ISSN 1473-9348 VOLUME 19 ISSUE 4 SUMMER 2020

ACNRwww.acnr.co.uk ADVANCES IN CLINICAL & REHABILITATION

In this issue

Rimona Weil, Suzanne Reeves – Hallucinations in Parkinson’s disease: new insights into mechanisms and treatments

Rueben Beer, Stefan Blum – Overview of new developments in myasthenia gravis Gerry Christofi, Ann Holland, Anne Rodger, Rebecca Kimber – An expert opinion: Facial rehabilitation: combining the science and the art

Hasaan Ahmed, Anthony Jones and Manoj Sivan – NEW series: The brain alpha rhythm in the perception and modulation of pain

Srikirti Kodali, Richard Rees, Mike Kemp – The many faces of COVID: Experiences of deployment and redeployment by Registrars

BOOK REVIEWS > INDUSTRY NEWS > CONFERENCE PREVIEWS AND REPORTS > EVENTS DIARY f r o m t h e c o - e d i t o r ...

or this issue, ACNR has endeav- oured to publish prescient arti- CONTENTSSUMMER 2020 F cles dealing with the COVID-19 crisis, without neglecting other areas of neurology and rehabilitation. We CLINICAL VIEWPOINT hope you agree that this has resulted 05 Hospital based rehabilitation services; Rising to the in a Summer edition rich with salient challenge of the COVID-19 pandemic content. Valerie Stevenson, Rachel Farrell, Gita Ramdharry, Orlando Swayne, Nick Concerns about providing Ward, Siobhan Leary, Sarah Holmes adequate care and resources to the 07 Specialist Rehabilitation: The impact of commissioning rehabilitation of patients who have changes during the COVID-19 pandemic Anton Pick been critically ill with COVID-19 is 09 Preparing for the storm: impact of the COVID-19 covered in an article from Valerie Todd Hardy, Co-Editor. pandemic on rehabilitation services Fahim Anwar, Stevenson, Rachel Farrell, Gita Judith Allanson, Katie Bond, Emer McGilloway, Harry Mee Ramdharry, Orlando Swayne, Nick Ward, Siobhan Leary and Sarah 12 The many faces of COVID: Experiences of deployment Holmes from London, who exhort new models of care and call for and redeployment by Neurology Registrars Srikirti Kodali, greater investment in rehabilitation services to cope with increased Richard Rees, Mike Kemp demand. Also, Fahim Anwar, Judith Allanson, Katie Bond, Emer 14 Assessing long-term rehabilitation needs in COVID-19 McGilloway, and Harry Mee from Cambridge discuss the detailed survivors using a telephone screening tool (C19-YRS tool) re-organisation of rehabilitation and hospital resources in the face of Manoj Sivan, Stephen Halpin and Jeremy Gee the pandemic. Anton Pick reflects on the commissioning of a specialist rehabilitation service at his centre in Oxford. REVIEW & REHABILITATION ARTICLES Srikirti Kodali, Richard Rees and Mike Kemp from Cambridge offer a 20 Hallucinations in Parkinson’s disease: new insights into personal perspective on the COVID-19 pandemic leading to the re-de- mechanisms and treatments Rimona Weil, Suzanne Reeves ployment of neurology trainees who found important and meaningful 24 A month of Sundays? What technology can tell us about roles as part of general medical services. on lockdown Alastair Paterson Manoj Sivan, Stephen Halpin and Jeremy Gee from Leeds have 28 Overview of new developments in myasthenia gravis devised a novel telephone screening tool (C19 YRS) to help identify therapy Rueben Beer, Stefan Blum multidomain impairments in COVID-19 patients after their discharge from acute care, to facilitate appropriate community rehabilitation 44 An expert opinion: Facial rehabilitation: combining the follow up. Alastair Paterson from North East England looks at what Big science and the art Gerry Christofi, Ann Holland, Anne Rodger, Data captured from internet sources such as Google tell us about popu- Rebecca Kimber lation-wide changes in sleeping habits during the COVID-19 lockdown. PAIN SERIES ARTICLE Rimona Weil and Suzanne Reeves from London review the current 31 The brain alpha rhythm in the perception and modulation understanding of visual hallucinations in Parkinson’s disease. Thomas of pain Hasaan Ahmed, Anthony Jones and Manoj Sivan Mace and Charlie Peel from Hull introduce Parkinson’s Hub, a SPECIAL FEATURES multidisciplinary integrated community care model focusing on frail Parkinson’s patients. 34 Can a Type-2 Diabetes Mellitus drug be hope for Multiple Reuben Beer and Stefan Blum from Brisbane survey developments System Atrophy? Yeliz Demir in myasthenia gravis therapy covering potential new monoclonal anti- 38 Parkinson’s Hub: An integrated pathway for people with body and a possible role for cladribine. Parkinson's and frailty Thomas Mace Gerry Christofi, Ann Holland, Anne Rodger and Rebecca Kimber 42 Case Report: Occurrence of Balínt Syndrome in a patient from London review the field of facial rehabilitation. with Hypereosinophilic Syndrome Philipp Klocke, Anna Whalen- The first of a planned series of articles on chronic pain is from Browne, Mohamed Panju, Elliot Hepworth Hasaan Ahmed, Anthony Jones and Manoj Sivan from Manchester 47 Neurological Signs: Syllogomania; with a note on looking at how the brain alpha rhythm is modulated by pain. Diogenes of Sinope Andrew Larner Also in this issue, JMS Pearce explains the provenance of Kayser- Fleischer rings and AJ Larner discusses hoarding, Diogenes syndrome 48 Historical note: The Kayser-Fleischer ring JMS Pearce and the novelist Barbara Pym. REGULARS Our case report is of Balint’s syndrome in a patient with hypereosin- 22 & 27 Book reviews ophilic syndrome. Lastly, we have all the latest conference reports and 37 Industry News book reviews. We hope you enjoy this edition of ACNR. 50 Conference previews and reports Todd Hardy, Co-Editor 51 Events diary E. [email protected]

Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by any person acting or refraining from action as a result of material in or omitted from this magazine. Any new methods and techniques ACNR described involving drug usage should be followed only in conjunction with drug manufacturers’ own published Published by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ. literature. This is an independent publication - none of those contributing are in any way supported or remunerated Publisher. Rachael Hansford E. [email protected] by any of the companies advertising in it, unless otherwise clearly stated. Comments expressed in editorial are those of the author(s) and are not necessarily endorsed by the editor, editorial board or publisher. The editor’s decision is final PUBLISHER AND ADVERTISING and no correspondence will be entered into. Rachael Hansford, T. 01747 860168, M. 07989 470278, ACNR's paper copy is published quarterly, E. [email protected] with Online First content and additional email updates. COURSE ADVERTISING Rachael Hansford, E. [email protected] Sign up at www.acnr.co.uk/subscribe-to-acnrs-e-newsletter EDITORIAL Anna Phelps E. [email protected] Printed by Stephens & George @ACNRjournal /ACNRjournal/

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Valerie Stevenson, MBBS, MRCP, MD, Hospital based is a Consultant Neurologist and Clinical Director for Rehabilitation at University College London Hospitals. She is the Lead of the Multidisciplinary Spasticity Management Service. rehabilitation services; Rachel Farrell, MB BCh MRCPI PhD, is a Consultant Neurologist at the National Hospital Queen Square, and an honorary Rising to the challenge associate Professor in the Department of , Queen Square, Institute of Neurology, UCL. Dr Farrell specialises in and complex spasticity of the COVID-19 management including Intrathecal baclofen and botulinum toxin. Dr Farrell also leads a multidisciplinary service to manage walking impairment in people with MS. Her research activity involves commercial and investigator led pandemic trials in spasticity and MS.

Gita Ramdharry, PhD, MSc, Key Points PGCert BSc, • Prioritising rehabilitation is essential in the UK’s recovery plan for the is a Consultant Allied Health Professional in COVID-19 pandemic. Neuromuscular Diseases at the National Hospital • Currently there is a mismatch between rehabilitation needs and for Neurology and . She is an available services; investment is critical for inpatient, community and Honorary Senior Lecturer at UCL and a Visiting Professor at Kingston University. Her research technological service delivery models. interests include rehabilitation interventions for • Embracing technological solutions and creating novel partnerships people with and muscle disease. with businesses, the private and charitable sectors are pivotal to success in developing rehabilitation strategies for the UK to cope with Orlando Swayne, MA (Cantab) the COVID-19 pandemic. MB BS MRCP (Neurol) PhD, is a Consultant Neurologist at the National Hospital for Neurology & Neurosurgery, and at Northwick Park Hospital, Honorary Associate Professor at the UCL Institute of Neurology. Abstract Orlando Swayne trained at Cambridge University As elective hospital activity resumes there is an increasing demand on and then in London, and obtained a Neuroscience rehabilitation services to manage those with COVID-19 related impairments, PhD from UCL. He has published work on the control of movement and on Neurorehabilitation patients who had their rehabilitation terminated to release resources to the following stroke, from research done at UCL and at the NIH in the USA. He acute emergency response and those living with long term conditions. completed a post-training fellowship in Neurorehabilitation. Investment equal to or above that needed to manage the acute pandemic response will be required along with innovative and novel strategies to Nick Ward, MBBS BSc, MD, FRCP, deliver rehabilitation through technologies and partnership with business is a Professor of Clinical Neurology and Neurorehabilitation and Honorary Consultant and charitable organisations. Neurologist. His clinical and research interest is in stroke and neurorehabilitation and in particular the assessment and treatment of upper limb dysfunction. he COVID-19 pandemic has stressed all areas of the health and social care network. Services across all sectors radically reconfig- Tured to support the acute response in anticipation of large numbers Siobhan Leary, of patients and staff affected by COVID-19. Services now face many new MBBS, MD, FRCP, challenges, including how we deal with the need for physical distancing is a Consultant Neurologist at the National within patients and staff, the effects of social isolation on patients denied Hospital for Neurology and Neurosurgery. She visitors in hospital and social care settings, and the difficulties in delivering has specialist interests in and 1 vocational rehabilitation. rehabilitation interventions without hands on treatment.

Acute phase effects on inpatient rehabilitation services In the early phase of the pandemic response the focus was on saving lives. Sarah Holmes The imperative was to ensure that there were sufficient beds available for is a Clinical Specialist Physiotherapist. She acute care. Many patients had their rehabilitation programme cut short completed her physiotherapy BSc (hons) at as specialist units suddenly changed their focus away from managing Birmingham University in 1999. She was accepted patients with complex needs to rapidly discharging such patients from onto an NIHR Masters of research programme at St Georges in 2010. Following this she completed hospital and creating capacity. For inpatient neurorehabilitation units this a leadership and management masters module. meant making difficult decisions about goal prioritisation and discharge She continues research into Neuromuscular destinations. The rehabilitation needs of these patients however remain conditions at the National Hospital for and are likely to be exacerbated by interruption of their treatment. Neurology and Neurosurgery. COVID-19 itself has generated a new cohort of patients with serious rehabilitation requirements secondary to the neurological, cardio-pul- Correspondence to: Val Stevenson, monary, musculoskeletal, psychological and psychiatric consequences The National Hospital for Neurology and Neurosurgery UCLH, Queen of the disease and prolonged stays in intensive care units.2 Neurological Square, presentations include novel COVID-related stroke,3 critical illness myop- London WC1N 3BG. E. [email protected] athy or neuropathy, Guillain-Barré Syndrome, brain injury from prolonged hypoxia, acute disseminated encephalomyelitis and necrotising haem-

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orrhagic encephalopathy affecting the brain- sive and harder to get right than the acute Vocational rehabilitation: With the asso- stem.4 All of these conditions result in signifi- response.10 Recovery is defined as the process ciated economic downturn, keeping people cant and often complex neurological impair- of rebuilding, restoring and rehabilitating the with disabilities in work has never been more ment requiring in-patient multidisciplinary community following an emergency, but it is crucial. Vocational Rehabilitation is an area rehabilitation. It has been estimated that 45% more than simply the replacement of what has which lends itself to telephone and video of hospital COVID-19 patients will require been lost. There is a clear opportunity here to consultations which can be run from specialist support from health and social care and 4% regenerate the field of rehabilitation through centres. There are some exceptions where face- will need inpatient rehabilitation.5 raising aspirations, improving skills and opti- to-face consultations are required including COVID-19 has also had indirect effects on mising environments whilst introducing new cognitive and upper limb assessments along healthcare. There has been an unexpected people, collaborations, team working and with workplace visits (although these could and alarming reduction in patients presenting dynamism.10,11 These are essential principles be explored with hand held devices via video to hospital with early neurological symptoms that we, the rehabilitation community, must when people return to work); these small because of fears of coming into contact with get right. numbers can be managed with appropriate the virus.6 The consequences for healthcare As COVID-related admissions are declining social distancing. Home working has anec- services, as patients once again seek medical and we begin cautiously to re-open our hospi- dotally been beneficial to many patients who help, are unclear. Patients who have faith- tals, rehabilitation must be a priority. It is well suffer from fatigue and has always been a fully adhered to the lockdown, particularly established that rehabilitation is both clin- commonly requested reasonable adjustment, in the poorer sections of society already at ically and cost-effective through increasing but is sometimes resisted by employers; it is higher risk, are accumulating unmet primary independence, social reintegration and return hoped that the general shift to home working healthcare needs; untreated hypertension or to work, reduction of ongoing care costs and will facilitate this adjustment in the future and diabetes, reduced exercise, all of which could appropriate long-term disability management help many of our patients living with neurodis- contribute to a further late rise in neuro- and and .1 Prioritising rehabilitation ability or LTCs to stay in work.​ cardiovascular disease. will take serious organisational and financial We must also not forget those patients with investment in the necessary resources with Long term conditions and rare neuro- pre-existing long-term neurological conditions clear understanding of the issues involved. logical disorders: Alongside telephone (LTCs); an estimated 10 million people in the Not only do the direct physical and/or and video consultations there are additional United Kingdom.7 Concerns regarding immuno- pulmonary consequences of COVID-19 need opportunities for innovative working that may suppression, re-deployment of staff, changes to addressing but the complex needs of many, better meet the needs of some people with the hospital environment and patient anxiety particularly those living with LTCs have to be LTCs. Different models of care can incorporate have created a risk of treatment interruption or considered.2,5 video clinics with local therapists, carers or delay for those receiving infused disease modi- Due to the national healthcare strategy family members and exercise professionals, fying treatments (e.g. for multiple sclerosis, of increasing capacity in acute hospital limiting travel and fostering local support immune-mediated neuropathies) increasing the settings for COVID-19 cases, many patients for the patient. Remote group interventions risk of relapse and subsequent deterioration. In with unmet rehabilitation needs are now left provide connection for people who can feel addition many of these patients rely on timely untreated at home or in social care settings. isolated with the rarity of their disease, setting access to specialist rehabilitation services for The responsibility for managing these patients the foundation for peer as well as professional ongoing symptom management including cannot be allowed to fall solely to community support. Groups are also important for educa- botulinum toxin, intrathecal baclofen, splinting teams. Community rehabilitation and support tion elements about conditions (e.g. newly and functional electrical stimulation. Delays services have been drastically under-resourced diagnosed multiple sclerosis group) or inter- in access lead to distress, loss of function and in recent years with reductions in staffing or ventions such as fatigue. Self-management reduced quality of life.8 Similarly patients with provision of community rehabilitation teams, strategies are amenable to virtual platforms, Rare Neurological Disorders (RNDs), often life early supported discharge teams, re-ablement as demonstrated by the Bridges programme, limiting conditions such as the muscular dystro- teams, neuro-navigators and community an initiative developed by a healthcare organi- phies, struggle to access therapy and rehabilita- nurse specialists. Similarly, the provision of sation partnering with a social enterprise.13 Set tion services in normal times. Specialist clinics borough-based Level 2 neurorehabilitation up and facilitation of “blended care” requires with detailed understanding of these condi- units (specialist neurorehabilitation suitable additional technological and personnel tions are few and face significant challenges in for a person with a moderate stroke), is inad- resource to current specialist service set up, serving a population dispersed around the UK. equate with some entire counties having no but has the potential not only to meet the gap Shielding and other COVID-19 restrictions such facility at all. in support but to enhance care for people with enforce extended sedentary periods with It is therefore imperative that we make a LTCs and RNDs. potential for profound effects. Reduced case for investment in all areas of rehabili- aerobic capacity, muscle strength and general tation; community based, local Level 2/3 Neuro Rehab OnLine (N-ROL): Rapid deconditioning will impact on mobility, falls inpatient services, specialist regional Level 1 implementation of new ideas into healthcare risk, function, independence, mood and well- inpatient services and facilitation of innov- settings is notoriously difficult. N-ROL is an being, contributing to increased care and ative, flexible and highly skilled delivery of example of what can be achieved by the NHS equipment needs with their associated costs. specialist rehabilitation to patients in their through partnership with academic (University Access to rehabilitation services for those own homes. College London) and charitable organisations living with LTCs has always been a low priority (SameYou, sameyou.org). N-ROL is a novel for both inpatient and community based New models of care (currently) London based service established rehabilitation, but now represents an even Necessity certainly breeds innovation and rapidly to provide group-based online virtual bigger healthcare challenge. It seems likely the current situation has forced us to chal- rehabilitation and support, allowing one or that in the wake of COVID-19 the mismatch lenge ourselves and adopt new approaches two clinicians to work with groups of up to 10 between rehabilitation needs and the services of rehabilitation delivery. In many cases this or 20 patients at a time in their own homes. available will become starker.6,9 has proved to be a way to improve or enhance Groups can focus on functional fitness, upper existing delivery pathways, although it is essen- limb function, communication and cognitive Recovery phase and case for investment tial to recognise that significant investment in difficulties, fatigue management, as well as The recovery phase of an emergency and the equipment and training is necessary to ensure emotional support for patients and importantly necessary structures, processes and relation- successful implementation of technologies also for carers. The aim is to complement, not ships that underpin it are often more expen- such as video clinics.12 replace, stretched community teams; close

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communication between the two is crucial. Setting up such a service may never have happened outside of a pandemic, but the rapid release of charit- able funds to allow secondment of University academics into this new NHS Specialist service has been truly ground breaking. N-ROL provides a template for how different stakeholders can come together to provide the ideal conditions for rapid development of desperately needed innovative new services driven Rehabilitation: by patient need.

Conclusion The impact of The COVID-19 pandemic has created an urgent need for rehabilitation services to take centre stage during the recovery process. Given the chronic under-resourcing of rehabilitation services over recent years significant commissioning financial and human resource investment is critical to our success. Alongside this there is the opportunity to build on what already works and evolve how we deliver rehabilitation interventions by embracing techno- changes during logical advances and creating novel partnerships with businesses, the private and charitable sectors. the COVID-19 REFERENCES

1. Rehabilitation in the wake of Covid-19 – A phoenix from the ashes. British Society of pandemic Rehabilitation (BSRM) https://www.bsrm.org.uk/downloads/covid-19bs- rmissue1-published-27-4-2020.pdf Accessed 21/05/2020 2. FICM Position Statement and provisional Guidance: Recovery and Rehabilitation for patients following the pandemic. May 2020. https://www.ficm.ac.uk/sites/default/files/ficm_rehab_ Do not worry that your life is turning upside down. How do provisional_guidance.pdfAccessed 21/05/2020. you know that the side you are used to is better than the 3. Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, Humphries F, Jäger one to come? – Rumi HR, Losseff NA, Perry RJ, Shah S, Simister RJ, Turner D, Chandratheva A, Werring DJ. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg . 2020 Apr 30. pii: jnnp-2020-323586. doi: 10.1136/jnnp-2020-323586. [Epub ahead of n March 23rd 2020, the COVID-19 pandemic leapt print]. out of the 24 hour news cycle and into the lives of 4. Calcagno N, Colombo E, Maranzano A, Pasquini J, Keller Sarmiento IJ, Trogu F, Silani V. Rising everyone in the UK. That day, the Prime Minister evidence for neurological involvement in COVID-19 pandemic. Neurol Sci. 2020 May 12. doi: O 10.1007/s10072-020-04447-w. [Epub ahead of print] announced the ‘lockdown’ of UK society and the country was 5. Murray A, Gerada C, Morris J. We need a Nightingale model for rehab after covid-19. 8 April suddenly faced with indefinite uncertainty and a profound 2020. https://www.hsj.co.uk/commissioning/we-need-a-nightingale-model-for-rehab-after- change to its long established way of life. Meanwhile, the covid-19-/7027335.article Accessed 21/05/2020. National Health Service was hurriedly preparing for the 6. Leocani L, Diserens K, Moccia M, Caltagirone C. Disability through COVID-19 pandemic: Neurorehabilitation cannot wait. Eur J Neurol. 2020 May 13. doi: 10.1111/ene.14320. [Epub predicted ‘tsunami’ of COVID-19 cases on the horizon. ahead of print] Hospitals re-organised to create acute medical and intensive 7. Long-term neurological conditions: management at the interface between neurology, reha- care treatment capacity. All elective and outpatient work was bilitation and palliative care. British Society of Rehabilitation Medicine (BSRM). March abruptly cancelled. Although not on the front line, specialist 2008. https://www.bsrm.org.uk/downloads/long-term-neurological-conditions-concise. pdf Accessed 21/05/2020. rehabilitation services were immediately affected. Some 8. Farrell R, Baker D. Optimisation of pharmacological management of multiple sclerosis related services were forced to close, in order to create space for spasticity. ACNR 2019;19(1):13-15. new acute medical wards or allow for redeployment of staff 9. Rose L, McKim D, Leasa D, et al. Trends in incidence, prevalence, and mortality of neuro- to acute services. Others had their gyms repurposed as new muscular disease in Ontario, Canada: A population-based retrospective cohort study (2003- wards or intensive care units. In order to prevent hospital 2014). PLoS One. 2019;14(3):e0210574. Published 2019 Mar 26. doi:10.1371/journal. pone.0210574 trusts from facing financial penalty in responding to this 10. HM Government Emergency Response and Recovery. https://assets.publishing.service.gov. unprecedented challenge, local and national uk/government/uploads/system/uploads/attachment_data/file/253488/Emergency_Response_ commissioners quickly adapted their systems of payment. and_Recovery_5th_edition_October_2013.pdf This article discusses changes in commissioning of specialist 11. National Recovery Guidance. https://www.gov.uk/guidance/national-recovery-guid- ance Accessed 21/05/2020. rehabilitation services, focusing on the particular experience 12. Wherton J, Shaw S, Papoutsi C, et al. BMJ Leader Published Online First: doi:10.1136/leader- of the Level 1 specialist rehabilitation service in Oxford. As 2020-000262. https://bmjleader.bmj.com/content/early/2020/05/17/leader-2020-000262. the peak of the outbreak begins to fade into the rear-view Accessed 21/05/2020. mirror and services plan a return to some version of business 13. Bridges Self-management: Adapting to life with a neuromuscular condition. https://nmd.bridges- as usual, it is worth stopping for a moment to reflect. selfmanagement.org.uk/ Accessed 21/05/2020.

Anton Pick, MRCP, MBChB, The rehabilitation department at University College Conflict of interest statement: is a Consultant in Rehabilitation Medicine London Hospitals has received educational grants from Medtronic. Dr Farrell and Clinical Lead at the Oxford Centre has received honoraria and hospitality from Merck, TEVA, Novartis, Genzyme, for Enablement, part of Oxford University Allergan, Merz, Ipsen, GW Pharma and Biogen. Dr Farrell’s current research activity Hospitals NHS Foundation Trust. is supported by the NIHR Biomedical Research Centre UCLH. Correspondence to: [email protected] Provenance and peer review: Submitted and reviewed internally Conflict of interest statement: None declared Date first submitted: 28/5/2020 Provenance and peer review: Submitted and Acceptance date after peer review: 28/7/20 externally reviewed Published online: 30/7/20 Date first submitted: 8/5/20 This is an open access article distributed under the terms & conditions of the Date submitted after peer review: 8/6/20 Creative Commons Attribution license http://creativecommons.org/licenses/ Acceptance date: 16/6/20 by/4.0/ Published online first: 29/6/20 To cite: Stevenson V, Farrell R, Ramdharry G, Swayne O, Ward N, Leary S, This is an open access article distributed under the terms & conditions of Holmes S, ACNR 2020;19(4):5-7 the Creative Commons Attribution license http://creativecommons.org/ licenses/by/4.0/ To cite: Pick A. ACNR 2020;19(4):7-8

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NHS England Specialised Commissioned Rehabilitation Ward serving the entire South prognosis meetings and best interest meetings Rehabilitation for patients with highly East of England. The service, adapted to continued to be held, only now via a virtual complex needs follow national infection prevention guidance, platform. NHS England published the Specialised remained operational throughout the early Commissioning Contract for Rehabilitation of stages of the pandemic. At the beginning of Discussion Patients with Highly Complex Needs in 2013.1 the lockdown, as part of the effort to create The 2013 Specialised Commissioning Contract Prior to this, services were remunerated on a acute capacity to accommodate the expected for Rehabilitation of Patients with Highly block contract. The new contract was part of influx of patients with COVID-19, NHS England Complex Needs proclaims on its first page that a general strategic shift in England away from officially requested NHS hospitals to discharge it would be due for review after 12 months. block contracts, towards payment-by-results all medically stable patients occupying Seven years on, it does not appear that this contracts. It stipulated strict criteria for services acute beds. Regional inpatient rehabilitation or any later review happened. Just prior to to be designated as ‘specialist’. Services were facilities, including the nearby Spinal Cord the pandemic, NHS England Specialised broken down into ‘Level 1’ or ‘Level 2a’, Injury Centre, were either closed, no longer Commissioning held the first of a series of determined by the type and level of need of accepting admissions or overwhelmed with planned workshops to begin the process patients being admitted. Tariffs were based patients with COVID-19. As a result, very soon of reviewing how it commissions specialist on submitted outcome data for every patient after the lockdown was announced, the OCE rehabilitation. This project was put on hold admitted and calculated by a centrally oper- started receiving increased numbers of refer- when the pandemic struck. Clinicians working ated database, known as the UK Rehabilitation rals. In addition, with few other rehabilitation in the field have long debated the merits and Outcomes Collaborative (UKROC). One of options available, acute providers began refer- limitations of how rehabilitation is commis- the main criteria for services to maintain ring patients that would not normally have sioned. Through its detailed service specifica- their status as ‘specialist’ providers, was the been referred to OCE. Unconstrained from tions and tightly controlled admission criteria, requirement to submit to UKROC a complete the commissioning contract, the team at OCE the system is likely to have raised the quality dataset for each patient; this included demo- designed a system to both create capacity and and improved the standardisation of rehabili- graphics, two weekly collected Rehabilitation enable the service to effectively respond to the tation care across England. Conversely, the Complexity Scales (RCS), two weekly needs of these different patient groups. Three huge amount of mandated data collection collected Northwick Park Dependency Scores admission ‘tracks’ were established: was arguably unwieldy and the unmistakable (NPDS), regularly collected Northwick Park emphasis on neurological injury left patients Therapy Dependency Scores (NPDTA), admis- Track A – Complex discharges with complex non-neurological rehabilitation sion and discharge Neurological Impairment Track A was designed to accommodate needs, underserved. The absence of a robust Scale (NIS), FIM/FAM and admission Patient patients requiring mainly disability manage- review process and the excessively centralised Categorisation Tool (PCAT) scores. This seven ment and intensive discharge planning. These control over services stipulated in the contract year old system changed overnight when the patients had medical and nursing needs that may have also stifled development in the field. pandemic struck. were best met in a specialist rehabilitation The complete reorganisation of healthcare environment. An example of a Track A patient services in the UK in response to the COVID-19 COVID-19 Commissioning changes was one with a spinal cord injury, and a large pandemic opened the door to, for the first Within days of the start of the lockdown, NHS sacral pressure sore requiring them to remain time in many years, real innovation for some England issued a memorandum, outlining on complete bed rest. Acute ward staff did specialist rehabilitation services. This report changes to the way specialist rehabilitation not have the capacity, and in some cases the describes the response of one such service in services were going to be reimbursed during capability to coordinate discharges for these the UK during the early stages of the pandemic. the pandemic. The memorandum stated that, patients. Working collaboratively with NHS A devastating number of people have already effective immediately, funding would be England and CCG partners, the team at OCE died from the virus, but some are at the begin- reverting back to a block contract system. were able to enact these complex discharges ning of a road to recovery. Creating additional Reimbursement would no longer be calcu- and maintain patient flow. rehabilitation capacity for these patients whilst lated on the basis of outcome data, but rather also establishing a more dynamic and equit- on the basis of the income a service received Track B – Shorter term goal directed able system to meet the needs of all patients during the same period in the previous year. rehabilitation requiring rehabilitation is a huge challenge for UKROC published a much smaller set of Track B was designed to provide short goal- the health service. Innovation will be needed outcome measures it ‘recommended’ services directed rehabilitation admissions. Patients to rise to this challenge and reverting back to submit during this period. This new dataset admitted on this track had mostly sustained the old commissioning contract may hinder was made up of patient demographics, and non-dominant hemispheric strokes, non-neuro- this. Until a new, fit-for-purpose specialised a single RCS on admission and discharge. logical trauma, or spinal cord injuries, and commissioning contract for rehabilitation From a commissioning perspective, the some were recovering from COVID-19. is approved, extension of the current block remuneration change allowed services that Multidisciplinary rehabilitation goals were set contract or establishment of a provisional were shut down or severely limited, not to with these patients every two weeks. At the pared down payment by results scheme will lose funding during the pandemic. For those end of each two weeks, a collaborative deci- empower services to respond resourcefully to services that did remain operational, the sion was made to either set new goals for the this evolving situation. Rehabilitation services change in data submission requirement and coming two weeks or to trigger discharge in in England could indeed rise from these ashes the loosening of admission constraints facili- the next two weeks. Patients on Track B often like a phoenix, but only if leaders in the tated new autonomy to determine a service had short admissions of two to six weeks. field are bold enough to learn from what has level response to the crisis. happened, abandon redundant procedures, Track C – Complex rehabilitation and truly start anew. Operational response at the Oxford Track C was designed to accommodate Centre for Enablement patients with particularly complex rehabili- The Oxford Centre for Enablement (OCE) is tation, nursing and medical needs. These REFERENCES a standalone building, removed from where patients included those in prolonged disorders much of the acute care is delivered within of consciousness or those who had sustained 1. NHS England. NHS Standard Contract for Specialised Oxford University NHS Foundation Trust. In severe acquired brain injuries. Patients on this Rehabilitation for Patients with Highly Complex Needs (all ages). https://www.england.nhs.uk/wp-content/ addition to a range of outpatient services, track had their need for on-going admission uploads/2014/04/d02-rehab-pat-high-needs-0414.pdf, it contains an inpatient Level 1 Specialist reviewed every four weeks. Diagnosis and 2013.

