected subgroup≥40 years3.1%Louis2014USAAnalysis of 3 population-based prevalence studiesTotal population2.2%Bharucha1988IndiaDoor to door, community-based surveyTotal population1.7%Oh2014South KoreaProspective cohort studyelderly persons ≥65 years3.6%Yao2015ChinaEpidemiological survey≥45 years3.6%≥75 years4.3%Dogu2003TurkeyScreening surveys and subsequent examinations with neurologists≥40 years4.0%Seijo Martinez 2013SpainDoor-to-door evaluations and subsequent neurological examinations≥65 years8.4%Source: Table 3, p32 of the application formET = essential tremorPASC noted that currently, there is no Australian prevalence data available to estimate the size of the proposed population, using an epidemiological approach. PASC noted the applicant estimated the population size using a market-share approach, but did not include the number of deep brain stimulation (DBS) procedures performed in public hospitals, which would underestimate the size of the proposed population. PASC considered that the utilisation estimates would need to be adequately explained in the assessment phase.The applicant agreed that an estimation of utilisation of DBS for ET in the public hospital setting will be required and will be presented in the Applicant Developed Assessment Report. RationaleThe point of entry for care is typically a general practitioner (GP), who makes a diagnosis or referral to a neurologist based on a comprehensive patient history review and neurologic examination. Routine laboratory testing to exclude abnormalities that can carry a predisposition to enhanced physiologic tremor should include thyrotropin, electrolyte levels, and liver and kidney function measurements PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXViZW5iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFs

bGV0dCAyMDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4

ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MDYzIj4yNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGF1YmVuYmVyZ2VyLCBELjwvYXV0aG9yPjxhdXRo

b3I+SGFsbGV0dCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5Gcm9tIHRoZSBDbGluaWNhbCBUcmlhbHMgVW5pdCwgT2ZmaWNlIG9mIHRoZSBDbGluaWNh

bCBEaXJlY3RvciAoRC5ILiksIGFuZCB0aGUgSHVtYW4gTW90b3IgQ29udHJvbCBTZWN0aW9uLCBN

ZWRpY2FsIE5ldXJvbG9neSBCcmFuY2ggKE0uSC4pLCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1

cm9sb2dpY2FsIERpc29yZGVycyBhbmQgU3Ryb2tlIEludHJhbXVyYWwgUmVzZWFyY2ggUHJvZ3Jh

bSwgTmF0aW9uYWwgSW5zdGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRC48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5Fc3NlbnRpYWwgVHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmds

YW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5UaGUgTmV3IEVuZ2xh

bmQgam91cm5hbCBvZiBtZWRpY2luZTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl

cz4xODAyLTE4MTA8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xOTwvbnVtYmVy

PjxlZGl0aW9uPjIwMTgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFibGF0aW9u

IFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWRyZW5lcmdpYyBiZXRhLUFudGFnb25pc3Rz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRpY29udnVsc2FudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNvbnRyYWluZGljYXRpb25zLCBEcnVnPC9rZXl3

b3JkPjxrZXl3b3JkPkRlZXAgQnJhaW4gU3RpbXVsYXRpb24vYWR2ZXJzZSBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVz

c2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzL2RydWcgdGhlcmFweS8qdGhlcmFweTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJh

Y3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmltaWRvbmUvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByb3ByYW5vbG9sL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5UaGFsYW11cy9zdXJnZXJ5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTA8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk3

NDIzNzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDU2L05FSk1jcDE3MDc5Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdl

PmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXViZW5iZXJnZXI8L0F1dGhvcj48WWVhcj4yMDE4PC9Z

ZWFyPjxSZWNOdW0+MjQ8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFs

bGV0dCAyMDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDwvcmVjLW51bWJl

cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4

ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MDYzIj4yNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+SGF1YmVuYmVyZ2VyLCBELjwvYXV0aG9yPjxhdXRo

b3I+SGFsbGV0dCwgTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk

cmVzcz5Gcm9tIHRoZSBDbGluaWNhbCBUcmlhbHMgVW5pdCwgT2ZmaWNlIG9mIHRoZSBDbGluaWNh

bCBEaXJlY3RvciAoRC5ILiksIGFuZCB0aGUgSHVtYW4gTW90b3IgQ29udHJvbCBTZWN0aW9uLCBN

ZWRpY2FsIE5ldXJvbG9neSBCcmFuY2ggKE0uSC4pLCBOYXRpb25hbCBJbnN0aXR1dGUgb2YgTmV1

cm9sb2dpY2FsIERpc29yZGVycyBhbmQgU3Ryb2tlIEludHJhbXVyYWwgUmVzZWFyY2ggUHJvZ3Jh

bSwgTmF0aW9uYWwgSW5zdGl0dXRlcyBvZiBIZWFsdGgsIEJldGhlc2RhLCBNRC48L2F1dGgtYWRk

cmVzcz48dGl0bGVzPjx0aXRsZT5Fc3NlbnRpYWwgVHJlbW9yPC90aXRsZT48c2Vjb25kYXJ5LXRp

dGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmds

YW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5UaGUgTmV3IEVuZ2xh

bmQgam91cm5hbCBvZiBtZWRpY2luZTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdl

cz4xODAyLTE4MTA8L3BhZ2VzPjx2b2x1bWU+Mzc4PC92b2x1bWU+PG51bWJlcj4xOTwvbnVtYmVy

PjxlZGl0aW9uPjIwMTgvMDUvMTA8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFibGF0aW9u

IFRlY2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QWRyZW5lcmdpYyBiZXRhLUFudGFnb25pc3Rz

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRpY29udnVsc2FudHMvdGhlcmFw

ZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNvbnRyYWluZGljYXRpb25zLCBEcnVnPC9rZXl3

b3JkPjxrZXl3b3JkPkRlZXAgQnJhaW4gU3RpbXVsYXRpb24vYWR2ZXJzZSBlZmZlY3RzPC9rZXl3

b3JkPjxrZXl3b3JkPkRpYWdub3NpcywgRGlmZmVyZW50aWFsPC9rZXl3b3JkPjxrZXl3b3JkPkVz

c2VudGlhbCBUcmVtb3IvZGlhZ25vc2lzL2RydWcgdGhlcmFweS8qdGhlcmFweTwva2V5d29yZD48

a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UHJh

Y3RpY2UgR3VpZGVsaW5lcyBhcyBUb3BpYzwva2V5d29yZD48a2V5d29yZD5QcmltaWRvbmUvdGhl

cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlByb3ByYW5vbG9sL3RoZXJhcGV1dGljIHVz

ZTwva2V5d29yZD48a2V5d29yZD5UaGFsYW11cy9zdXJnZXJ5PC9rZXl3b3JkPjwva2V5d29yZHM+

PGRhdGVzPjx5ZWFyPjIwMTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTA8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjk3

NDIzNzY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51

bT4xMC4xMDU2L05FSk1jcDE3MDc5Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdl

PmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Haubenberger and Hallett 2018).Where tremor affects ADL or quality of life, pharmacological treatment is offered to control the symptoms as a first-line treatment. The two most commonly used drugs for ET are propranolol and primidone PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFybWE8L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxS

ZWNOdW0+MzA8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFsbGV0dCAy

MDE4LCBTaGFybWEgYW5kIFBhbmRleSAyMDIwKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj4zMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1

ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MTI2

Ij4zMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2hhcm1hLCBTLjwv

YXV0aG9yPjxhdXRob3I+UGFuZGV5LCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPk5ldXJvbG9neSwgR292aW5kIEJhbGxhYmggUGFudCBJbnN0aXR1dGUg

b2YgUG9zdGdyYWR1YXRlIE1lZGljYWwgRWR1Y2F0aW9uIGFuZCBSZXNlYXJjaCwgTmV3IERlbGhp

LCBJbmRpYS4mI3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9sb2dpY2FsIFNjaWVuY2Vz

LCBMb25kb24gSGVhbHRoIFNjaWVuY2VzIENlbnRyZSwgV2VzdGVybiBVbml2ZXJzaXR5LCBMb25k

b24sIE9udGFyaW8sIENhbmFkYS4mI3hEO05ldXJvbG9neSwgR292aW5kIEJhbGxhYmggUGFudCBJ

bnN0aXR1dGUgb2YgUG9zdGdyYWR1YXRlIE1lZGljYWwgRWR1Y2F0aW9uIGFuZCBSZXNlYXJjaCwg

TmV3IERlbGhpLCBJbmRpYSBzYW5qYXlzZ3BnaTIwMDJAeWFob28uY28uaW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+VHJlYXRtZW50IG9mIGVzc2VudGlhbCB0cmVtb3I6IGN1cnJlbnQg

c3RhdHVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBvc3RncmFkIE1lZCBKPC9zZWNvbmRhcnkt

dGl0bGU+PGFsdC10aXRsZT5Qb3N0Z3JhZHVhdGUgbWVkaWNhbCBqb3VybmFsPC9hbHQtdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UG9zdGdyYWQgTWVkIEo8L2Z1bGwtdGl0

bGU+PGFiYnItMT5Qb3N0Z3JhZHVhdGUgbWVkaWNhbCBqb3VybmFsPC9hYmJyLTE+PC9wZXJpb2Rp

Y2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qb3N0Z3JhZCBNZWQgSjwvZnVsbC10aXRs

ZT48YWJici0xPlBvc3RncmFkdWF0ZSBtZWRpY2FsIGpvdXJuYWw8L2FiYnItMT48L2FsdC1wZXJp

b2RpY2FsPjxwYWdlcz44NC05MzwvcGFnZXM+PHZvbHVtZT45Njwvdm9sdW1lPjxudW1iZXI+MTEz

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTkvMTAvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PmJldGEtIGJsb2NrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPmJvdHVsaW51bSB0b3hpbjwva2V5d29y

ZD48a2V5d29yZD5lc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPmZvY3VzZWQgdWx0

cmFzb3VuZDwva2V5d29yZD48a2V5d29yZD50aGFsYW1vdG9teSwgZGVlcCBicmFpbiBzdGltdWxh

dGlvbjwva2V5d29yZD48a2V5d29yZD50cmVhdG1lbnQgb2YgZXNzZW50aWFsIHRyZW1vcjogY3Vy

cmVudCBzdGF0dXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAyMDwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMzIt

NTQ3MzwvaXNibj48YWNjZXNzaW9uLW51bT4zMTU3NTczMDwvYWNjZXNzaW9uLW51bT48dXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMzYvcG9zdGdyYWRtZWRqLTIwMTkt

MTM2NjQ3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhdWJlbmJlcmdlcjwvQXV0aG9yPjxZZWFyPjIw

MTg8L1llYXI+PFJlY051bT4yNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUy

ZGU3eGYwMDEydnRkZHN0ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjA2MyI+MjQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhdWJlbmJlcmdlciwgRC48L2F1dGhvcj48

YXV0aG9yPkhhbGxldHQsIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+RnJvbSB0aGUgQ2xpbmljYWwgVHJpYWxzIFVuaXQsIE9mZmljZSBvZiB0aGUgQ2xp

bmljYWwgRGlyZWN0b3IgKEQuSC4pLCBhbmQgdGhlIEh1bWFuIE1vdG9yIENvbnRyb2wgU2VjdGlv

biwgTWVkaWNhbCBOZXVyb2xvZ3kgQnJhbmNoIChNLkguKSwgTmF0aW9uYWwgSW5zdGl0dXRlIG9m

IE5ldXJvbG9naWNhbCBEaXNvcmRlcnMgYW5kIFN0cm9rZSBJbnRyYW11cmFsIFJlc2VhcmNoIFBy

b2dyYW0sIE5hdGlvbmFsIEluc3RpdHV0ZXMgb2YgSGVhbHRoLCBCZXRoZXNkYSwgTUQuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXNzZW50aWFsIFRyZW1vcjwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRoZSBOZXcg