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Preparing for the

Fahim Anwar, MRCS, FRCP, FEBPRM, storm: impact of the is a Consultant in Rehabilitation Medicine at the Cambridge University Hospital NHS Foundation Trust. He is an Associate Lecturer at Cambridge COVID-19 pandemic University. His specialist interests include early rehabilitation following major trauma including head injuries, progressive neurological conditions, spasticity and posture management. on rehabilitation Judith Allanson, FRCP, PhD, is a Consultant in Rehabilitation Medicine in Cambridge University Hospital NHS Foundation services Trust. She has been involved in major trauma rehabilitation developments in the region, setting core standard for rehabilitation medicine following trauma. She also set up Evelyn n December 2019 several cases of acute respiratory distress Neurorehabilitation project for head injuries syndrome were reported in Wuhan City in China. A novel corona- and has broad areas of interest in rehabilitation medicine. She is an executive committee member Ivirus was soon identified as the cause of these cases and the of the BSRM and sits on their Research and syndrome was called Coronavirus disease (COVID-19). It is caused Clinical Standards Committee. by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which belongs to the same family coronoviridae which caused the Katie Bond, BSc Hons SARS and MERS outbreaks in 2002 and 2012 respectively. The WHO, Physiotherapy, on 11th March 2020, declared the rapidly spreading COVID-19 as is Senior Acute Stroke and Neuro Rehabilitation a pandemic. According to the World Health Organization (WHO), Physiotherapist at Cambridge University Hospital NHS Foundation Trust. She is involved in setting most people infected with the COVID-19 virus will either be asymp- up stroke early discharge service within the tomatic or experience a mild to moderate respiratory flu-like illness Cambridgeshire area. and recover without requiring specialist treatment or hospitalisation. However, vulnerable groups such as those patients over 70 with Emer McGilloway, FRCP, underlying health conditions or patients with underlying cardio- is a Lead Consultant in Rehabilitation Medicine at King’s College Hospital Trust since 2014. She vascular disease, diabetes, chronic respiratory disease, and cancer studied Medicine at Queen’s University Belfast are more likely to develop serious illness.1 and worked in different hospitals in Ireland. She Since the detection of early cases in the United Kingdom (UK) joined Headley Court in 2010 where she was from late February, the National Health Service (NHS) has been Consultant Lead for Neurorehabilitation. She represents London on the National CRG for preparing to deal with a surge of cases by creating bed capacity Disability and Rehabilitation. She was elected within the hospitals partly by increasing provision of their ventilated Regional Specialty Adviser for Rehabilitation beds. The priority of a health service in any pandemic is to ensure Medicine in 2017. that emergency care is provided to individuals who need it in a Harry Mee, MBBS, MRCP, timely fashion. With regard to COVID-19 this entailed that almost is a Specialist Registrar in Rehabilitation Medicine all planned care and elective admissions were delayed to ensure in Colman Centre of Neurological Rehabilitation. adequate capacity for the likely increased bed demands across He graduated from the Peninsula both general wards and in the intensive care units. The World in 2009, and spent the first 8 years of his career Health Organization Guidance Note on Disability and Emergency in the South West before starting his specialist 2 rehabilitation medicine training in the East of Risk Management for Health states that disability is included in England in 2016. He is currently undertaking a emergency risk management policies and people with disability are clinical PhD at the University engaged in the development, implementation and monitoring/evalu- of Cambridge, with a particular interest in ation of policies, legislation, strategies and programmes. It also states rehabilitation following traumatic brain injury. that the human rights framework should be applied in policies and Correspondence to: Fahim Anwar, practices to support people with disabilities and to prevent all forms Consultant in Rehabilitation Medicine, Addenbrooke’s Hospital, of discrimination. The specialist rehabilitation providers within Cambridge, UK. E. [email protected] the UK have responded well in preparing the NHS to deal with the challenges of COVID-19 since it was declared as pandemic. With a Conflict of interest statement: None declared. broad training, rehabilitation medical staff are better placed to offer Provenance and peer review: submitted and internally reviewed. a holistic approach and monitor the long-term needs of the patients. Date first submitted:27/4/20 At the local level, rehabilitation leads have come up with unique Date accepted: 29/4/20 and innovative solutions relevant to their geography, population and Published online: 7/5/20 services available. This is an open access article distributed under the terms & conditions of the Creative Commons Attribution license http://creativecommons.org/ licenses/by/4.0/ Specialist Rehabilitation Services during the COVID-19 outbreak To cite: Anwar F, Allanson J, Bond K, McGilloway E, Mee H. ACNR NHS England published a clinical guide for the management of 2020;19(4):9-11 patients requiring transfer for specialist rehabilitation during the coronavirus pandemic on 6th April 2020.3 This emphasised the fact that the acute services (including hyperacute services in the trauma centres) needed to continue to make referrals to inpatient specialist rehabilitation services. It emphasised that it was imperative that spinal cord injury centres and rehabilitation services were protected

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and maintained to facilitate patient transfer phone. Often the clinicians have not met Interim Beds in Specialist Nursing Homes from an acute setting in a reasonable period relatives face to face and due to restrictions Most of the clinical commissioning groups of time. From the rapid access acute rehabili- with visiting, carers' have not seen how their (CCGs) in the East of England commission tation perspective, we are continuing to make relative is emotionally, communicatively, Level 2 rehabilitation in specialist nursing referrals to the post-acute specialist rehabili- cognitively and physically in person for many homes to provide interim care for these tation units (Level 1 and Level 2). However, days/weeks. This means that the rehabilita- patients while they wait for Level 1, 2 and as these services are under a huge pres- tion keyworkers had to spend extra-time on spinal injuries units and in many cases for the sure due to various factors, a timely transfer the telephone to give feedback to the family rest of their rehabilitation. There are several of patients from the acute settings to the and friends and discuss important issues advantages to rehabilitation patients moving rehabilitation setting is not always possible. regarding discharge planning. from major trauma centres into the specialist Due to the pandemic, the trauma centres also The MDT have had to consider how to nursing homes with complex rehabilitation lost the valuable in-reach support and advice support and manage patient and carer needs, such as some continuity of rehabili- from the spinal cord injury services for spinal expectations of on-going rehabilitation (and tation assessments, some therapy input and injury patients. location) when the future of in-patient and safe care provision. However, not all of community services is unpredictable and these specialist nursing homes have 24-hour Re-organisation of Rehabilitation unknown. Senior hospital managers have nursing cover, often lack capabilities to cater Services in the Acute Hospital encouraged twice daily reviews of discharge for patients with unstable tracheostomies, Most of the major trauma centres (MTC) plans, ensuring multiple safe pre-planned and some are unable to manage challenging in the United Kingdom host a hyperacute options are set in advance. As acute rehabili- behaviours and complex mental health prob- rehabilitation unit and some have post-acute tation providers, the priority is to ensure lems in patients with severe head injuries Level 1 or Level 2 rehabilitation beds for patient’s early neurological and have very little medical cover and over- both trauma and non-trauma patients with is maximised. The COVID-19 pandemic has sight from the Consultants in Rehabilitation complex rehabilitation needs. Cambridge disrupted this priority. Acute rehabilitation Medicine. It is worth noting that many of the University Hospital NHS Foundation Trust clinicians are rapidly considering how to specialist nursing homes were isolating all the is the major trauma centre for the East of adapt their practice to maximise therapy acute transfers from the acute hospitals for 14 England with 10 rapid access acute rehabili- input and plan to support patients through days which means that the patients lost any tation (RAAR) beds for trauma patients a potential period of no rehabilitation. The therapy input during that period. (often delivering rehab to up to 17 trauma continued close working with community patients in the RAAR bed) and 8 Level 2b colleagues is fundamental for these rapidly Early discharges with Community rehabilitation beds. In the preparation phase, changing pathways to ensure the best Therapy Input the RAAR ward was identified for possible outcome for our patients during this crisis. Patients who were deemed to be relatively COVID-19 patients due to its physical location With the increasing pressure from the medically stable and could be managed within the hospital and the RAAR beds were COVID-19 crisis, junior doctors’ rotas were in the community with therapy input were absorbed into the existing neurosciences reorganised which meant that our trainees discharged home. Most community therapy block. This meant that the therapy team for were redeployed. The Rehabilitation teams were restricting face-to-face consulta- the RAAR beds were also relocated to look Medicine Consultants were designated as tions and therapy sessions in the community after these patients. However, the ethos of secondary tier cover for the stroke rehabili- and seeing only urgent patients where there the rehabilitation team changed from rapid tation ward. was a high risk of deterioration without assessment and provision of on-going hyper- further therapy. Some community therapists acute rehabilitation to the rapid assessment Use of Community Hospital Beds were utilising technology to provide some (if at all possible) and repatriation to the Patients who were still medically unstable and continuity of rehabilitation at home. Due to local trauma units with recommendations needed acute care with rehabilitation were the lockdown, most of the family members for post-acute rehabilitation. These patient transferred to the smaller community-based were available to provide 24-hour care and groups included patients with prolonged hospitals (where available). Most of these support to their relatives. An additional chal- disorders of consciousness, multiple complex community hospitals are run by either the GPs lenge was that some community therapy staff orthopaedic trauma with inability to weight or by the community Geriatricians and with an were redeployed, and community services bear, patients in post-traumatic amnesia, already overstretched case load now having were often run with long waiting lists, so those with severe cognitive impairments, to manage and care for patients with complex they were not able to react quickly to meet challenging behaviours, mental health prob- rehabilitation needs added further challenges complex needs. Furthermore, access to care lems and spinal cord injury patients at all and pressures. Feeding plans and courses packages was more limited than ever due to levels. Most of these repatriations would not of intravenous antibiotics would usually be staff illness, self-isolation and lack of personal have happened so quickly in normal circum- completed before transfer to a community protective equipment (PPE). A recent article stances as the trauma units often do not hospital but with earlier discharges having to be from Italy has focused on the impact of the have the training and capabilities to manage made an increase in community management COVID-19 outbreak on rehabilitation services such complex patients. As the spread of of these is being seen. While these hospitals and physical and rehabilitation medicine COVID-19 progressed, the impact on the prac- have therapy input, the skill mix of the treating (PMR) ’s activity in Italy.4 The tice of rehabilitation medicine increased. therapists to treat patients with complex needs authors have emphasised that outpatient and Physically, it became difficult to conduct was not known. Although these hospitals often home based rehabilitation services should interdisciplinary team meetings while main- have excellent multi-disciplinary team input, ensure continuity of care for patients with taining the necessary social distance in the trying to understand the variable skill mix recent sequelae of of different acute hospital where space is always a chal- was hard but so important in planning for origin, where interventions are needed to lenge. Increasing infection control measures the ongoing treatment and rehabilitation of minimise functional deficits which, if left meant that one-to-one hands-on therapy these patients and their complex rehabilita- untreated, could lead to long term or perma- sessions were time consuming for individual tion needs. As Consultants in Rehabilitation nent disability and further deterioration.4 therapists. As the hospital was locked down Medicine, working within a major trauma For our Rehabilitation Medicine colleagues for all visitors, face-to-face family meetings and neuroscience centre, we found ourselves working in the community with complex were not possible. Many acute rehabilitation liaising with these community teams, and brain injury patients, the activity increased keyworkers have to prepare for challenging managing the transfers of appropriate patients significantly as patients were getting less conversations with family members over the to these hospitals. support from other professionals and families

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It is imperative for rehabilitation colleagues working in the major trauma centres, neuroscience centres and specialist rehabilitation services to keep a record of all the patients discharged with rehabilitation needs.

were more anxious than ever. There were appropriate consent. The NHSmail system,6 patients who have complex rehabilitation reports of several problems in complex which is a national secure collaboration needs at the time of discharge from the major patients reported by the colleagues in the service for health and social care in England trauma centre. community such as emerging behavioural, and Scotland, enabled the Microsoft Teams7 safeguarding issues and care package issues. software free for all its users to facilitate quick Post-COVID pandemic challenges for the This meant that medical colleagues had to communication with colleagues through the rehabilitation services spend extra time on telephone consultations use of instant messaging, audio and video We know from SARS and MERS outbreaks that to manage complex issues, offering specific calls to share advice and updates on patients. survivors can have long-term biopsychosocial information on brain injuries (cognition, For rehabilitation services, this is proving a problems that will need MDT rehabilitation. communication, mood, behaviours etc) and great tool to conduct multidisciplinary meet- There is emerging evidence from Italy and supporting patients and their family members. ings, interagency case conferences and other China that COVID-19 patients present with meetings remotely. There are other similar significant acute and post-acute rehabilita- Use of Technology teleconference tools available with variable tion needs and the early rehabilitation of The experience from the other viral respira- efficacy, reliability and security options. these needs is needed to improve function to tory epidemics shows that technology can be premorbid levels and restore quality of life.8,9 It used in various situations to manage patients Tracking patients with specialist is therefore anticipated that the rehabilitation in rehabilitation settings.5 To minimise the rehabilitation needs and recording services will face another huge challenge once risk of viral transmission, we changed all outcomes during the pandemic the pandemic is over. There is an urgent need outpatient clinic appointments to telephone It is clear that there is a cohort of patients who for local, national and international collabora- appointments unless an examination was have been discharged from the major trauma tion to manage the surge of COVID-19 positive absolutely necessary. This reduced the centres and acute hospitals to a host of places patients with significant rehabilitation needs in amount of outpatient activity significantly with or without some rehabilitation input. It the coming months and years. and we were able to concentrate on flow is worth noting that patients are also being of inpatients within our hospital. We were discharged early from specialist rehabilitation Conclusion also unable to see patients routinely in our services as they focus on supporting patient Specialist rehabilitation services are currently spasticity clinic for phenol nerve blocks and flow from acute hospitals and expediting safe under stretch as they deal with the sudden botulinum toxin injections. However, our discharge. Many patients have significant influx of patients being discharged from the baclofen pump refill service continued to rehabilitation needs at the time of discharge. acute settings. The focus of rehabilitation avoid any baclofen pump withdrawal symp- It is imperative for rehabilitation colleagues interventions during the COVID-19 pandemic toms in our patients. To avoid cross contam- working in the major trauma centres, neuro- has been to expedite safe discharge. Patients ination of the various hospital areas, we science centres and specialist rehabilitation with ongoing rehabilitation needs are having started remote reviewing and consultations services to keep a record of all the patients to be prematurely discharged to create more through our hospital electronic record system discharged with rehabilitation needs. This capacity in hospitals. Services and clinicians where possible. The record system could should help to either review these patients in are adapting innovative ways of maintaining be accessed anywhere from the hospital the outpatient clinics at a later date or arrange contact with their patients and providing terminals and from home through secure appropriate inpatient specialist rehabilita- as much input as possible. Once the acute servers with individual passwords. Outpatient tion once the pandemic is over. Within our phase of this pandemic is over, there needs consultations consisted of recommendations hospital electronic medical records system to be considerable planning to reinstate full to change any medications, request any there are options to track these patients and MDT rehabilitation services (Level 1 and tests, arranging appropriate therapy input or we are maintaining a list of all these patients 2) for all patients whose goal attainment referral to our colleagues for any complica- with rehabilitation needs. Similarly, recording was compromised by the crisis and also to tions. Some patients struggled in these consul- any outcome measure during the pandemic provide functional recovery programmes to tations due to their cognitive and communi- period is a challenge due to various factors. COVID-19 survivors. cation difficulties and their family member/ We have agreed to record Rehabilitation next of kin were contacted and involved with Complexity Scale (RCS) for all trauma

REFERENCES

1. https://www.who.int/health-topics/coronavirus#tab=tab_1 2. World Health Organization. Guidance note on disability and emergency risk management for health. Geneva: World Health Organization; 2013. 3. https://www.england.nhs.uk/coronavirus/wp-content/uploads/sites/52/2020/04/C0199-Specialty-guide_specialist-rehabilitation-v1-03-April_.pdf 4. Boldrini P, Bernetti A, Fiore P. Impact of COVID-19 outbreak on rehabilitation services and Physical and Rehabilitation Medicine (PRM) ’ activities in Italy. An official document of the Italian PRM Society (SIMFER). European Journal of Physical and Rehabilitation Medicine 2020; DOI: 10.23736/S1973-9087.20.06256-5 5. Lim PA, Ng YS, Tay MB. Impact of a Viral Respiratory Epidemic on the Practice of Medicine and Rehabilitation: Severe Acute Respiratory Syndrome. Arch Phys Med Rehabil 2004; 85:1365-1370. 6. www.nhs.net 7. https://products.office.com/en-US/microsoft-teams/group-chat-software 8. Mao L, Wang M, Chen S, He Q, Chang J, Hong C, et al. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.02.22.20026500v1. 9. Talan J. COVID-19: Neurologists in Italy to colleagues in US: Look for poorly-defined neurologic conditions in patients with the coronavirus. Neurology Today, American Academy of Neurology 2020 Mar 27. Available from: https://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=920

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The many faces of COVID: Experiences of deployment and

Srikirti Kodali, MBBS, MA, redeployment by Neurology MRCP, is a first year Neurology Registrar at Addenbrooke’s hospital. She trained at the Registrars Universities of Cambridge and London. Her research interests are in remyelination in the central . She also has a keen he first UK cases of COVID-19 were loss and that of unusual presentations for interest in developing innovative educational detected on 29th January. Within weeks which a neurologist is arguably the most suit- initiatives at an undergraduate and postgraduate level. In her spare time, Sri enjoys travel, culture, Tthe normal functioning of the National able to provide the initial review. These pres- and painting; taking inspiration from neurology. Health Service ground to an effective halt. entations would constitute at least 10% of the By mid-March elective had stopped, medical take. Having only recently completed non-urgent hospital admissions were post- core medical training, I embraced the prospect poned and staff of all specialties and grades of reviewing patients with systemic complaints were assigned to new roles and working as well. Infection control policy meant that environments to deal with the anticipated aspects of bedside examination such as fundos- surge of coronavirus patients. The initial focus copy had to be omitted, and working around was on creating capacity: identifying patients face masks to perform a cranial nerve examin- who could be safely discharged home in order ation was laborious. to free up beds in acute hospitals, and ensuring My contribution however was not just limited Richard Rees, MBChB, BSc, that new patients were only admitted in an to being an extra person to aid the medical take, MRCP, emergency. Specialist wards were converted to there were other benefits too. Assessing patients is the Training & Education rep for the ABNT. take patients with a variety of conditions. at the front door to offer specialist input directly, He graduated from the University of Sheffield Neurology trainees found themselves reduced the number of encounters between in 2011, and following foundation and core deployed in a variety of ways to meet the each patient and multiple clinicians, which in medical training in London, has been studying prodromal Parkinson’s as a doctoral student in local need. Trainees in academia answered turn frees up clinician time and reduces the the Predict-PD team at UCL. He has trained as a a personal or institutional call to rejoin the burden on patients. It allowed the patients to Neurology Registrar at Imperial, the Royal Free ‘front lines’, sometimes after several months or have relevant investigations in A&E, avoided and is now an Academic Clinical Fellow at St years out of routine clinical practice, and to a unnecessary investigations, and aided decision Georges University Hospital. He is a keen triath- lete and the proud father of 3 children. very different clinical environment – such as making within four hours. This in turn avoided the emergency department or intensive care. admissions for specialist input, thereby limiting Meanwhile, the risks of front-line working were time patients spent in hospital. In addition, this palpable. With well over 100 NHS workers process reduced the inpatient referral burden reported to have died of COVID-19 and count- and acute neurology clinic bookings, thereby less others gravely ill, going to work became streamlining and simplifying our service. untenable for some due to risks to their health Redeployment of other specialities into the or that of their immediate family. For them acute medical take also meant that patients work took on a different meaning, and working requiring multidisciplinary input received this at from home, as a doctor, became a new chal- the front door – a true luxury, which seemed to lenge and new opportunity. be patient-centred acute care at its best. Mike Kemp, MBChB, MRCP, In this article we report three very different Powerful hospital information management is a Neurology ST4 in the North West. He graduated from the University of Manchester in experiences of neurology trainees in the UK: systems were hugely beneficial during this 2013, and is training less than full time. He is the continuing with the provision of neurology pandemic. With a well-established and fully inte- proud father of his baby daughter who has been care, redeployment to uncharted territory and grated electronic patient record, we were able thriving in lockdown. Mike is the current Liaison working while shielding. Each of these endeav- to provide remote reviews on COVID-19 wards, Officer of the ABNT, and is on the BMA Junior Doctors Committee Executive Subcommittee. ours brought new experiences, new challenges home working for those staff at high risk and and new insights into the role of the physician, easier remote management of outpatient clinics. Helen Grote, ABNT Correspondence to: personal development and the potential future Unusual times also meant an unusual pattern Communications Representative, E: [email protected] of neurology. of disease presentation. At the start of lock- down we saw almost no cases of functional Conflict of interest:None declared Neurology as never before neurological disorder, but very sick people with Provenance and peer review: Submitted and inter- Srikirti Kodali encephalitis, myasthenia, rapidly progressing nally reviewed Guillain-Barré Syndrome continued to present. Date first submitted: 3/8/20 y experience of redeployment in They were investigated quickly and we had Acceptance date: 4/8/20 MAddenbrooke’s has been shared between capacity to start plasma exchange within 48 Published online: 5/8/20 inpatient neurosurgery, neurology and the hours of admission. Inpatient management was This is an open access article distributed under the terms & conditions of the Creative acute medical take. beautifully efficient and incredibly satisfying. Commons Attribution license http:// Being part of the medical take has been an We had our share of COVID-19-related neur- creativecommons.org/licenses/by/4.0/ eye opening experience, one that advocates a ology including cases of opsoclonus myoclonus To cite: Kodali S, Rees R, Kemp M. ACNR permanent role for neurology at the front door. and mononeuritis multiplex. It was unfortunate 2020;19(4):12-14 I was kept busy with a filtered take list of head- that in an attempt to stay home and not burden aches, seizures, visual loss, weakness, sensory the NHS, some patients presented too late with

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strokes and severe systemic illness to a point of As the ICU doubled in size from 34 beds to deep connections can be made through the no reversibility with treatment. supporting over 70 critically unwell people, pixels and intermittent connection. However, Two months into lockdown, the psycho- the capacity for engaging with and supporting I will know that the in-person, whole person logical effects of the national situation was the patients’ families was quickly over- interactions can never be replaced and I look reflected in the number of patients who whelmed. I joined what will probably be the forward to not just physically examining my presented with functional neurological disor- most multi-disciplinary team I will ever be part patients but physically connecting with them. ders. We were also involved in the care of of: there were specialist nurses for organ dona- patients with an exacerbation of underlying tion (as that service was totally suspended) Shielding and working from psychiatric illness who were then attended to and redeployed consultants from paediatrics, home by our front-door liaison psychiatry service. fetal medicine, orthopaedics, , as Mike Kemp Redeployment to ward based neurosurgery well as haematology registrars and a team of gave the opportunity for reviewing a different academic dentists who provided logistic and ince the end of March I have been working perspective on neurological presentations, coordination support. Sfrom home to shield my infant daughter. and brought the neurosciences community Our role was to contact the families of the The results of this overnight change of circum- within the hospital closer together. ICU patients, find out more about our patients stance have been profound and in other As the infection rates fall, we continue to as people, and facilitate video calls between ways trivial. From having to adapt and almost adapt our service and hope to use lessons learnt patients and their families in lieu of in person re-learn to practice medicine remotely, to during the pandemic to better shape future visits. At first glance I wondered if we were not teaching myself to cut my own hair, and finally services. Front door neurology has become a much more than highly trained iPad stands in getting round to some of those long-procras- permanent fixture. We continue to manage PPE. However, I quickly realised that our role tinated DIY jobs, these changes have been far outpatient services remotely with a long-overdue was much more crucial to the families as well as reaching to all corners of my life, including to establishment of telemedicine and endeavour to the patients. In this faceless world of healthcare, what time I get up in the morning and what I support primary care through a 48-hour advice where physical and emotional contact was so wear each day, as well as my eating habits and and guidance service. We have closer ties limited, we brought uncovered faces to the general routine. through shared experiences with our physician bedside. We brought tears and laughter, song There is a profound cognitive dissonance in and neurosurgical colleagues which will lead to and prayer to the sterility of the ICU. After the having to stay at home to keep your family safe, a more integrated medical community. end of what would be the last call that a mother and feeling you can’t be there to help colleagues had with her son in his 30s, she said “I just want on the wards. I have been very fortunate to be ICU family communications to know that someone is holding his hand”. able to work clinically during this time and Richard Rees This crystalised for me the importance of touch. provide meaningful support to my colleagues. Touch is something we do as neurologists – the Initially, a significant part of my workload while aving been in academia for three physical examination involves the laying on of working from home was stratifying the risk of Hyears, and coming towards the end of hands, not just for data collection for the refine- our neurology outpatients according to the ABN my research, I had hoped to spend March ment of a differential diagnosis, but as a positive guidelines to facilitate the addition of patients finishing data collection and then focus purely social construct that is not just an aspect of our with neurological disease to the Shielded Patient on analysis and writing up prior to the arrival profession but the sine qua non of what it is List. This was a large piece of work with a huge of my third child. As the pandemic took hold, to be a physician.1,2 Margaret Atwood wrote time burden on clinicians, which I was able and my A&E locum shifts showed me the “Touch comes before sight, before speech. It is to contribute to remotely, easing pressure on reality of COVID-19, it was clear that my plans the first language and the last, and it always tells colleagues still working face-to-face. For much were about to evaporate. My university made the truth.” (The Blind Assassin, 2000). of this time, in addition to continuing all of my it very clear that any clinical academic who While their relatives were in deep anaes- regular clinics remotely, I have been able to wanted to, was free to step back into a clinical thesia, we became a conduit of care and provide additional capacity and also cross-cover role, and I knew that this was the path for me. emotion from their families to them. As some clinics for colleagues who had to perform other Given how many clinicians within the patients recovered and regained their voices, duties or were even redeployed. NHS were redeployed, it took a few days to I learned from them how this service was not I’ve been very fortunate to be able to also clarify with the trust’s redeployment team just a source of hope and strength for those contribute to some academic work from where exactly I would be of most use. I was dutifully (but painfully) staying at home, but home, as well as to my roles on the BMA Junior first asked to join a small team providing also for the patients as they fought against the Doctors Committee and my Lead Employer general medical support at Queen Square, muddle, confusion and delirium of the ICU Local Negotiating Committee, addressing the as I was familiar with the institution, neuro- and the existential challenge of their illness. issues faced by doctors working in all environ- logical aspects of care, and also had main- The benefits were also shared by the ICU ments and circumstances. tained general medical experience. Although nurses and doctors, who not only had been Telephone clinics have been an eye opener geographically distinct from University stretched to the very limits of their capacity, to the world of telemedicine, to which I was College London Hospital (UCLH) and without but had done so without any of the usual previously a skeptic, but I’m now a convert. an A&E entrance, there was an expectation interactions they had with the families, which There are huge benefits to telemedicine for (or fear) that the neurology wards may end suddenly became so precious and vital to their routine follow up or screening of some new up full of patients with COVID-19, regardless experiences too. referrals to get appropriate investigations of other . I continued this for a As I move back to full time clinical neur- quickly. However there are also some complex month before being redeployed to a novel ology in this brave new world, I will understand limitations, including the selection of appro- team at UCLH Intensive Care Unit (ICU). the necessity of telemedicine and know that priate patients, which may only be overcome

Redeployment of other specialities into the acute medical take also meant that patients requiring multidisciplinary input received this at the front door – a true luxury, which seemed to be patient-centred acute care at its best.

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with detailed outpatient clinical coding. For many patients living with neurological disease being able to fit their care into their normal Assessing long-term working day without disruption, or needing to take leave, is a great asset. There are of course patients where communication barriers limit the feasibility and appropriateness of telemedi- rehabilitation needs in cine. Telemedicine requires adapting skills, for those of us who use diagrams to explain concepts to patients, and due to lack of body COVID-19 survivors using language cues from both doctor and patient, not to mention the inability to examine; it does however re-enforce the old adage that the a telephone screening tool lion’s share of the diagnosis is in the history. Adapting to teleconferencing and video- conferencing for departmental meetings, MDTs, teaching, clinical supervision, external meet- (C19-YRS tool) ings… everything, has also been an eye-opener. I had always preferred to meet face-to-face to By Manoj Sivan, Stephen Halpin and Jeremy Gee get a better read of people, especially when Full author details on page 17 meetings were a mixture of people present in person and others joining remotely, whereas Abstract and/or lung infiltrates within 24-48 hours. everyone joining the same way has made meet- The COVID-19 pandemic has caused more A small but significant minority (5%) ings via these technologies more successful. than 5 million infections and 300,000 develop critical disease with respiratory I’ve also found myself engaging much more deaths worldwide. Many survivors of the failure, septic shock and/or multiple organ with web-based learning resources. Having illness are likely to have long-term symp- dysfunction/failure needing management long been a fan of the paper journal, I am toms and disability that will pose a signifi- in ITU. Case fatality rate has been reported now quite happy to read things online for cant burden to the healthcare systems to range between 2% and 10% in different convenience (and in the absence of access to and economies all over the world. Given countries depending on extent of testing a library). I am also finding more time for this the scale of the burden and lockdown and reporting of deaths related to the now without my usual commute. measures in most countries, there is a infection. I am not sure the way I practice medicine need for a pragmatic tele-assessment tool COVID-19 is truly a multi-system illness and the way I work and learn will ever go back to screen for needs and target rehabilita- with known common complications to the way it was, but I am also certain that in tion interventions in time. A comprehen- affecting the respiratory system (ARDS), part that is a good thing. sive multi-system telephone screening tool cardiac (arrhythmias, myocardial injury), called COVID-19 Yorkshire Rehabilitation renal (acute kidney injury), gastrointes- Conclusion Screening (C19-YRS) tool has been tinal, nervous (neuropathy, encephal- The life of a trainee in the UK can often feel developed by multi-disciplinary-rehabili- opathy), endocrine and musculoskeletal like one of constant upheaval and change. As tation teams from Leeds, Airedale and (weakness, pain, fatigue) systems.2 The a nation (or indeed species) we have under- Hull NHS Trusts to assess and capture long-term problems for survivors are gone one of the most challenging periods symptoms and guide rehabilitation inter- currently unknown but lessons can be in recent history. Our resilience and adapt- ventions for these individuals. The tool has learnt from previous major coronavirus ability have been pushed to their limits and been shown to cover all the components outbreaks of Severe Acute Respiratory as a cohort of physicians and physicians-in- of the WHO ICF Framework. Syndrome (SARS) in 2002 and Middle East training, we have proven our ability not just to Respiratory Syndrome (MERS) in 2012. A adapt but to thrive and find ways of helping meta-analysis of follow-up studies in SARS our patients and colleagues. As our working and MERS show reduced lung function lives start to resemble normality (whatever that Introduction and reduced exercise capacity in up to word means), we bring back incredible experi- The first cases of Coronavirus disease 2019 one-fourth of survivors at 6 months after ences individually and collectively. With those (COVID-19) were reported in Wuhan in discharge from hospital.3 Mental health experiences come new ways to look at old December 2019, rapidly spreading to other problems including post-traumatic stress problems, and an understanding that even countries and a pandemic was declared disorder, anxiety and depression were monolithic organisations can change and by the World Health Organisation (WHO) observed in around one-third of survivors adapt. As the medical leaders of the future, on 11th March 2020. The United Kingdom at 12 months after discharge. The quality we should have the courage and ability to is one of the worst affected countries with of life was observed to be low even one make sure that the new normal builds on our over 250,000 infected cases and more year after discharge from the hospital. learning from the pandemic, and is the best it than 35,000 deaths at the time of writing This research recommends rehabilitation can be for our patients and colleagues; a more this article. The condition is a respiratory clinicians and services to anticipate similar sustainable and effective NHS, and not just a illness caused by coronavirus SARS-CoV-2 long-term health problems in survivors of reversion to how things were before. and presents with a clinical spectrum COVID-19, investigate them accordingly that varies from asymptomatic or mildly and plan timely treatments to enable best symptomatic forms to life-threatening possible recovery and quality of life for multi-organ failure and death. Wu et al survivors.3 (2020) reported that the majority (81%) The NHS Long Term Plan (2019) REFERENCES of cases have a mild presentation with pledges to improve outcomes for those either no symptoms or mild upper respira- with serious conditions by investing in 1. Horton R. Offline: Touch-the first language. Lancet 1 (London, England), 2019;394(10206):1310. tory tract infection symptoms. About 14% out-of-hospital care and community 2. Verghese A. et al. The bedside evaluation: ritual and of cases have severe disease with dysp- services.4 The emphasis is to provide reason. Annals of , 2011;155(8):550- noea, increased respiratory rate, hypoxia personalised digitally-enhanced care that 553.

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Covid 19 Yorkshire Rehab Screen (C19-YRS) 2. Laryngeal/ Have you developed any changes in the sensitivity of your throat such as troublesome airway or noisy breathing? Yes ☐ No ☐ complications If Yes: rate the significance of impact on a scale of 0-10 (0 being no impact, 10 being Patient name and NHS number: significant impact) 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐

Time and date of call: 3. Voice Have you or your family noticed any changes to your voice such as difficulty being heard, altered quality of the voice, your voice tiring by the end of the day or an inability Staff member making call: to alter the pitch of your voice? Yes ☐ No ☐

If Yes: rate the significance of impact on a scale of 0-10 (0 being no impact, 10 being ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ We are getting in touch with people who have been discharged after having had a diagnosis of significant impact) 0 1 2 3 4 5 6 7 8 9 10 coronavirus disease (Covid-19). The purpose of this call is to find out if you are experiencing problems 4. Swallowing Are you having difficulties eating, drinking or swallowing such as coughing, choking or related to your recent illness with coronavirus. We will document this in your clinical notes. We will avoiding any food or drinks? Yes ☐ No ☐ use this information to direct you to services you may need and inform the development of these services in the future. If Yes: rate the significance of impact on a scale of 0-10 (0 being no impact, 10 being significant impact) 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ This call will take around 15 minutes. If there’s any topics you don’t want to talk about you can stop the conversation at any point. Do you agree to talk to me about this today? Yes ☐ No ☐ 5. Nutrition Are you or your family concerned that you have ongoing weight loss or any ongoing nutritional concerns as a result of Covid-19? Yes ☐ No ☐ Opening questions: Please rank your appetite or interest in eating on a scale of 0-10 since Covid-19 (0 being Have you had any further medical problems or needed to go back to hospital since your discharge? same as usual/no problems, 10 being very severe problems/reduction) Re-admitted? Yes ☐ No ☐ 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐

Details: 6. Mobility On a 0-10 scale, how severe are any problems you have in walking about? 0 means I have no problems, 10 means I am completely unable to walk about. Have you used any other health services since discharge (e.g. your GP?) Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Yes ☐ No ☐ 7. Fatigue Do you become fatigued more easily compared to before your illness? Yes ☐ No ☐ Details: If yes, how severely does this affect your mobility, personal cares, activities or enjoyment of life? (0 being not affecting, 10 being very severely impacting)

I’ll ask some questions about how you might have been affected since your illness. If there are other ways Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ that you’ve been affected then there will be a chance to let me know these at the end. Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐

1. Breathlessness On a scale of 0-10, with 0 being not breathless at all, 8. Personal-Care On a 0-10 scale, how severe are any problems you have in personal cares such as and 10 being extremely breathless, how breathless Now Pre-Covid washing and dressing yourself? are you: 0 means I have no problems, 10 means I am completely unable to do my personal care. Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ (n/a if does not perform this activity) Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ a) At rest? 0-10: ____ 0-10: ____ 9. Continence Since your illness are you having any new problems with: b) On dressing yourself? 0-10: ____ 0-10: ____ N/a ☐ N/a ☐ • controlling your bowel Yes ☐ No ☐ c) On walking up a flight of stairs? 0-10: ____ 0-10: ____ • controlling your bladder Yes ☐ No ☐ N/a ☐ N/a ☐

10. Usual On a 0-10 scale, how severe are any problems you have in do your usual activities, such 17. Global How good or bad is your health overall? 10 means the best health you can imagine. 0 Activities as your household role, leisure activities, work or study? Perceived Health means the worst health you can imagine. 0 means I have no problems, 10 means I am completely unable to do my usual ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ activities. Now: 0 1 2 3 4 5 6 7 8 9 10 Pre-Covid: ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ 0 1 2 3 4 5 6 7 8 9 10 ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ Pre-Covid: 0 1 2 3 4 5 6 7 8 9 10 18. Vocation What is your employment situation and has your illness affected your ability to do your 11. Pain/ On a 0-10 scale, how severe is any pain or discomfort you have? usual work? discomfort 0 means I have no pain or discomfort, 10 means I have extremely severe pain Occupation: ______Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Employment status before Covid-19 Lockdown: ______

12. Cognition Since your illness have you had new or worsened difficulty with: Employment status before you became ill: ______

• concentrating? Yes ☐ No ☐ Employment status now: ______• short term memory? Yes ☐ No ☐ 19. Family/carers Do you think your family or carer would have anything to add from their perspective? 13. Cognitive- Have you or your family noticed any change in the way you communicate with people, views

Communication such as making sense of things people say to you, putting thoughts into words, difficulty reading or having a conversation? Yes ☐ No ☐

If Yes: rate the significance of impact on a scale of 0-10 (0 being no impact, 10 being Closing questions: significant impact) ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ ☐ 0 1 2 3 4 5 6 7 8 9 10 Are you experiencing any other new problems since your illness we haven’t mentioned?

14. Anxiety On a 0-10 scale, how severe is the anxiety you are experiencing? 0 means I am not anxious, 10 means I have extreme anxious. Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐

15. Depression On a 0-10 scale, how severe is the depression you are experiencing? Any other discussion (clinical notes): 0 means I am not depressed, 10 means I have extreme depression. Now: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐ Pre-Covid: 0 ☐ 1 ☐ 2 ☐ 3 ☐ 4 ☐ 5 ☐ 6 ☐ 7 ☐ 8 ☐ 9 ☐ 10 ☐

16. PTSD screen a) Have you had any unwanted memories of your illness or hospital admission whilst you were awake, so not counting dreams? Yes ☐ No ☐ If yes, how much do these memories bother you?

(is the distress: mild ☐ / moderate ☐ / severe ☐ / extreme ☐) b) Have you had any unpleasant dreams about your illness or hospital admission? Yes☐ No☐ If yes, how much do these dreams bother you? (is the distress: ☐ ☐ ☐ ☐) mild / moderate / severe / extreme c) Have you tried to avoid thoughts or feelings about your illness or hospital admission? Yes ☐ No ☐ If yes, how much effort do you make to avoid these thoughts or feelings? (mild ☐ / moderate ☐ / severe ☐ / extreme ☐) d) Are you currently having thoughts about harming yourself in any way? Yes ☐ No ☐ Figure 1. The C19-YRS tool

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Figure 2. Mapping of the C19-YRS tool onto ICF framework.

can be sustained long-term. Managing the term problems after COVID-19 infection based The C19-YRS screening tool aftermath of COVID-19 will require a holistic, on their clinical experience of managing Two introductory questions address medical multi-disciplinary team (MDT)-led integrated these patients and also from reviewing the problems since discharge and utilisation of care in the community, whilst minimising face literature on SARS and MERS follow-up healthcare services including re-admission to to face contact. Telemedicine is a well-es- studies. Through an iterative process they acute care hospital. The structured questions tablished method of assessing, monitoring then decided on best pragmatic questions follow, and the tool ends with the opportunity and providing interventions in a wide range that would capture these domains concisely, to capture any other new problems or consul- of health conditions. Applying telemedicine without placing undue burden on the patient tation discussions in free text recording. The to the current challenge of aftercare in the in the telephone screening process. questionnaire can also be completed (even COVID-19 pandemic is an obvious choice for The final list of main problems identi- if not all questions) by family members or healthcare services across the globe. fied by the specialists included breathless- carers if the patient is unable to do the tele- ness, voice, swallowing, nutrition, mobility, phone consultation themselves due to cogni- Aims fatigue, personal care, usual activities, pain/ tive or language impairments. The respondent We have developed a telephone screening discomfort, anxiety, depression, post-trau- is asked for consent to be called again for tool (C19-YRS) for the rehabilitation clinician matic stress disorder, continence, cognition, future follow-up telephone assessments. to capture the multi-system impairments and perceived health status and family/carers The clinician also provides specialist advice functioning in these individuals and use it views. and directs the patient to local resources or as an intervention guide to provide needed support in the community.

Methods Table 1. COVID-19 MDT Rehab team The tool was developed by multidisciplinary teams of clinicians involved in providing COVID-19 rehabilitation care across the three regions of Yorkshire: West Yorkshire (Leeds Teaching Hospitals NHS Trust and Leeds Community Healthcare NHS Trust); North Yorkshire (Airedale NHS Foundation Trust) and East Yorkshire (Hull Hospitals NHS Trust). The teams comprised of physiother- apists, occupational therapists, speech and language therapists, psychologists, dietitians and physicians in Rehabilitation Medicine. Specialists from Respiratory Medicine and were also consulted. These teams used virtual meeting methods to discuss and finalise a list of potential long-

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services which are captured in the free text and also to patient’s GP service. C19-YRS tool options of the tool. The tool took around 15 has also been programmed to automatically minutes to administer in some of our initial export responses into a Microsoft Excel file telephone consultations. to avoid the need for manual data input. This allows rapid data analysis and generation of Discussion summary statistics. The C19-YRS telephone screening tool captures the main potential long-term clin- Evaluation and next steps ical problems COVID-19 survivors are likely C19-YRS is currently being used by at least 10 to encounter after discharge from acute NHS Trusts in the UK to audit the long-term care services. It is a quick screening tool to outcomes in COVID-19 discharged patients. be administered over a telephone (or video Its use as a screening tool to identify those call) interview and not aimed at this stage requiring additional rehabilitation interven- Manoj Sivan, MD, FRCP, to be a valid outcome measure on its own tions can be tailored depending on local is Associate Professor and Consultant in for this population. The tool is likely to be pathways, services and available resources. Rehabilitation Medicine, University of Leeds, further developed in an iterative fashion Interventions may include immediate advice Leeds Teaching Hospitals NHS Trust and Leeds Community Healthcare Trust. based on clinicians’ experiences during the from the administering clinician, directing consultations and suitable changes will be to online resources for further information, made to suit the needs and expectations of signposting to Adult Social Care, or making COVID-19 survivors. referrals to community or specialist services. The findings of the audit in all the Trusts Mapping of tool to the ICF framework using it are likely to influence local policy, The World Health Organisation (WHO)’s commissioning and service delivery that is International Classification of Functioning, needed to manage these individuals during Disability and Health (ICF) provides us the pandemic. with a framework to understand the rela- tionship between different aspects of any Conclusion Stephen Halpin, MRCP, is Senior Research Fellow and Consultant in 5 health condition. The domains covered A pragmatic, comprehensive tele-assess- Rehabilitation Medicine, University of Leeds, by the C19-YRS tool when mapped to ment tool C19-YRS has been developed Leeds Teaching Hospitals NHS Trust and Leeds the components of ICF (Figure 2) shows to screen for needs and target rehabilita- Community Healthcare Trust. that there is satisfactory capture of all the tion interventions in COVID-19 survivors components (body functions and struc- after discharge from hospital care. The tool tures, activities, participation, environ- covers the multiple body systems affected mental factors and personal factors) in COVID-19 and covers all domains of the making it suitable for a comprehensive WHO ICF framework. biopsychosocial assessment. Using the tool Integration of services The C19-YRS tool is free to use and the The telephone screen can be adminis- MS Word/ PDF copy of the tool is avail- tered by rehabilitation clinicians across able on the ACNR website at www.acnr. Jeremy Gee MSc, the hospital and community Trusts. This co.uk/2020/06/c19-yrs/. The programmed is Community Advanced Clinical Practioner and promotes seamless care for these individ- version that can automatically export Physiotherapist, Airedale NHS Foundation Trust. uals after discharge from hospital. These responses to MS Excel can be requested Correspondence to: work stream have been set up to support by contacting the corresponding author of E: [email protected] the survivors during the pandemic and in this article. the long run will provide a model of inte- Conflict of interest statement:Manoj Sivan is Editor of ACNR’s Pain and Rehabilitation Section. grated MDT follow-up for a wide range of The other authors have declared no conflicts other patient groups, in line with the NHS REFERENCES of interest. long-term plan. Provenance and peer review: 1. Wu Z and McGoogan JM. Characteristics of and Submitted and internally reviewed. COVID-19 MDT Rehabilitation Team important lessons from the coronavirus disease 2019 An ideal MDT Rehabilitation Team (Table 1) (COVID-19) outbreak in China: summary of a report Date first submitted: 29/5/20 should have specialists trained in managing of 72 314 cases from the Chinese Center for Disease Date resubmitted after peer review: 6/6/20 Control and Prevention. Journal of the American aspects of care of these individuals and those Acceptance date: 8/6/20 Medical Association, 2020;323(13):1239-42. This is an open access article distributed with skills in managing chronic conditions. 2. Zhang G, Hu C, Luo L, Fang F, Chen Y, Li J, Peng Z, under the terms & conditions of the Creative The team needs to have strong links with Pan H. Clinical features and short-term outcomes of Commons Attribution license http:// 221 patients with COVID-19 in Wuhan, China. J Clin creativecommons.org/licenses/by/4.0/ Respiratory Medicine and Intensive Care Unit Virol. 2020 Apr 9;127:104364. teams and together develop network path- 3. Ahmed H, Patel K, Greenwood D, Halpin S, Acknowledgements: The authors would like ways for provision of appropriate care to these Lewthwaite P, Salawu A, Eyre L, Breen A, O’Connor to declare that the screening tool has been patients. R, Jones A, Sivan M. Long-term clinical outcomes developed by all the members of the COVID-19 in survivors of Severe Acute Respiratory Syndrome Multidisciplinary Team (MDT) Rehabilitation and Middle East Respiratory Syndrome coronavirus Teams of Leeds, Airedale and Hull NHS Trusts. Information technology and data outbreaks after hospitalisation or ICU admission: sharing a systematic review and meta-analysis. Journal of Rehabilitation Medicine 2020 May 25. DOI: To cite: Sivan M, Halpin S, Gee J. ACNR The completed tool can be uploaded to the 10.2340/16501977-2694. Online ahead of print. 2020;19(4):14-17 patient’s electronic records by the clinician 4. The NHS Long Term Plan. https://www.longtermplan. conducting the telephone consultation. Both nhs.uk/publication/nhs-long-term-plan/ acute and community Trusts in Yorkshire 2019 Accessed 23/05/2020 have full integrated electronic medical 5. World Health Organization (WHO). The International Classification of Functioning, Disability records that are accessible to each other and Health – ICF2001. Geneva: WHO.

ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 > 17 sponsored feature

Major Depressive Sponsored by

Disorder This feature has been funded by and developed in conjunction with, Janssen-Cilag Ltd, based on an interview with Professor Ramin Nilforooshan. Prof Where are we falling short? Nilforooshan has received a consultancy honorarium from Janssen for his contribution to this article. The views expressed in this article are his own clinical opinions. Job code: CP-164940 Professor Ramin Nilforooshan, Consultant Psychiatrist, Date of preparation: June 2020 Surrey and Borders Partnership NHS Foundation Trust, University of Surrey.

t any one time, one in six adults are affected by mental ill health, with the burden of disease estimated to cost £105 A 1 billion a year in England alone. There is no question that this is a field that urgently needs our attention. In particular, major depressive disorder (MDD), which refers to severe and persistent symptoms of depression, is taking a devastating toll, causing significant ill-health, disability and suffering for patients and their families, as well as an incredible strain on our healthcare system and economy.1,2,3 Depression affects all aspects of a person’s life, physically, socially and emotionally. Consider the multifaceted effects of suicide, the long-lasting impact on physical health (depression is a major contributor to coronary heart disease), and the fact that so many patients simply don’t remember what it means to be happy.1 they’re likely to claim a headache, back pain, undertaken training in a mental health setting.15 It is clear this is a significant problem. But is or that they can’t sleep.6 To add to the issue, But when time is limited, proactive educa- it being addressed? Is access to care for mental patients’ willingness to divulge information is tion is critical. We all need to know the guide- health equal to that for physical health? The compromised by their MDD.7 lines, receive the relevant updates, and know answer is no. Patients are also commonly deterred by what to look for and what questions to ask Mental illness is the largest single cause of negative experiences with healthcare profes- in that crucial time. The information is out disability, representing 23 percent of all ill-health sionals and are worried they won’t get taken there already. Right now, a diagnosis of MDD in the UK. Yet only 13.8 percent of England’s seriously.5 This is sadly understandable – UK requires two of the cardinal features of depres- health budget is spent on mental health.4 GPs have reported feelings of ambivalence in sion, plus five additional features that represent Without the resources, the majority of such working with depressed people, a lack of confi- a distinct change from previous functioning, services are struggling to provide better services, dence in their ability to manage the condition for a continuous period of 14 days.16,17 The key and although we’ve opened up the debate on parity of esteem in recent years, much more with the options available, and a belief that word here is function; MDD affects someone’s needs to be done. The voice of the patient is some patients will feel stigmatised by a diag- global functioning, from their work, to their 8,9 one of the strongest factors in improving and nosis of depression. The end result is that relationships, to their day-to-day-activities. It expanding services, and unfortunately, those many patients do not seek early help, and it can is their whole life. That’s why it’s so important 10 with MDD and other conditions just don’t instead take them years to seek out. As few as to be able to spot it. have the energy or motivation. We must, as a a quarter of adults with depression or anxiety 11 collective, take this into our own hands and receive treatment in the UK. The right treatment, at the right time take responsibility for our patients. So, we can’t leave it all to patients and char- Unfortunately, mental health treatment often ities. Our responsibility, as clinicians, and the falls very short of the standards for physical The difficulty with diagnosis public health service, is to make sure that we health. In physical health, clinicians aim for full The first step towards effective treatment is the are as prepared as possible to spot MDD even recovery, but frequently this is not the case with right diagnosis. Yet, for MDD, this is confounded in the midst of stigma. How might we do that? MDD. We need to be aiming for full recovery of by multiple factors. Unfortunately, our first and Currently in the UK, around 90 percent function, not just some improvement in some immediate issue is that patients are not so willing of those with mental health disorders are symptoms, or to ‘just coping’. If we don’t get to open up about their mental health. diagnosed and managed in primary care, and our patients back to their full function, can we Despite celebrity outreach and campaigns almost one-third of GP appointments involve really say their treatment is complete? like Time to Change, launched in 2007, there an underlying mental health component.12 Yet It is therefore crucial that we treat our is still a big mental health stigma in the UK GPs only have, on average, just over nine patients effectively, and as early as we can. stopping people getting the help they need.5 minutes to make their diagnosis and only Both prospective and retrospective studies have It is both a social problem, meaning friends a small fraction of that consists of actual found that the sooner MDD is treated, the and family might not push individuals to see eye-to-eye contact.13,14 In addition, one study better the long-term outcomes, and earlier a clinician, and a personal one – if they do go, found that fewer than half of trainee GPs had optimisation can prevent long-term suffering

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and help avoid inpatient treatment.18,19 improving the treatment of depression. While References Right now, the majority of patients with the application of AI is improving, clinical 1. Mental Health First Aid (MHFA) England. (2020). depression are treated with medications or health still lags behind other fields, potentially Mental health statistics. Available at: https://mhfaeng- land.org/mhfa-centre/research-and-evaluation/ psychological therapy (talking Therapy). Yet it because of a reluctance to use such technology mental-health-statistics/. Accessed: June 2020. shouldn’t have to be one or the other – in fact, when people’s lives are involved – but the 2. Harvard Health Publishing. Major Depression. Available at: https://www.health.harvard.edu/a_to_z/major-de- NICE guidelines recommend a combination possibilities to advance care are extraordinary. pression-a-to-z. Accessed: June 2020. for those with moderate or severe depression.20 Apps and passive monitoring systems could 3. Blumenthal JA, Babyak MA, Doraiswamy PM, et al. Exercise and Pharmacotherapy in the Treatment of Major If a patient feels they would benefit from both, gather more in-depth and longer-term data Depressive Disorder. Psychosom Med. 2007;69(7):587–96. shouldn’t that be an option? on how our patients are coping. Their walking 4. The National Mental Health Development Unit (NMHDU). The Costs of Mental Ill Health. Available We need to weigh up what is best for our speed, the angle of their neck (related to eye at: https://www.networks.nhs.uk/nhs-networks/region- patients – and then continue to assess them contact), the quality of their sleep, the tone of al-mental-health-workshop-mids-east/documents/ regularly. NICE recommends reviewing their voice, their activity per day (step count) supporting-materials/nmhdu-factfile-3.pdf. 5. Henderson C, Evans-Lacko S, Thornicroft G. Mental patients two weeks after prescription, identified – all of this could be analysed with machine Illness Stigma, Help Seeking, and Public Health Programs. as the optimal point to evaluate early improve- learning to chart improvements with treatment Am J Public Health. 2013;103(5):777–78. 6. Gerber PD, Barrett JE, Barrett JE, et al. The Relationship 23 ment and predict the likelihood of remission in ways that humans simply cannot. of Presenting Physical Complaints to Depressive in the next 10 weeks.9,21 If a lack of response Technology may seem scary, and while it Symptoms in Primary Care Patients. J Gen Intern Med. 1992;7(2):170–3. is evident, the patient should continue to be cannot replace real, human interaction, if used 7. Kupferber A, Bicks L, Hasler G. Social functioning evaluated after three to eight weeks, and if their correctly, it could help a great deal. Using such in major depressive disorder. Neurosci Biobehav Rev. 2016;69:313–332. depression is complex and severe, they must be a system could even help patients be seen when 8. Barley EA, Murray J, Walters P, et al. Managing depres- referred to a specialist mental health service.9,19 they actually need to be seen – by monitoring sion in primary care: A metasynthesis of qualitative and If they aren’t showing the right results after and then calling them on the day – while those quantitative research from the UK to identify barriers and facilitators. BMC Family Practice. 2011;12:47. those two weeks – i.e. an improvement in func- that can, avoid the discomfort of an unneces- 9. Arroll B, Moir F, Kendrick T. Effective management of tioning – the dose or the treatment needs to sary appointment. This kind of system could depression in primary care: a review of the literature. BJGP Open. 2017;1(2):bjgpopen17X101025. be changed. At the moment, however, studies truly help us to do more for our patients. 10. Ng CWM, How CH, Ng YP. Major depression in suggest this is not happening. One study found primary care: making the diagnosis. Singapore Med J. 2016;57(11):591–597. that 48 percent of patients with at least moderate The system needs to change 11. Department of Health. (2014). Achieving Better Access MDD received no treatment despite exhibiting Improving access to mental health treatment to Mental Health Services by 2020. Available at: https:// assets.publishing.service.gov.uk/government/uploads/ all relevant symptoms to warrant initiation of is everyone’s responsibility, and the health system/uploads/attachment_data/file/361648/mental- antidepressant therapy. Of those who did receive economy has a massive part to play. health-access.pdf. Accessed: June 2020. treatment, 84 percent failing to respond to their Funding is currently a big issue. The Quality 12. NHS Oxfordshire CCG. (2017) Commissioning for Value Mental health and dementia pack. Available at: https:// current medication had no change in therapy for and Outcomes Framework (QOF) scheme www.england.nhs.uk/wp-content/uploads/2017/07/ at least 8 weeks, and were treated for an average offers significantly fewer incentives for mental cfv-oxfordshire-mhidp.pdf. Accessed: June 2020. 13. Irving G, Neves AL, Dambha-Miller H, et al. 19 of 37 weeks with the same drug. health compared to physical health – another International variations in primary care physician consul- Numbers like these are shocking, but sign that parity of esteem has a long way to tation time: a systematic review of 67 countries. BMJ Open. 2017;7:e017902. sadly the reality. We must act quickly and be go in the UK. Measurements aren’t the same, 14. Pulse Today. What's stopping GPs looking their patients proactive if we want the best for our patients. and clinicians need to spend double the time in the eye? Available at: http://www.pulsetoday. co.uk/whats-stopping-gps-looking-their-patients-in- We must improve training for clinicians, so for those with mental illness as they do with the-eye/11016268.article. Accessed: June 2020. they stay up to date, and know which treatment physical illness. That should be considered; we 15. MIND. (2016). GPs and practice nurses aren’t getting need a fairer way of incentivising treatment for enough mental health training. Available at: https://www. is best according to guidelines. mind.org.uk/news-campaigns/news/gps-and-practice- The attitude of clinicians needs to change, mental health vs physical health. nurses-aren-t-getting-enough-mental-health-training/. and we need better access to a range of resources. As for new treatments, they are hard to come Accessed: June 2020. 16. American Psychiatric Association. (2013) Diagnostic and Some areas hold promise; in secondary care, for by compared with other therapy areas. The statistical manual of mental disorders. 5th ed. Arlington: example, patients are offered a wider range total expenditure on mental health research American Psychiatric Association. 17. WHO. The ICD-10Classification of Mental and of medications and a more holistic approach from 2014–17 was £497 million, on average Behavioural Disorders Diagnostic criteria for research, to treatment akin to many £124 million per year. These figures translate https://www.who.int/classifications/icd/en/bluebook. pdf. areas. The Improving Access to Psychological to just over £9 spent on research per year, 18. Kraus C, Kadriu B, Lanzenberger R, et al. Prognosis Therapies (IAPT) programme, which began for each person affected by mental illness. By and Improved Outcomes in Major Depression: A Review. in 2008, is also making a difference. Its aim comparison, £612 million is spent on cancer Transl Psychiatry. 2019;9(1):127. 19. Herzog DP, Wagner S, Ruckes C, et al. Guideline adher- is to offer evidence-based therapy, routine research each year, which translates to £228 per ence of antidepressant treatment in outpatients with monitoring, and regular supervision, so clin- person affected – or 25 times more per person.24 major depressive disorder: a naturalistic study. Eur Arch Psychiatry Clin Neurosci. 2017;267(8):711–721. icians have the right support to continually Clinical trials are often delayed because of 20. National Institute for Clinical Excellence. (2009) improve their service offering. The NHS has recruitment and retention issues, and compounds Depression in adults: recognition and management. Available at: https://www.nice.org.uk/guidance/cg90. committed to allowing 1.9 million people a are more costly for pharmaceutical companies to Accessed: June 2020. year access to this programme by 2023/4.22 develop.25,26 We need the right funding to incen- 21. Hicks PB, Sevilimedu V, Johnson GR, et al. Predictability of Nonremitting Depression After First 2 Weeks of tivise progress, but even treatments approved by Antidepressant Treatment: A VAST-D Trial Report. How can technology help us? NICE must be pushed for us to access. Clinicians PRCP. 2019: doi.org/10.1176/appi.prcp.20190003. 22. NHS. Adult Improving Access to Psychological Therapies It’s one thing to say that if something isn’t are chasing local Clinical Commissioning Groups programme. Available at: https://www.england.nhs.uk/ working, we should change it, or step it up. But (CCGs) for approval – but we need the push to mental-health/adults/iapt/. Accessed: June 2020. how do we know if a treatment is working or come from somewhere else. 23. National Institute of Mental Health. (2019). Technology and the Future of Mental Health Treatment. Available not? How do we know if a patient is improving? at: https://www.nimh.nih.gov/health/topics/technology- Unfortunately, there aren’t many biomarkers Where next? and-the-future-of-mental-health-treatment/. Accessed: June 2020. when it comes to MDD. Clinical interviews, It’s clear that some big changes need to happen 24. MQ. UK Mental Health Research Funding 2014–2017. while important, are subjective and hard to before we can claim parity of esteem in the UK. Available at: https://s3.eu-central-1.amazonaws.com/ www.joinmq.org/UK+Mental+Health+Research+Fun compare when patients switch between clin- Diagnosing and treating depression sits with ding+2014-2017+digital.pdf icians. We need a more generalised measure- every clinician – but in order to do so, we need 25. Liu Y, Pencheon E, Hunter RM, et al. Recruitment and Retention Strategies in Mental Health Trials - A Systematic ment that excludes human bias. the right tools, up-to-date training and educa- Review. PLoS One. 2018;13(8):e0203127. Artificial intelligence (AI) and machine tion. Only then can we provide the care that 26. Tufts Impact Report. 2012. Pace of CNS drug development learning could have a big role to play in our patients desperately need. and FDA approvals lags other drug classes.