RW5nbGFuZCBqb3VybmFsIG9mIG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk4gRW5nbCBKIE1lZDwvZnVsbC10aXRsZT48YWJici0xPlRoZSBO

ZXcgRW5nbGFuZCBqb3VybmFsIG9mIG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48

cGFnZXM+MTgwMi0xODEwPC9wYWdlcz48dm9sdW1lPjM3ODwvdm9sdW1lPjxudW1iZXI+MTk8L251

bWJlcj48ZWRpdGlvbj4yMDE4LzA1LzEwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BYmxh

dGlvbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BbnRhZ29u

aXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWNvbnZ1bHNhbnRzL3Ro

ZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Db250cmFpbmRpY2F0aW9ucywgRHJ1Zzwv

a2V5d29yZD48a2V5d29yZD5EZWVwIEJyYWluIFN0aW11bGF0aW9uL2FkdmVyc2UgZWZmZWN0czwv

a2V5d29yZD48a2V5d29yZD5EaWFnbm9zaXMsIERpZmZlcmVudGlhbDwva2V5d29yZD48a2V5d29y

ZD5Fc3NlbnRpYWwgVHJlbW9yL2RpYWdub3Npcy9kcnVnIHRoZXJhcHkvKnRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlByYWN0aWNlIEd1aWRlbGluZXMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UHJpbWlkb25l

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Qcm9wcmFub2xvbC90aGVyYXBldXRp

YyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VGhhbGFtdXMvc3VyZ2VyeTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5IDEwPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI5NzQyMzc2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTA1Ni9ORUpNY3AxNzA3OTI4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5n

dWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGFybWE8L0F1dGhvcj48WWVhcj4yMDIwPC9ZZWFyPjxS

ZWNOdW0+MzA8L1JlY051bT48RGlzcGxheVRleHQ+KEhhdWJlbmJlcmdlciBhbmQgSGFsbGV0dCAy

MDE4LCBTaGFybWEgYW5kIFBhbmRleSAyMDIwKTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51

bWJlcj4zMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1

ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MTI2

Ij4zMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUi

PjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2hhcm1hLCBTLjwv

YXV0aG9yPjxhdXRob3I+UGFuZGV5LCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPk5ldXJvbG9neSwgR292aW5kIEJhbGxhYmggUGFudCBJbnN0aXR1dGUg

b2YgUG9zdGdyYWR1YXRlIE1lZGljYWwgRWR1Y2F0aW9uIGFuZCBSZXNlYXJjaCwgTmV3IERlbGhp

LCBJbmRpYS4mI3hEO0RlcGFydG1lbnQgb2YgQ2xpbmljYWwgTmV1cm9sb2dpY2FsIFNjaWVuY2Vz

LCBMb25kb24gSGVhbHRoIFNjaWVuY2VzIENlbnRyZSwgV2VzdGVybiBVbml2ZXJzaXR5LCBMb25k

b24sIE9udGFyaW8sIENhbmFkYS4mI3hEO05ldXJvbG9neSwgR292aW5kIEJhbGxhYmggUGFudCBJ

bnN0aXR1dGUgb2YgUG9zdGdyYWR1YXRlIE1lZGljYWwgRWR1Y2F0aW9uIGFuZCBSZXNlYXJjaCwg

TmV3IERlbGhpLCBJbmRpYSBzYW5qYXlzZ3BnaTIwMDJAeWFob28uY28uaW4uPC9hdXRoLWFkZHJl

c3M+PHRpdGxlcz48dGl0bGU+VHJlYXRtZW50IG9mIGVzc2VudGlhbCB0cmVtb3I6IGN1cnJlbnQg

c3RhdHVzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlBvc3RncmFkIE1lZCBKPC9zZWNvbmRhcnkt

dGl0bGU+PGFsdC10aXRsZT5Qb3N0Z3JhZHVhdGUgbWVkaWNhbCBqb3VybmFsPC9hbHQtdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UG9zdGdyYWQgTWVkIEo8L2Z1bGwtdGl0

bGU+PGFiYnItMT5Qb3N0Z3JhZHVhdGUgbWVkaWNhbCBqb3VybmFsPC9hYmJyLTE+PC9wZXJpb2Rp

Y2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Qb3N0Z3JhZCBNZWQgSjwvZnVsbC10aXRs

ZT48YWJici0xPlBvc3RncmFkdWF0ZSBtZWRpY2FsIGpvdXJuYWw8L2FiYnItMT48L2FsdC1wZXJp

b2RpY2FsPjxwYWdlcz44NC05MzwvcGFnZXM+PHZvbHVtZT45Njwvdm9sdW1lPjxudW1iZXI+MTEz

MjwvbnVtYmVyPjxlZGl0aW9uPjIwMTkvMTAvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PmJldGEtIGJsb2NrZXJzPC9rZXl3b3JkPjxrZXl3b3JkPmJvdHVsaW51bSB0b3hpbjwva2V5d29y

ZD48a2V5d29yZD5lc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPmZvY3VzZWQgdWx0

cmFzb3VuZDwva2V5d29yZD48a2V5d29yZD50aGFsYW1vdG9teSwgZGVlcCBicmFpbiBzdGltdWxh

dGlvbjwva2V5d29yZD48a2V5d29yZD50cmVhdG1lbnQgb2YgZXNzZW50aWFsIHRyZW1vcjogY3Vy

cmVudCBzdGF0dXM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAyMDwveWVhcj48

cHViLWRhdGVzPjxkYXRlPkZlYjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMzIt

NTQ3MzwvaXNibj48YWNjZXNzaW9uLW51bT4zMTU3NTczMDwvYWNjZXNzaW9uLW51bT48dXJscz48

L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExMzYvcG9zdGdyYWRtZWRqLTIwMTkt

MTM2NjQ3PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhdWJlbmJlcmdlcjwvQXV0aG9yPjxZZWFyPjIw

MTg8L1llYXI+PFJlY051bT4yNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MjQ8L3JlYy1u

dW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUy

ZGU3eGYwMDEydnRkZHN0ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjA2MyI+MjQ8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhhdWJlbmJlcmdlciwgRC48L2F1dGhvcj48

YXV0aG9yPkhhbGxldHQsIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRo

LWFkZHJlc3M+RnJvbSB0aGUgQ2xpbmljYWwgVHJpYWxzIFVuaXQsIE9mZmljZSBvZiB0aGUgQ2xp

bmljYWwgRGlyZWN0b3IgKEQuSC4pLCBhbmQgdGhlIEh1bWFuIE1vdG9yIENvbnRyb2wgU2VjdGlv

biwgTWVkaWNhbCBOZXVyb2xvZ3kgQnJhbmNoIChNLkguKSwgTmF0aW9uYWwgSW5zdGl0dXRlIG9m

IE5ldXJvbG9naWNhbCBEaXNvcmRlcnMgYW5kIFN0cm9rZSBJbnRyYW11cmFsIFJlc2VhcmNoIFBy

b2dyYW0sIE5hdGlvbmFsIEluc3RpdHV0ZXMgb2YgSGVhbHRoLCBCZXRoZXNkYSwgTUQuPC9hdXRo

LWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+RXNzZW50aWFsIFRyZW1vcjwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5OIEVuZ2wgSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRoZSBOZXcg

RW5nbGFuZCBqb3VybmFsIG9mIG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBF

bmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJp

b2RpY2FsPjxmdWxsLXRpdGxlPk4gRW5nbCBKIE1lZDwvZnVsbC10aXRsZT48YWJici0xPlRoZSBO

ZXcgRW5nbGFuZCBqb3VybmFsIG9mIG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48

cGFnZXM+MTgwMi0xODEwPC9wYWdlcz48dm9sdW1lPjM3ODwvdm9sdW1lPjxudW1iZXI+MTk8L251

bWJlcj48ZWRpdGlvbj4yMDE4LzA1LzEwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BYmxh

dGlvbiBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BbnRhZ29u

aXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWNvbnZ1bHNhbnRzL3Ro

ZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Db250cmFpbmRpY2F0aW9ucywgRHJ1Zzwv

a2V5d29yZD48a2V5d29yZD5EZWVwIEJyYWluIFN0aW11bGF0aW9uL2FkdmVyc2UgZWZmZWN0czwv

a2V5d29yZD48a2V5d29yZD5EaWFnbm9zaXMsIERpZmZlcmVudGlhbDwva2V5d29yZD48a2V5d29y

ZD5Fc3NlbnRpYWwgVHJlbW9yL2RpYWdub3Npcy9kcnVnIHRoZXJhcHkvKnRoZXJhcHk8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlByYWN0aWNlIEd1aWRlbGluZXMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+UHJpbWlkb25l

L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5Qcm9wcmFub2xvbC90aGVyYXBldXRp

YyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VGhhbGFtdXMvc3VyZ2VyeTwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5IDEwPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI5NzQyMzc2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+MTAuMTA1Ni9ORUpNY3AxNzA3OTI4PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5n

dWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA (Haubenberger and Hallett 2018, Sharma and Pandey 2020). Medical therapy rarely achieves complete tremor control and according to ADDIN EN.CITE <EndNote><Cite AuthorYear="1"><Author>Sharma</Author><Year>2020</Year><RecNum>30</RecNum><DisplayText>Sharma and Pandey (2020)</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="p5z2edva7sfr05e2de7xf0012vtddstz5ae9" timestamp="1582766126">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sharma, S.</author><author>Pandey, S.</author></authors></contributors><auth-address>Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India.&#xD;Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Ontario, Canada.&#xD;Neurology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India sanjaysgpgi2002@yahoo.co.in.</auth-address><titles><title>Treatment of essential tremor: current status</title><secondary-title>Postgrad Med J</secondary-title><alt-title>Postgraduate medical journal</alt-title></titles><periodical><full-title>Postgrad Med J</full-title><abbr-1>Postgraduate medical journal</abbr-1></periodical><alt-periodical><full-title>Postgrad Med J</full-title><abbr-1>Postgraduate medical journal</abbr-1></alt-periodical><pages>84-93</pages><volume>96</volume><number>1132</number><edition>2019/10/03</edition><keywords><keyword>beta- blockers</keyword><keyword>botulinum toxin</keyword><keyword>essential tremor</keyword><keyword>focused ultrasound</keyword><keyword>thalamotomy, deep brain stimulation</keyword><keyword>treatment of essential tremor: current status</keyword></keywords><dates><year>2020</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0032-5473</isbn><accession-num>31575730</accession-num><urls></urls><electronic-resource-num>10.1136/postgradmedj-2019-136647</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>Sharma and Pandey (2020), their mean efficacy is about 50% in terms of tremor. Drug tolerance occurs after chronic treatment, and 30-50% of patients may be completely resistant to first-line pharmacotherapy. When first-line drugs are contraindicated or not tolerated, second-line treatment includes topiramate, gabapentin, and alprazolam. Patients who fail to derive adequate benefit from pharmacological treatment and/or are intolerant to medical intervention are considered to have medically refractory ET.Following failure to achieve an adequate response to pharmacological therapy, patients are typically referred to a neurologist within a movement disorder clinic for assessment of suitability for therapeutic interventions. After initial appraisal, patients may undergo an extensive work up to assess suitability for further treatment including surgery in a movement disorder clinic by a specialist team, which includes a movement disorder neurologist and neurosurgeon. The team may also include other specialists such as a movement disorders nurse, neuropsychiatrist, and neuropsychologist, depending on the team's usual protocol. This process aims to determine the likely benefit and risks of performing each type of procedure on an individual basis. Treatment of medically refractory ET often includes persisting further with pharmacological therapy as described above (optimised medical therapy). DBS may also be considered in this difficult to treat population. At present, DBS is the only MBS reimbursed intervention for patients with medically refractory ET. The treatment is limited to patients whose symptoms cause severe disability. Patients contraindicated or not suitable for surgery are continued to be managed through best supportive care (BSC). Magnetic resonance-guided focused ultrasound (MRgFUS) has been developed to assess whether ablative therapy may be beneficial for people with medically refractory ET, where the patient’s symptoms cause severe disability. The applicant acknowledges that the definition of failure to derive adequate benefit to treatment is open to interpretation. There are currently no set guidelines that define the duration of treatment or thresholds of benefit when defining medically refractory ET. It should, however, be noted that the decision to undergo MRgFUS would not be undertaken lightly, and it is likely that most patients would trial a range of pharmacologic therapies before considering the procedure. PASC confirmed the population as stated in the draft PICO. PASC queried whether ‘medically refractory’ should be defined in the proposed population and what duration is required before a patient is considered medically failed. PASC noted there are currently no set guidelines that define the duration of treatment or thresholds of benefit when defining ‘medically refractory’ but noted the pivotal trial (Elias et al. 2016) recruited patients with tremor that was refractory to at least two trials of medical therapy, including at least one first-line agent (propranolol or primidone).The trial population in the pivotal RCT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGlhczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