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Hallucinations in Parkinson’s disease: new insights into mechanisms and treatments

Rimona Weil, MBBS, PhD Abstract that are both effective and safe is an area is a Wellcome Clinician Scientist and Hallucinations are common in Parkinson’s of great unmet need as antipsychotic drugs Honorary Consultant Neurologist at disease and can be distressing to patients and worsen Parkinson’s symptoms, are associated the National Hospital for Neurology their families. They are associated with higher with cognitive deterioration and an increased and Neurosurgery. Her main clinical and 3 research interests are in clinical and rates of nursing home placement and with risk of stroke and death. predictors of Parkinson’s increased mortality. Their underlying mechan- disease and in visual hallucinations in isms have been elusive, but recent advances Mechanisms Parkinson’s disease and Dementia with in network imaging provides some intriguing Network changes and thalamic drivers Lewy Bodies. She runs specialist clinics for patients with Parkinson’s Dementia insights into possible underlying drivers. Visual hallucinations have fascinated neurolo- and Dementia with Lewy Bodies and is a Treatment is complicated by risk of worsening gists and for many years, with their collaborator on the Parkinson’s UK-funded Parkinson’s motor symptoms and by higher tantalisingly rich and often narrative detail. Due to Trial of Ondansetron as a Parkinson’s rates of mortality with antipsychotics, but new their transient nature, they have been challenging HAllucinations Treatment: TOP HAT therapeutic avenues are emerging that offer to investigate, with no clear mechanism found, potential hope. but many theories have been proposed. Previous models for visual hallucinations considered them as “cortical release” phenomena, where spon- taneous activity occurs in the absence of visual isual hallucinations are common in stimuli. Alternative models suggested that hallu- Parkinson’s disease, affecting up to 75% cinations arise due to incorrect binding of objects Vof patients over the disease course. The into visual scenes.4 emergence of visual hallucinations has a signifi- Advances in computational modelling Suzanne Reeves, MBBS, cant impact on the quality of life of both patients and network neuroscience have opened up and their families: they are strongly associated approaches to understanding the brain in new MRCP (UK), MRCPsych, PhD with cognitive decline and increased mortality ways. Recent models suggest that Parkinson’s is Professor of Old Age Psychiatry and (University College and they are the strongest predictor of earlier hallucinations could arise due to a shift in London), Academic MBBS Mental Lead, placement in care homes.1 dominance of difference networks. Specifically, and an Honorary Consultant in Care Although often initially benign and even there is thought to be a breakdown in those Home Liaison (Camden and Islington NHS entertaining, they can become distressing with networks directed to attention and perception, Foundation Trust). Her main clinical and research interests are to optimise the disease progression, when insight is lost, and and overactivity of the default mode network treatment of delusions and hallucinations when associated with depression or delusions. (DMN),5,6 a large-scale network that becomes in older people, with a primary focus on They almost invariably involve perception of activated during rest, and in day dreaming and Alzheimer’s disease and the Parkinson’s people and animals, often in vivid detail, with mind-wandering. Indeed abnormal levels of disease spectrum. She is the Chief Investigator of the Parkinson’s UK-funded patients describing scenes of Victorian women default mode network activation are seen in Trial of Ondansetron as a Parkinson’s and small children playing. They often occur patients with Parkinson’s hallucinations.7 HAllucinations Treatment: TOP HAT at specific times of day, usually in the evening, Related to this is the theory that hallucinations and in specific places, usually in the patient’s arise as a result of failure to integrate sensory Correspondence to: 8 Dr Rimona S Weil, Dementia Research own home. At early stages of disease, patients information with prior knowledge and we Centre, UCL Institute of Neurology, can describe minor hallucinations with misin- recently showed that patients with Parkinson’s 8-11 Queen Square, London WC1N 3BG. terpretation of innocuous objects such as piles who hallucinate over rely on prior knowledge E: [email protected] of clothes as dogs and cats. They also experi- compared with those that do not hallucinate E: [email protected] ence passage hallucinations, which involve the (See Figure 1).9 In this way, hallucinations arise Conflict of interest statement: illusion of objects passing across the periph- due to over interpretation of visual input. The Dr Weil received personal fees from GE eries of vision2 and extracampine hallucina- thalamus is likely to be important as a driver of Healthcare. tions, or the sense of a presence. shifting network control, and release of DMN 6 Provenance and peer review: Submitted and Less frequently, patients have hallucinations inhibition. Consistent with this, we recently externally reviewed in other modalities as the illness progresses, showed reduced white matter connectivity in although these are usually less well-formed. posterior thalamic projections in patients with Date first submitted: 17/6/2020 For example, auditory hallucinations in people Parkinson’s hallucinations.10 Date submitted after peer review: 23/6/2020 Acceptance date: 23/6/2020 with Parkinson’s disease are largely non-verbal, Published online: 13/7/20 with muffled, undistinguishable sounds. and hallucinations This is an open access article distributed Occasionally patients describe tactile, gusta- The role of dopamine in the pathophysiology under the terms & conditions of the tory or olfactory hallucinations, which tend to of psychotic symptoms has long been studied. Creative Commons Attribution license http://creativecommons.org/licenses/ co-occur with visual hallucinations. In Parkinson’s disease, it is recognised that by/4.0/ Visual hallucinations pose a particular visual hallucinations increase with the dose challenge in Parkinson’s disease as the very and duration of levodopa treatment,11 and that To cite: Weil R, Reeves S. ACNR treatments for motor symptoms in Parkinson’s dopamine agonists are linked with higher rates 2020;19(4):20-22 disease can also trigger and worsen hallucin- of visual hallucinations.12 It has been suggested ations. Finding treatment for hallucinations that hypersensitisation of nigrostriatal dopa-

20 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 r e v i e w a r t i c l e

Figure 1. Patients with visual hallucinations over rely on prior information. A. Two-tone test image shown to patients with visual hallucinations. B. Greater improvement in image recognition is seen in Parkinson’s hallucinators than those with no hallucin- ations after viewing the template image. C. Template colour image, from which the two-tone image was generated.

Adapted from Zarkali A, Adams RA, Psarras S, Leyland LA, Rees G, Weil RS. Increased weighting on prior knowledge in Lewy body-associated visual hallucinations. Brain Commun. 2019;1(1):fcz007. doi:10.1093/braincomms/fcz007

minergic neurones by anti-Parkinson’s drugs the early disruption of serotonergic and pine).3 However the evidence for its use is is an important extrinsic contributor to visual cholinergic neurotransmission that occurs in weak as RCTs have shown no superiority hallucinations.13 Parkinson’s disease may play a key role in over placebo, apart from one study which Visual processing involves a complex inter- thalamic driven decoupling of the DMN17 and excluded patients with delusions.22 play between dopaminergic, serotonergic, this is a major area of research interest. Clozapine has the strongest evidence for cholinergic, and GABAergic neurons14 and efficacy in treating distressing hallucina- disruption of this dynamic balance, due to Treatment approaches tions in Parkinson’s disease. Two good size intrinsic, disease-related changes underpins The general principle for treating visual RCTs have shown effectiveness in reducing the emergence of visual hallucinations in hallucinations in Parkinson’s disease is to hallucinations and associated delusions, Parkinson’s disease. The distinct contribution look for recent triggers, such as infection, or with no worsening of Parkinson’s motor of each has however proved recent medication changes. The next step symptoms, following very low dose treat- difficult to disentangle, due to the overlapping is to reduce or stop medications that could ment (10% of the dose used to treat schizo- functional networks involved in the interpret- be worsening hallucinations and only then phrenia).23,24 However, concern of agranu- ation of visual stimuli.14 to consider specific treatments.18 Importantly, locytosis, daily pulse and blood pressure Perceptual inference (filling in the gaps in specific interventions for visual hallucinations checks, and weekly blood monitoring for the what our senses tell us) relies on the brain’s should only be initiated if patients are both- first 18 weeks, make this impractical outside ability to make accurate predictions about ered by the experiences, as in most cases, side of specialist mental health settings. the reliability of sensory data. The thalamor- effects can outweigh benefits of treatment. Serotonergic agents have attracted eticular nucleus, a shell of GABA-releasing There is no evidence base for the order of considerable attention as candidate drug neurones surrounding the thalamic circuits, withdrawal, and best practise is to withdraw treatments for hallucinations, as they offer plays a key role in perceptual inference, whatever triggered the hallucinations. With an alternative approach that is not medi- as it modulates information flow to facili- no clear trigger, withdrawal should start with ated via direct antagonism of dopamine tate salient stimuli and suppress less relevant the least efficacious. A useful order has been D2/3 receptors. The 5HT2A inverse agonist, stimuli.15 Acetyl choline is a critical modulator recently provided: anticholinergics, followed Pimavanserin, was recently shown in a large of the thalamoreticular nucleus via nicotinic by amantadine, rasagaline, dopamine agon- randomised controlled trial to improve psych- alpha 7 and muscarinic M2 receptors, and ists, monoamine oxidase (MAO) B inhibitors, osis and visual hallucinations in Parkinson’s acts as a ‘sensory precision signal’.16 entacapone and then levodopa.19,20 disease,25 with greatest improvement The serotonergic system is involved in Cholinesterase inhibitors are widely thought observed in patients with poorer cognition.26 early sensory processing, complex visual to reduce hallucinations. However, there are Initial concerns of higher rates of mortality processing and (with noradrenaline), modu- no supportive randomised controlled trial were shown to be no higher than those in this lates behavioural responses (inhibition/ (RCT) data where visual hallucinations have already frail patient group.27 arousal) to visual inputs.14 This multiplicity been the treatment indication or primary An alternative serotonergic agent is the of function reflects the widely distributed outcome. The best evidence for their benefit 5HT3 antagonist, ondansetron, which is network and functional diversity of recep- is the observation that Rivastigmine improved already in use and licensed as an anti-emetic. tors which modulate the activity of sensory cognitive performance most in those patients Ondansetron showed early promise in the cortices, the thalamoreticular nucleus and with visual hallucinations.21 early 1990s as treatment of severe, persistent thalamocortical circuitry. Receptor subtypes Treatment options for persistent hallucin- visual hallucinations in a case series of people that are most closely involved in visual ations are limited to antipsychotic drugs, with Parkinson’s disease28 and a subsequent processing include 5HT1A (expressed on which are associated with significant side-ef- open study, with marked improvement in cortical pyramidal ), 5HT1B and fects (falls, sedation, worsening of cognitive hallucinations and delusions.29 At the time, 5HT2A (densely expressed in the primary and motor function) and increased mortality. the then high cost of ondansetron prevented visual cortex), and 5HT3 receptors (expressed National Institute of Clinical Excellence further studies, but this is no longer the on GABAergic neurones) which modulate (NICE 2017, www.nice.org.uk/) guidance case and the first placebo-controlled trial of the release of acetyl choline, dopamine and supports use of quetiapine, as it is safer than ondansetron as a Parkinson’s hallucinations glutamate.14,17 other atypical antipsychotics (odds ratio of treatment (TOP HAT) is planned for Autumn Viewed in the context of ‘network control’, mortality 2.16 compared to 2.79 for olanza- 2020, funded by Parkinson’s UK.

ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 > 21 r e v i e w a r t i c l e

REFERENCES

1. Goetz CG, Stebbins GT. Risk factors for nursing home 11. Sweet RD, McDowell FH, Feigenson JS, Loranger AW, 22. Shotbolt P, Samuel M, David A. Quetiapine placement in advanced Parkinson’s disease. Neurology. Goodell H. Mental symptoms in Parkinson’s disease in the treatment of psychosis in Parkinson’s 1993;43:2227-2229, doi:10.1212/wnl.43.11.2227. during chronic treatment with levodopa. Neurology. disease. Ther Adv Neurol Disord. 2010;3:339- 1976;26:305-310, doi:10.1212/wnl.26.4.305. 2. Fenelon G, Mahieux F, Huon R, Ziegler M. Hallucinations 350, doi:10.1177/1756285610389656 . 12. Poewe W. Psychosis in Parkinson’s disease. Mov Disord. in Parkinson’s disease: prevalence, phenomenology 23. Pollak P, et al. Clozapine in drug induced psychosis in 2003;18 Suppl 6:S80-87, doi:10.1002/mds.10567. and risk factors. Brain 2000;123 (Pt 4):733- Parkinson’s disease: a randomised, placebo controlled 745, doi:10.1093/brain/123.4.733. 13. Zahodne LB, Fernandez HH. Pathophysiology and treat- study with open follow up. J Neurol Neurosurg ment of psychosis in Parkinson’s disease: a review. Drugs 3. Weintraub D et al. Association of Antipsychotic Use With Psychiatry. 2004;75:689-695, doi:10.1136/ Aging. 2008;25:665-682, doi:10.2165/00002512- Mortality Risk in Patients With Parkinson Disease. JAMA 200825080-00004. jnnp.2003.029868. Neurol 2016;73:535-541, doi:10.1001/jaman- 24. Clozapine in drug-induced psychosis in Parkinson’s eurol.2016.0031. 14. Jacob SN, Nienborg H. Monoaminergic of Sensory Processing. Front Neural Circuits. 2018;12:51, disease. The French Clozapine Parkinson Study 4. Collerton D, Perry E, McKeith I. Why people see things doi:10.3389/fncir.2018.00051. Group. Lancet. 1999:353;2041-2042. that are not there: a novel Perception and Attention 15. Pratt JA, Morris BJ. The thalamic reticular nucleus: 25. Cummings J, et al. Pimavanserin for patients with Deficit model for recurrent complex visual hallucina- a functional hub for thalamocortical network Parkinson’s disease psychosis: a randomised, place- tions. Behav Brain Sci 2005;28;737-757; discussion dysfunction in schizophrenia and a target for drug 757-794, doi:10.1017/S0140525X05000130. bo-controlled phase 3 trial. Lancet. 2014;383:533- discovery. J Psychopharmacol. 2015;29:127- 540, doi:10.1016/S0140-6736(13)62106-6. 5. Shine JM, O’Callaghan C, Halliday GM, Lewis SJ. Tricks 137, doi:10.1177/0269881114565805. 26. Espay AJ, et al. Pimavanserin for Parkinson’s Disease of the mind: Visual hallucinations as disorders of atten- 16. Parr T, Friston KJ. The active construction of the tion. Prog Neurobiol. 2014;116:58-65, doi:10.1016/j. visual world. Neuropsychologia. 2017;104:92- psychosis: Effects stratified by baseline cognition pneurobio.2014.01.004. 101, doi:10.1016/j.neuropsychologia.2017.08.003. and use of cognitive-enhancing medications. Mov Disord 2018;33:1769-1776, doi:10.1002/mds.27488. 6. Onofrj M, et al. Psychosis in parkinsonism: an unorthodox 17. Russo M, et al. The Pharmacology of Visual approach. Neuropsychiatr Dis Treat. 2017;13:1313- Hallucinations in Synucleinopathies. Front Pharmacol. 27. Moreno GM et al. Mortality in patients with Parkinson 1330, doi:10.2147/NDT.S116116. 2019;10:1379, doi:10.3389/fphar.2019.01379. disease psychosis receiving pimavanserin and quet- 7. Yao N, et al. The default mode network is disrupted in 18. O’Brien J, et al. Visual hallucinations in neurological and iapine. Neurology 2018;91:797-799, doi:10.1212/ Parkinson’s disease with visual hallucinations. Hum Brain ophthalmological disease: pathophysiology and manage- WNL.0000000000006396. Mapp. 2014;35:5658-5666, doi:10.1002/hbm.22577. ment. J Neurol Neurosurg Psychiatry. 2020;91:512- 28. Zoldan J, Friedberg G, Goldberg-Stern H & Melamed E. 519, doi:10.1136/jnnp-2019-322702. 8. Muller AJ, Shine JM, Halliday GM, Lewis SJ. Visual hallu- Ondansetron for hallucinosis in advanced Parkinson’s 19. Connolly BS, Lang AE. Pharmacological treatment of cinations in Parkinson’s disease: theoretical models. Mov disease. Lancet 1993;341:562-563, doi:10.1016/0140- Parkinson disease: a review. JAMA. 2014;311:1670- Disord 2014;29:1591-1598, doi:10.1002/mds.26004. 6736(93)90327-d. 1683, doi:10.1001/jama.2014.3654. 9. Zarkali A, et al. Increased weighting on prior knowledge 29. Zoldan J, Friedberg G, Livneh M & Melamed E. 20. Friedman JH. Pharmacological interventions for in Lewy body-associated visual hallucinations. Brain psychosis in Parkinson’s disease patients. Expert Psychosis in advanced Parkinson’s disease: treat- Commun. 2019;1:fcz007, doi:10.1093/braincomms/ Opin Pharmacother. 2018;19:499- ment with ondansetron, a 5-HT3 receptor antago- fcz007. 505, doi:10.1080/14656566.2018.1445721. nist. Neurology 1995;45:1305-1308, doi:10.1212/ 10. Zarkali A, McColgan P, Leyland LA, Lees AJ, Rees 21. Burn D et al. Effects of rivastigmine in patients with and wnl.45.7.1305 (1995).15. Specialised Clinical Frailty G, Weil RS. Fibre-specific white matter reductions in without visual hallucinations in dementia associated Network CFS Training [Internet]. [cited 2020 Apr 17]. Parkinson’s hallucinations and visual dysfunction. In with Parkinson’s disease. Mov Disord. 2006;21:1899- Available from: https://www.scfn.org.uk/clinical-frail- Press. Neurology 2020. 1907, doi:10.1002/mds.21077. ty-scale-training

r e g u l a r s – b o o k r e v i e w s

Oxford Handbook of Rehabilitation Medicine. 3rd Edition

n the best tradition of Oxford Handbooks, this is a small traditional areas of neurological and spinal cord rehabilita- book that packs a heavy punch. This third edition repre- tion who find themselves working with increasingly complex Isents a significant expansion in scope and detail compared conditions and co-morbidities. to the second edition of 2009. With over 650 pages miracu- Between the second and third editions the title has shifted lously compressed into less than two and a half centimetres, from Clinical Rehabilitation to Rehabilitation Medicine, which this edition adeptly fulfils its role in providing for jobbing is indicative of a change of emphasis towards greater rigorous clinicians a succinct, easily navigable overview of key clinical pathophysiological detail and is accompanied by an authori- topics at their fingertips. tative, brisk editorial style. Medics, from students and junior The volume is structured in two sections, the first of which doctors to specialists in Rehabilitation Medicine (but also ‘Common Clinical Approaches’ provides 25 chapters on , Neurology, Stroke Medicine and beyond) will be cross-cutting areas from Communication, to Chronic Pain, the main users of this handbook, but it also has much to offer Sexual Function and Mobility and Gait. Section 2 addresses to the whole multi-professional rehabilitation team. Editors: Manoj Sivan, ‘Condition-Specific Approaches’ in 16 chapters including The chapter authors are largely drawn from the UK and Margaret Phillips, Traumatic Brain Injury, Multiple Sclerosis, Prolonged Disorders Australia, and sections on models of care and organisation Ian Baguley, Melissa Nott of Consciousness and Amputee Rehabilitation. Where there is of services reflect those settings. Inevitably, some details have Published by: Oxford overlap, this is usefully signposted within the text, directing already been superseded by new guidelines, for example that University Press the reader to other relevant chapters. The text is helpfully in TIA risk stratification, but in general this edition does an Paperback price: £34.99 Pages: 658 presented, easy to scan and interspersed with many useful excellent job of succinctly bringing the reader up to date, and ISBN: 9780198785477 illustrations and diagrams. signposting further reading. Reviewed by: The devotion of two chapters to musculoskeletal condi- In its main aim of concisely presenting both the core Stephen Halpin, tions, as well as the inclusion of Cancer Rehabilitation and principles and practical clinical details of Rehabilitation Senior Clinical Research Geriatric Rehabilitation reflects the editors’ timely desire to Medicine practice across an expanded scope of conditions, Fellow and Consultant in Rehabilitation Medicine, see the focus of rehabilitation as a in the UK this handbook has certainly succeeded and it will undoubt- Academic Department of broaden to address conditions of greatest population burden. edly become a familiar sight in MDT rooms and doctors’ Rehabilitation Medicine, They will also be useful to rehabilitation practitioners in the offices across the rehabilitation landscape. University of Leeds.

22 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 QUEEN SQUARE MULTIDISCIPLINARY NEURO- COURSE

COURSE ORGANISER:

Dr Jeremy Rees The National Hospital for Neurology & Neurosurgery, Queen Square

23/09/20 13/01/21 Principles of Neuro- Benign & Malignant Oncology Tumours

1. Learn about state of the art imaging and pathological diagnosis of brain tumours

2. See how experts manage brain tumours including Proton Beam Therapy, Clinical Trials and Gamma Knife

3. Gain a broader understanding of multidisciplinary management in neuro- oncology

Delivered over two days throughout the 2020/ 21 academic year by Consultants of the UCLH/ Queen Square Neuro-Oncology Multidisciplinary team, this course will address the need for better understanding between the diverse clinical specialities involved in the care of Neuro- Oncology patients

FOR MORE INFORMATION AND TO BOOK A PLACE ON THE COURSE VISIT: https://www.ucl.ac.uk/ion/study/queen-square-courses/queen-square- multidisciplinary-neuro-oncology-teaching-course r e v i e w a r t i c l e

A month of Sundays? What technology can tell us about sleep on lockdown

Abstract Few physiological processes are as influ- The COVID-19 pandemic has undoubtedly had enced by our behaviour as sleep. Given the a sizeable impact on the health and day and sudden and extreme rift in the behaviour of night time behaviours of populations around society, it is reasonable to assume that the lock- the world. In the UK, lockdown and social down has had some impact on how the popula- distancing measures vastly reduced mobility as tion is now sleeping. This paper examines ways citizens worked from home and the clinically in which big data can be used to understand vulnerable began shielding indoors. Compared shifts in behaviour and sleeping patterns. to pandemics of old, large datasets now exist which give fascinating insight into pandemic-re- The role of structure in entraining the lated behavioural change. This paper investi- circadian rhythm gates how publicly available data from tech- The circadian rhythm, in the absence of zeit- Alastair Paterson, nology companies can be examined to build gebers (light, food, temperature) usually spans (MPharm), up a picture of how sleep and circadian rhythm longer than 24 hours. When light is received by is a Pharmacist working in adult changes in locked down populations. the retina, a signal travels to the suprachiasmatic in the North East of nucleus (SCN) causing the pineal gland to stop England. His research interests include sleep, deprescribing, educational releasing melatonin, encouraging the sleeper to interventions and behavioural change. wake and entraining the rhythm to 24-hours.6 This He has recently published reviews on he social distancing measures introduced negative feedback loop is also triggered by artifi- insomnia and was part of a larger study by governments around the world in cial light from phones and TV screens.7 The social team examining practical interventions on inpatient wards to improve sleep. Tresponse to the COVID-19 pandemic has zeitgeber theory proposes that social changes brought about sudden and massive change to also act as zeitgebers, with disruption negatively Correspondence to: the lives of entire populations.1 The lockdown affecting circadian synchronicity, disrupting Alastair Paterson, has inevitably had an effect on the behav- biological processes and predisposing individuals Specialist Clinical Pharmacist, 8 Cumbria, Northumberland, Tyne and Wear iours and quality of life of the general public, to insomnia and depression. Combined with the NHS Foundation Trust, UK. from employment rates to mental health.2 effect of artificial light on sleep times, circadian E: [email protected] A symptom of this change was seen in late disruption is therefore likely in a pandemic.9 March when media giants Netflix and YouTube Conflict of interest statement: None declared. reduced the quality of their streaming services What the Big Data Giants tell us about to cope with increased demand.3,4 In response behavioural change Provenance and peer review: to the coronavirus pandemic, Netflix experi- Google Trends (Figure 1) shows a sharp Submitted and externally reviewed. enced 15 million new subscribers, and Spotify increase in ‘coronavirus’ searches over the 5 Date first submitted: 1/7/2020 6 million new Premium users. course of the pandemic. Date submitted after peer review: 26/7/2020 Acceptance date: 28/7/2020 Figure 1: Google Trends search data. This is an open access article distributed under the terms & conditions of the Google Trends data: Interest over time Creative Commons Attribution license http://creativecommons.org/licenses/ 120 by/4.0/ 12th January 2020 – China publicly share genetic sequence of novel coronavirus

To cite: Paterson A. ACNR 2020;19(4):24-27 100

80

60

40

20 Interest as a percentage of highest value

0

9/8/2019 2/9/2020 3/8/2020 4/5/2020 5/3/2020 6/30/20197/14/20197/28/20198/11/20198/25/2019 9/22/201910/6/201910/20/201911/3/201911/17/201912/1/201912/15/201912/29/20191/12/20201/26/2020 2/23/2020 3/22/2020 4/19/2020 5/17/20205/31/20206/14/2020

Coronavirus Weather News Music Sports

Figure 1: Google Trends search data 24 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020

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Figure 2: Changes in Spotify monthly listeners to ambient music (ref 10).

Figure 2: Changes in Spotify monthly listeners to ambient music (10) Spotify The music streaming giant commented “morning routines have changed signifi- cantly. Every day now looks like a weekend.” Streaming via mobile devices decreased, whilst streaming via static devices increased by over 50%, indicating more from home listening. ‘Chill’ and ‘ambient’ genres were sought after whilst rap and rock music were less so (Figure 2).10 This may indicate listeners were streaming music for calming effect, including managing anxiety and insomnia.

Sleep analytics European data from Fitbit (Figure 3) showed an increase in the average number of minutes slept per night since the lockdown took place in each city.11

Internet traffic The London INternet eXchange (LINX) is a network of internet routers in London.12

Although this data is not representative of total UK internet usage, it is likely to shadow FigureFigure 3:3: Fitbit datadata showing an increase in sleep times after initiation of lockdownlockdown(11) (ref 11). national usage.

Figure 4: Internet traffic on the LINX LON1 network from 01/01/20 to 01/06/20 (ref 12).

23rd March 2020 – UK lockdown announced

Figure 4: Internet traffic on the LINX LON1 network from 01/01/20 to 01/06/20. (12) ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 > 25

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Figure 5: Internet traffic over a 24-hour period pre- and post-lockdown (ref 12). Orange area 18/02/20 – 19/02/20 (before lockdown). Grey area 24/03/20 – 25/03/20 (after lockdown). Blue area 29/06/20 – 30/06/20 (lockdown measures easing).

FigureA significant 5: Internet change traffic wasover seen a 24- in hourthe LINX period weekends,pre- and postand -lockdowndaily consumption (12) higher on overnight (Figure 5). Comparing an average LON1 internet traffic throughout 2020. In the weekdays (Figure 4). This may indicate those 24-hour period before lockdown versus one 10 days preceding the lockdown, a rise in the in lockdown working from home and turning immediately after (controlling for weekday), baseline of internet traffic can be seen. The to streaming services for entertainment. greater traffic can be seen at every hour of

structure of internet traffic over time changes The network traffic has a circadian-like the 24-hour period following lockdown. Three too, with clear troughs in total daily traffic at cycle, peaking in the day and dropping to nadir months later as lockdown measures ease,

Sleep and wake estimations using internet traffic data

Estimated sleep point Estimated wake point

12:00 23rd March 2020 – UK lockdown announced

09:36

07:12

04:48 Time (24 hour clock)

02:24

00:00 1/5/2020 3/5/2020 5/4/2020 7/3/2020 1/25/2020 2/14/2020 3/25/2020 4/14/2020 5/24/2020 6/13/2020 12/16/2019

Date

Figure 6: Estimated6: Estimated internet sleepinternet window sleep over time, window derived fromover LINX time, LON1 derived data (ref 12). from LINX LON1 data (12)

26 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 r e v i e w a r t i c l e internet traffic throughout the day resembles population are treating their evenings more 3. Gold H. Netflix, YouTube slow down streaming in more the pre-lockdown figures, whilst late like weekends and staying up later, yet waking Europe [Internet]. CTVNews. 2020 [cited 2020 Jun 30]. Available from: https://www.ctvnews.ca/enter- night and small-hours traffic remains almost at a similar time to pre-lockdown (possibly tainment/netflix-youtube-slow-down-streaming-in- exactly the same. due to working from home), and experiencing europe-1.4861059 At around midnight each night, traffic greater social jetlag at weekends because of 4. Netflix to slow Europe transmissions to avoid broadband falls below 2Tbps until around 7:30am the this self-inflicted sleep compression. overload [Internet]. the Guardian. 2020 [cited 2020 Jun 30]. Available from: http://www.theguardian.com/ following day. Using this as an estimate for media/2020/mar/19/netflix-to-slow-europe-transmis- the sleep and wake times of the popula- Conclusion sions-to-avoid-broadband-overload tion, changes to internet traffic may indicate This paper highlights the potential to derive 5. Spotify Technology S.A. Announces Financial Results changes to circadian rhythms. inferences about population level circadian for First Quarter 2020 [Internet]. [cited 2020 Jun 30]. The data was extracted from each 24-hour Available from: https://investors.spotify.com/financials/ rhythm from big data. Internet traffic data is press-release-details/2020/Spotify-Technology-SA- period of LINX LON1 network data at points identified as an indicator for population level Announces-Financial-Results-for-First-Quarter-2020/ where the internet traffic falls below 2Tbps (esti- sleep disturbances. Lockdown has caused a default.aspx mated population sleep point) and rises above transient shift in sleeping patterns, delaying 6. Arendt J, Broadway J. Light and Melatonin as Zeitgebers in Man. Chronobiol Int. 1987 Jan 1;4(2):273–82. 2Tbps (estimated population wake point) for the circadian phase of the population through the time period 01/01/20 - 30/06/20 (Figure 6). 7. Stevens RG, Zhu Y. Electric light, particularly at night, loss of circadian entrainment as daily routines disrupts human circadian rhythmicity: is that a problem? A clear change can be seen around the time have dissolved. Whilst staying at home and Philos Trans R Soc B Biol Sci. 2015 May 5;370(1667). of the lockdown. Greater traffic post-lockdown saving lives, the UK population went to bed 8. Ehlers CL, Frank E, Kupfer DJ. Social Zeitgebers and indicates increased use of technology until later, woke slightly later on weekdays and later Biological Rhythms: A Unified Approach to Understanding later into the night, and likely a later bedtime the Etiology of Depression. Arch Gen Psychiatry. 1988 still on weekends suggesting that paradox- Oct 1;45(10):948–52. by an extra 1-2 hours. ically, social distancing increased social jetlag. 9. Erren TC, Lewis P. SARS-CoV-2/COVID-19 and physical A small delay (~30 minutes) was seen in Perhaps rather than a month of Sundays, lock- distancing: risk for circadian rhythm dysregulation, advice the increase in morning traffic post-lockdown, down has created a month of Saturday nights to alleviate it, and natural experiment research opportuni- indicating that people are sleeping in for ties. Chronobiol Int. 2020 Jun 5;0(0):1–4. followed by Monday mornings. longer. Overall total sleep time has reduced. 10. Joven J, Rosenborg RA, Seekhao N, Yuen M. COVID- This contrasts with Fitbit data presented earlier REFERENCES 19’s Effect on the Global Music Business, Part 1: Genre [Internet]. 2020 [cited 2020 Jun 30]. Available from: in this article. Those using Fitbit may be more 1. Elmer T, Mepham K, Stadtfeld C. Students under lock- https://blog.chartmetric.com/covid-19-effect-on-the- sleep aware and capitalise on extra sleep down: Assessing change in students’ social networks global-music-business-part-1-genre/ opportunities in lockdown. and mental health during the COVID-19 crisis 2020. 11. The Impact Of COVID-19 On Global Sleep Patterns Post-lockdown a clearer distinction is doi:10.31234/osf.io/ua6tq. [Internet]. Fitbit Blog. 2020 [cited 2020 Jun 30]. Available from: https://blog.fitbit.com/covid-19-sleep- evident between weekdays and weeknights: 2. Cellini N, Canale N, Mioni G, Costa S. Changes in sleep pattern, sense of time and digital media use during patterns/ every five weekdays is followed by two later COVID-19 lockdown in Italy. J Sleep Res. e13074. doi: 12. LANs Flow | LINX Portal [Internet]. [cited 2020 Jun 30]. weekend points. This would suggest that the 10.1111/jsr.13074 Available from: https://portal.linx.net/lans_flows

r e g u l a r s – b o o k r e v i e w s

Brain Fables. The hidden history of neurodegenerative diseases and a blueprint to conquer them

n this short book, a neuroscience researcher and a The proposed solution is a biology-first approach, agnostic patient with early onset Parkinson’s disease team up to to phenotype, with secondary definition of patient subgroups Ipresent an account (critique, diatribe, invective, reflec- according to biomarkers, a segregation which may not result tion, corrective?) concerning the state of understanding of in homogeneous clinical clusters. However, the greater homo- neurodegenerative diseases, in particular Parkinson’s (PD) geneity of biological subtypes may enhance the chances of and Alzheimer’s (AD), and suggest ways forward. This is success in treatment trials (examples of this approach in prompted by a belief that current research is focused too oncology are cited as a possible model), perhaps using known exclusively on aggregated proteins in the pathogenesis of therapeutics repurposed from previous failed trials. Such these diseases (alpha-synuclein, -peptides, tau) trials may target much smaller, selected patient groups (e.g. and by the recurrent failure in AD of treatment trials targeted carriers of autosomal dominant genetic mutations) with no at these molecular species. necessary expectation that any efficacy will translate to other The culprit is exposed as clinical diagnosis. Specifically, by biologically defined groups. Authors: Alberto Espay, prioritising clinical diagnosis over biological understanding, No one working in the field of AD can be unaware of the Benjamin Stecher clinical definition has been allowed to dictate biological truth. shortcomings of the amyloid hypothesis, nor that the failure Published by: Cambridge As a result, there has been a tendency to fit data to purpose of all recent treatment trials may in part be due to the clinical University Press, 2020 rather than purpose to data, leading to, for example, biasing of definition of study participants resulting in heterogeneity in Price: £14.99 Pages: 162 genome-wide association studies. Another illustration of the trial cohorts. The imperfect mapping of clinical diagnosis to ISBN: 9781108744621 error of this approach is the frequency of mixed pathology, a pathology is well recognised. Few then, I think, would demur Reviewed by: AJ Larner, finding indicative of the biological overlap of clinical defin- from the suggestions made. But what are the consequences WCNN, Liverpool. itions. According to the authors, PD and AD are hence, for clinical practice in the meantime? However biologically biologically speaking, “fictional constructs,” a formulation appropriate, this approach may engender little immediate which will not sit comfortably for many clinicians and patients. hope for patients and carers.

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Overview of new developments in myasthenia gravis therapy

Abstract MG, such as mycophenolate or rituximab, were Reuben Beer, BPharm, Myasthenia gravis (MG) is an autoimmune not found to be superior to placebo in phase MBBS, disease of the neuromuscular junction. Whilst 2 and 3 trials.2 Of note, thymectomy for gener- is a Research Fellow in Multiple Sclerosis a number of immune therapies have been and at the Princess alised AChR positive MG has shown promising established in recent decades, there is an Alexandra and Mater Hospitals in Brisbane, evidence over a three-year period for reducing Australia. He was a qualified Pharmacist ongoing need for safe and effective therapies, corticosteroid requirements, improvement in prior to completing his postgraduate especially for treatment refractory patients. clinical scoring tools and reducing hospital- degree in medicine at the University of A number of recent trials have studied the Queensland. He completed specialist isations.3 effect of modern immunotherapies, targeting neurology training at the Sunshine Coast Improved understanding of the underlying and Gold Coast University Hospitals. circulating immune cells, complement and Fc of MG has led to a number of new Dr Beer’s areas of interest include multiple receptor inhibition. We will review these agents agents being studied in recent years. These sclerosis, antibody mediated neurological and the data relating to their use in MG. disorders and myasthenia gravis. His agents have targeted biological features of MG, research focus is on diagnosis, treatment, including the role of T helper cells promoting and imaging studies in early multiple sclerosis. B cell maturation and antibody production, AChR antibodies activating complement, and Key take-home messages pathogenic IgG subclasses.4 Arising evidence • A number of agents, including several for the usage of these novel agents in MG will monoclonal antibodies using new mech- be reviewed here. anisms of action, have shown promising results in MG in recent studies. B Cell directed therapy • Therapies targeting B cells, such as Rituximab (RTX) is an intravenously adminis- rituximab, have become more established, tered monoclonal antibody which binds CD20 although adequate randomised controlled and causes depletion of circulating B cells. trial data is lacking. Newer anti-CD19/20 It is used for treatment of lymphomas as well Stefan Blum, Dr. med. PhD, therapies may offer opportunities for future as a range of autoimmune diseases, including trials. FRACP, MG. A number of retrospective case series is a Staff Specialist in Neurology at the • Complement inhibition, notably with have reported short-term and long-term effi- Princess Alexandra Hospital (PAH) with a eculizumab, has progressed to FDA listing focus on neuroimmunology and multiple cacy in patients with AChR and MuSK positive for MG treatment after phase 3 trials. sclerosis and a Senior Lecturer at the MG, whilst maintaining an acceptable side • FcR inhibitors, including efgartigimod and University of Queensland. He is involved effect profile.5-7 Described adverse effects have in a number of investigator driven and rozanolixuzumab, that decrease pathogenic included infusion reactions and flushing, with pharma sponsored studies on autoimmune IgG have shown positive results in phase 2 encephalitis, myasthenia gravis and infections occurring uncommonly.5 In contrast, trials. multiple sclerosis. a phase 2 randomised controlled trial (RCT) of

RTX in AChR positive MG patients was nega- Correspondence to: Reuben Beer, tive (BeatMG, presented AANEM 2019, unpub- Princess Alexandra Hospital, lished). At present, RTX is commonly used for Woolloongabba, Queensland, Australia, yasthenia gravis (MG) is an uncommon treatment of refractory MG, with a wide-spread E. [email protected] disorder of immune mediated dysfunc- perception that MuSK positive patients respond 8 Conflict of interest statement: Mtion of the neuromuscular junction, particularly well. A more formal analysis based Submitted and externally reviewed. typically presenting with fatigable muscle on a sufficiently powered RCT is needed. weakness. Around 80% of cases are positive Several new monoclonal antibodies targeting Provenance and peer review: for the acetylcholine receptor (AChR) anti- CD19 and CD20 are an area of interest for treat- Submitted and externally reviewed. body, with the remainder made up of less ment of MG, but are yet to enter clinical trials. Date submitted: 26/5/2020 common antibodies including muscle-specific Obinutuzumab, a novel anti-CD20 monoclonal Date submitted after peer review: 1/8/2020 kinase (MuSK), lipoprotein receptor-related antibody, was reported to induce remission of Acceptance date: 3/8/2020 protein-4 (LRP4), and so-called seronegative MG in a patient co-treated for chronic lympho- This is an open access article distributed 9 under the terms & conditions of the cases. Treatment for myasthenia gravis includes cytic leukaemia. Creative Commons Attribution license inhibition of acetylcholine breakdown with Another avenue of B cell directed therapy http://creativecommons.org/licenses/ acetylcholinesterase inhibitors, corticosteroids, is B cell activation factor (BAFF), a by/4.0/ a range of immunosuppressive steroid sparing important in survival and differentiation of To cite: Beer R, Blum S. ACNR agents and immunomodulatory therapy such B cells. A number of agents targeting BAFF, 2020;19(4):28-30 as intravenous immunoglobulin (IVIg), plasma such as belimumab, have been trialled in exchange and thymectomy.1 Performing other autoimmune conditions, such as lupus randomised trials in MG with a positive erythematosus. outcome has proven repeatedly challenging Identification of increased BAFF levels in in the last decades, because of the rarity of the MG lead to examination for potential treatment disease, the complexity of treatment avenues efficacy. A phase 2, double-blind, placebo-con- and the heterogeneity of clinical presentations. trolled study randomising 40 patients to intra- Even agents widely accepted to be beneficial in venous belimumab 10mg/kg and placebo did

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not show any statistical significance in the associated with decreased disease severity in placebo with a mean improvement of 2.8 Quantitative Myasthenia Gravis (QMG) score, animal models of MG.12 Complement causes points in 0.3mg/kg arm. No significant adverse the primary outcome for this study.10 Adverse and mediates damage to the events were described in the trial.14 events included influenza, nausea and post-in- postsynaptic NMJ membrane.13 In summary, complement inhibition fusion reactions.10 Eculizumab is a monoclonal antibody appears to be modestly beneficial in patients designed to bind to human terminal comple- with refractory MG; the use of these agents is Cladribine ment C5, thereby inhibiting mediation of impacted by the risk of bacterial infections Cladribine is a deoxyadenosine analogue proinflammatory cell chemotaxis by C5a and and high costs of some of these agents. which induces a rapid and selective B and T formation of the membrane attack complex lymphocyte toxicity through accumulation of by C5b.13 Eculizumab is used in comple- FcR Antibody Antagonists 2-chlorodeoxyadenosine nucleotides. It has ment mediated diseases, such as paroxysmal Depletion of pathogenic circulating immuno- established indications in hairy cell leukaemia nocturnal haemoglobinuria and atypical globulins, usually with plasma exchange, is an and multiple sclerosis. haemolytic uraemic syndrome. established treatment modality for immuno- The use of cladribine in myasthenia gravis A phase 3 RCT, REGAIN, examined the effect logic disorders. More recently, molecules was examined in a recent prospective open of eculizumab in 125 patients with refractory specifically antagonising the neonatal Fc label study in Poland.11 Thirteen patients with generalised MG and seropositive AChR status. receptor to rapidly reduce circulating IgG seropositive generalised and ocular MG were Eculizumab was administered intravenously levels have been examined. enrolled, and immunosuppressant therapy each week for four weeks then fortnightly to Efgartigimod is an anti-neonatal Fc receptor other than prednisolone was stopped prior to complete 26 weeks. Primary outcome was immunoglobulin fragment. A double-blind, receiving cladribine. Cladribine was adminis- measured by change in the MG-ADL, another placebo-controlled, phase 2 RCT randomised tered subcutaneously at 0.3mg/kg divided into validated scoring tool designed to assess MG 12 patients with seropositive AChR MG to two doses over two days. This was repeated severity, after 26 weeks. Statistical significance receive intravenous efgartigimod and 12 to after one month, and one patient had another was not reached for the primary endpoint; placebo for a period of three weeks.15 Rapid dose at month three. The primary outcome however, there was measured improvement and sustained reduction in all IgG subtypes of Improvement in the Myasthenia Gravis in secondary outcomes, including hospitalisa- was observed, including levels of the AChR Composite (MGC) scale of at least three points tions and exacerbations. Vaccination against antibody levels, which persisted for around 29 after six months was met in 11 of the 13 Neisseria meningitides was a mandatory inclu- days. Secondary outcomes included clinical patients. Eleven patients were on predniso- sion criterion due to the increased risk of infec- measures, which demonstrated an improve- lone when cladribine was started, after six tion secondary to complement inhibition.13 ment in the QMG score after the first dose months eight of those had ceased predniso- On the basis of promising trial results, and MG-ADL at 29 and 36 days. No significant lone. Transient lymphopenia was reported.11 eculizumab was the first biologic agent to be adverse events were noted during the study.15 Limitations of the study included the absence FDA approved for MG, although its place in A second FcR antibody antagonist, rozano- of a control population and blinding. therapy relative to cost remains to be seen. lixizumab, demonstrated proof-of-concept in The role of immune reconstitution therapies Zilucoplan is a macrocytic peptide which a recent phase 2a trial.16 Twenty-one patients in MG requires further investigation. binds C5 and prevents cleavage into C5a and received weekly subcutaneous rozanolix- C5b.14 Zilucoplan given by daily subcutaneous izumab and 22 received placebo prior to Complement Inhibition injection was studied in a phase 2 trial, with re-randomisation at day 29 to either 7mg/kg Complement plays an important role in double-blind randomisation of 45 patients or 4mg/kg of rozanolixizumab. The primary disease pathogenesis in myasthenia gravis. between doses of 0.1mg/kg, 0.3mg/kg and outcome was not reached, with non-significant Patients with MG demonstrate the presence placebo for a period of 12 weeks. Differences difference in QMG score between rozanolix- of C3 and the membrane attack complex at in QMG score were recorded in both the izumab and placebo groups. Rozanolixizumab the NMJ and complement inhibition has been 0.1mg/kg and 0.3mg/kg arms compared with has progressed to phase 3 trials which are

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ongoing (NCT03971422). The drug appeared apies in common usage. Relatively short tically significant improvements. As such, well tolerated, although headache was durations of clinical trials may understate it is encouraging to see renewed interest to reported.16 treatment effect and reduce the likelihood study novel agents in this vulnerable patient of significant findings. Lack of standardisa- group. The relative risk of additive immuno- Conclusion tion of clinical scoring tools can hamper suppression in this group requires careful Performing RCTs in MG has proven difficult comparison between studies. Remaining on consideration and patient discussion and in the last decades, due to the rarity of standard therapy at trial commencement can will benefit from greater understanding with this illness, clinical and biological hetero- create a floor effect, where already low MG further studies. geneity and the numerous overlapping ther- severity scale scores fail to demonstrate statis-

Summary Table Level of Class Drug Trials Outcome Dose Reported Side Effects Evidence Overall minimal Case series, manifestations or better 375mg/m², IV, weekly 5 Infusion reactions, flushing, Anti-CD20 Rituximab n= 169 total Class III achieved in 72% with for 4 weeks or 500mg on pneumonia Phase 2 MuSK MG and 30% with days 1 and 14 AChR MG 10mg/kg, IV, fortnightly Efficacy outcome not Influenza, nausea, post- Anti-BAFF Belimumab Phase 2, n=4010 Class I for 4 weeks then every 4 met infusion reactions weeks until week 20 Primary efficacy outcome not met, although 13 900mg, IV, weekly for 4 Eculizumab Phase 3, n=125 Class I Headache, respiratory tract positive secondary doses then 1200mg, IV, infection Complement outcomes fortnightly until week 26 Inhibition

0.1 or 0.3mg/kg, SC, self- No significant adverse Zilucoplan Phase 2, n=4414 Class I Efficacy outcome met administered daily events in treatment arms 0.3mg/kg over 2 days, SC, Transient lymphopenia, Immune Cladribine Phase 2, n=1311 Class III Efficacy outcome met repeated monthly if no headache, respiratory tract Reconstitution clinical response infection Primary outcomes (safety and tolerability) 10mg/kg, IV, 4 doses over No significant adverse Efgartigimod Phase 2, n=2415 Class I met, secondary efficacy 3 weeks events in treatment arm outcomes met FcR Antibody Antagonists 7mg/kg, SC, weekly for 3 weeks then rerandomised Primary efficacy outcome Rozanolixuzumab Phase 2a, n=4316 Class I to either 7mg/kg or Headache not met 4mg/kg for another 3 weeks IV = intravenous, SC = subcutaneous

REFERENCES

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Introduction to Pain Series – The enigma and burden of chronic pain

hronic non-cancer pain is a global health tice since the 1980s. They alter neural plas- post-treatment and delivery of CBT needs crisis and affects more than one-third ticity at the spinal cord level to alleviate skilled professionals, service resources, and Cof the population in most countries. symptoms and have been tested in a variety good compliance. Alternative treatments such Healthcare costs of managing chronic pain of chronic pain conditions. They lack superior as Transcutaneous Electric Nerve Stimulation exceed those spent on cancer, diabetes and efficacy (compared to control treatments) in (TENS), acupuncture, yoga, tai-chi and exer- heart disease. £12 billion per year is spent most conditions except chronic intractable cise therapy have been shown to be effective on chronic pain treatments in the UK alone. neuropathic pain and this remains the only in some patients but again not transform- 40% of this current treatment is not effective condition for which NICE recommends their ational in efficacy. Comprehensive Pain and patients continue to struggle with psych- use. The complication rate has been reported Management Programmes (PMPs) that are ological distress, low mood and comprom- as up to 50% and implantation is associated approved by NICE are expensive and can ised quality of life. The last few decades of with high healthcare costs (up to £10k per cost at least £5k per individual for a 4-week research have enhanced our understanding of device) limiting their cost-effectiveness. programme. The average pain reduction via the of chronic pain in terms Surgical interventions such as lumbar PMPs is around 35%. of neural biomarkers and modulation of the fusion surgery and joint replacement surgery Therefore, this area of medicine needs nervous system to manage pain. However are effective for pain relief, but not in all further attention from clinicians, researchers treatment options still remain limited and far patients. There is now conclusive evidence and funding bodies that can invest in discov- from effective. that outcomes (effect size) are similar to ering novel therapeutic approaches. In this Current pharmacological interventions even non-operative PMPs. Costs associated with series for ACNR, we will focus on four areas: with regular use, at their best, have shown only back surgery (£8k per surgery on average) 1) advances in understanding the neuro- an average of 30% reduction in pain symp- are higher than PMP costs. Joint replacement physiology of chronic pain 2) epidemiology toms in half of treated individuals. Opioids surgery for specific pathologies such as knee of chronic pain and relationship with other remain the most efficacious analgesic medica- and hip arthritis are effective in providing symptoms such as sleep, mood and fatigue tions, but long-term usage has serious adverse long-term benefits in only 80% of patients, 3) biospychosocial model of chronic pain effects of and dependence. There but significant side effects. Recent evidence and rehabilitation and 4) novel therapeutic are some novel disease modifying non-opioid suggests that other orthopaedic procedures approaches to managing chronic pain, and combination treatments that are being such as shoulder and knee arthroscopy are no particularly new neuromodulation treatments. developed and tested but are yet to be shown better than placebo or exercise therapy. to overcome the issues of side-effects and Psychological therapies for chronic pain inadequate efficacy in all individuals. have been extensively investigated, but with Implanted neuromodulation devices such variable results. Evidence suggests a small Manoj Sivan, MD FRCP, Editor of ACNR as spinal cord stimulators have been in prac- (~20%) short-term improvement in pain Pain and Rehabilitation Section

The brain alpha rhythm in the perception and modulation of pain By Hasaan Ahmed, Anthony Jones and Manoj Sivan, Full author details on page 33

Abstract activity by external stimuli reduces the percep- (NSAIDs) and opioids is limited. Furthermore, Chronic pain is a major cause of disability tion of experimental pain. Future research long-term use of opioids as would be required and healthcare burden worldwide. Despite should investigate the potential of such novel in the treatment of chronic pain results in this, there are currently few medications avail- treatments to reduce clinical pain. dependency. A greater understanding of pain able to manage chronic pain, due to poor physiology, particularly the central mechan- understanding of the underlying mechanisms. isms involved, is therefore required to improve Studies in the current literature suggest that the Introduction . brain alpha rhythm may be involved in pain Chronic pain is one of the most common The alpha rhythm is one of the main EEG perception. There is an inverse association causes of disability worldwide.1 It is estimated rhythms and represents oscillations ranging between alpha activity and the perception that around 20% of adults in Europe suffer from 8-13Hz. Traditionally, alpha was thought of acute and chronic pain, which applies chronic pain with a large disease burden of as an “idling” rhythm as high alpha to alpha power in frontal and central brain due to loss of productivity and difficulty in power is associated with relaxed wakeful- regions specifically. As Alpha activity increases successful rehabilitation of these individuals.2 ness. However, a more active role of alpha in frontal and central regions, pain perception Despite these issues, the mechanisms under- activity in neural processing has recently decreases. Conversely increased attention to lying chronic pain are poorly understood been proposed. Alpha is actively involved in pain or expectation of pain suppresses alpha and effective treatments are lacking. Indeed, modulation of sensory processing via a mech- activity and increases pain perception. There evidence for the effectiveness of commonly anism of functional inhibition and is thought is nascent evidence that increased alpha used non-steroidal anti-inflammatories to reflect top down control or attentional

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suppression.3 Interestingly, studies investi- relationship between alpha and pain is known as the individual alpha frequency gating EEG responses to pain suggest the expectations about pain. Our research group (IAF), and then providing external stimulation alpha rhythm may play an active role in the used a placebo experiment to investigate at this personalised frequency. processing of pain. how expectation of pain relief can influence Ecsy et al. from our research group inves- resting state alpha power in 73 healthy indi- tigated whether auditory entrainment (using Alpha activity reduces in acute experi- viduals (n=73).11 The study involved providing binaural beats) or visual alpha entrainment mental pain a placebo cream and testing the alpha power (rhythmic visual stimulation) could increase There is evidence to suggest pain decreases when subjected to a painful stimulus of the alpha activity and reduce the perception of alpha activity through a process known as same intensity before and after application experimental acute pain in 64 healthy individ- event-related desynchronisation (ERD), of the cream. There was an increase in alpha uals.15,16 The study involved entraining at 8Hz, whereas pain relief increases alpha activity power accompanied by reduced pain percep- 10Hz and 12Hz. We found that entrainment through a process known as event-related tion suggesting a modulation of alpha power using 10Hz visual stimulation resulted in the synchronisation (ERS). For example, Ohara by reduced expectations of pain. Source greatest analgesic effect, reducing pain by 1.1 et al. found in four healthy subjects that localisation estimated that the increase of on the 10-point scale. Whilst this may not be alpha ERD occurred as a response to tran- alpha originated from more frontal compon- regarded as a large clinically significant effect, it sient noxious laser stimulation in several pain ents of the pain network (and not the somato- does demonstrate a proof of concept that alpha related brain regions including the primary sensory area). These findings provide correla- entrainment can reduce pain perception. somatosensory cortex and medial frontal tive evidence that frontal alpha is actively cortex.4 Chang et al. found that the alpha involved in the top-down control of pain via Alpha entrainment reduces clinical pain rhythm is supressed following muscle pain expectations about pain. Arendsen et al. used a form of transcranial elec- but enhanced again upon waning pain in trical stimulation known as transcranial alter- 15 healthy subjects.5 These studies suggest Low baseline alpha activity in chronic nating current stimulation (tACS) to attempt an inverse relationship between changes in pain patients to modulate the perception of experimental alpha activity in response to a painful stimulus A number of studies have demonstrated that pain in healthy individuals in conditions where and the perception of pain, particularly in alpha activity is reduced in chronic pain the intensity of upcoming noxious stimula- somatosensory and frontal brain regions. patients compared to healthy controls. tion was certain or uncertain (n=23).17 This Camfferman et al. investigated the correlation crossover trial involved participants receiving Enhancing alpha activity before the between alpha activity and pain intensity in 10Hz somatosensory tACS or sham stimula- onset of pain reduces pain intensity a much more diverse sample of 103 patients tion on separate days with a 7-day washout Babiloni et al. investigated the effect of with chronic pain.12 They found that alpha period in between. The study found a signifi- pre-stimulus alpha during the anticipation of activity was inversely associated with pain cant reduction in perceived pain intensity pain on the intensity of experimental pain intensity at frontal and central electrodes. and unpleasantness during the alpha tACS subsequently experienced in healthy individ- Jensen et al. found that the proportion of alpha compared to sham stimulation, but only when uals (n=10).6 A statistically significant negative activity was significantly lower in patients with the intensity of upcoming pressure stimulation correlation between pre-stimulus somatosen- SCI and pain (n=38) compared to both SCI was uncertain. In a more recent crossover sory alpha and pain intensity ratings was found patients without pain (n=16) and healthy sham-controlled study, 20 participants with during the early anticipation period (1 to 0.5s controls (n=28).13 They however found that chronic lower back pain (CLBP) who received before pain stimulus onset). Tu et al. in a absolute alpha activity in three frontal elec- 40 minutes of alpha tACS were able to signifi- study involving 96 healthy individuals found a trodes was positively correlated with pain cantly increase alpha activity in somatosensory significant negative association between alpha intensity recorded. The authors hypothesised regions and decrease pain score compared to power, specifically in the central brain regions that an increase in frontal alpha activity may sham control stimulation.18 Our recent study and primary sensorimotor cortex, 0.2 to 0.03 occur to suppress pain and patients with the on visual alpha entrainment in individuals with seconds before the onset of pain and the inten- largest pain ratings therefore would likely chronic pain shows analgesic effect in some sity of pain subsequently experienced.7 exhibit high frontal alpha activity to suppress individuals with chronic pain.19 These findings it. This would actually be in line with the are of great interest as they provide strong Alpha activity is influenced by attention hypotheses made by Huneke et al. suggesting causal evidence that the alpha rhythm reduces and expectations about pain that frontal alpha activity is involved in top the perception of chronic pain and indicate a May et al. investigated the effects of attention down modulation of pain and highlights that possible dose-effect of increased alpha activity on alpha power prior to the onset of noxious alpha activity in frontal and somatosensory on reduced pain perception. stimulation.8 They found that attending to regions may play different roles.11 the arm when pain is expected imminently Neurofeedback for alpha entrainment in suppresses alpha power in the contralateral Alpha entrainment reduces the chronic pain primary somatosensory cortex. Ploner et al. perception of acute experimental pain Jensen et al. investigated whether individ- found that transient pain results in bilateral Alpha entrainment is one of the ways in uals actively increasing alpha power using suppression of alpha activity in sensorimotor which a causal relationship between the neurofeedback techniques could reduce centres.9 They hypothesised that this occurs alpha rhythm and pain can be established. chronic pain.20 The process involves subjects to “open the pain gate” and draw attention This process involves increasing alpha activity receiving biofeedback on their own EEG and to pain so that an appropriate response can by providing rhythmic visual, auditory or learning how to enhance certain rhythms. occur. Ohara et al. and Peng et al. found that transcranial electrical stimulation at an They found chronic pain perception was attending to noxious stimulation results in a alpha range frequency.14 This allows cortical significantly reduced from baseline to directly larger alpha ERD and perceived pain whereas neurons to synchronise with the frequency after the intervention of increasing their alpha distraction results in a lower alpha ERD and of external stimulation, hence increasing the power. There were no significant changes a subsequent analgesic effect.4,10 The above activity of neural oscillations in the alpha in the quality of sleep, fatigue or pain inter- studies demonstrate that attention to pain band. Open loop alpha entrainment involves ference, suggesting the alpha rhythm may supresses the alpha rhythm and increases providing external stimulation at a pre-de- modulate experience of pain independently pain perception, whereas distraction from the termined fixed frequency within the alpha of these other factors. Our recent system- pain maintains the alpha rhythm and reduces band, such as 10Hz. Closed loop entrainment atic review and meta-analysis concluded pain perception. involves first capturing the peak frequency of neurofeedback to be a safe and effective Another factor that might influence the the alpha band in each subject using EEG, therapy in chronic pain.21

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Figure 1: Proposed role of the alpha rhythm in the perception and modulation of pain. Various factors involved in the perception of pain are given and the interactions between each are denoted by either straight headed arrows denoting suppression or arrow headed arrows denoting stimulation.

Key: A – Noxious stimulation suppresses the alpha rhythm.4 B – Expectation of pain suppresses the alpha rhythm.6 C – Attention to pain suppresses the alpha rhythm.13 D – The alpha rhythm suppresses the perception of pain.16,17 E – The alpha rhythm suppresses the wider ability to form an appropriate response to pain.9 F – Placebo suppresses the expectation of pain.11 G – Alpha entrainment increases alpha power.16 H – Alpha entrainment may cause distraction and hence suppress attention to pain.

Discussion Further studies are also required to peutic effect of each dose, and subsequently Current evidence suggests the alpha rhythm establish if there is a dose-response effect what the optimum combinations of open or is a negative modulator of pain perception of enhancing alpha activity on pain relief. closed loop entrainment or neurofeedback and is itself negatively modulated by noxious Future studies on alpha entrainment and might be and how these interact with more stimulation, attention and pain expectancy. A neurofeedback should explore whether such conventional therapies. Clinical acceptability model for the role of the alpha rhythm in the therapy can be delivered in “doses” similar to studies with patients should also be performed perception and modulation of pain in concep- pharmacological interventions. There is also to determine whether potential therapies tualised in Figure 1. a possibility that those with a greater degree could be tolerated, whether there are any side Whilst the emerging causal evidence for of central sensitisation may respond better effects, and how best to deliver modulation the role of alpha in pain is promising, the to entrainment. An understanding of this will of alpha activity in the home setting, through small sample sizes and lack of a control help personalise such novel treatments based alpha entrainment or neurofeedback. group in some studies limit the confidence on symptoms and optimal dose of entrain- in the conclusions that can be made. Larger ment for every individual. We have recently Conclusions sham-controlled studies are required to shown the usability and acceptability of smart- In summary, studies suggest the alpha rhythm investigate whether alpha entrainment and phone-based applications for alpha entrain- may act as a top-down negative modulator neurofeedback can increase alpha activity ment in individuals with chronic pain.22 We of pain and is itself negatively modulated by and decrease perceived pain. Alpha modu- also have ongoing clinical studies involving attention and pain expectancy. This suggests latory studies into chronic pain should also the use of neurofeedback to increase alpha the alpha rhythm is a promising target for include participants with a variety of common activity and decrease chronic pain in our non-pharmacological pain management strat- painful conditions, such as osteoarthritis, research group. egies. However, further causal evidence is chronic widespread pain and fibromyalgia. If the underlying physiological role of the required to better establish the relationship Our current understanding of neurophysi- alpha rhythm in chronic pain is confirmed, between alpha and pain and to determine ology supports common central mechanisms there will be a requirement for large clinical whether the treatment strategies of entrain- in chronic pain irrespective of the patho- randomised controlled trials to assess the ment and neurofeedback could be clinically logical diagnosis. efficacy, optimal dose, duration of the thera- effective and individualised.