Y051bT4zODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRWxpYXMsIExpcHNtYW4gZXQgYWwuIDIwMTYp

PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRlN3hmMDAxMnZ0ZGRz

dHo1YWU5IiB0aW1lc3RhbXA9IjE1ODI3NjYyMTIiPjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5FbGlhcywgVy4gSi48L2F1dGhvcj48YXV0aG9yPkxpcHNtYW4sIE4u

PC9hdXRob3I+PGF1dGhvcj5PbmRvLCBXLiBHLjwvYXV0aG9yPjxhdXRob3I+R2hhbm91bmksIFAu

PC9hdXRob3I+PGF1dGhvcj5LaW0sIFkuIEcuPC9hdXRob3I+PGF1dGhvcj5MZWUsIFcuPC9hdXRo

b3I+PGF1dGhvcj5TY2h3YXJ0eiwgTS48L2F1dGhvcj48YXV0aG9yPkh5bnluZW4sIEsuPC9hdXRo

b3I+PGF1dGhvcj5Mb3phbm8sIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5TaGFoLCBCLiBCLjwvYXV0

aG9yPjxhdXRob3I+SHVzcywgRC48L2F1dGhvcj48YXV0aG9yPkRhbGxhcGlhenphLCBSLiBGLjwv

YXV0aG9yPjxhdXRob3I+R3dpbm4sIFIuPC9hdXRob3I+PGF1dGhvcj5XaXR0LCBKLjwvYXV0aG9y

PjxhdXRob3I+Um8sIFMuPC9hdXRob3I+PGF1dGhvcj5FaXNlbmJlcmcsIEguIE0uPC9hdXRob3I+

PGF1dGhvcj5GaXNobWFuLCBQLiBTLjwvYXV0aG9yPjxhdXRob3I+R2FuZGhpLCBELjwvYXV0aG9y

PjxhdXRob3I+SGFscGVybiwgQy4gSC48L2F1dGhvcj48YXV0aG9yPkNodWFuZywgUi48L2F1dGhv

cj48YXV0aG9yPkJ1dHRzIFBhdWx5LCBLLjwvYXV0aG9yPjxhdXRob3I+VGllcm5leSwgVC4gUy48

L2F1dGhvcj48YXV0aG9yPkhheWVzLCBNLiBULjwvYXV0aG9yPjxhdXRob3I+Q29zZ3JvdmUsIEcu

IFIuPC9hdXRob3I+PGF1dGhvcj5ZYW1hZ3VjaGksIFQuPC9hdXRob3I+PGF1dGhvcj5BYmUsIEsu

PC9hdXRob3I+PGF1dGhvcj5UYWlyYSwgVC48L2F1dGhvcj48YXV0aG9yPkNoYW5nLCBKLiBXLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIFVu

aXZlcnNpdHkgb2YgVmlyZ2luaWEgSGVhbHRoIFNjaWVuY2VzIENlbnRlciwgQ2hhcmxvdHRlc3Zp

bGxlIChXLkouRS4sIEIuQi5TLiwgRC5ILiwgUi5GLkQuKTsgVG9yb250byBXZXN0ZXJuIEhvc3Bp

dGFsIChOLkwuLCBBLk0uTC4pIGFuZCBTdW5ueWJyb29rIEhlYWx0aCBTY2llbmNlcyBDZW50cmUg

KE0uUy4sIEsuSC4pLCBUb3JvbnRvOyBNZXRob2Rpc3QgTmV1cm9sb2dpY2FsIEluc3RpdHV0ZSwg

SG91c3RvbiAoVy5HLk8uKTsgU3RhbmZvcmQgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUs

IFN0YW5mb3JkLCBDQSAoUC5HLiwgQy5ILkguLCBLLkIuUC4pOyBZb25zZWkgVW5pdmVyc2l0eSBD

b2xsZWdlIG9mIE1lZGljaW5lLCBTZW91bCwgU291dGggS29yZWEgKFkuRy5LLiwgVy5MLiwgSi5X

LkMuKTsgU3dlZGlzaCBOZXVyb3NjaWVuY2UgSW5zdGl0dXRlLCBTZWF0dGxlIChSLkcuLCBKLlcu

LCBTLlIuLCBSLkMuKTsgVW5pdmVyc2l0eSBvZiBNYXJ5bGFuZCBTY2hvb2wgb2YgTWVkaWNpbmUs

IEJhbHRpbW9yZSAoSC5NLkUuLCBQLlMuRi4sIEQuRy4pOyBVbml2ZXJzaXR5IG9mIE1pYW1pIFNj

aG9vbCBvZiBNZWRpY2luZSwgTmlja2xhdXMgQ2hpbGRyZW4mYXBvcztzIEhvc3BpdGFsLCBNaWFt

aSAoVC5TLlQuKTsgQnJpZ2hhbSBhbmQgV29tZW4mYXBvcztzIEhvc3BpdGFsLCBCb3N0b24gKE0u

VC5ILiwgRy5SLkMuKTsgYW5kIFNoaW4teXVyaWdhb2thIEdlbmVyYWwgSG9zcGl0YWwsIEthd2Fz

YWtpIChULlkuKSwgYW5kIFRva3lvIFdvbWVuJmFwb3M7cyBNZWRpY2FsIFVuaXZlcnNpdHksIFRv

a3lvIChLLkEuLCBULlQuKSAtIGJvdGggaW4gSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+QSBSYW5kb21pemVkIFRyaWFsIG9mIEZvY3VzZWQgVWx0cmFzb3VuZCBUaGFsYW1vdG9t

eSBmb3IgRXNzZW50aWFsIFRyZW1vcjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OIEVuZ2wgSiBN

ZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRoZSBOZXcgRW5nbGFuZCBqb3VybmFsIG9m

IG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBF

bmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2Yg

bWVkaWNpbmU8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxl

Pk4gRW5nbCBKIE1lZDwvZnVsbC10aXRsZT48YWJici0xPlRoZSBOZXcgRW5nbGFuZCBqb3VybmFs

IG9mIG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+NzMwLTk8L3BhZ2Vz

Pjx2b2x1bWU+Mzc1PC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wOC8y

NTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWN0aXZpdGllcyBvZiBEYWlseSBMaXZpbmc8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0

aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvKnRoZXJhcHk8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3

b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc3RvcGVyYXRpdmUg

Q29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+

PGtleXdvcmQ+VGhhbGFtdXMvKnN1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+KlVsdHJhc29uaWMg

VGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5VbHRyYXNv

bm9ncmFwaHksIEludGVydmVudGlvbmFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1NTczMDE8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDU2L05F

Sk1vYTE2MDAxNTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGlhczwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

Y051bT4zODwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oRWxpYXMsIExpcHNtYW4gZXQgYWwuIDIwMTYp

PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM4PC9yZWMtbnVtYmVyPjxmb3JlaWdu

LWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0icDV6MmVkdmE3c2ZyMDVlMmRlN3hmMDAxMnZ0ZGRz

dHo1YWU5IiB0aW1lc3RhbXA9IjE1ODI3NjYyMTIiPjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJl

Zi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+

PGF1dGhvcnM+PGF1dGhvcj5FbGlhcywgVy4gSi48L2F1dGhvcj48YXV0aG9yPkxpcHNtYW4sIE4u

PC9hdXRob3I+PGF1dGhvcj5PbmRvLCBXLiBHLjwvYXV0aG9yPjxhdXRob3I+R2hhbm91bmksIFAu

PC9hdXRob3I+PGF1dGhvcj5LaW0sIFkuIEcuPC9hdXRob3I+PGF1dGhvcj5MZWUsIFcuPC9hdXRo

b3I+PGF1dGhvcj5TY2h3YXJ0eiwgTS48L2F1dGhvcj48YXV0aG9yPkh5bnluZW4sIEsuPC9hdXRo

b3I+PGF1dGhvcj5Mb3phbm8sIEEuIE0uPC9hdXRob3I+PGF1dGhvcj5TaGFoLCBCLiBCLjwvYXV0

aG9yPjxhdXRob3I+SHVzcywgRC48L2F1dGhvcj48YXV0aG9yPkRhbGxhcGlhenphLCBSLiBGLjwv

YXV0aG9yPjxhdXRob3I+R3dpbm4sIFIuPC9hdXRob3I+PGF1dGhvcj5XaXR0LCBKLjwvYXV0aG9y

PjxhdXRob3I+Um8sIFMuPC9hdXRob3I+PGF1dGhvcj5FaXNlbmJlcmcsIEguIE0uPC9hdXRob3I+

PGF1dGhvcj5GaXNobWFuLCBQLiBTLjwvYXV0aG9yPjxhdXRob3I+R2FuZGhpLCBELjwvYXV0aG9y

PjxhdXRob3I+SGFscGVybiwgQy4gSC48L2F1dGhvcj48YXV0aG9yPkNodWFuZywgUi48L2F1dGhv

cj48YXV0aG9yPkJ1dHRzIFBhdWx5LCBLLjwvYXV0aG9yPjxhdXRob3I+VGllcm5leSwgVC4gUy48

L2F1dGhvcj48YXV0aG9yPkhheWVzLCBNLiBULjwvYXV0aG9yPjxhdXRob3I+Q29zZ3JvdmUsIEcu

IFIuPC9hdXRob3I+PGF1dGhvcj5ZYW1hZ3VjaGksIFQuPC9hdXRob3I+PGF1dGhvcj5BYmUsIEsu

PC9hdXRob3I+PGF1dGhvcj5UYWlyYSwgVC48L2F1dGhvcj48YXV0aG9yPkNoYW5nLCBKLiBXLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkZyb20gdGhlIFVu

aXZlcnNpdHkgb2YgVmlyZ2luaWEgSGVhbHRoIFNjaWVuY2VzIENlbnRlciwgQ2hhcmxvdHRlc3Zp

bGxlIChXLkouRS4sIEIuQi5TLiwgRC5ILiwgUi5GLkQuKTsgVG9yb250byBXZXN0ZXJuIEhvc3Bp

dGFsIChOLkwuLCBBLk0uTC4pIGFuZCBTdW5ueWJyb29rIEhlYWx0aCBTY2llbmNlcyBDZW50cmUg

KE0uUy4sIEsuSC4pLCBUb3JvbnRvOyBNZXRob2Rpc3QgTmV1cm9sb2dpY2FsIEluc3RpdHV0ZSwg

SG91c3RvbiAoVy5HLk8uKTsgU3RhbmZvcmQgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUs

IFN0YW5mb3JkLCBDQSAoUC5HLiwgQy5ILkguLCBLLkIuUC4pOyBZb25zZWkgVW5pdmVyc2l0eSBD

b2xsZWdlIG9mIE1lZGljaW5lLCBTZW91bCwgU291dGggS29yZWEgKFkuRy5LLiwgVy5MLiwgSi5X

LkMuKTsgU3dlZGlzaCBOZXVyb3NjaWVuY2UgSW5zdGl0dXRlLCBTZWF0dGxlIChSLkcuLCBKLlcu

LCBTLlIuLCBSLkMuKTsgVW5pdmVyc2l0eSBvZiBNYXJ5bGFuZCBTY2hvb2wgb2YgTWVkaWNpbmUs

IEJhbHRpbW9yZSAoSC5NLkUuLCBQLlMuRi4sIEQuRy4pOyBVbml2ZXJzaXR5IG9mIE1pYW1pIFNj

aG9vbCBvZiBNZWRpY2luZSwgTmlja2xhdXMgQ2hpbGRyZW4mYXBvcztzIEhvc3BpdGFsLCBNaWFt

aSAoVC5TLlQuKTsgQnJpZ2hhbSBhbmQgV29tZW4mYXBvcztzIEhvc3BpdGFsLCBCb3N0b24gKE0u

VC5ILiwgRy5SLkMuKTsgYW5kIFNoaW4teXVyaWdhb2thIEdlbmVyYWwgSG9zcGl0YWwsIEthd2Fz

YWtpIChULlkuKSwgYW5kIFRva3lvIFdvbWVuJmFwb3M7cyBNZWRpY2FsIFVuaXZlcnNpdHksIFRv

a3lvIChLLkEuLCBULlQuKSAtIGJvdGggaW4gSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+QSBSYW5kb21pemVkIFRyaWFsIG9mIEZvY3VzZWQgVWx0cmFzb3VuZCBUaGFsYW1vdG9t

eSBmb3IgRXNzZW50aWFsIFRyZW1vcjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OIEVuZ2wgSiBN

ZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRoZSBOZXcgRW5nbGFuZCBqb3VybmFsIG9m

IG1lZGljaW5lPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBF

bmdsIEogTWVkPC9mdWxsLXRpdGxlPjxhYmJyLTE+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2Yg

bWVkaWNpbmU8L2FiYnItMT48L3BlcmlvZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxl

Pk4gRW5nbCBKIE1lZDwvZnVsbC10aXRsZT48YWJici0xPlRoZSBOZXcgRW5nbGFuZCBqb3VybmFs

IG9mIG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+NzMwLTk8L3BhZ2Vz

Pjx2b2x1bWU+Mzc1PC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGVkaXRpb24+MjAxNi8wOC8y

NTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWN0aXZpdGllcyBvZiBEYWlseSBMaXZpbmc8

L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0

aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvKnRoZXJhcHk8L2tleXdvcmQ+

PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29y

ZD5NYWduZXRpYyBSZXNvbmFuY2UgSW1hZ2luZzwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3

b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvc3RvcGVyYXRpdmUg

Q29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+

PGtleXdvcmQ+VGhhbGFtdXMvKnN1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+KlVsdHJhc29uaWMg

VGhlcmFweS9hZHZlcnNlIGVmZmVjdHMvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5VbHRyYXNv

bm9ncmFwaHksIEludGVydmVudGlvbmFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMTY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgMjU8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDI4LTQ3OTM8L2lzYm4+PGFjY2Vzc2lvbi1udW0+Mjc1NTczMDE8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDU2L05F

Sk1vYTE2MDAxNTk8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA (Elias, Lipsman et al. 2016) included patients with ET, diagnosed by a neurologist specialising in movement disorders. It was noted the pivotal trial used the Clinical Rating Scale for Tremor (CRST) scores to recruit the trial population: patients were eligible if they had a postural or intention tremor of the hand that was moderate to severe (defined by a score of ≥2 on the CRST [scores range from 0 to 4 per component assessed, and higher scores indicate more severe tremor]) and disabling (defined by a score of ≥2 on any of the eight items in the disability subsection of the CRST [scores range from 0 to 4 per item, and higher scores indicate greater disability]). It should be noted that the use of the CRST score is one of the major flaws of the RCT, as it is a new scale and it is not clear what a minimum clinically important difference (MCID) would be and what difference in scale would correlate with patient improvement and satisfaction with treatment.Additional eligibility criteria were: tremor that was refractory to at least two trials of medical therapy, including at least one first-line agent (propranolol or primidone); and, for patients receiving concurrent medical therapy, medication doses had to be stable for 30 days before randomisation. This means patients might also receive concurrent medical treatment alongside MRgFUS, as reflected in the algorithm ( REF _Ref34056807 \h Figure 2). Patients were excluded if they had a neurodegenerative condition, unstable cardiac disease, coagulopathy, risk factors for deep-vein thrombosis, severe depression (defined by a score ≥20 on Patient Health Questionnaire 9 [scores range from 0 to 27, with higher scores indicating more severe depression]), or cognitive impairment (defined by a score of <24 o the Mini–Mental State Examination [scores range from 0 to 30, with lower values indicating greater impairment]) or if they had undergone a previous brain procedure (transcranial magnetic stimulation, DBS, stereotactic lesioning, or electroconvulsive therapy). A skull density ratio (the ratio of cortical to cancellous bone) of 0.45 or more was required from the screening computed tomographic (CT) scan. Under the proposed listing, eligibility for MRgFUS therapy can only be determined by a neurologist. Once MRgFUS is prescribed, the patient will be referred to a trained physician working as part of the treatment team to assess suitability for and the undertaking of MRgFUS.PASC considered excluding patients with Parkinson’s disease was reasonable given the evidence basis did not pertain to this patient group, but noted it can be difficult to differentiate ET from Parkinson’s disease in some cases (see Proposed MBS item descriptor and MBS fee). PASC considered inclusion of this separate patient group may result in considerable leakage and largely experimental treatment of patients with Parkinson’s disease.The Applicant noted it agreed with the population proposed and the exclusion of true Parkinson’s disease patients but considered that patients diagnosed with ET, including ET Plus patients who may display additional neurologic signs such as dystonia, ataxia, and parkinsonism, should be eligible for treatment (noting that these features did not exclude patients from the clinical trials evidence base).INTERVENTIONMRgFUS is a non-invasive, one-step method of targeted tissue thermal ablation used to treat medically refractory ET. The ablation target is the ventral intermediate nucleus (VIM) of the thalamus. MR imaging (MRI) provides detailed images of the brain in real time during the surgery and permits precise localisation and real-time monitoring of the targeted tissue to prevent collateral damage to surrounding healthy tissue. A high-intensity focused ultrasound transducer allows for ultrasound beam steering and focusing without attenuation. Ultrasound waves interact with biological tissue and produce a variety of effects including acoustic cavitation, shear stress, and thermal effect through a vibration of molecules, which in turn generate frictional heat. Protein denaturation or coagulative necrosis occur in the cells at a temperature of 56?C for 1 second PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2hhbW1lZDwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+

PFJlY051bT4zMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTW9oYW1tZWQsIFBhdHJhIGV0IGFsLiAy

MDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2

dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MTM1Ij4zMTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TW9oYW1tZWQsIE4uPC9hdXRob3I+PGF1dGhvcj5QYXRyYSwg

RC48L2F1dGhvcj48YXV0aG9yPk5hbmRhLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9zdXJnZXJ5LCBMb3Vpc2lhbmEg

U3RhdGUgVW5pdmVyc2l0eSBIZWFsdGggU2NpZW5jZXMgQ2VudGVyLCBTaHJldmVwb3J0LCBMb3Vp

c2lhbmEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBtZXRhLWFuYWx5c2lzIG9mIG91

dGNvbWVzIGFuZCBjb21wbGljYXRpb25zIG9mIG1hZ25ldGljIHJlc29uYW5jZS1ndWlkZWQgZm9j

dXNlZCB1bHRyYXNvdW5kIGluIHRoZSB0cmVhdG1lbnQgb2YgZXNzZW50aWFsIHRyZW1vcjwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3N1cmcgRm9jdXM8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5ldXJvc3VyZ2ljYWwgZm9jdXM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5OZXVyb3N1cmcgRm9jdXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb3N1

cmdpY2FsIGZvY3VzPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5OZXVyb3N1cmcgRm9jdXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb3N1cmdpY2FsIGZv

Y3VzPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+RTQ8L3BhZ2VzPjx2b2x1bWU+NDQ8

L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE4LzAyLzAyPC9lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5EZWVwIEJyYWluIFN0aW11bGF0aW9uLyptZXRob2RzPC9rZXl3b3Jk

PjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvKmRpYWdub3N0aWMgaW1hZ2luZy8qc3VyZ2VyeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25h

bmNlIEltYWdpbmcvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9zdXJnaWNhbCBQcm9j

ZWR1cmVzLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVkIFRyaWFscyBhcyBUb3BpYy9tZXRo

b2RzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5

d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5VbHRyYXNvbm9ncmFwaHks

IEludGVydmVudGlvbmFsLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPipDUlNUID0gQ2xpbmlj

YWwgUmF0aW5nIFNjYWxlIGZvciBUcmVtb3I8L2tleXdvcmQ+PGtleXdvcmQ+KkNUVCA9IGNlcmVi

ZWxsb3RoYWxhbWljIHRyYWN0PC9rZXl3b3JkPjxrZXl3b3JkPipEQlMgPSBkZWVwIGJyYWluIHN0

aW11bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFVCA9IGVzc2VudGlhbCB0cmVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+KkdLVCA9IEdhbW1hIEtuaWZlIHRoYWxhbW90b215PC9rZXl3b3JkPjxrZXl3

b3JkPipNUi1ndWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipNUmdG

VVMgPSBNUi1ndWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipQUklT

TUEgPSBQcmVmZXJyZWQgUmVwb3J0aW5nIEl0ZW1zIGZvciBTeXN0ZW1hdGljIFJldmlld3MgYW5k

IE1ldGEtQW5hbHlzZXM8L2tleXdvcmQ+PGtleXdvcmQ+KlFVRVNUID0gUXVhbGl0eSBvZiBMaWZl

IGluIEVzc2VudGlhbCBUcmVtb3IgUXVlc3Rpb25uYWlyZTwva2V5d29yZD48a2V5d29yZD4qUkNU

ID0gcmFuZG9taXplZCBjb250cm9sbGVkIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPipWaW0gPSB2

ZW50cmFsIGludGVybWVkaWF0ZSBudWNsZXVzPC9rZXl3b3JkPjxrZXl3b3JkPiplc3NlbnRpYWwg

dHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPip0aGFsYW1vdG9teTwva2V5d29yZD48a2V5d29yZD4q

dmVudHJhbCBpbnRlcm1lZGlhdGUgbnVjbGV1czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTA5Mi0wNjg0PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5Mzg1OTE3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzE3MS8y

MDE3LjExLkZvY3VzMTc2Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJh

c2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwv

bGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2hhbW1lZDwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+

PFJlY051bT4zMTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTW9oYW1tZWQsIFBhdHJhIGV0IGFsLiAy

MDE4KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zMTwvcmVjLW51bWJlcj48Zm9y

ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InA1ejJlZHZhN3NmcjA1ZTJkZTd4ZjAwMTJ2

dGRkc3R6NWFlOSIgdGltZXN0YW1wPSIxNTgyNzY2MTM1Ij4zMTwva2V5PjwvZm9yZWlnbi1rZXlz

PjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0

b3JzPjxhdXRob3JzPjxhdXRob3I+TW9oYW1tZWQsIE4uPC9hdXRob3I+PGF1dGhvcj5QYXRyYSwg

RC48L2F1dGhvcj48YXV0aG9yPk5hbmRhLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTmV1cm9zdXJnZXJ5LCBMb3Vpc2lhbmEg