Correspondence to: Dr Manoj Sivan, Associate Professor and Honorary Consultant, University of Leeds, Honorary Senior Lecturer, Human Pain Research Group, University of Manchester, UK. E: [email protected]

Conflict of interest statement:None declared

Acknowledgements: The authors would like to thank all the members of the Human Pain Research Group from Universities of Hassaan Ahmed, Anthony Jones, MD FRCP, Manoj Sivan, MD, FRCP, Manchester, Leeds and Liverpool for their valuable research in this area over the past two decades. MRes, is a 5th Year is professor of Neuro- is an Associate Clinical Professor and Medical Student at the at the University of Manchester and Honorary Consultant in Rehabilitation leads the Human Pain Research Group. Medicine at the University of Leeds Date first submitted:30/3/2020 University of Manchester. Date submitted after peer review: 8/7/2020 He intercalated Over the last thirty five years he has and Honorary Senior Lecturer in the Acceptance date: 13/7/2020 with a Masters in pioneered the use of a number of Human Pain Research Group at the This is an open access article distributed under Research, graduating functional brain imaging techniques University of Manchester. His research the terms & conditions of the Creative Commons with distinction. He is to understand how the brain responds interests are chronic pain management, Attribution license http://creativecommons.org/ interested in elderly care, to pain. The insights gained from neuromodulation, rehabilitation neurology and stroke this are now being used to develop a technology and outcome measurement. licenses/by/4.0/ medicine. new platform for smart brain-based His research is supported by MRC, EPSRC, therapies and to encourage a more ISRT and Research England. To cite: Hassaan A, Jones A, Sivan M. ACNR rational use of existing therapies. 2020;19(4):31-34

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REFERENCES Can a Type-2 Diabetes 1. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2163-2196. doi:10.1016/S0140- Mellitus drug be hope for 6736(12)61729-2 2. van Hecke O, Torrance N, Smith BH. Chronic pain epidemiology and its clinical relevance. Br J Anaesth. 2013;111(1):13-18. doi:10.1093/bja/aet123 Multiple System Atrophy? 3. Jensen O, Mazaheri A. Shaping functional architecture by oscil- latory alpha activity: gating by inhibition. Front Hum Neurosci. 2010;4:186. doi:10.3389/fnhum.2010.00186 Abstract ical features of MSA include autonomic 4. Ohara S, Crone N., Weiss N, Lenz F. Attention to a painful Multiple System Atrophy (MSA) is a dysfunction, parkinsonism and cere- cutaneous laser stimulus modulates electrocorticographic fatal neurodegenerative disease with a event-related desynchronization in humans. Clin Neurophysiol. bellar ataxia. There are two main types 2004;115(7):1641-1652. doi:10.1016/J.CLINPH.2004.02.023 mean survival of 10 years after symptom of MSA which are classified depending 5. Chang P, Arendt-Nielsen L, Graven-Nielsen T, Svensson P, onset. The pathological characteristics on the patients predominant motor Chen A. Different EEG topographic effects of painful and of MSA are glial cytoplasmic inclu- non-painful intramuscular stimulation in man. Exp Brain Res. features; MSA-P is a type of MSA where 2001;141(2):195-203. doi:10.1007/s002210100864 sions (GCIs) in . There patients present with clinical signs 6. Babiloni C, Brancucci A, Percio C Del, et al. Anticipatory is an urgent need to further under- of parkinsonism such as tremor and Electroencephalography Alpha Rhythm Predicts Subjective Perception stand the pathophysiological mechan- rigidity, and MSA-C is the MSA type of Pain Intensity. J Pain. 2006;7(10):709-717. doi:10.1016/J. isms involved in MSA, and to find JPAIN.2006.03.005 where patients predominantly show disease modifying treatments which 7. Tu Y, Zhang Z, Tan A, et al. Alpha and gamma oscillation ampli- features of cerebellar impairment for tudes synergistically predict the perception of forthcoming nociceptive slow disease progression. Pre-clinical example, dysarthria and ataxia.4 The stimuli. Hum Brain Mapp. 2016;37(2):501-514. doi:10.1002/ research has suggested the presence of hbm.23048 pathological hallmark of MSA is glial insulin resistance in the MSA brain and cytoplasmic inclusions (GCIs). These 8. May ES, Butz M, Kahlbrock N, Hoogenboom N, Brenner M, that a type 2 diabetes mellitus (T2DM) Schnitzler A. Pre- and post-stimulus alpha activity shows differ- protein aggregates, which have been ential modulation with spatial attention during the processing drug, exenatide, has the potential to be found in the brain oligodendrocytes, of pain. Neuroimage. 2012;62(3):1965-1974. doi:10.1016/j. a disease modifying treatment for MSA. neuroimage.2012.05.071 contain alpha-synuclein, hence MSA In this review, I discuss the pre-clinical 9. Ploner M, Gross J, Timmermann L, Pollok B, Schnitzler A. is additionally known as an alpha-sy- Pain Suppresses Spontaneous Brain Rhythms. Cereb Cortex. evidence for this approach in MSA nucleinopathy. GCIs have typically 2006;16(4):537-540. doi:10.1093/cercor/bhj001 as well as propose possible outcome been found located in the areas where 10. Peng W, Hu L, Zhang Z, Hu Y. Changes of spontaneous oscilla- measures for use in any such MSA most occurs in the tory activity to tonic heat pain. PLoS One. 2014;9(3):e91052. clinical trial. doi:10.1371/journal.pone.0091052 MSA brain; namely the striatonigral and 11. Huneke NTM, Brown CA, Burford E, et al. Experimental placebo olivopontocerebellar systems.5 analgesia changes resting-state alpha oscillations. PLoS One. MSA is a rapidly progressive disease 2013;8(10):e78278. doi:10.1371/journal.pone.0078278 that currently has no disease modi- 12. Camfferman D, Moseley GL, Gertz K, Pettet MW, Jensen MP. Waking EEG Cortical Markers of Chronic Pain and Sleepiness. Pain ultiple System Atrophy (MSA) fying treatment. Recent research into Med. 2017;18(10):1921-1931. doi:10.1093/pm/pnw294 is categorised as an atypical the aetiology and pathophysiological 13. Jensen MP, Sherlin LH, Gertz KJ, et al. Brain EEG activity correlates Mparkinsonian syndrome. It is mechanisms of MSA has suggested the of chronic pain in persons with spinal cord injury: clinical implica- a rare disease with an approximate presence of insulin resistance. A drug tions. Spinal Cord. 2013;51(1):55-58. doi:10.1038/sc.2012.84 prevalence of 5 per 100,000 people licenced for treating type 2 diabetes 14. Thut G, Schyns PG, Gross J. Entrainment of Perceptually Relevant Brain Oscillations by Non-Invasive Rhythmic Stimulation of worldwide.1 Patients with MSA have mellitus (T2DM), exenatide, has there- the . Front Psychol. 2011;2:170. doi:10.3389/ an estimated median survival of 10 fore been proposed to be a possible fpsyg.2011.00170 years after symptom onset.2,3 The clin- treatment option in slowing down the 15. Ecsy K, Jones AKP, Brown CA. Alpha-range visual and audi- tory stimulation reduces the perception of pain. Eur J Pain. 2017;21(3):562-572. doi:10.1002/ejp.960 16. Ecsy K, Brown CA, Jones AKP. Cortical nociceptive processes are reduced by visual alpha-band entrainment in the human brain. Eur J Pain. 2018;22(3):538-550. doi:10.1002/ejp.1136 17. Arendsen LJ, Hugh-Jones S, Lloyd DM. Transcranial Alternating Current Stimulation at Alpha Frequency Reduces Pain When Yeliz Demir, BSc, MRes the Intensity of Pain is Uncertain. J Pain. 2018;19(7):807-818. is a . She obtained her BSc in Neuroscience doi:10.1016/j.jpain.2018.02.014 at Queen Mary University of London. She is currently completing her MRes in Translational Neuroscience at 18. Ahn S, Prim JH, Alexander ML, McCulloch KL, Fröhlich F. University College London. Her research interests are in Identifying and Engaging Neuronal Oscillations by Transcranial Alternating Current Stimulation in Patients With Chronic Low Back neurodegenerative diseases. She is fascinated particularly Pain: A Randomized, Crossover, Double-Blind, Sham-Controlled in understanding the mechanisms of neurodegenerative Pilot Study. J Pain. 2019;20(3):277.e1-277.e11. doi:10.1016/j. disease pathophysiology and finding ways to translate jpain.2018.09.004 results to the clinic. 19. Arendsen LJ, Henshaw J, Brown CA, Sivan M, Taylor JR, Trujillo- Barreto NJ, Casson AJ, Jones AKP Entraining alpha activity using Correspondence to: [email protected] visual stimulation in patients with chronic musculoskeletal pain. A feasibility study. Frontiers in Neuroscience (accepted) https:// Conflict of interest statement: None declared www.frontiersin.org/articles/10.3389/fnins.2020.00828/abstract 20. Jensen MP, Gertz KJ, Kupper AE, et al. Steps Toward Developing an Provenance and peer review: submitted and externally reviewed EEG Biofeedback Treatment for Chronic Pain. Appl Psychophysiol Biofeedback. 2013;38(2):101-108. doi:10.1007/s10484-013-9214-9 Date first submitted: 22/5/20 21. Patel K, Sutherland H, Henshaw J, Taylor JR, Brown CA, Casson Date accepted: 25/5/20 AJ, Trujillo-Barreton NJ, Jones AKP, Sivan M. Effects of neurofeed- Published online: 22/6/20 back in the management of chronic pain: A systematic review and This is an open access article distributed under the terms & conditions of the Creative meta-analysis of clinical trials. Eur J Pain. 2020 Jun 5 Commons Attribution license http://creativecommons.org/licenses/by/4.0/ 22. Locke HN, Brooks J, Arendsen LJ, Jacob NK, Casson A, Jones AKP, Sivan M. Acceptability and usability of smartphone-based brain- To cite: Demir Y. ACNR 2020;19(4):34-36 wave entrainment technology used by individuals with chronic pain in a home setting. British Journal of Pain. Published online first Feb 21, 2020

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Figure 1 – Exenatide transduction pathways in alpha- synucleinopathies.15 This figure shows the possible pathways which are activated and inactivated with exenatide activation. The regulation of these pathways promotes neuronal survival. Abbreviations: GLP-1, glucagon like peptide-1; PI3K, phosphoinositide 3-kinase; MAPK, mitogen associated protein kinase; NFkB, nuclear factor kappa-light- chain-enhancer of activated B cells.

progression of MSA. Exenatide (synthetic MSA motor function assessment scale, the to the wildtype controls. Furthermore, in this version exendin-4) is a glucagon-like United Multiple System Atrophy Rating Scale study exenatide was given to the PLP-SYN peptide-1 (GLP-1) receptor agonist which is, (UMSARS) part II.10 These results imply there mice to see whether it had an effect on in normal physiological conditions, activated is an abnormality in the processing of IGF-1 in insulin resistance, cell death and disease by the GLP-1 hormone secreted by L-cells the body, possibly insulin resistance, which progression namely, any disease modifying in the gut after ingestion of food; to induce is leading to higher serum levels of IGF-1 in effect on MSA. Nine six-week old PLP-SYN insulin secretion, reduce glucagon secretion MSA. The results also suggest that serum IGF-1 mice were given placebo, nine were given and to reduce appetite. The mechanisms levels correlate with disease severity in MSA, 3.5pmol/kg/min of exendin-4 and seven mice of action of exenatide in T2DM is similar although no causal links have yet been found were given a higher dose of 8.75pmol/kg/min to GLP-1 in that it reduces hyperglycaemia, between these two findings. of exendin-4 for twelve weeks. Analyses of the induces a glucose-dependent increase of Further investigation into insulin resist- three groups showed that the administration insulin secretion and decrease of abnormally ance in MSA using mouse models and of exendin-4 reduced insulin resistance in the elevated glucagon secretion, slows gastric human brain samples has also supported brain and decreased cell death. In addition, emptying and lowers food intake.7 the concept of insulin resistance in the the higher dose of exendin-4 significantly Insulin-like growth factor-1 (IGF-1) is a MSA brain. Immunofluorescent staining reduced alpha-synuclein load in the striatum hormone predominantly secreted by the liver techniques using MSA brain samples although, disappointingly, behaviour and but can also be produced by many other (n=7, controls n=5) found that neurones motor symptom analyses did not show any organs including the brain. It has a broad in the putamen expressed higher levels of significant improvement in motor perform- range of functions within the central nervous insulin resistance markers (IRS-1pS312 and ance with administration of exendin-4.11 system which include modulating early brain IRS-1pS616). Furthermore, the levels of the Overall, these results suggest that exena- development, oligodendrogenesis and myel- IRS-1pS312 marker correlated positively with tide does have potential in slowing down ination as well a role in synaptic neurotrans- disease duration, again pointing towards an disease progression in MSA, but does it have mission. Moreover, IGF-1 may also play a association between the degree of insulin the potential to reduce motor progression in role in neuroinflammation.8 An abnormally resistance in the brain and disease severity. humans? This is a question only a clinical trial high level of IGF-1 as measured in bodily Investigation into MSA patient oligoden- can answer. fluids (blood or cerebrospinal fluid) would drocytes also showed the presence of the The exact mechanism by which exena- suggest the existence of a problem in the insulin resistant markers however, specific- tide promotes neuronal survival is not entirely IGF-1 and/or insulin signalling system in the ally IRS-1pS312 expression was found to be understood, however, knowledge of path- body possibly pointing towards the presence most apparent in the oligodendrocytes that ways associated with GLP-1 receptor activa- of insulin resistance. Exenatide activates contained GCIs in MSA.11 tion (as seen in Figure 1) demonstrates that the same effectors as IGF-1 and therefore, Insulin resistance in MSA has been further in neurones, exenatide activates the phos- has the potential to activate or deactivate explored in the PLP-SYN transgenic mice; a phoinositide 3-kinase (PI3K) pathway which pathways associated with IGF-1 if there is any model expressing human wild-type alpha-sy- promotes axonal growth, neuronal regener- dysfunction. nuclein using a specific ation and protein synthesis. Additionally, A study investigating biomarkers proteolipid (PLP) promotor.11,12 In this model, the receptor activates the mitogen associ- in MSA has shown that there are signifi- both GCI-like structures develop in oligoden- ated protein kinase (MAPK) pathway which cantly increased serum levels of IGF-1 in drocytes and clinical features of MSA, such inhibits and encourages neur- MSA (n=25) compared to healthy controls as bladder dysfunction13 and parkinsonism.14 onal survival. Both activation of PI3K and (n=25).9 This finding was validated in a Investigation into insulin resistance in the MAPK pathways inhibit caspase 9, blocking second study that showed a significant eleva- PLP-SYN model (n=7, wildtype n=7) further apoptosis. Consequently, these pathways tion in levels of serum IGF-1 in MSA (n=25) supported the above finding of insulin also inhibit the nuclear factor kappa-light- when compared to healthy controls (n=52) resistance in the MSA brain because the chain-enhancer of activated B cells (NFkB) and those with Parkinson’s disease (PD, PLP-SYN mice had a significantly higher level pathway preventing oxidative stress and n=79).10 Additionally, IGF-1 levels positively of insulin marker IRS-1pS307, equal to the neuroinflammation.15 correlated with MSA disease duration and the human IRS-1pS312, in the striatum compared Exenatide has been studied previously as

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a disease modifying drug for Parkinson’s there must be a reliable means of showing a found to correlate with disease severity thus, disease (PD) in a single-centre, random- potential treatment effect. Currently, the main IGF-1 levels may also have the potential to ised, double-blind, placebo-controlled trial way to measure disease modification in MSA objectively correspond to disease modifica- in 62 patients with PD; 32 patients treated is by using UMSARS scores. UMSARS scores tion in a clinical investigation.10 Combining with exenatide and 30 patients treated with take into account the ability of the patient to IGF-1 and NfL levels in bodily fluids with placebo. Patients self-administered exena- conduct their activities of daily living (UMSARS UMSARS scores has the potential to be a tide (2mg) or placebo subcutaneously once I-Historical Review section), their movement better more objective endpoint in assessing weekly for 48 weeks. They were followed features (UMSARS-II Motor Examination), disease modification and progression in a up every 12 weeks from baseline for a total their autonomic problems (UMSARS-III clinical trial for MSA. of 60 weeks. The results of the trial showed Autonomic Examination) and their Global Other disease modifying treatments that are that the mean change in Movement Disorders Disability Scale score (UMSARS-IV). Similar to being investigated for MSA through non-clin- Society Unified Parkinson’s Disease Rating MDS-UPDRS, UMSARS scores are a subjective ical or clinical trials include mesenchymal Scale (MDS-UPDRS) motor subscale (part 3) measure, and this suggests that there may be stem cell therapy,17 Verdiperstat (a myelop- scores in the exenatide group were signifi- bias and potential inter-rater variability in eroxidase inhibitor),18 CoQ10 supplementa- cantly different to the placebo group with the measurements. Hence, UMSARS may not tion19 and new molecules aiming to block the exenatide group having an improvement be the ideal way to demonstrate any disease oligomeric alpha-synuclein from forming new in motor scores over time, in contrast to the modifying effect of exenatide. toxic oligomers.20 placebo group.16 This result could be due An objective biomarker of treatment effi- to the drug truly having a disease modifying cacy would be a better way of monitoring In summary, pre-clinical experiments have effect, however it may be because the partici- disease modification. Unfortunately, there is revealed insulin resistance in the MSA brain. pants in the exenatide group plateaued in no such biomarker for MSA although recent Additionally, these experiments suggest that their disease progression and the therapy is research into neurofilament light (NfL) exenatide, a T2DM drug, has the potential only having a symptomatic effect. Further levels has shown promising results. NfL is a to function as a disease modifying treatment research needs to be conducted with a larger biomarker of axonal damage and CSF and for MSA through this pathway. More research cohort in order to validate these results and serum levels have been shown to correlate is required to find more reliable biomarkers this is currently ongoing in an about to start with disease progression in many neuro- which correlate with disease severity and Phase III study. degenerative diseases including MSA.21,22 progression to inform MSA clinical trial design The exenatide in PD trial illustrates that to Moreover, as mentioned previously, IGF-1 and help assess whether exenatide truly has conduct a successful clinical trial for MSA, levels in the serum of patients with MSA was disease modifying effects in MSA.

REFERENCES

1. Levin J, Kurz A, Arzberger T, Giese A, Höglinger GU. The Differential Diagnosis and 13. Boudes M, Uvin P, Pinto S, et al. Bladder dysfunction in a transgenic mouse model of Treatment of Atypical Parkinsonism. Dtsch Arztebl Int. 2016;113(5):61-69. multiple system atrophy. Mov Disord. 2013;28(3):347-355. 2. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a 14. Refolo V, Bez F, Polissidis A, et al. Progressive striatonigral degeneration in a transgenic prospective European cohort study. Lancet Neurol. 2013;12(3):264-274. mouse model of multiple system atrophy: translational implications for interventional thera- 3. Low PA, Reich SG, Jankovic J, et al. Natural history of multiple system atrophy in the USA: a pies. Acta Neuropathol Commun. 2018;6(1):2. prospective cohort study. Lancet Neurol. 2015;14(7):710-719. 15. Bassil F, Fernagut PO, Bezard E, Meissner WG. Insulin, IGF-1 and GLP-1 signaling in neuro- 4. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of degenerative disorders: targets for disease modification? Prog Neurobiol. 2014;118:1-18. multiple system atrophy. Neurology. 2008;71(9):670-676. 16. Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in 5. Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendro- Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. cytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol. 2017;390(10103):1664-1675. doi:10.1016/S0140-6736(17)31585-4. 1998;44(3):415-422. 17. Singer W, Dietz AB, Zeller AD, et al. Intrathecal administration of autologous mesenchymal 6. int. 2020. Diabetes. [online] Available at: https://www.who.int/news-room/fact-sheets/ stem cells in multiple system atrophy. Neurology. 2019;93(1):e77-e87. detail/diabetes [Accessed 14 May 2020]. 18. Stefanova N, Georgievska B, Eriksson H, Poewe W, Wenning GK. Myeloperoxidase inhi- 7. Bhavsar S, Mudaliar S, Cherrington A. Evolution of exenatide as a diabetes therapeutic. Curr bition ameliorates multiple system atrophy-like degeneration in a transgenic mouse model. Diabetes Rev. 2013;9(2):161-193. Neurotox Res. 2012;21(4):393-404. 8. Labandeira-Garcia JL, Costa-Besada MA, Labandeira CM, Villar-Cheda B, Rodríguez- 19. Mitsui J, Koguchi K, Momose T, et al. Three-Year Follow-Up of High-Dose Ubiquinol Perez AI. Insulin-Like Growth Factor-1 and Neuroinflammation.Front Aging Neurosci. Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous 2017;9:365. Published 2017 Nov 3. COQ2 Mutations. Cerebellum. 2017;16(3):664-672. 9. Pellecchia MT, Pivonello R, Longo K, et al. Multiple system atrophy is associated with 20. gov. 2020. A First-In-Human Study Of Single And Multiple Doses Of Anle138b In Healthy changes in peripheral insulin-like growth factor system. Mov Disord. 2010;25(15):2621- Subjects – Full Text View – Clinicaltrials.Gov. [online] Available at: https://www.clinical- 2626. trials.gov/ct2/show/NCT04208152 [Accessed 23 May 2020]. 10. Numao A, Suzuki K, Miyamoto M, Miyamoto T, Hirata K. Clinical correlates of serum 21. Hansson O, Janelidze S, Hall S, Magdalinou N, Lees A, Andreasson U, Norgren N, Linder J, insulin-like growth factor-1 in patients with Parkinson’s disease, multiple system atrophy and Forsgren L, Constantinescu R, Zetterberg H and Blennow K. Blood-based NfL: A Biomarker progressive supranuclear palsy. Parkinsonism Relat Disord. 2014;20(2):212-216. for Differential Diagnosis of Parkinsonian Disorder. Neurology, 2017;88(10):930-937. 11. Bassil F, Canron MH, Vital A, et al. Insulin resistance and exendin-4 treatment for multiple 22. Magdalinou N, Paterson R, Schott J, Fox N, Mummery C, Blennow K, Bhatia K, Morris system atrophy. Brain. 2017;140(5):1420-1436. H, Giunti P, Warner T, de Silva R, Lees A and Zetterberg H. A panel of nine cerebrospinal 12. Kahle PJ, Neumann M, Ozmen L, et al. Hyperphosphorylation and insolubility of alpha-synu- fluid biomarkers may identify patients with atypical parkinsonian syndromes. Journal of clein in transgenic mouse oligodendrocytes. EMBO Rep. 2002;3(6):583-588. Neurology, Neurosurgery & Psychiatry, 2015;86(11):1240-1247.

COVID-19: UK data on rehabilitation needs & management pathways, Webinar recording available to watch

If you missed this webinar, which took place on the 20th of July, we are pleased to offer you the opportunity to watch it online at https://bit.ly/2YAlYyy

The objective of the webinar was for professionals to share local data on COVID-19 short-term and long-term symptoms in survivors and local care pathways to meet rehabilitation needs. Plus, share experiences and to also help learn best practices in the country and foster consensus on best possible care for COVID-19 survivors in the NHS, UK.

36 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 r e g u l a r s – i n d u s t r y n e w s

Teva announces UK launch of pre-filled pen for anti-CGRP migraine therapy AJOVY®▼ (fremanezumab)

On 21st July 2020, Teva UK Limited announced research and development site in Abbots Park, that a pre-filled pen for AJOVY® (fremanezumab) Runcorn, Cheshire. injection is now available, which will give patients “At our Combination Product and Device R&D on AJOVY® added convenience and flexibility not site in Runcorn we developed the AJOVY® pre-filled previously available with the AJOVY® pre-filled pen out of a deep desire to improve the lives of syringe. Indicated for the prevention of migraine in chronic migraine sufferers,” said Paul Bridges, adults who have at least 4 migraine days per month, Senior Director CPD R&D at Teva UK’s Abbots AJOVY® offers quarterly and monthly dosing options. Park, R&D site in Runcorn, Cheshire. “We’re really It is the first and only anti-CGRP drug recommended proud that the pre-filled pen was designed and for use on the NHS in England and Wales by the developed here in the UK, and will offer more National Institute for Health and Care Excellence user friendly treatment options for patients with References (NICE) for chronic migraine patients. Within NHS migraine.” 1. The Migraine Trust - www.migrainetrust. Scotland, it is accepted for restricted use by the “We’re delighted to now be able to offer the org/living-with-migraine/treatments/ Scottish Medicine Consortium (SMC) for chronic and option of a pre-filled pen device for AJOVY® calcitonin-gene-related-peptide-path- 1 ® way-monoclonalantibodies/. Last episodic migraine. AJOVY is an option for migraine patients in the UK,” said Kim Innes, General patients who have not responded to at least three accessed: July 2020 Manager of Teva UK and Ireland. “Earlier this year 2. Khan S. et al. ‘CGRP, a target for 1 prior preventive treatments. AJOVY® was the first anti-CGRP medicine recom- preventive therapy in migraine and “Chronic migraine is a debilitating neurological mended by NICE, and we’re pleased to be able to cluster headache: Systematic review of clinical data’. Cephalalgia (2019); disorder which can, without the right treatment, offer people struggling with migraine even greater strike at any time leaving the sufferer feeling help- 39(3): 374-389 flexibility and control over their treatment.” Patients 3. Botox® SmPC. Allergan Ltd. 2019. less,” comments Dr Mark Weatherall, Chair of may self-inject at home once instructed in subcuta- Available at www..org.uk/emc/ the British Association for the Study of Headache. neous self-injection technique by a healthcare product/859/smpc 4. Two Human Factor studies assessed “Fremanezumab is well tolerated, effective and professional. This has the potential to free up NHS particularly useful for complex migraine patients, evaluators’ ability to complete critical resources such as nurse or consultant time. tasks in order to demonstrate use of the where other treatments have failed. Patients are Patients can use the Rain Free Days application AJOVY Autoinjector in simulated-use often worried about using traditional syringes for guidance about using AJOVY®, and instructional sessions. When asked “Was the auto- to inject themselves. A pen device is simple to injector easy to use?”, 97% in study 1 videos are available from products.tevauk.com. self-administer and increases patients’ control over (N=30) and 98% in study 2 (N=47) Teva is also providing a fully funded Homecare answered “Yes.” Data on file, Parsippany, their own management of their condition.” service which includes training by a nurse. NJ Teva Pharmaceuticals USA, Inc. “As healthcare professionals, we want to be able 5. AJOVY® SmPC. Teva UK Ltd. 2019. to get patients onto migraine specific treatments Available at https://www.medicines. About AJOVY® (fremanezumab) expediently. However, headache/migraine specialist org.uk/emc/product/10386/smpc. Last AJOVY® (fremanezumab) is indicated for the clinics are often challenged by high caseloads,” accessed: July 2020 prophylaxis of migraine in adults who have at 6. Pavone E. et al. ‘Patterns of triptans adds Neurology Nurse Prescriber Rebecca Stuckey, least four migraine days per month. AJOVY® is use: a study based on the records of a University Hospitals Plymouth NHS Trust, “A pen community pharmaceutical department’. available as a 225mg/1.5mL single dose injection device which patients can easily self-administer will Cephalalgia (2007); 27: 1000-1004. in a pre-filled syringe or pre-filled pen with two reduce appointments and waiting times. This option 7. NHS – Migraine (www.nhs.uk/conditions/ dosing options – 225mg monthly administered migraine/symptoms/) Last accessed: July will also be welcomed by my patients, who can as one subcutaneous injection, or 675mg every 2020 travel 2-3 hours to the clinic for appointments.” 8. Migraine Trust – Facts and Figures three months (quarterly), administered as three Previously migraine prevention therapies were https://www.migrainetrust.org/about-mi- subcutaneous injections. Like all injections, there limited to treatments repurposed from other disease graine/migraine-what-is-it/facts-figures/ (figure based on current UK adult popula- areas (such as beta-blockers, anti-epileptics, is a chance of a skin reaction around the injection site e.g. redness, hardness or itching. AJOVY® can tion from the Office of National Statistics anti-depressants and botulinum toxin injections).2 - www.ons.gov.uk/peoplepopulationand- Botulinum toxin, requiring a minimum of 31 injec- be administered at home by a patient or care- community/populationandmigration/popu- tions into the head or neck per treatment, has to giver, if instructed by a healthcare professional. lationestimates/articles/overviewoftheuk- Full product information can be accessed from population/february2016) Last accessed: be administered by a healthcare professional at July 2020 3 ® the Teva website: http://products.tevauk.com/p/ a specialist centre. AJOVY belongs to a class of 9. Buse DC. et al. ‘Chronic Migraine treatments called anti-CGRP (calcitonin gene-re- fremanezumab-728?productId=19035 • The Prevalence, Disability, and lated peptide) monoclonal antibodies, which have Scottish Medicines Consortium (SMC) accepted Sociodemographic Factors: Results From ® the American Migraine Prevalence and been specifically designed to target the underlying AJOVY for restricted use within NHS Scotland Prevention Study’. J Head Face Pain; ® (January 2020), for the treatment of patients causes of migraine. AJOVY is the only long-acting 52: 1456-1470. doi:10.1111/j.1526- anti-CGRP injection with the option of dosing with chronic and episodic migraine who have had 4610.2012.02223.x four times or twelve times per year using either a prior failure on three or more migraine preventive 10. Chronic migraine population calculated pre-filled syringe or the new pre-filled pen. treatments. The guidance can be viewed online by using 12% of migraine population (1 in 7 total population) as cited by ® on the SMC website: https://www.scottishmedi- The new AJOVY pre-filled pen has several Buse (above) amongst context of current features that make it easy-to-use including a cines.org.uk/medicines-advice/fremanezum- UK population statistics from Office of button-free, push-down mechanism, audible ab-ajovy-fullsmc2226/ • National Institute for National Statistics. Population estimates cues that signal progress of administration, and Health and Care Excellence (NICE) recommended for the UK, England and Wales, Scotland and Northern Ireland: mid-2018. https:// AJOVY® (fremanezumab) for use within NHS a window that displays when the dose has been www.ons.gov.uk/peoplepopulationand- delivered.4 Additionally, the pre-filled pen is for England and Wales (June 2020) for the prophyl- community/populationandmigration/ one-time use only and locks after use. AJOVY® axis of migraine in adults with chronic migraine populationestimates/bulletins/annualmid- can be injected into areas of the abdomen, thigh, who have not responded to at least three prior yearpopulati onestimates/mid2018 Last accessed: July 2020 or upper arm that are not tender, bruised, red or preventive treatments. The technology appraisal indurated. Injection sites should be alternated/ guidance can be viewed online on the NICE AJO-UK-NP-00007 Date of Preparation: rotated.5 It was developed in the UK at Teva’s website: https://www.nice.org.uk/guidance/ta631 July 2020