U3RhdGUgVW5pdmVyc2l0eSBIZWFsdGggU2NpZW5jZXMgQ2VudGVyLCBTaHJldmVwb3J0LCBMb3Vp

c2lhbmEuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QSBtZXRhLWFuYWx5c2lzIG9mIG91

dGNvbWVzIGFuZCBjb21wbGljYXRpb25zIG9mIG1hZ25ldGljIHJlc29uYW5jZS1ndWlkZWQgZm9j

dXNlZCB1bHRyYXNvdW5kIGluIHRoZSB0cmVhdG1lbnQgb2YgZXNzZW50aWFsIHRyZW1vcjwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5OZXVyb3N1cmcgRm9jdXM8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5ldXJvc3VyZ2ljYWwgZm9jdXM8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5OZXVyb3N1cmcgRm9jdXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb3N1

cmdpY2FsIGZvY3VzPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5OZXVyb3N1cmcgRm9jdXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5OZXVyb3N1cmdpY2FsIGZv

Y3VzPC9hYmJyLTE+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+RTQ8L3BhZ2VzPjx2b2x1bWU+NDQ8

L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE4LzAyLzAyPC9lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5EZWVwIEJyYWluIFN0aW11bGF0aW9uLyptZXRob2RzPC9rZXl3b3Jk

PjxrZXl3b3JkPkVzc2VudGlhbCBUcmVtb3IvKmRpYWdub3N0aWMgaW1hZ2luZy8qc3VyZ2VyeTwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFnbmV0aWMgUmVzb25h

bmNlIEltYWdpbmcvKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TmV1cm9zdXJnaWNhbCBQcm9j

ZWR1cmVzLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UmFuZG9taXplZCBDb250cm9sbGVkIFRyaWFscyBhcyBUb3BpYy9tZXRo

b2RzPC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5

d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48a2V5d29yZD5VbHRyYXNvbm9ncmFwaHks

IEludGVydmVudGlvbmFsLyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPipDUlNUID0gQ2xpbmlj

YWwgUmF0aW5nIFNjYWxlIGZvciBUcmVtb3I8L2tleXdvcmQ+PGtleXdvcmQ+KkNUVCA9IGNlcmVi

ZWxsb3RoYWxhbWljIHRyYWN0PC9rZXl3b3JkPjxrZXl3b3JkPipEQlMgPSBkZWVwIGJyYWluIHN0

aW11bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFVCA9IGVzc2VudGlhbCB0cmVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+KkdLVCA9IEdhbW1hIEtuaWZlIHRoYWxhbW90b215PC9rZXl3b3JkPjxrZXl3

b3JkPipNUi1ndWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipNUmdG

VVMgPSBNUi1ndWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipQUklT

TUEgPSBQcmVmZXJyZWQgUmVwb3J0aW5nIEl0ZW1zIGZvciBTeXN0ZW1hdGljIFJldmlld3MgYW5k

IE1ldGEtQW5hbHlzZXM8L2tleXdvcmQ+PGtleXdvcmQ+KlFVRVNUID0gUXVhbGl0eSBvZiBMaWZl

IGluIEVzc2VudGlhbCBUcmVtb3IgUXVlc3Rpb25uYWlyZTwva2V5d29yZD48a2V5d29yZD4qUkNU

ID0gcmFuZG9taXplZCBjb250cm9sbGVkIHRyaWFsPC9rZXl3b3JkPjxrZXl3b3JkPipWaW0gPSB2

ZW50cmFsIGludGVybWVkaWF0ZSBudWNsZXVzPC9rZXl3b3JkPjxrZXl3b3JkPiplc3NlbnRpYWwg

dHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPip0aGFsYW1vdG9teTwva2V5d29yZD48a2V5d29yZD4q

dmVudHJhbCBpbnRlcm1lZGlhdGUgbnVjbGV1czwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDE4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTA5Mi0wNjg0PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI5Mzg1OTE3PC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMzE3MS8y

MDE3LjExLkZvY3VzMTc2Mjg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJh

c2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwv

bGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA (Mohammed, Patra et al. 2018). The delivery of the thermal ablation is done through an intact skull, without the need for incision or craniotomy.MRgFUS is an inpatient procedure, which is performed by a physician (currently a neurosurgeon, this may change over time to include adequately trained physicians) and takes approximately 3-4 hours. A neurologist is also present to perform intraoperative clinical evaluations throughout the procedure. The application form stated that a radiologist is also present to perform the intraoperative MRIs.For radiology requirements, it was noted a compatible MRI is used to perform MRgFUS. The procedure can be considered to comprise four stages as follows:Patient preparationSeveral days before treatment, a CT scan is done to detail the shape, thickness and density of the patient’s skull and confirm suitability for the procedure. A pre-operative MRI is also performed - fused with the CT to more accurately guide treatment.On the day of treatment, the patient’s head is shaved, and a stereotactic frame is affixed to the skull under local anaesthetic. The patient is positioned on the treatment bed with his/her head secured to the phased-array ultrasound transducer (the Exablate Neuro helmet). Cold water is circulated around the scalp.Planning and target verificationIntraoperative MRI images are taken and may be fused with pre-op images to plan the treatment and identify the target.Prior to treatment, low energy sonications (application of ultrasound energy) are used to accurately pinpoint the target on the real-time MRI. Next, moderate level sonications allow assessment of patient response and any potential adverse effects before making the final lesion.TreatmentThe focused ultrasound treatment consists of up to 1024 ultrasound waves directed to the target in the VIM. At the focal point, temperatures increase to near 140°F/60°C, causing thermal ablation of the target tissue. The treatment is continuously guided by MRI for real-time thermal feedback of temperature changes (MR thermography) at the target, as well as non-focal temperature trends. The treatment is unilateral, generally treating the dominant hand.Intraoperative and interactive patient assessment is done to correctly identify the anatomical target and intraoperative MRI images are taken to evaluate the lesion formation.Assessment Treatment outcome is confirmed through neurological assessments as well as using a post-treatment scan immediately post-procedure. In a successful procedure, patients may experience an immediate reduction in their tremor. They are admitted overnight for observation. They may return to normal activities the following day in the absence of complications.Patients are required to undergo a post-operative MRI scan at 3 and/or 6 months follow up to assess lesion formation and dynamics. The post-operative MRI should be completed at around 3 months. Should the treating physician feel that a further follow up is required, an additional MRI may be requested at 6 months post-procedure.A trained specialist is required to deliver the proposed service. A training plan devised by the applicant is attached to the application form. A movement disorder specialist present at the procedure will provide intraoperative clinical evaluation. The applicant proposes that there should not be any limitations on who will be able to deliver the proposed service, such that a radiologist, neurologist or neurosurgeon with adequate training may be able to perform more than one of these roles during the procedure. The applicant notes that whilst the proposed MBS items identify tasks and MBS fees for the neurology, neurosurgery and radiology components of the procedure, it is feasible, and indeed probable, that over time (as physicians become more adept at executing the procedure) the tasks may be performed by, and fees reimbursed to, physicians of any of the three disciplines mentioned (radiology, neurology and neurosurgery). That is to say, the three item numbers proposed for the intraoperative component of MRgFUS will be performed and charged to the MBS by only two physicians performing the three components of the procedure. The proposed medical service is not currently funded or reimbursed in the private or public setting in Australia for the same or another clinical indication. The TGA approved indication(s) is for malignant or benign tumours, or other disease conditions and is thus broader than the proposed population (for medically refractory ET). There are two ARTG listings for the device (260438, 128137).The application form indicated that currently, only one centre in Australia offers MRgFUS for the treatment of medically refractory ET. Due to capital costs of the technology, it is anticipated that MRgFUS will be limited to only a very small number of centres, therefore potentially limiting access for some patients. The application form also identified additional supply side constraints, including availability of specialists to perform the procedure. PASC noted that the intervention is complex and is only available at one centre in Australia, and that there would be significant equity of access issues.The Applicant noted, that since lodgement of the Application form, a second centre in Australia at the Future Medical Imaging Group Center in Melbourne has acquired the Exablate Neuro technology and is now treating ET patients with MRgFUS. While this has increased access, it is acknowledged that equity of access issues still remain. Access is expected to continue to improve over time as more hospitals take up the MRgFUS technology – especially if approved for funding on the MBS. PASC noted the applicant’s advice which stated that a high proportion of the costs relate to service costs for capital and that out-of-pocket costs will be determined on the agreed MBS rebate.Based on current MBS utilisation of DBS ( REF _Ref35342198 \h Table 3), the application form estimated that demand for MRgFUS would be less than 100 patients per annum. It should be noted that this estimation of demand for the procedure might be very uncertain, because the utilisation data from the estimate cover private procedures only. Moreover, MRgFUS is considered less invasive than DBS, so the real patient population may be considerably larger.The application form provided breakdown costs for delivery of the MRgFUS procedure (see REF _Ref35344383 \h Table 4 in Appendix A). The application form also indicated an intention to submit an application to the Prostheses List (Part C) for potential funding of the disposable patient kit.PASC noted that the prosthesis cost (treatment kit) is likely to be substantial and not covered in detail in this application. PASC noted the applicant intended to submit an application to the Prostheses List (Part C) for potential funding of the disposable patient kit.The applicant confirmed it will provide a detailed evaluation of cost, including for the prosthesis and service costs for capital, in the ADAR.RationaleIn Australian clinical practice, MRgFUS is currently provided once on the dominant affected side as a unilateral treatment. PASC confirmed the proposed intervention should be once-only treatment with unilateral MRgFUS thalamotomy. PASC agreed with the applicant who advised that contralateral treatment is not relevant to this application, noting that contralateral treatment is currently considered investigational. However PASC noted, the application form (not the PICO) stated that the proposed service would first be delivered once per patient on the dominant side and that treatment of the contralateral side may be performed after a minimum of six months after successful treatment of the dominant side. Further, PASC also noted that retreatment was uncommon and that the vast majority of patients are expected to only have one unilateral procedure on the basis that the majority of clinical benefits of treatment with MRgFUS are derived by treating the dominant side.The applicant considered that treatment of the contralateral side is not irrelevant to this application. While the applicant considered that treatment of the contralateral side is currently investigational, the primary concern regarding contralateral treatment is with safety. It is argued that as the safety data supporting contralateral treatment transpires, patients should be able to access contralateral treatment if they so wish and are indicated for the procedure, at the discretion of the treating neurologist and neurosurgeon (noting that the number of patients seeking contralateral treatment is expected to be low given the benefits of treating the dominant side). Conversely, should the adverse event profile associated with contralateral MRgFUS appear to be unfavourable, treating physicians would simply not perform the procedure. Accordingly, the applicant was of the view that inclusion of the contralateral treatment in the item descriptor would be considered PARATORPatients who have failed treatment with pharmacotherapy and have functional limitations in everyday activities may be treated surgically, with lesional surgery or neuromodulation techniques (DBS). DBS is the most used surgical procedure for ET and the only reimbursed intervention for patients with medically refractory ET in Australia ( REF _Ref34056840 \h Figure 1). DBS involves inserting a permanent electrode into the thalamus or other region causing tremor through a burr hole in the skull and electrically stimulating the VIM. Electrode stimulation is generated by an implantable neurostimulator (pacemaker box) located in the chest region and connected by a wire PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWFyb29yPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

UmVjTnVtPjM2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihaYWFyb29yLCBTaW5haSBldCBhbC4gMjAx

OCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzY8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRk

ZHN0ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjE4OSI+MzY8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlphYXJvb3IsIE0uPC9hdXRob3I+PGF1dGhvcj5TaW5haSwgQS48

L2F1dGhvcj48YXV0aG9yPkdvbGRzaGVyLCBELjwvYXV0aG9yPjxhdXRob3I+RXJhbiwgQS48L2F1

dGhvcj48YXV0aG9yPk5hc3NhciwgTS48L2F1dGhvcj48YXV0aG9yPlNjaGxlc2luZ2VyLCBJLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnRz

IG9mMU5ldXJvc3VyZ2VyeS4mI3hEOzJUZWNobmlvbiBGYWN1bHR5IG9mIE1lZGljaW5lLCBIYWlm

YSxJc3JhZWwuJiN4RDszUmFkaW9sb2d5LCBhbmQuJiN4RDs0TmV1cm9sb2d5LCBSYW1iYW0gSGVh

bHRoIENhcmUgQ2FtcHVzOyBhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TWFnbmV0

aWMgcmVzb25hbmNlLWd1aWRlZCBmb2N1c2VkIHVsdHJhc291bmQgdGhhbGFtb3RvbXkgZm9yIHRy

ZW1vcjogYSByZXBvcnQgb2YgMzAgUGFya2luc29uJmFwb3M7cyBkaXNlYXNlIGFuZCBlc3NlbnRp

YWwgdHJlbW9yIGNhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9zdXJnPC9zZWNv

bmRhcnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG5ldXJvc3VyZ2VyeTwvYWx0LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zdXJnPC9mdWxsLXRpdGxl

PjxhYmJyLTE+Sm91cm5hbCBvZiBuZXVyb3N1cmdlcnk8L2FiYnItMT48L3BlcmlvZGljYWw+PGFs

dC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zdXJnPC9mdWxsLXRpdGxlPjxhYmJyLTE+

Sm91cm5hbCBvZiBuZXVyb3N1cmdlcnk8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4y

MDItMjEwPC9wYWdlcz48dm9sdW1lPjEyODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0

aW9uPjIwMTcvMDMvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RXNzZW50aWFsIFRy

ZW1vci8qZGlhZ25vc3RpYyBpbWFnaW5nLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nLCBJbnRl

cnZlbnRpb25hbDwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBhcmtpbnNvbiBEaXNlYXNlLypkaWFnbm9zdGljIGlt

YWdpbmcvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+UXVhbGl0eSBvZiBMaWZlPC9rZXl3b3Jk

PjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+VGhh

bGFtaWMgTnVjbGVpPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3Jk

PjxrZXl3b3JkPipVbHRyYXNvbmljIFRoZXJhcHkvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPipBQy1QQyA9IGFudGVyaW9yIGNvbW1pc3N1cmUtcG9zdGVyaW9yIGNvbW1pc3N1cmU8

L2tleXdvcmQ+PGtleXdvcmQ+KkNSU1QgPSBDbGluaWNhbCBSYXRpbmcgU2NhbGUgZm9yIFRyZW1v

cjwva2V5d29yZD48a2V5d29yZD4qREJTID0gZGVlcCBicmFpbiBzdGltdWxhdGlvbjwva2V5d29y

ZD48a2V5d29yZD4qRVQgPSBlc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPipNUi1n

dWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipNUmdGVVMgPSBNUi1n

dWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipQRCA9IFBhcmtpbnNv

biZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qUERRLTM5ID0gUEQgUXVlc3Rpb25u

YWlyZTwva2V5d29yZD48a2V5d29yZD4qUGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPipRVUVTVCA9IFF1YWxpdHkgb2YgTGlmZSBpbiBFc3NlbnRpYWwgVHJlbW9yPC9r

ZXl3b3JkPjxrZXl3b3JkPipSRiA9IHJhZGlvZnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPipV

UERSUyA9IFVuaWZpZWQgUGFya2luc29uJmFwb3M7cyBEaXNlYXNlIFJhdGluZyBTY2FsZTwva2V5

d29yZD48a2V5d29yZD4qVklNID0gdmVudHJhbCBpbnRlcm1lZGlhdGUgbnVjbGV1czwva2V5d29y

ZD48a2V5d29yZD4qZXNzZW50aWFsIHRyZW1vcjwva2V5d29yZD48a2V5d29yZD4qZnVuY3Rpb25h

bCBuZXVyb3N1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+KnRoYWxhbW90b215PC9rZXl3b3JkPjxr

ZXl3b3JkPip0cmVhdG1lbnQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjItMzA4NTwvaXNibj48YWNjZXNzaW9uLW51bT4yODI5ODAyMjwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMxNzEvMjAxNi4xMC5KbnMx

Njc1ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5O

TE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWFyb29yPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

UmVjTnVtPjM2PC9SZWNOdW0+PERpc3BsYXlUZXh0PihaYWFyb29yLCBTaW5haSBldCBhbC4gMjAx

OCk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzY8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJwNXoyZWR2YTdzZnIwNWUyZGU3eGYwMDEydnRk

ZHN0ejVhZTkiIHRpbWVzdGFtcD0iMTU4Mjc2NjE4OSI+MzY8L2tleT48L2ZvcmVpZ24ta2V5cz48

cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9y

cz48YXV0aG9ycz48YXV0aG9yPlphYXJvb3IsIE0uPC9hdXRob3I+PGF1dGhvcj5TaW5haSwgQS48

L2F1dGhvcj48YXV0aG9yPkdvbGRzaGVyLCBELjwvYXV0aG9yPjxhdXRob3I+RXJhbiwgQS48L2F1

dGhvcj48YXV0aG9yPk5hc3NhciwgTS48L2F1dGhvcj48YXV0aG9yPlNjaGxlc2luZ2VyLCBJLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnRz

IG9mMU5ldXJvc3VyZ2VyeS4mI3hEOzJUZWNobmlvbiBGYWN1bHR5IG9mIE1lZGljaW5lLCBIYWlm

YSxJc3JhZWwuJiN4RDszUmFkaW9sb2d5LCBhbmQuJiN4RDs0TmV1cm9sb2d5LCBSYW1iYW0gSGVh

bHRoIENhcmUgQ2FtcHVzOyBhbmQuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TWFnbmV0

aWMgcmVzb25hbmNlLWd1aWRlZCBmb2N1c2VkIHVsdHJhc291bmQgdGhhbGFtb3RvbXkgZm9yIHRy

ZW1vcjogYSByZXBvcnQgb2YgMzAgUGFya2luc29uJmFwb3M7cyBkaXNlYXNlIGFuZCBlc3NlbnRp

YWwgdHJlbW9yIGNhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogTmV1cm9zdXJnPC9zZWNv

bmRhcnktdGl0bGU+PGFsdC10aXRsZT5Kb3VybmFsIG9mIG5ldXJvc3VyZ2VyeTwvYWx0LXRpdGxl

PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zdXJnPC9mdWxsLXRpdGxl

PjxhYmJyLTE+Sm91cm5hbCBvZiBuZXVyb3N1cmdlcnk8L2FiYnItMT48L3BlcmlvZGljYWw+PGFs

dC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogTmV1cm9zdXJnPC9mdWxsLXRpdGxlPjxhYmJyLTE+

Sm91cm5hbCBvZiBuZXVyb3N1cmdlcnk8L2FiYnItMT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4y

MDItMjEwPC9wYWdlcz48dm9sdW1lPjEyODwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxlZGl0

aW9uPjIwMTcvMDMvMTc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+RXNzZW50aWFsIFRy

ZW1vci8qZGlhZ25vc3RpYyBpbWFnaW5nLyp0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFs

ZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Kk1hZ25ldGljIFJlc29uYW5jZSBJbWFnaW5nLCBJbnRl

cnZlbnRpb25hbDwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBhcmtpbnNvbiBEaXNlYXNlLypkaWFnbm9zdGljIGlt

YWdpbmcvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+UXVhbGl0eSBvZiBMaWZlPC9rZXl3b3Jk

PjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+VGhh

bGFtaWMgTnVjbGVpPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3Jk

PjxrZXl3b3JkPipVbHRyYXNvbmljIFRoZXJhcHkvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPipBQy1QQyA9IGFudGVyaW9yIGNvbW1pc3N1cmUtcG9zdGVyaW9yIGNvbW1pc3N1cmU8

L2tleXdvcmQ+PGtleXdvcmQ+KkNSU1QgPSBDbGluaWNhbCBSYXRpbmcgU2NhbGUgZm9yIFRyZW1v

cjwva2V5d29yZD48a2V5d29yZD4qREJTID0gZGVlcCBicmFpbiBzdGltdWxhdGlvbjwva2V5d29y

ZD48a2V5d29yZD4qRVQgPSBlc3NlbnRpYWwgdHJlbW9yPC9rZXl3b3JkPjxrZXl3b3JkPipNUi1n

dWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipNUmdGVVMgPSBNUi1n

dWlkZWQgZm9jdXNlZCB1bHRyYXNvdW5kPC9rZXl3b3JkPjxrZXl3b3JkPipQRCA9IFBhcmtpbnNv

biZhcG9zO3MgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD4qUERRLTM5ID0gUEQgUXVlc3Rpb25u

YWlyZTwva2V5d29yZD48a2V5d29yZD4qUGFya2luc29uJmFwb3M7cyBkaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPipRVUVTVCA9IFF1YWxpdHkgb2YgTGlmZSBpbiBFc3NlbnRpYWwgVHJlbW9yPC9r

ZXl3b3JkPjxrZXl3b3JkPipSRiA9IHJhZGlvZnJlcXVlbmN5PC9rZXl3b3JkPjxrZXl3b3JkPipV

UERSUyA9IFVuaWZpZWQgUGFya2luc29uJmFwb3M7cyBEaXNlYXNlIFJhdGluZyBTY2FsZTwva2V5

d29yZD48a2V5d29yZD4qVklNID0gdmVudHJhbCBpbnRlcm1lZGlhdGUgbnVjbGV1czwva2V5d29y

ZD48a2V5d29yZD4qZXNzZW50aWFsIHRyZW1vcjwva2V5d29yZD48a2V5d29yZD4qZnVuY3Rpb25h

bCBuZXVyb3N1cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+KnRoYWxhbW90b215PC9rZXl3b3JkPjxr

ZXl3b3JkPip0cmVhdG1lbnQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjItMzA4NTwvaXNibj48YWNjZXNzaW9uLW51bT4yODI5ODAyMjwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjMxNzEvMjAxNi4xMC5KbnMx