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Parkinson’s Hub: An integrated pathway for people with Parkinson's and frailty

n innovative, integrated and multi-disci- and “off” states and response to treatment plinary-led community pathway for is less well understood. Kempster describes Apeople with Parkinson's and related that although younger patients usually have disorders with co-existing frailty has been a more prolonged maintenance phase, once commissioned by Hull clinical commissioning events such as visual hallucinations, falls and group (CCG). This is part of the CCG’s strategy cognitive dysfunction occur, the prognosis is to address frailty within its local population, similar regardless of age.8 Parkinson’s requires a working both proactively and reactively to holistic approach and sensitivity to the patient’s Thomas Mace, support patients to live well and reduce strain own goals throughout the disease especially MbChB, MRCP(UK), on the local hospital. when multiple frailty syndromes affect their is a Consultant Physician in Elderly Kingston-Upon-Hull is a city within Yorkshire quality of life. Hence, the referral criteria Medicine at Hull University Teaching in the United Kingdom and has an estimated into the service is loose with no exclusion Hospitals. He has a special interest in 1 movement disorders and acute frailty. population of approximately 260,000. It is in criteria, although a CFS score of 6 (moderate) He has recently led on the development the 5% most deprived local authorities.2 With onwards is used as guidance for those living of the Parkinson's Hub for patients with a move towards integrated care, there have with multiple ‘frailty syndromes’. There are no Parkinson's and frailty in Kingston-Upon- been many challenges; existing systems are not age restrictions. Hull. designed for this new way of working. These Until recently, the existing Parkinson’s Additional medical writing difficulties have been overcome by enthusi- service followed a common model of diagnosis Charlie Peel, Health Writer, astic cross-working between the Hull CCG, Hull by a Consultant and routine Neurology Academy. University Teaching Hospitals NHS Trust, City follow-up with a Parkinson’s disease Specialist Correspondence to: Thomas Mace, Health Care Partnership CIC and Hull Local Nurse, with referral back to the specialist when Hull University Teaching Hospital, Authority with assistance from the voluntary required with no MDT meeting. Anlaby Rd, Hull HU3 2JZ. sector including Parkinson’s UK. A push by Hull CCG towards providing holistic care for patients living with frailty in Conflict of interest statement: None declared the community has resulted in the opening of the Jean Bishop Integrated Care Centre. Provenance and peer review: Background Comprehensive Geriatrics Assessments (CGAs) Submitted and externally reviewed. The NHS Long Term Plan (2019) encourages a are performed on patients invited for review, Date first submitted:9/2/2020 move to a more holistic, multi-disciplinary team after screening using the electronic frailty index Date submitted after peer review: 7/8/2020 (MDT)-led integrated care in the community, algorithm. Briefly, a CGA is a diagnostic process Acceptance date: 10/8/2020 closer to where patients live.3 Furthermore, it performed by members of the multidisciplinary This is an open access article distributed has placed a focus on frailty. Clegg et al defines team, assessing: physical and mental health, under the terms & conditions of the Creative Commons Attribution license frailty as: socioeconomic, environmental, mobility and http://creativecommons.org/licenses/ 'a state of vulnerability to poor resolution functional factors and a medication review, by/4.0/ of homoeostasis after a stressor event and is a culminating in a personalised plan of interven- consequence of cumulative decline in many tions to address the issues raised. Mace T, Peel C. ACNR To cite: 4 2020;19(4):38-41 physiological systems during a lifetime'. As an in-patient tool, CGAs have been shown Non-frail patients can usually expect to to demonstrate a decrease in those admitted to return to their baseline once they recover from nursing homes compared to routine medical the stressor. However, those who are frail or care.9 In the outpatient setting, outcomes are vulnerable to frailty are at risk of not achieving less well understood but one study found it this and thus have an increased risk of devel- “may delay the progression of frailty and may oping a higher level of dependence, disability contribute to the improvement of frail patients or death.5 in older persons with multi-morbidity”.10 The association between Parkinson’s and frailty is interesting in that it leaves the body’s Aims physiological systems and mind vulnerable to The service aims are identified in Table 1; these stressors and is highly associated with condi- were created following a focus group of people tions such as falls, cognitive dysfunction, with Parkinson's and their carers and through immobility, incontinence and susceptibility to the specialist healthcare team. side effects of medications, often seen as ‘frailty A framework was developed: the syndromes’.6 ‘Comprehensive Parkinson’s Assessment’ Parkinson’s may directly cause or co-exist (CPA). This is very closely influenced by and and compound frailty. The Rockwood Clinical aligned with CGA which is advocated by the Frailty Scale (CFS) is a useful way of classifying British Geriatric Society11 and augmented by non-frail and frail states, viewing frailty as a Parkinson’s specific questions. It takes into spectrum of a physiological state.7 However, account themes from the NHS RightCare the effect of more advanced Parkinson’s Progressive Neurological Conditions Toolkit,12 and the variability of living with daily “on” the Non-motor Symptoms Questionnaire13 and

38 > ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 s p e c i a l f e a t u r e

Table 1: Aims of the Parkinson’s Hub and of any MDT-led community frailty service Table 2: The core themes included as identified by patient and healthcare communities in Comprehensive Parkinson's Assessments Identified by people with Parkinson’s and Identified by the healthcare team, CGA, and their carers Parkinsons UK National Audit Cognition, mood, More information / education about their neuropsychiatric, Improve quality of life disease General Health sleep and social services (ICD) Quicker access to healthcare professionals assessments Responsive service with an interest in Parkinson’s Frailty, Hoehn & Yahr Continence and Expertise from their healthcare professionals Reduction in non-elective hospital admissions and observations bowel function Quicker medication changes Reduction in falls and fragility fractures Nutrition, swallowing, speech issues and Function and pain Reduction in pain oral health Rationalising of polypharmacy Movement, motor- Sensory function Advanced care planning symptoms and falls Reduction in permanent care home admission Environmental and Bone health Improvement in respecting a patient’s preferred carer requirements place of death Medication and Future care plans and Improved links with mental health services polypharmacy review wishes

Table 3: The personnel comprising the new Parkinson’s Hub team Staff involved Their role / further information Consultant Geriatrician with an interest in 2 morning clinics (2 x 4 hours) per week to perform the clinical aspect of Parkinson’s assessments, routine movement disorders and rapid-access follow-ups and lead the MDT meeting. Acts as Clinical Lead for the service. Parkinson’s disease Nurse Specialist (1 whole Currently working a part-time 27.5 hours per week. Work is a mixture of clinics, home visits, care home time equivalent) work, MDTs and networking with other agencies. Consultant Neurologist Offer second opinion, education and shared decision making for complex cases. On an annual rotational basis linked with other rotations including ‘frailty’. Supervised by a Band 7 Band 6 Physiotherapist Neuro-Physiotherapist with a special interest in Parkinson’s. 2 days per week with 3 days working within the closely aligned “core frailty” team. Support to develop a Band 6 Occupational Therapist specialist Parkinson’s interest is available. Band 4 Therapy Assistant Supports both the physiotherapy and Occupational Therapy team. Split between 2 colleagues, to ensure cross-cover. They are the patient’s single point of access to the Full-time MDT Coordinator role service and maintain the comfort of the patient alongside the smooth running of the service. They complete administrative tasks and ensure all tasks are completed from the patient’s individualised plan. 2 days per week to assess medication concordance and dexterity whilst suggesting possible Technician improvements in prescribing and ensuring medication changes occur in a timely fashion. the Parkinson’s UK National Audit.14 Parkinson’s UK (when capacity allows). pathway has been strengthened for those who The core themes included can be found Throughout the assessment, there is seam- have declined further hospital admissions in Table 2. The NHS RightCare Progressive less working and data sharing with the local and have chosen to be cared for within the Neurological Conditions Toolkit is influential authority’s social services team and Dove community only and supported through the in its promotion of MDT work, signposting House Hospice (where applicable). dying process. They are referred to the district of Parkinson’s UK local advisors and the use nursing team who provide the majority of of care coordinators. The Parkinson’s UK The Parkinson’s Hub service community palliative care. Multiple patients National Audit prompts questions that are The service flows in three parts: a referral, an attend the Dove House day hospice service Parkinson’s specific, e.g. regarding hypersali- assessment in two parts, and a follow-up. This who also support the patient if symptoms vation and psychosis. can be seen in Figures 1-3. become difficult to manage. Data is shared At the mini-MDT meeting following the between the services and communication is Integration and Personnel clinic, each patient is given a stability classifi- open both ways to obtain clinical advice for A team, working seamlessly as an extension of cation to determine whether they are ‘Stable’, all the teams mentioned above. the current team at Hull University Teaching ‘At-risk’, ‘Pre-crisis/Crisis’ (defined as likely to Hospitals, and comprising current and new result in hospital or 24 hour care admission) Information technology and data sharing healthcare professionals has been formed to or ‘Palliative’. All individualised plans will be Locally, 'SystmOne' is the main software used support the new service. The team is formed sent by the next working day to the patient, amongst GP practices, although some prac- of colleagues (Table 3) with various employers their General Practitioner (GP) and the local tices do use 'EMIS'. A dataset for the group working within a structure provided by the hospital. Those deemed as Pre-crisis/Crisis of patients has been established. Templates aforementioned agencies, all working to a will be discussed in the monthly Grand MDT based on the CPA to frame each patient common goal: to provide great commun- which has attendance by the usual MDT, with contact have been created on SystmOne with ity-based care. Hull CCG has significantly additional representation from social services, read codes used wherever possible to aid data increased the resource into the team. care home staff, and any other parties involved sharing and analysis. In addition to the core team, there is input in the patient’s care. As the service spans multiple agencies, a from pharmacy technicians, a clinical support There is close collaboration with the local thorough consent process for data sharing has worker, carer support agency workers and care home frailty team. The palliative care been agreed. After verbal, then written patient

ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 > 39 Pharmacy Technician 2 days per week to assess medication concordance and dexterity whilst suggesting possible improvements in prescribing and ensuring medication changes occur in a timely fashion.

In addition to the core team, there is input from pharmacy technicians, a clinical support worker, carer support agency workers and Parkinson’s UK (when capacity allows). Throughout the assessment, there is seamless working and data sharing with the local authority’s social services team and Dove House Hospice (where applicable).

The Parkinson’s Hub service The service flows in three parts: a referral, an assessment in two parts, and a follow- up. This can be seen in figures 1-3. s p e c i a l f e a t u r e

Figure 1: The Parkinson’s Hub service flow : referral

consent, the Parkinson’s Hub requests patient records from the GP and can share these within the services including social services. Further, the Individualised Patient Plan can be shared with the patient, the patient’s GP and the local hospital.

Evaluation and next steps During the Parkinson’s Hub induction workshop for the whole team, a service culture was identified which was: “Be Kind, Be Helpful, Be Patient-Centred” and early feedback suggests this culture is tenable. The service welcomed its first patient on 1st November 2019, following a home assessment on the 29th October 2019. The number of patients has been kept low initially so that learning can take place and the team can become familiar with new systems. Using the ‘Friends and Family’ test, so far 100% of patients have stated they are “extremely likely” to recommend the service (15 completed surveys). Most individualised plans have between 8 and 20 outcomes and timely follow-up on these changes has become imperative. It is currently too early to assess what objective impact they have but there is an ambition to publish outcomes of the

Figure 1: The Parkinson’s Hub service flow: referral. service in due course. Figure 2: The Parkinson’s Hub service flow : assessment Moving forward, there are many improvements and additions to the service to be developed as outlined in Table 4.

Conclusion The Parkinson’s Hub service remains in its infancy but is well placed to deliver on its ambition to potentially slow the progression of frailty and lessen the deleterious effect on people with Parkinson’s and their carer’s quality of life that frailty syndromes cause. We hope that by sharing the learning of this early work we will encourage colleagues in other areas and open discussion on working in an integrated fashion across organisations and services, ensuring that people living with Parkinsons and their carers experi- ence joined up and timely care.

Table 4: next steps and forward planning for the service Ambitions for the Rationale for that ambition Parkinson's Hub service Evaluate and modify the Ensure the service is always optimised service as required to best support those it serves ReferencesFigure 2: The within Parkinson’s figure 2: Hub Non service-motor flow:Symptoms assessment questionnaire [13], Lindop Scale [15]. A diagrammaticReferences within model Figure of the 2: service Non-motor can be Symptoms found in appendix questionnaire A. [13], Lindop Scale [15]. A Ensure support for the with Parkinson's diagrammatic model of the service can be found in Appendix 1. who develop psychosis, Parkinson's Improve links with Mental dementia or more severe forms of Health services Figure 3: The Parkinson’s Hub service flow : follow-up depression and apathy associated with the condition Work with colleagues to Enable more variety, sample size and develop research links type, and a broader range of research in with local centres Parkinson's to be made possible To have a permanent Occupational Support an Occupational Therapist within the hub to support Therapist to develop an motor symptom management e.g. gait, interest in Parkinson’s freezing, overall mobility, etc Continue building links Enabling support of people in their with Dove House Hospice homes or within palliative settings as and District Nurses and when this may be required To offer strategies to manage Rapid access Speech & hypophonia, communication issues and Language Therapy Team swallow dysfunction (to reduce the risk of aspiration pneumonia) Clozapine has been found most effective for treating psychosis in Develop an outpatient people with Parkinson's; having a Clozapine service designated clinic to treat this symptom

Figure 3: The Parkinson’s Hub service flow: follow-up would expand the service use At the mini-MDT meeting following the clinic, each patient is given a stability Sharing positive practice to inform classification to determine whether they are ‘Stable’, ‘At-risk’, ‘Pre-crisis/Crisis’ Share learning from the other services can enable service (defined as likely to result in hospital or 24 hour care admission) or ‘Palliative’. All development and delivery improvements in other areas of the individualised plans will be sent by the next working day to the patient, their general of the Parkinson’s Hub practitioner (GP) and the local hospital. Those deemed as Pre-crisis/Crisis will be country discussed in the monthly Grand MDT which has attendance by the usual MDT, with additional representation from social services, care home staff, and any other parties involved40 > ACNRin the > patient’s VOLUME 19 care. NUMBER 4 > SUMMER 2020 There is close collaboration with the local care home frailty team. The palliative care pathway has been strengthened for those who have declined further hospital admissions and have chosen to be cared for within the community only and supported through the dying process. They are referred to the district nursing team who provide the majority of community palliative care. Multiple patients attend the Dove House day hospice service who also support the patient if symptoms become difficult to manage. Data is shared between the services and communication is open both ways to obtain clinical advice for all the teams mentioned above.

Information technology and data sharing s p e c i a l f e a t u r e

REFERENCES Appendix 1

1. Park N, 'Dataset: Estimates of the population for the UK, England and Wales, Scotland and Northern Ireland', The Office for National Statistics, June 2020 2. Hull City Council, 'Hull Public Health: Deprivation' accessed http://www.hullcc.gov. uk/pls/hullpublichealth/deprivation.html 3. National Health Service, 'The NHS Long Term Plan', January 2019, accessed https:// www.longtermplan.nhs.uk/publication/nhs-long-term-plan/ 4. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K, 'Seminar: Frailty in elderly people', The Lancet, Vol 381, Is 9868, 2–8 March 2013, pps 752-762, https://doi. org/10.1016/S0140-6736(12)62167-9 5. https://www.sciencedirect.com/science/article/pii/S0140673612621679 6. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-M156. doi:10.1093/ gerona/56.3.m146 7. Turner G, 'Recognising Frailty', Good practice guide, The British Geriatrics Society, June 2014, accessed https://www.bgs.org.uk/resources/recognising-frailty 8. Rockwood K, Song X, MacKnight C, Bergman H, Hogan DB, McDowell I, Mitnitski A, 'A global clinical measure of fitness and frailty in elderly people', CMAJ. Aug 30, 2005; 173(5): 489–495. 9. Kempster PA, O’Sullivan SS, Holton JL, Revesz T, Lees AJ, 'Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study', Brain, Volume 133, Issue 6, June 2010, pps 1755–1762, https://doi.org/10.1093/brain/ awq059 10. Ellis G, Gardner M, Tsiachristas A, Langhorne P, Burke O, Harwood RH, Conroy SP, Kircher T, Somme D, Saltvedt I, Wald H, O'Neill D, Robinson D, Shepperd S, 'Comprehensive geriatric assessment for older adults admitted to hospital', Cochrane Review, September 2017 accessed online at https://www.cochrane.org/CD006211/ EPOC_comprehensive-geriatric-assessment-older-adults-admitted-hospital 11. Mazya AL, Garvin P, Ekdahl AW. Outpatient comprehensive geriatric assessment: effects on frailty and mortality in old people with multimorbidity and high health care 14. Parkinson's UK, 'The non-motor symptoms (NMS) questionnaire' accessed at https://www.parkin- utilization. Aging Clin Exp Res. 2019;31(4):519-525. doi:10.1007/s40520-018- sons.org.uk/professionals/resources/non-motor-symptoms-questionnaire 1004-z 15. The UK Parkinson's Excellence Network, 'UK Parkinson's Audit' carried out each year via 12. The British Geriatrics Society, 'Comprehensive Geriatric Assessment Toolkit for https://www.parkinsonsaudit.uk/ ; last reported as '2019 UK Parkinson’s Audit: Summary Primary Care Practitioners', 2015, accessed https://www.bgs.org.uk/sites/default/ report', accessed https://www.parkinsons.org.uk/sites/default/files/2020-01/CS3524%20 files/content/resources/files/2019-02-08/BGS%20Toolkit%20-%20FINAL%20 Parkinson%27s%20UK%20Audit%20-%20Summary%20Report%202019%20%281%29. FOR%20WEB_0.pdf pdf#:~:text=The%202019%20UK%20Parkinson%E2%80%99s%20Audit%20provides%20 13. NHS RightCare, 'Progressive Neurological Conditions Toolkit', August 2019, accessed the%20largest,the%20numbers%20of%20services%20involved%20this%20time%20around. https://www.england.nhs.uk/rightcare/wp-content/uploads/sites/40/2019/08/ 16. Lindop Parkinson’s Assessment Scale, accessed via Parkinson's UK website: https://www.parkin- progressive-neuro-toolkit.pdf sons.org.uk/sites/default/files/2017-12/lindopparkinsonsassessmentscale.pdf

Hereditary Spastic Paraplegia (HSP) Support Group

The Hereditary Spastic Paraplegia (HSP) Support Group is a small UK charity run by volunteers. It aims to provide support to those with HSP, their families and their carers. The group Expert training for HCPs creates a friendly community allowing its members to feel less Neurology Academy is an innovative education provider isolated and share their stories with each other. The charity for clinicians, specialist nurses and professions allied regularly runs local meetings across the country, with a larger to medicine. The training programmes’ focus is on both AGM in July. They publish a newsletter two to three times disease management and service transformation. a year and keep their website up to date (https://hspgroup. org/). They also have a private Facebook page, which can be MS Intermediate MasterClass accessed (https://www.facebook.com/hspgroup.org/), where � Module 1: 7-8 Oct 2020 + Module 2: TBC 2021 members can discuss anything they want. Members can apply Sheffield (in person) / virtual attendance for funding for mobility aids or other equipment to improve their quality of life. Members fundraise and the charity are MS Academy Basecamp proud of their annual Potato Pants Festival (http://potatopants- � 19-20 October 2020 festival.co.uk/). They also provide research grants to promote Sheffield (in person) HSP research, part funding two UK PhDs this year.The charity are striving to make themselves better known to relevant MS Advanced MasterClass � healthcare professionals, so that patients with HSP can be Module 1: 4-6 Nov 2020 + Module 2: 13-14 May 2021 directed to them for support. They are there for the whole Sheffield (in person) journey, not just the diagnosis, and would appreciate if health- MS Service Provision in the UK 2020: care professionals can: 1.Advertise the group to patients/carers Raising the Bar with HSP under your care and your colleagues. 2.Become � 4, 10 & 11 November 2020 honorary members of the group. 3.Help to identify guest speakers for their meetings. 4.Apply for small research grants Fully virtual which can be provided annually. Parkinson’s Advanced MasterClass Please contact: [email protected] or � Module 1: 29-30 Sept + Module 2: 8-9 Dec 2020 [email protected] if you would like more information or Sheffield FULLY BOOKED / virtual attendance leaflets. neurologyacademy.org/courses

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Philipp Klocke, BMBS BMedSc, completed his medical Occurrence of Balínt degree at the University of Southampton, UK. In his final year of his studies, Philipp spent Syndrome in a patient with part of his degree in Canada, working with local clinical teams. Currently he Hypereosinophilic Syndrome is completing his foundation year 1 (FY1) in renal medicine and neurology. His interests include translational neuroscience and degenerative neurological conditions. Abstract left ventricular dysfunction (LVEF 44%), Balínt Syndrome is an acquired disorder however, no hemodynamically significant Anna Whalen- manifesting in the inability to recognise valve disease or thrombus were found. several objects at once (simultagnosia), Normal IgE, tryptase levels and lack of Browne, MD, inaccurate visually guided limb move- compelling history ruled out a hypersensi- is a Resident Physician in Internal Medicine at ments despite intact motor function tivity or parasitic aetiology. Autoimmune McMaster University, (optic ataxia) and the inability to make markers including ANA, ANCA, RF, and in Hamilton, Ontario. accurate voluntary saccades to visual ACPAs were normal. Also, serum protein Anna’s research interest targets despite demonstrating unrestricted electrophoresis, flow cytometry, a periph- is in conditions of atopy and immunomodulation range of eye movements (ocular motor eral blood smear and a lumbar puncture which complements her apraxia). Here, we report the first case of were not diagnostic. clinical focus. a patient presenting with Balínt Syndrome Repeat blood work showed progres- caused by a platelet-derived growth factor sive rising leukocytosis and eosinophilia 9 9 Mohamed receptor A mutation (PDGFRA)-induced to a peak of 80.6x10 /L and 45.6x10 /L, Hypereosinophilic Syndrome (HES). respectively, eight days following admis- Panju, MSc, MD sion. The patient was empirically started on FRCPC, high dose methylprednisolone (125mg PO is an Associate daily). His visual field defects recovered, Professor of Medicine 58-year-old retired male construc- power in all his limbs returned and his at McMaster University. He is the Deputy tion worker was referred to our simultagnosia resolved completely. Programme Director for A institution with a diagnosis of HES His residual deficit comprised bilateral the Internal Medicine presenting with nonspecific symptoms dysmetria, intention tremor and mild past training program. He is of jaw pain, nocturnal diaphoresis and pointing. Upon discharge, methylpredniso- the Ambulatory CTU directory and the Competence Committee Co-Chair. general malaise. On first admission, he was lone was switched to prednisone (75mg found to have significant leukocytosis of PO daily). Elliot Hepworth, 56.9x109/L with eosinophilia of 29.6x109/L. Eventually, a bone marrow aspirate taken MD, Past medical history was unremarkable shortly after admission indicated a FIP1L1- completed his residency and no recent changes to medication were PDGFRA translocation as the underlying training in Internal reported. Family history for rheumatologic aetiology. Following discharge, steroids and Medicine at McMaster or malignant conditions was negative, as hydroxyurea were switched to imatinib due University. He is were travel history, farm stock exposure to hydroxyurea-induced cytopenia, upon currently completing his residency and . which his count returned to near- training in Rheumatology Neurological examinations showed normal range within one week. at the University of normal colour vision, loss of smooth visual Ottawa. pursuit, positive saccadic movements and Discussion Correspondence to: vertical skew deviation with difficulties Considered a rare occurrence, Balínt Philipp Klocke, describing the content of all eight visual Syndrome has been described in cases of University of Southampton, fields. All other cranial tested ischaemia to both posterolateral occipital Southampton, UK. normal. Cerebellar examination revealed lobes (visual association area), the pari- E: [email protected] bilateral past-pointing, bilateral dysmetria, eto-occipital junction and both posterior Conflict of interest statement:The authors (PK, EH, dysdiadochokinesia and positive left- aspects of the parietal lobes.1 These areas AWB) all contributed substantially to the conception sided heel-shin testing. Interestingly, all of the brain are particularly vulnerable to and design of this case report, drafted the work and of his cerebellar symptoms improved watershed infarcts as they represent the revised it critically for important intellectual content; MP reviewed the manuscript and served as a content following bilateral eye closure, indicating locations of terminal branches of both expert. None of the named authors have stated any a component of visual ataxia. Moreover, the middle and posterior cerebral artery conflict of interest, financial or otherwise. he was noted to demonstrate right-sided and can frequently become under-per- sensory neglect, bilateral astereognosis, fused in arterial occlusive disease or acute Provenance and peer review: 2,3 Submitted and reviewed externally agraphesthaesia and simultagnosia which hypotension. Other occurrences of Balínt were suggestive of a rare presentation Syndrome are listed in Table 1. It has been Date first submitted: 27/2/20 known as “Balínt Syndrome”. suggested that Balínt Syndrome results from Date accepted after peer review: 14/5/2020 Subsequent imaging revealed bilateral lesions to specific functional brain areas This is an open access article distributed under the terms & conditions of the Creative Commons supra- and inferior-tentorial white and responsible for reaching, saccades, grasp, Attribution license http://creativecommons.org/ grey matter hypodensities. Additional MRI attention and state estimation. Damage to licenses/by/4.0/ imaging showed multiple areas of bilateral the parieto-occipital junction, responsible acute and subacute ischaemia, predomin- for coordinating visual and hand move- To cite: Klocke P, Whalen-Browne A, Panju M, Hepworth E. ACNR 2020;19(4):42-43 antly following a watershed distribution ments, has therefore been postulated as (Figure 1). Both echocardiography and a prime cause of optic ataxia while some cardiac MRI showed evidence of global forms of simultagnosia have been observed

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demonstrate slow rehabilitation progress in Table 1. Medical conditions associated with the strength in his arms with dysmetria on Balínt Syndrome:1-3 finger-to-nose testing and persistence of mild • Acute Hypotension lower extremity discoordination with inability • Alzheimer's Disease to perform tandem gait. EMG showed axonal predominant neuropathy thought to be • Anti-NMDA receptor encephalitis secondary to his eosinophilia. He continues to • Arterial Occlusive Disease see an ophthalmologist for mild visual impair- ment causing difficulty reading. Functionally, • Brain Tumours/Metastases he continued to require the use of a walker • Cerebral Toxoplasmosis as a gait aid for unsteadiness due to ataxia. • Corticobasal Degeneration He noted some residual confusion with mild difficulty retaining new memories, but his • Creutzfeldt Jakob Disease cognition remained largely unchanged. • Head Trauma/Acute Brain Injury Figure 1. Axial T1-weighted magnetic resonance imaging Conclusion • Lewy Body Dementia (MRI) of the patient demonstrating multifocal areas of high To our knowledge, Balínt Syndrome has not diffusion-weighted signals corresponding to areas of acute to • Parkinson’s Disease subacute ischaemia in both cerebral hemispheres. been previously described in association with • Posterior Cortical Atrophy HES. This current case of Balínt Syndrome The effects of and their products secondary to HES highlights the importance of • Posterior Reversible Encephalopathy on the coagulation cascade are not well watershed infarcts being a potential complica- Syndrome (PRES) understood, however, fibrinous material on tion of acute hypereosinophilia-induced organ • Pre-eclampsia the endocardial surface is an optimal location damage. In particular, the heart remains a loca- 4 • Progressive Multifocal for thrombus propagation. tion of micro-emboli formation which might Leukoencephalopathy In the present case, our patient presented not be detectable by cardiac imaging. with mild troponin elevation (1.7ng/ml) in the • Subacute HIV Encephalitis absence of chest pain or shortness of breath. Cardiac involvement in HES occurs in three stages; an acute necrotic stage, followed by Key points Table 2. Differential diagnoses of thrombotic, and finally fibrotic stages.6 During • Balínt Syndrome can be caused by hypereosinophilia in this patient the acute necrotic stage, the endocardium watershed infarcts, secondary to • Hypereosinophilic syndrome (HES) and myocardium are infiltrated by eosinophils Hypereosinophilic Syndrome. • /Atopy and lymphocytes resulting in , eosin- • Hypereosinophilic Syndrome can give rise ophilic degranulation, and micro-abscess to micro-emboli formation at the site of • Drug hypersensitivity formation. Micro-emboli formation at the site eosinophil degranulation-induced endo- • Neoplastic syndrome of eosinophil degranulation-induced endo- thelial necrosis which is not necessarily thelial necrosis is known to give rise to early detectable by cardiac MRI and/or ultra- • Infectious disease (Parasite infection, 4,6 travel history) signs such as splinter haemorrhages. Given sonography. troponin elevation, evidence of reduced • A mutational deletion on chromosome 4 • Immunological (Sarcoidosis, Amyloidosis, ventricular function without evidence of producing a fusion gene (PDGRFA), among Eosinophilic Granulomatosis with intraventricular thrombus or overt fibrosis, the causes for HES, can be treated with low Polyangiitis, Churg-Strauss Syndrome) and MRI evidence of diffuse subendocardial dose imatinib (100-200mg/week), thereby late gadolinium enhancement, it is likely that avoiding drug toxicity. in inferior occipito-temporal lobe lesions.3 our patient experienced the acute necrotic HES is a rare condition defined as persis- stage of cardiac involvement. Unseen by both tent marked serum eosinophilia (>1.5x109/L echocardiography and cardiac MRI, cardiac for more than six months) alongside evidence micro-emboli becoming dislodged and swept of eosinophilia-induced organ damage. Other into cerebral arteries are a likely explanation causes contributing to eosinophilia such as for the bilateral cortical watershed infarcts allergic reactions, parasites or malignant thereby giving rise to the clinical triad of REFERENCES disorders should be excluded beforehand.4 Balínt Syndrome. For decades HES had been termed idio- Regarding the specific rehabilitation of 1. Chechlacz M. Bilateral parietal dysfunctions and discon- pathic. However, recent work could iden- Balínt syndrome, treatment approaches are nections in simultanagnosia and Balint syndrome. Handb Clin Neurol. 2018;151:249-67. tify a novel kinase derived from a muta- multifaceted as visual disturbances can take 2. Kumar S, Abhayambika A, Sundaram AN, Sharpe tional deletion on chromosome 4 produ- place both at lower and/or higher function JA. Posterior reversible encephalopathy syndrome cing a fusion gene (FIP1L1-PDGFRA). As this levels. Moreover, spontaneous recovery in presenting as Balint syndrome. J Neuroophthalmol. mutation can be expressed in multiple cell this condition is assumed to be low. However, 2011;31(3):224-7. lineages, increased serum levels of neutro- individual case reports pointing out different 3. Andersen RA, Andersen KN, Hwang EJ, Hauschild M. Optic ataxia: from Balint's syndrome to the parietal reach phils and tryptase levels can frequently be rehabilitation protocols have come to show region. . 2014;81(5):967-83. observed. Patients displaying this chromo- similarity among their treatment approaches. 4. Gleich GJ, Leiferman KM. The hypereosinophilic somal abnormality are classified as having One of them is applying visuo-perceptual syndromes: current concepts and treatments. Br J Haematol. 2009;145(3):271-85. chronic eosinophilic leukaemia (CEL).4 retraining and a functional adaptation 7 5. Moore PM, Harley JB, Fauci AS. Neurologic dysfunction Clinical manifestations of HES can be programme to restore functionality. in the idiopathic hypereosinophilic syndrome. Ann Intern broad. However, major end organs affected Although still very incomplete, a scientific Med. 1985;102(1):109-14. by HES compromise the heart, skin, respira- foundation about the rehabilitation of this 6. Mankad R, Bonnichsen C, Mankad S. Hypereosinophilic tory apparatus and condition is currently growing and there are syndrome: cardiac diagnosis and management. Heart. 2016;102(2):100-6. (CNS), specifically encephalopathy, periph- approaches giving valuable information that 7. Heutink J, Indorf DL, Cordes C. The neuropsychological eral neuropathy or focal CNS deficits from can be built upon in the future. rehabilitation of visual agnosia and Balint's syndrome. either thromboembolism or haemorrhage.4,5 Post-discharge, our patient continued to Neuropsychol Rehabil. 2018:1-20.