Njc1ODwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5O

TE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA (Zaaroor, Sinai et al. 2018).Following a DBS procedure, patients are transferred to the intensive care unit for overnight observation. A cerebral CT scan is performed post operatively as routine. In most patients, stimulation is commenced on the evening following surgery. Patients are transferred to the Neurosurgical Ward the following morning and required to stay in hospital for a minimum of one week.Once discharged, patients are required to return to their treating neurologist frequently for several months in order to have the stimulation adjusted and optimised. Doctors must also supervise reductions in patients’ medications. Similar to MRgFUS, patients might also receive BSC alongside DBS, as reflected in the algorithm ( REF _Ref34056807 \h Figure 2). After a few months, the number of medical visits usually decreases significantly, though patients are still required to return to have their stimulator checked regularly for monitoring and adjustment of hardware settings. Complications that can arise requiring re-intervention include:Fracture or breakage of the wire or cableBattery failure (life span of the pulse generator battery is typically 3-5 years)Erosion of the cable or device through the skinMigration of the electrode in the brain due to failure of the anchorInfection at the implant site(s).In Australian clinical practice, DBS is generally preferred over lesional surgery, as it can be reversed, it leaves little or no residual damage, and it is adjustable with the use of a programmable stimulator. Only DBS is funded through Medicare (see MBS items for DBS in REF _Ref35333795 \h Table 2) and as such, it is considered the primary comparator for the submission. DBS may be performed unilaterally or bilaterally; however as both procedures are performed at the same time many patients elect to undergo bilateral surgery due its superior clinical effectiveness. The application form provided historical (5-year) utilisation of DBS in Table 3, estimating approximately 250 procedures performed annually, mostly bilateral.Table SEQ Table \* ARABIC 2MBS items for Deep Brain StimulationMBS item numberMBS item descriptorFee40850DEEP BRAIN STIMULATION (unilateral) functional stereotactic procedure including computer assisted anatomical localisation, physiological localisation including twist drill, burr hole craniotomy or craniectomy and insertion of electrodes $2,300.7040851DEEP BRAIN STIMULATION (bilateral) functional stereotactic procedure including computer assisted anatomical localisation, physiological localisation including twist drill, burr hole craniotomy or craniectomy and insertion of electrodes$4,026.4040852DEEP BRAIN STIMULATION (unilateral) subcutaneous placement of neurostimulator receiver or pulse generator $346.0540854DEEP BRAIN STIMULATION (unilateral) revision or removal of brain electrode$534.8040856DEEP BRAIN STIMULATION (unilateral) removal or replacement of neurostimulator receiver or pulse generator$259.5540858DEEP BRAIN STIMULATION (unilateral) placement, removal or replacement of extension lead$534.8040860DEEP BRAIN STIMULATION (unilateral) target localisation incorporating anatomical and physiological techniques, including intra-operative clinical evaluation, for the insertion of a single neurostimulation wire$2,055.0540862DEEP BRAIN STIMULATION (unilateral) electronic analysis and programming of neurostimulator pulse generator$163.85Source: p29 of Application FormNote: All above MBS item codes are indicated for “Essential tremor or dystonia where the patient's symptoms cause severe disability”.Table SEQ Table \* ARABIC 3Utilisation of MBS items for DBSMBS itemDescription2014201520162017201840850Unilateral DBS161210161940851Bilateral DBS217245235233226-Total DBS233257245249245Source: Table 4, p32 of application formPASC confirmed that the main comparator is deep brain stimulation (DBS), unilateral or bilateral, noting that DBS is used to treat a broader range of conditions including Parkinsonian tremor, ET and dystonia. PASC noted that DBS has the advantage of being reversible, and appears to have a different safety profile compared with MRgFUS.The applicant agreed that the main comparator is DBS, unilateral or bilateral. While DBS is used for a broader range of conditions, the applicant noted only data relevant to ET will be used in the ADAR.It is, however, acknowledged that there may be a group of medically refractory ET patients who are currently receiving BSC because they are unwilling to accept the risks associated with DBS or are contraindicated for the procedure. This may include continued optimised medical therapy, as described above, despite its limited efficacy where no alternative options are available. MRgFUS offers these patients a treatment option that does not require burr-hole craniotomy, craniectomy or general anaesthesia. As such, BSC may be a potential secondary comparator in a subgroup of the proposed population.As per the clinical algorithm shown in REF _Ref34056807 \h Figure 2, the positioning of MRgFUS will be in line with DBS and BSC. The application form indicated that MRgFUS will replace DBS, but will be used in addition to BSC. That is, for use in patients shown to be refractory or intolerant to medical therapy, and whose symptoms cause severe disability.PASC noted DBS might be given in addition to best supportive care (BSC), which might include continued optimised medical therapy (i.e. medically refractory). PASC noted BSC alone would be a potential secondary comparator, given in a subgroup of the proposed population contraindicated or not suitable for surgery.OUTCOMESPASC noted that outcomes in the Draft PICO were aligned with outcomes chosen from a pivotal RCT, which was funded by the applicant (and others). PASC considered that objective and validated outcomes typically used for health technology assessment purposes should be chosen, rather than aligning the outcomes from a single trial. For example, health-related quality of life outcomes ideally should be reported with a standardised tool (e.g. 36-Item Short Form Survey [SF-36]) and disease specific tool (e.g. Quality of Life in Essential Tremor Questionnaire [QUEST]). Importantly, PASC considered it was unclear what the minimum clinically important difference (MCID) was for the Clinical Rating Scale for Tremor (CRST), which would be critical to interpreting the comparative clinical benefit. The applicant agreed and stated it would investigate this further during the assessment phase. PASC also advised that long-term outcomes should be included when available.PASC suggested the following outcomes:Patient-relevant outcomesSafety Outcomes:Adverse Events:Numbness, paraesthesiaes, ataxia, dysarthria, dysphagia, in short and long term (>12 months)Intraprocedural harms (due to helmet or other events) as noted in RCT and observational studiesFailed procedure rate (skull thickness, claustrophobia/anxiety, other)Efficacy/ Effectiveness including, but not limited to, patient-relevant outcomes:Number of patients with benefit (number reaching MCID threshold of tremor scale (if validated)Median (not mean) benefit in tremor, using MCID of Clinical Rating Scale for Tremor (CRST)Duration of adequate benefit (using MCID)Recurrence of tremor necessitating further treatmentNeed for retreatment with DBSAbility to cease medicationsQuality of life (QoL) outcomes – standardised (SF36) and disease-specific (Quality of Life in Essential Tremor Questionnaire [QUEST])Return to employment/productivityChange in social disabilityHealthcare system outcomesHealthcare resourcesCosts to deliver the intervention, including cost of the helmetRe-intervention costsCost-effectivenessTotal Australian Government healthcare costsTotal cost to the Medicare Benefits Schedule (MBS)Total cost to the Pharmaceutical Benefits Scheme (PBS)Total cost to other healthcare servicesThe Applicant noted, the outcomes were not selected based on the outcomes of a single trial but rather from the outcomes reported in the evidence base for MRgFUS overall. It is not possible to present outcomes in the ADAR that are not reported in the relevant trials. To date, no studies of MRgFUS in ET have reported SF-36 or EQ5D outcomes before and after treatment, therefore the ADAR will be reliant on the QUEST instrument in order to be able to compare with DBS and BSC. Currently, there are long term outcomes reported up to five years post procedure. The applicant confirmed that all long-term studies will be included in the ADAR.The Applicant noted that to date, there is no defined level for the MCID of CRST, but the paper by Elble et al (2013) which evaluates the various ET rating scales make the point that CRST is sensitive to clinical change in treatment trials. Reflecting the lack of an established MCID, the Applicant considered it may not be possible to report the number of responders or the duration of adequate benefit defined by this threshold.The Applicant confirmed that adverse events will be reported for both MRgFUS and the comparator, noting that these have very different profiles. As an invasive therapy, adverse events associated with DBS also include intracranial bleeding and infection, and hardware issues such as lead breakage and these should also be itemised in the outcomes listed.The Applicant clarified that as previously stated, the RCT will also be supported by prospective cohort studies of MRgFUS. While there are risks of bias in any study, these will be addressed when the studies are formally critiqued in the assessment of bias in the ADAR. After the PASC meeting, PASC noted concerns about possible bias in the single RCT (published in NEJM) that will underpin evidence for Application 1614 and that they should be considered during the assessment phase of the application. The Applicant considered that a discussion of the quality of the evidence base for the comparator should also be included. Current and proposed clinical management algorithmsCurrent clinical management algorithm for identified populationPASC advised in the current algorithm, that BSC should be clearly defined, including reference to medical optimisation.14605095250BSCaLong term follow upDiagnosis of ET with severe functional or social disabilityTreatment with pharmacological agentsResponds/tolerates medical therapy?Continued medical therapyYesMedically refractory ETContinued benefit?NoNoReferral to a neurologistUnilateral or bilateral DBS ± BSCOptimisation and programmingbRe-intervention, e.g. Battery replacementFigure SEQ Figure \* ARABIC 1. Current clinical management algorithm for ETa In those unwilling to accept the risks associated with DBS or are contra-indicated for the procedureb The Ontario HTA 2018 stated that according to the literature and clinical expert opinion tremor recurrence can nearly always be controlled by adjusting the stimulation level of the device (reprogramming) and therefore does not require reoperation00BSCaLong term follow upDiagnosis of ET with severe functional or social disabilityTreatment with pharmacological agentsResponds/tolerates medical therapy?Continued medical therapyYesMedically refractory ETContinued benefit?NoNoReferral to a neurologistUnilateral or bilateral DBS ± BSCOptimisation and programmingbRe-intervention, e.g. Battery replacementFigure SEQ Figure \* ARABIC 1. Current clinical management algorithm for ETa In those unwilling to accept the risks associated with DBS or are contra-indicated for the procedureb The Ontario HTA 2018 stated that according to the literature and clinical expert opinion tremor recurrence can nearly always be controlled by adjusting the stimulation level of the device (reprogramming) and therefore does not require reoperation45834301468352YesYesProposed clinical management algorithm for identified populationPASC advised that in the proposed algorithm, there should be more detail in the MRgFUS clinical pathways, including stepping out the pre- and post-procedure imaging workup (specifically how many MRIs and the timing of these) and including relevant downstream outcomes and their associated management options.952549530BSCaLong term follow upaDiagnosis of ET with severe functional or social disabilityTreatment with pharmacological agentsResponds/tolerates medical therapy?Continued medical therapyYesMedically refractory ETContinued benefit?YesNoNoReferral to a neurologistUnilateral or bilateral DBS ± BSCUnilateral MRgFUS b,c ± BSCOptimisation and programmingdRe-intervention, e.g. Battery replacementFigure SEQ Figure \* ARABIC 2. Proposed clinical management algorithm for ETa In those unwilling to accept the risks associated with DBS or are contra-indicated for the procedureb In Australian clinical practice currently, MRgFUS is provided as unilateral treatment. The application form stated that treatment of the contralateral side may be performed after a minimum of 6-12 months.c Following results from Elias et al. (2016), the Ontario HTA 2018 estimated 40% of people who undergo MRgFUS (or radiofrequency thalatomy) may undergo a second surgery once tremor recursd The Ontario HTA 2018 stated that according to the literature and clinical expert opinion tremor recurrence can nearly always be controlled by adjusting the stimulation level of the device (reprogramming) and therefore does not require reoperationBSCaLong term follow upaDiagnosis of ET with severe functional or social disabilityTreatment with pharmacological agentsResponds/tolerates medical therapy?Continued medical therapyYesMedically refractory ETContinued benefit?YesNoNoReferral to a neurologistUnilateral or bilateral DBS ± BSCUnilateral MRgFUS b,c ± BSCOptimisation and programmingdRe-intervention, e.g. Battery replacementFigure SEQ Figure \* ARABIC 2. Proposed clinical management algorithm for ETa In those unwilling to accept the risks associated with DBS or are contra-indicated for the procedureb In Australian clinical practice currently, MRgFUS is provided as unilateral treatment. The application form stated that treatment of the contralateral side may be performed after a minimum of 6-12 months.c Following results from Elias et al. (2016), the Ontario HTA 2018 estimated 40% of people who undergo MRgFUS (or radiofrequency thalatomy) may undergo a second surgery once tremor recursd The Ontario HTA 2018 stated that according to the literature and clinical expert opinion tremor recurrence can nearly always be controlled by adjusting the stimulation level of the device (reprogramming) and therefore does not require reoperationThe Applicant agreed with the PASC and confirmed that detailed descriptions of BSC and the proposed algorithm will be provided in the ADAR.Proposed economic evaluationThe clinical claim is that MRgFUS in patients with medically refractory ET is non-inferior in safety and non-inferior in clinical effectiveness when compared with DBS, and that MRgFUS is inferior in safety and superior in clinical effectiveness when compared with BSC. PASC confirmed that a cost-effectiveness analysis or cost-utility analysis is most appropriate. Although claiming non-inferiority, the technologies, side effects and outcomes appear different, so a cost-minimisation is not appropriate. The Applicant agreed with the PASC.It should be noted that the cost-effectiveness analysis should include also the price of the prostheses/devices and other consumable material needed for the delivery of DBS, as the material cost is far greater than the cost of the procedure itself (Appendix A, REF _Ref42170692 \h Table 4).The applicant claims that DBS has already been established as cost-effective against BSC (MSAC Application 1109), and assuming MRgFUS is proven to be non-inferior to DBS and with lower costs, an economic evaluation of MRgFUS against BSC should not be required. It would automatically mean that MRgFUS would provide value for money relative to BSC.Proposed MBS item descriptor and MBS feeMBS item descriptors for radiology, neurology and neurosurgery components of the service are presented below. It was considered that the justification of the proposed items and fees will be important in the assessment report.Patient preparation and pre-surgical planningBefore treatment, a specialised CT scan is performed to detail the shape, thickness and density of the patient’s skull. The skull density ratio is calculated by the radiologist to assess whether sufficient energy can be delivered during the MRgFUS procedure and confirm patient suitability. A pre-operative MRI scan is also performed to exclude contraindications, assess the patient’s anatomy and plan the treatment. The pre-operative MRI scan is fused with the CT to more accurately guide treatment. Patients with suitable imaging evaluations are progressed towards planning for the procedure. It was noted 5/81 patients from the pivotal RCT were excluded following randomisation but before their procedures due to: unsuitable skull (identified by skull density ratio from CT; n=2); patient withdrawal due to anxiety; vascular risk identified on MRI (missed on first interpretation) and investigator discretion.The proposed MBS item wording and MBS fee for the pre-operative MRI scan of the brain (to assess suitability for MRgFUS) is based on other MBS ‘MRI Scan of the Head’ services.Category 5 – DIAGNOSTIC IMAGING SERVICESMAGNETIC RESONANCE IMAGING (including Magnetic Resonance Angiography if performed), performed under the professional supervision of an eligible provider at an eligible location where the patient is referred by a specialist or by a consultant physician - scan of head for:- assessment of suitability for treatment of essential tremor with MRI guided focussed ultrasoundEssential tremor where:Symptoms cause severe disability, andTremor has proven refractory to, or recurred following, maximal medical therapyBulk bill incentive(Anaes.)MBS Fee: $403.20 Benefit: 75% = $302.40 85% = $342.75Planning and target verificationOn the day of treatment, new images are acquired, with the patient positioned with the stereotactic frame and MRgFUS system in situ (utilising body coil). These images are co-registered with the pre-operative imaging data.The proposed MBS item wording and MBS fee for MRI of the brain (and associated planning reports) is based on an existing MBS item for planning of stereotactic neurosurgery (MBS item 63010). The applicant notes that a new MBS item for this service may not be required.Category 5 – DIAGNOSTIC IMAGING SERVICESMAGNETIC RESONANCE IMAGING (including Magnetic Resonance Angiography if performed), performed under the professional supervision of an eligible provider at an eligible location where the patient is referred by a specialist or by a consultant physician - scan of head for:- stereotactic scan of brain, with Fiducials in place, for the sole purpose to allow planning for MRI guided focussed ultrasoundBulk bill incentive(Anaes.)MBS Fee: $336.00 Benefit: 75% = $252.00 85% = $285.60Treatment/intraoperative procedureThree items for unilateral MRgFUS are proposed for the intraoperative procedure: one for the neurosurgery, neurology, and radiology services provided, respectively. The applicant has advised against placing restrictions on the specialty of physicians performing these services, provided they are adequately trained and qualified. The applicant noted it is feasible the tasks may be performed by a physician from any of the three disciplines mentioned. The application form stated that the proposed service would be delivered once per patient on the dominant side. The application form also stated that should the patient experience a recurrence of tremor, and the patient was assessed suitable by the treating physician for retreatment, then retreatment is permitted once only per patient, per side. However, it was noted that there were no restrictions applied to the frequency of use for the proposed MBS item descriptors.The proposed MBS item wording and MBS fee for neurology services provided during the procedure is based on the analogous service provided during DBS procedure (MBS item 40860).Category 3 – THERAPEUTIC PROCEDURESMRI GUIDED FOCUSSED ULTRASOUND (unilateral), target localisation incorporating anatomical and physiological techniques, including intra-operative clinical evaluationMultiple Operation Rule(Anaes.) (Assist.)Claimable only once per patient per lifetime.MBS Fee: $2,055.05 Benefit: 75% = $1,541.29The proposed MBS item wording and MBS fee for neurosurgery services is based on the surgical component (i.e. excluding placement of the generator and revision/programming) of the DBS procedure (MBS items 40850 and 40851).Category 3 – THERAPEUTIC PROCEDURESMRI GUIDED FOCUSSED ULTRASOUND (unilateral) procedure including computer assisted anatomical localisation, physiological localisation, and lesion production in the basal ganglia, brain stem, thalamus or deep white matter tracts, for the treatment of:Essential tremor where:Symptoms cause severe disability, andTremor has proven refractory to, or recurred following, maximal medical therapyMultiple Operation Rule(Anaes.) (Assist.)Claimable only once per patient per lifetime.MBS Fee: To be determined ($2,301 to $4,026) Benefit: 75% = to be determinedThe applicant notes that there seems to be no suitable, analogous MBS items upon which to base wording and MBS fee for radiology services provided during the procedure (intraoperative fused MRI images to plan the treatment and identify the target). It is anticipated the fee would be higher than a single MRI Scan of the Head, due to the amount of time the radiologist is with the patient, and the number of scans taken during the procedure. A suitable fee should be proposed and justified in the applicant-developed assessment report (ADAR).Category 3 – THERAPEUTIC PROCEDURESMRI GUIDED FOCUSSED ULTRASOUND (unilateral), target localisation incorporating anatomical and physiological techniques, including intra-operative MRI imaging Multiple Operation Rule(Anaes.) (Assist.)Claimable only once per patient per lifetime.MBS Fee: To be determined Benefit: 75% = to be determinedPASC noted that the proposed item descriptor for intraoperative procedure with MRgFUS should be restricted to patients who do not have Parkinson’s disease, noting that it is sometimes difficult to tell whether a patient has Parkinson’s disease or ET. This has not been included in the MBS item descriptors above, given the difficulty in determining whether a patient has Parkinson’s disease or ET. How to include this appropriately within the item descriptor, should be explored during the assessment phase. The Applicant accepted that MRgFUS should be restricted to patients without PD. However, as previously stated, the applicant considered that ET Plus patients, where the dominant diagnosis is one of ET where additional neurologic signs such as dystonia, ataxia, and parkinsonism, are present should be eligible for treatment. PASC noted retreatment was stated in the application to be permitted once only per patient, per side, but not included in the current item descriptor. The Applicant advised that retreatment was so uncommon that it would not impact the item descriptor. PASC also noted contralateral treatment was not relevant to this application as it was currently used for investigational purposes. Therefore, PASC considered as there is currently no evidence to support retreatment, the item descriptor should include a note stating that unilateral, once-only treatment is permitted. This has been updated in the item descriptors above.The Applicant disagreed with the PASC and considered that inclusion of the contralateral treatment in the item descriptor is reasonable (see ‘Population’).Confirmation whether the multiple operation rule applies, and whether this applies if different providers are billing for different parts of the procedure, will be undertaken.Treatment outcome assessmentTreatment outcome is confirmed using post-treatment MRI scans at various intervals. The application form specified patients would undergo a MRI at three and/or six months follow-up; however, they have not proposed any restrictions of frequency of use for the proposed item descriptor.The proposed MBS item wording and fee for MRI of the brain (to assess patient outcomes and exclude potential complications) is based on other MBS ‘MRI Scan of the Head’ services.PASC queried if an item descriptor was necessary for the post procedure MRI performed at 3 and/or 6 months.Category 5 – DIAGNOSTIC IMAGING SERVICESMAGNETIC RESONANCE IMAGING (including Magnetic Resonance Angiography if performed), performed under the professional supervision of an eligible provider at an eligible location where the patient is referred by a specialist or by a consultant physician - scan of head for:- assessment of treatment outcomes following MRI guided focussed ultrasound procedureBulk bill incentive(Anaes.)MBS Fee: $403.20 Benefit: 75% = $302.40 85% = $342.75Consultation feedbackPASC noted that support was received from the Neurosurgical Society of Australia and the Royal Australian New Zealand College of Radiologists. PASC also noted the Royal Australian and New Zealand College of Radiologists (RANZCR) requested that interventional radiologists should be eligible to provide the service.Next stepsPASC advised that, upon ratification of the post-PASC PICO, the application can proceed to the Evaluation Sub-Committee (ESC) stage of the MSAC process. PASC noted the applicant has elected to progress its application as an ADAR (applicant-developed assessment report). The applicant confirmed it intends to submit the ADAR in October 2020.Appendix ATable SEQ Table \* ARABIC 4Approximate cost profile for MRgFUS and comparison with DBS procedureCost itemMRgFUSDBSaResource ItemCostReferenceCostReferenceNeurosurgeon$2301-$4026Based on MBS items numbers 40850 and 40851$2301-$4026MBS items numbers 40850 and 40851Neuorologist MBS fee$2,055Based on MBS items numbers 40860$2,055MBS items number 40860Radiologist feesapprox $2000 to $3000Based on MBS item numbers for MRI Scan of the Head (5 to 6 in total before, during and after the procedure; see below)Not applicable$0Prostheses / Single use consumablesPrice / Fee to be determinedDisposable patient kitSee Question 12 of application formGenerator: $8598, $14307, $18193, $20,900PL number: 040401Leads: $1995, $3943, $4337PL number: 040403External programmer: $1330, $1876PL number: 040402Electrodes $1425PL number: 040404Accessories: $166, $190, $523PL number: 040405Total: approx $30,000 to $40,000 depending on brand and quantity of various devices usedAnaesthesiaVariable depending on individual patient needs, but is generally very rare/minor given the patient needs to be conscious during the procedureTo be investigated in the ADARVariable depending on individual patient needsTo be investigated in the ADARHospital admissionTo be determinedCosts to incorporate:operating theatreamortisation of capital equipmentALOS of 1 to 2 days$22,255 to $64,776(depending on complexity/complications)AR-DRGs B02A to B02C (as used in MSAC application 1109)ALOS of 6 to 19 daysSource: Table 5, p35 of application formNote: This comparison of the cost profile is intended to compare the cost of the respective procedures themselves. It does not include costs associated with maintaining and/or replacing the DBS system and components over the lifetime of the patient. These costs will be investigated in full in the economic evaluation to be included in the ADAR.References ADDIN EN.REFLIST Bhatia, K. P., P. Bain, N. Bajaj, R. J. Elble, M. Hallett, E. D. Louis, J. Raethjen, M. Stamelou, C. M. Testa and G. Deuschl (2018). "Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society." Mov Disord 33(1): 75-87.Clark, L. N. and E. D. Louis (2018). "Essential tremor." Handb Clin Neurol 147: 229-239.Elias, W. J., N. Lipsman, W. G. Ondo, P. Ghanouni, Y. G. Kim, W. Lee, M. Schwartz, K. Hynynen, A. M. Lozano, B. B. Shah, D. Huss, R. F. Dallapiazza, R. Gwinn, J. Witt, S. Ro, H. M. Eisenberg, P. S. Fishman, D. Gandhi, C. H. Halpern, R. Chuang, K. Butts Pauly, T. S. Tierney, M. T. Hayes, G. R. Cosgrove, T. Yamaguchi, K. Abe, T. Taira and J. W. Chang (2016). "A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor." N Engl J Med 375(8): 730-739.Haubenberger, D. and M. Hallett (2018). "Essential Tremor." N Engl J Med 378(19): 1802-1810.Louis, E. D. (2019). "The Roles of Age and Aging in Essential Tremor: An Epidemiological Perspective." Neuroepidemiology 52(1-2): 111-118.Louis, E. D. and J. J. Ferreira (2010). "How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor." Mov Disord 25(5): 534-541.Mohammed, N., D. Patra and A. Nanda (2018). "A meta-analysis of outcomes and complications of magnetic resonance-guided focused ultrasound in the treatment of essential tremor." Neurosurg Focus 44(2): E4.Sharma, S. and S. Pandey (2020). "Treatment of essential tremor: current status." Postgrad Med J 96(1132): 84-93.Zaaroor, M., A. Sinai, D. Goldsher, A. Eran, M. Nassar and I. Schlesinger (2018). "Magnetic resonance-guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases." J Neurosurg 128(1): 202-210. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download