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Gerry Christofi, BSc (Hons), Bm Bch, PhD, MRCP(UK), MRCP(Neurol), is a Consultant in Neurology and Neurorehabilitation at An expert opinion: Facial the National Hospital for Neurology and Neurosurgery and University College London Hospital NHS rehabilitation: combining the Foundation Trust. He special- ises in complex neurorehabili- tation including within the ITU setting, as well as gener- science and the art alised and focal spasticity. He is the clinical lead for the focal spasticity service at NHNN and also oversees the Key take home messages education on the cause of facial weakness, injection arm of the complex facial clinic at NHNN. 1. Facial rehabilitation is a clinical enhance the recovery of facial expression specialism that aims to improve and function and improve social participa- Ann Holland MSc, Grad Dip Phys, outcomes for people with facial weak- tion and well-being.1 This is done through MCSP, ness. optimisation of facial symmetry and align- is a Clinical Specialist 2. Optimal treatment requires an individ- ment as well as increased movement in Physiotherapist at the National Hospital for ualised package of care from a multi- facial expressions and function. Neurology and Neurosurgery disciplinary team. Frequent individualised goals include: and Bobath tutor. She 3. Clinically meaningful improvements • Improved eye closure; has expertise in Facial are possible in persons with acute and • Increased ability to smile/produce a Rehabilitation and was involved in the setting up and chronic facial weakness. more symmetrical smile; evolvement of the Complex 4. Clinicians develop skills and knowledge • Increased self-confidence; Facial Clinic including the of facial movement dysfunction after • Improved eating and drinking compe- injection arm. insult to the facial neuromotor system tence; resulting in advanced competencies and • Improved ease and clarity of speech Anne Rodger MSc, Grad Dip Phys, skill sets. sounds; MCSP, • Improved size of eye aperture; is a Clinical Specialist • Ease of applying makeup; Physiotherapist at the • Return to playing wind instruments; National Hospital for Neurology and Neurosurgery • Jaw/mouth opening. and is the physiotherapy acial weakness resulting from In published studies, improvements in clinical lead for Neuro damage to the corticobulbar tract, facial function are demonstrated using the Outpatients, Private Patients the facial nucleus or the facial nerve Sunnybrook Facial Grading System (SFGS). and the Neuromedical Wards. F She has a special interest in and its branches, causes resting and The SFGS is a clinician-graded perform- Facial Rehabilitation and has dynamic facial asymmetry. This can impact ance based measure of facial impairment recently become an injector on eating, drinking, speech sound produc- which reflects improvement in both resting in the Botulinum Toxin clinic arm of the Complex Facial tion and eye health, as well as psychosocial and dynamic symmetry and a reduction Clinic. well-being and participation. Facial weak- of mass movements. The SFGS assesses Rebecca Kimber, Bachelor of Applied ness is commonly associated with condi- resting posture of the eye, nasolabial fold tions such as Bell’s palsy, Ramsay-Hunt and corner of mouth; voluntary movement Science (Speech Pathology) Syndrome, Guillain-Barré Syndrome and for five standard facial expressions in five is a Speech and Language its variant, Miller-Fisher Syndrome. Other regions of the face (forehead wrinkle, eye Therapist at the National Hospital for Neurology causes include traumatic brain injury, skull closure, open mouth smile, snarl and pucker) and Neurosurgery. She has base trauma, and cortical and subcortical and synkinesis, associated with voluntary a special interest in Facial strokes. Damage to the facial nerve may movement. Its psychometric properties have Rehabilitation, Ataxia and also result from direct injury or tumour been defined including construct validity complex dysphagia in rare neurological disease and resection. The resulting facial weakness and responsiveness for clinically meaningful disorders. She currently works can be unilateral or bilateral and can vary change and inter-rater and intra-rater reli- in the Complex Facial Clinic. from a transient presentation to a more ability.7 Measurement of synkinesis however persistent and devastating weakness. has been found to be less reliable.8 Correspondence to: E: [email protected] There is emerging evidence for the effect- Therapeutic management for people iveness of facial rehabilitation; a process with facial weakness includes detailed Conflict of interest statement:None declared that involves facilitating intended facial assessment, incorporating observational movement patterns as well as eliminating analysis of both sides of the face, backed Provenance and peer review: Submitted and externally reviewed unwanted movements to advance recovery up by reliable, valid and sensitive evalu- of the facial nerve1,2,3,4,5,6 and the facial ation measures, including patient-graded Date first submitted:28/5/2020 motor system. instruments such as the Facial Disability Date submitted after peer review: 6/7/2020 A number of studies have shown statis- Index (FDI) which considers the impact Acceptance date: 13/7/2020 This is an open access article distributed under the terms tically significant and long lasting improve- of facial weakness on both physical and & conditions of the Creative Commons Attribution license ments after facial rehabilitation in persons social/well-being function, the FaCE Scale http://creativecommons.org/licenses/by/4.0/ with Bell’s palsy.2,3,6 A Cochrane review5 which is a measure of facial impairment also reported evidence for tailored facial and disability and the EuroQol (EQ-5D-5L) To cite: Christofi G, Holland A, Rodger A, Kimber R. ACNR 2020;19(4):44-46 exercises to improve facial function for which can identify low mood and/or pain people with chronic and moderate facial associated with health conditions. weakness. The reviewers suggested that In addition to observational analysis, facial exercise could also reduce secondary assessment employs palpation to identify sequelae in acute cases. specific areas of stiffness as well as signifi- Facial rehabilitation aims to provide cant areas of weakness. This allows for the

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Figure 1. Bar graph representing SFGS score for 73 people with facial weakness. Initial score (dark grey) and final score (light grey) SFGS (Sunnybrook Facial Grading System). Scores range from 0 (worst) to 100 (best). The light grey/white demonstrates amount of change with facial rehabilitation intervention.

generation of an individually tailored neuro- ineffective myelination leading to cross-talk muscle contraction (chemodenervation). The muscular facial programme, as indicated by between terminal facial nerve branches, or a effect is short-lasting (three to four months) the individual’s clinical presentation. This centralised, post injury hypersensitisation of and weakened muscle recovers over time. is an important shift away from historically the facial nucleus.13 The adjunctive use of low The duration of action and turnover of the prescribing non-specific exercises, which dose botulinum toxin type A (BoNT-A) injec- metalloprotease within the nerve terminal often promote exaggerated facial movements tions in an individual’s facial programme can cytoplasm appears to be the predominant, and secondary complications. Treatment selectively weaken synkinetic muscles and but not the only factor that contributes to intervention focuses on centring the face by improve resting and dynamic symmetry,6,11,14,15 the duration of paralysis. Other factors may using specific self-stretches to improve muscle especially when over-activity of the contralat- include transient neural sprouting and re-in- length and three to five facial exercises, with eral side of the face is also taken into account. nervation, although the role of this phenom- emphasis on the muscles being in appropriate BoNT-A is a potent produced by enon is unclear in humans.16,17,18,19,20,21 alignment, with inhibition of contralateral clostridium botulinum which inhibits the The use of BoNT-A is well established for the over-activity and/or synkinesis. release of presynaptic acetylcholine from treatment of hemifacial spasm and blepharo- Mirror feedback, due to a lack of facial the neuromuscular junction when injected spasm. There is accumulating evidence from muscle proprioceptors9 and perfect practice locally, causing temporary muscle weakness. prospective clinical studies for the use of are key elements in neuromuscular rehabili- The BoNT-A molecule is synthesised as a low dose BoNT-A injections in conjunction tation. Taping, either facilitatory or inhibitory, single inactive chain (150 kDa) and then with facial rehabilitation.6,11,14 Lower doses of may also be used as an adjunct to an indi- cleaved to form the active di-chain molecule, BoNT-A injections are used to treat synkinesis, vidual’s facial programme. Additionally thera- made up of a heavy chain of ~100 kDa and compared to other facial dyskinesias, to avoid peutic mobilisation of the temporomandibular a light chain of ~50 kDa, held together by adverse reactions such as excessive weakness, joint (TMJ) may facilitate improved mouth a disulphide bridge. The light chain acts ptosis and diplopia. Lower doses have been opening in both acute and chronic cases.10 as a (zinc-dependent) metalloprotease with reported to be as effective as higher doses.22 When there has been damage to the facial proteolytic activity located at the N-terminal Contralateral lower quadrant facial sensor- nerve and/or its branches, recovery may end. After the heavy chain is injected, toxin imotor impairment is common after a stroke be complicated by synkinesis. Synkinesis binds to presynaptic receptors on the terminal and there is an abundance of evidence for describes abnormal involuntary movement ends of neurones, and the peptide enters the neuromuscular plasticity.23 Facial rehabilita- of one set of facial muscles that accom- cytoplasm through endocytosis. Once in the tion in the stroke population aims to exploit panies purposeful movement of a different cytoplasm, the light chain cleaves compon- this phenomenon to enhance recovery of muscle group11 and may be part of the natural ents of the SNARE (soluble N-ethylmaleimide- the facial neuromotor system. Intervention recovery. Common presentations include sensitive factor attachment protein receptor), frequently incorporates the emotional oculo-oral, involuntary mouth movement a complex of proteins necessary for the motor system to produce spontaneous facial on eye closure and oral-oculo, involuntary exocytosis of acetylcholine. In the case of expressions9 with the face centred (reducing eye closure on mouth movement, as well BoNT-A, this specific site is known as SNAP-25 contralateral over-activity) as well selective as synkinetic activation of the platysma (synaptosome-associated protein of 25 kD). strengthening in function (talking, eating muscle. Clinically, synkinesis is presumed to As a result of this cleavage, acetylcholine and drinking). Low dose BoNT-A injections be due to aberrant axonal regeneration12 but remains in the neurone, and is unable to bind may also have a role in managing contralat- it has also been hypothesised to result from to receptors on muscle fibres and stimulate eral over-activity in conjunction with facial

ACNR > VOLUME 19 NUMBER 4 > SUMMER 2020 > 45 rehabilitation a r t i c l e

rehabilitation. Table 1 The adjunctive use of electrical stimulation Examples of (ES) remains controversial following damage Goal(s) Target Muscle(s) Rationale to the facial nerve and its branches. It has Therapeutic Input been suggested that ES may disrupt re-innerv- Selective stretch to ation and is thus contraindicated for individ- the lower pre-septal 24 fibres of orbicularis Stiffness will impact uals with facial nerve disorders. However, Orbicularis oculi oculi and levator on movement; need to some authors advocate that although ES used [orbital, pre-septal, Improved eye closure palpebrae; practice isolate and selectively during the acute phase of Bell's palsy is safe, it and pre-tarsal muscle of gentle eye closure strengthen orbicularis may not have added value over spontaneous sections] with the levator labi oculi recovery and multimodal physiotherapy.25 An superioris muscle RCT involving 60 patients with acute Bell’s stabilised Palsy showed that an additional three weeks of daily ES sessions improved functional Selective stretches [contralateral external facial movements and electrophysiological To centre face and and internal cheek outcome measures at three-month follow-up. reduce any stiffness muscles; ipsilateral The authors recommend further research on Increased ability to Zygomaticus major that will impact platysma]; practice 26 smile/improve smile and minor; levator on excursion of dosage and length of intervention. of small range smile symmetry anguli oris movement prior to With respect to ES and post stroke facial activity [with mental re-education of smile weakness, there is limited evidence for its imagery] with slowing activity use. However, two small studies found ES down of contralateral improved facial muscle strength and oral smile activity competence in people with dysphagia.27,28 The Complex Facial Clinic at the National Hospital for Neurology and Neurosurgery, a tive impact on resting and dynamic facial can help optimise management. Clinicians clinical service that provides facial rehabili- symmetry (Figure 1). need to develop in depth knowledge of the tation, was set up in 2011. The clinic is run Table 1 illustrates examples of therapeutic facial motor system and advanced competen- jointly by a Clinical Specialist Physiotherapist interventions in relation to an individualised cies and skill sets in order to manage facial and Highly Specialist Speech and Language goal as part of the facial programme. movement dysfunction. There is also a need Therapist and provides assessment and neuro- In summary, facial rehabilitation is a clinical for a description of optimal facial rehabili- muscular rehabilitation as well as offering the specialism that can improve the quality of care tation interventions using a format such as adjunctive use of low dose BoNT-A injections. and outcomes for people with facial weak- the template for intervention description and The injection arm of the service is overseen ness. Successful outcomes can be achieved replication (TIDIER) guidelines.29 This could by a Consultant Neurologist. Data collected using individually tailored programmes with inform future clinical trials and help gain using the SFGS shows the effectiveness of clearly identified goals. Adjunctive treatment consensus amongst facial rehabilitation ther- individualised facial rehabilitation with posi- in selected individuals with BoNT-A injection apists across this specialism.

REFERENCES

1. VanSwearingen JM. Facial rehabilitation: a neuromuscular re-education, patient-centered 15. Sadiq SA, Khwaja S, Saeed SR. Botulinum toxin to improve lower facial symmetry in facial approach. Facial 2008; 24(2): 250-59. nerve palsy. Eye 2012; 26:1431–36. 2. Lindsay RW, Robinson M, Hadlock TA. Comprehensive facial rehabilitation improves func- 16. Punga AR, Eriksson,A, Alimohammadi M. Regional diffusion of botulinum toxin in facial tion in people with facial paralysis: a 5-year experience at the Massachusetts Eye and Ear muscles: A randomised doubleblind study and a consideration for clinical studies with split- Infirmary. Physical Therapy 2010; 90: 391-97. face design. Acta Dermato-Venereologica 2015; 95:948–51. 3. Pereira LM, Obara K, Dias JM, Menacho MO, Lavado EL, Cardoso JR. Facial exercise therapy 17. Shoemaker CB, Oyler GA. Persistence of botulinum neurotoxin inactivation of nerve function. for facial palsy: systematic review and meta-analysis. Clinical Rehabilitation 2011; 25(7): Curr Top Microbiol Immunol 2013; 364:179–196. 649–58. 18. Pantano S, Montecucco C. The blockade of the neurotransmitter release apparatus by botu- 4. Ferreira M, Santos PC, Duarte J. Idiopathic facial palsy and physical therapy: an intervention linum . Cell. Mol. Life Sci. 2014; 71, 793–811. proposal following a review of practice. Physical Therapy Reviews 2011; 16(4): 237-43. 19. Whitemarsh RC, Tepp WH, Johnson EA & Pellett S. Persistence of botulinum neurotoxin A 5. Teixeira LJ, Valbuza,JS, Prado GF. Physical therapy for Bell’s palsy (idiopathic facial paral- subtypes 1–5 in primary rat spinal cord cells. PLoS ONE. 2014; 9, e90252. ysis). Cochrane Database of Systematic Reviews 2011; 7(12): CD006283. 20. Rossetto O, Pirazzini M, Montecucco C. Botulinum neurotoxins: genetic, structural and 6. Watson GJ, Glover S, Allen S, Irving RM. Outcome of facial physiotherapy in patients with mechanistic insights. Nat. Rev. Microbiol. 2014; 12, 535–549. prolonged idiopathic facial palsy. The Journal of Laryngology & Otology 2015; 129(4): 21. Eleopra R, Rinaldo S, Montecucco C, Rossetto O, Devigili, G. Toxicon 179. 2020; 84–91. 348-52. 22. Laskawi R. The use of botulinum toxin in head and face medicine: an interdisciplinary field. 7. Neely JG, Cherian NG, Dickerson CB, Nedzelski JM. Sunnybrook facial grading system: relia- Head & Face Medicine 2008; 4(1):5. bility and criteria for grading. Laryngoscope 2010; 120(5):1038-45. 8. Coulson SE, Croxson GR, Adams RD, O’Dwyer NJ. Reliability of the ‘Sydney’, ‘Sunnybrook’ 23. Nudo RJ. Neural bases of recovery after brain injury. Journal of Communication Disorders and ‘House Brackmann’ facial grading systems to assess voluntary movement and synkinesis 2011; 44:515–20. after facial nerve paralysis. Otolaryngeal Head Neck Surgery 2005; 132(4):543-49. 24. Manikandan N. Effect of facial neuromuscular re-education on facial symmetry in patients 9. Cattaneo L, Paves G. The facial motor system. Neuroscience and Biobehavioral Reviews with Bell’s palsy: A randomized control trial. Clinical Rehabilitation 2007;21:338-343 2014; 38:135–59. 25. Alakram P, Puckree T. Effects of electrical stimulation on House-Brackmann scores in early 10. Shaffer SM, Brisme´e JM, Sizer PS, Courtney CA. Temporomandibular disorders. Part 1: Bell's palsy. Physiotherapy Theory & Practice 2010;26(3):160-6. anatomy and examination/diagnosis. Journal of Manual and Manipulative Therapy 2014; 26. Tuncay F, Borman P, Taser B, Unlu I, Samim E. Role of electrical stimulation added to 22(1):2-12. conventional therapy in patients with idiopathic facial (Bell) palsy. American Journal 11. Toffola ED, Furini F, Redaelli C, Prestifilippo E, Bejor M.Evaluation and treatment of synki- Physical Medical Rehabilitation 2015;94(3):222-228. nesis with botulinum toxin following facial nerve palsy. Disability and Rehabilitation 2010; 27. Choi JB. Effect of neuromuscular electrical stimulation on facial muscle strength and oral func- 32(17):1414-18. tion in stroke patients with facial palsy. Journal Physical Therapy Science 2016;28(9):2541- 12. Husseman J, Mehta RP. Management of synkinesis. Facial Plastic Surgery 2008; 24(2): 2543. 242-49. 28. Oh DH, Park JS, Kim WJ. Effect of neuromuscular electrical stimulation on lip strength and 13. Cabin JA, Massry GG, Azizzadeh B. Botulinum toxin in the management of facial paralysis. closure function in patients with dysphagia after stroke. Journal Physical Therapy Science Curr Opin Otolaryngol Head Neck Surgery 2015; 23(4):272-80. 2017;29(11):1974-1975. 14. Lee JM, Choi KH, Lim BW, Kim MW, Kim J. Half-mirror biofeedback exercise in combination 29. Hoffman TC, Glasziou PP, Boultron I, Milne R and others. Better reporting of interventions: with three botulinum toxin A injections for long-lasting treatment of facial sequelae after template for intervention description and replication (TIDieR) checklist and guide. BMJ 2014; facial paralysis. Journal of Plastic, Reconstructive & Aesthetic Surgery 2015; 68:71-78. 348:g1687.

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Neurological Signs: Syllogomania; with a note on Diogenes of Sinope

is not a reader, indeed Letty wonders whether Although a syndrome characterised by Marcia “ever read”. self-neglect, domestic squalor, hoarding behav- In addition, to the milk bottles, Marcia iour, and social withdrawal with refusal of has a collection of tinned foods in a kitchen external help had been previously described, store cupboard: “meat, fish, fruit, vegetables, the term Diogenes syndrome was coined in soup … tomato purée, stuffed vine leaves … 1975 by Clarke et al., referring to Diogenes tapioca pudding”; “spam and stewing steak … of Sinope (ca. 412-323 BC), a cofounder of prawns and peach halves … sardines, soup, the Cynic school of philosophy in Athens, butter beans and … macaroni cheese”. The who was noted for his austere asceticism and drawer in her office desk also contains several self-sufficiency and his disregard for domestic Andrew Larner, MD, PhD, tins. Every week she buys more tins which comforts.5 Notionally he lived in a barrel or Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ require classifying and sorting: “the tins could tub, and rebuked Alexander the Great for UK. be arranged according to size or by types of standing in his sunlight. He has proved a Correspondence to: food. There was work to be done here and frequent subject for allegorical paintings. [email protected] Marcia enjoyed doing it”. Yet Marcia is repeat- Most patients diagnosed with Diogenes Provenance and peer review: Submitted and edly noted not to be a “big eater”, indeed one syndrome are elderly, single or living alone, of reviewed internally. evening she eats “a small tin of pilchards. It average or above average intelligence, and often Submitted 30/4/2020 and accepted 1/5/2020 was one left over from Snowy’s store, so it was with an adequate income (i.e. the condition Published online: 8/7/20 not really breaking into her reserves.” is not the result of poverty).6 Although cases This is an open access article distributed under the terms & conditions of the Creative Commons Finding a plastic bag in her kitchen, “Marcia may be “primary”, unrelated to any underlying Attribution license http://creativecommons. took the bag upstairs into … the spare bedroom cognitive or psychiatric illness, the possibility of org/licenses/by/4.0/ where she kept things like cardboard boxes, an underlying dementia,7 particularly of the fron- To cite: Larner AJ. ACNR 2020;19(4):47 brown paper and string, and stuffed it into a totemporal type,8 should always be considered. drawer already bulging with other plastic bags A variant characterised by the hoarding of … to be sorted into their different shapes and animals has been called the “Noah syndrome”.9 he novelist Barbara Pym (1913-80) has sizes”. Elsewhere she has “a drawer full of new Diogenes of Sinope should not be confused been called the “Jane Austen of our Marks and Spencer nighties … All brand new with two other individuals of the same name. Ttimes” because of her acute and comedic and never worn”. Diogenes of Apollonia (fl. 5th century BC) observations of social mores. Her work was I suggest that these features merit the was a pre-Socratic philosopher who has been admired by Philip Larkin, yet I suspect that designation of syllogomania, a name given claimed as a pioneer in vascular anatomy today few have heard of her. Her novel Quartet to a syndrome of hoarding,2 sometimes also and physiology.10 Diogenes Laertius (fl. 3rd in Autumn (1977), set in London in the early termed “disposophobia”, often of items which century AD) was a biographer of the Greek 1970s, includes a character whose description may be deemed rubbish. Syllogomania may philosophers who, to my current knowledge, seems positively to invite clinical diagnosis.1 occur in isolation,3 or may be part of a broader has no connections with medicine, other than (Spoiler alert: what follows discloses some of neurobehavioural syndrome of neglect. to record anecdotes of Diogenes of Sinope. the plot features of Pym’s novel). As noted, despite her store of food, Marcia’s Miss Marcia Ivory is in her sixties, and diet is poor. She is noted to be thin, then emaci- REFERENCES thought somewhat peculiar by her fellow ated, clothes hanging on her, and eats little of office workers, Edwin, Letty, and Norman the salad she orders when the quartet meet at 1. Pym B. Quartet in Autumn. London: Picador Classic (they constitute the quartet of the book’s title). a restaurant for lunch. By the end of the novel [1977] 2005. Marcia lives alone in the house she previously she weighs “only six stone”. Social rules are also 2. Larner AJ. A dictionary of neurological signs (4th shared with her mother and which nobody transgressed, as when Marcia talks too loudly edition). London: Springer, 2016:309. else enters; she is “set in [her] isolation”. The at the restaurant, attracting the attention of 3. Zuliani G, Soavi C, Dainese A, Milani P, Gatti M. Diogenes syndrome or isolated syllogomania? Four hetero- room where her mother died has been left the other diners, and when she noisily returns geneous clinical cases. Aging Clin Exp Res untouched, used only by the cat, Snowy, until Letty’s milk bottle to her in the library. 2013;25:473-478. he also died there. In addition to self-neglect, Marcia’s house is 4. Larner AJ, Coles AJ, Scolding NJ, Barker RA. A-Z of Marcia keeps empty milk bottles in a shed neurological practice. A guide to clinical neurology also neglected: “The dust on the hall table told (2nd edition). London: Springer, 2011:191. in her garden, a “special and rather unusual its own story” (cf. the milk bottles) as well as 5. Clarke ANG, Manikar GO, Gray I. Diogenes syndrome. arrangement”, with over 100 of them stacked “other evidences of long neglect”. “On the bed A clinical study of gross neglect in old age. Lancet on shelves, and “spotlessly clean”. These cover there was still an old fur ball, brought 1975;i:366-368. “needed to be checked from time to time up by Snowy in his last days, now dried up 6. Assal F. Diogenes syndrome. Front Neurol Neurosci 2018;41:90-97. and occasionally she even went as far as like some ancient mummified relic of long 7. Cipriani G, Lucetti C, Vedovello M, Nuti A. Diogenes dusting them”. The bottles are all “United ago.” Marcia declines a neighbour’s offer to syndrome in patients suffering from dementia. Dairy” bottles, and Marcia is irritated to find cut her grass and spurns repeated visits from Dialogues Clin Neurosci 2012;14:455-460. one is of an “alien brand”, namely “County a social worker. 8. Finney CM, Mendez MF. Diogenes syndrome in fronto- Dairies”, and plans to return it to Letty who temporal dementia. Am J Alzheimers Dis Other Demen Whether the character of Marcia was based 2017;32:438-443. gave it to her at the office one day. Marcia on the author’s own observations, or simply 9. Saldarriaga-Cantillo A, Rivas Nieto JC. Noah syndrome: leaves other types of rubbish, such as “bottles the product of a creative imagination, is not a variant of Diogenes syndrome accompanied by animal of a certain kind … certain boxes and paper known. Nevertheless, for this clinician, the hoarding practices. J Elder Abuse Negl 2015;27:270-275. bags and other unclassified articles” on the symptoms described prompt diagnostic specu- 10. Crivellato E, Mallardi F, Ribatti D. Diogenes of Apollonia: 4 shelves at the local library, “a good place to lation, specifically of Diogenes syndrome, a pioneer in vascular anatomy. Anat Rec B New Anat dispose of unwanted objects”, although she sometimes known as “squalor syndrome”. 2006;289:116-120.

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Historical note: The Kayser-Fleischer ring

toms.3 Renal tubular defects are common, Kayser but seldom a presenting feature. Wilson later Bernhard Kayser (1869-1954) observed10 in JMS Pearce MD, FRCP noted ‘the K–F ring is inconstant,’1* though it is 1902 the occurrence of an annular ‘congenital Emeritus Consultant Neurologist, Department of Neurology, now said to be present in over 95% of patients [sic] greenish discoloration of the cornea’ Hull Royal Infirmary, UK. with neurological symptoms and over half of in a patient with nervous symptoms attrib- those presenting with liver disease.4 Rarely, uted incorrectly to multiple sclerosis (Figure Correspondence to: J.M.S. Pearce, 304 Beverley Road Anlaby, East it is found in non-Wilsonian cases of chol- 2). Kayser was a student at Tübingen, who Yorks, HU10 7BG, UK. estasis and biliary cirrhosis. The underlying received his doctorate from the University E: [email protected] cause is a genetic mutation in ATP7B gene on of Berlin in 1893. After a varied early career Conflict of Interest statement: None declared chromosome 13q 14-3 that encodes a plasma he became a physician in Brandenburg and membrane copper-transport protein. Bremen, and interested himself in ophthal- Date first submitted: 14/6/19 Wilson’s powerful reputation lay in his mology. He edited the essay section of Acceptance date: 24/6/19 Published online first:11/7/19 philosophical, clinical approach to a vexed Klinische Monatsblätter für Augenheilkunde. problem, and in his brilliance as a clinician and To cite: Pearce JMS, ACNR 2020;19(4);48-49 writer.5 A theatrically impressive if self-aggran- dising teacher, in his MD thesis (Edinburgh, 1911) – for which he received a gold medal – Wilson described his four patients and two Abstract previous cases,2 those of WR Gowers’ tetanoid Kinnier Wilson’s hallmark paper on chorea, 1888; and JA Ormerod’s obscure and ‘Progressive Lenticular Degeneration’ in 1912 fatal nervous symptoms, 1890. made no mention of the copper containing With no mention of the K-F ring, Wilson’s corneal rings which were described a decade thesis reported: earlier by Kayser and Fleischer. Their descrip- tion and practical neurological significance Progressive lenticular degeneration may in the setting of Wilson’s disease is described. be defined as a disease which occurs in young people, which is often familial but not congenital or hereditary; it is essentially and chiefly a disease of the The meticulous, time-consuming elicitation extrapyramidal motor system, and is of history and neurological signs was the characterised by involuntary move- hallmark of the era of classical neurology, ments, usually of the nature of tremor, Figure 2: Kayser’s paper 1902. which continued until the later part of the 20th dysarthria, dysphagia, muscular weak- century. There was no more exacting expo- ness, spasticity, and contractures with Fleischer nent than the disciplinarian Samuel Alexander progressive emaciation; with these A year later the ophthalmologist Bruno Kinnier Wilson, (1878–1937). Feared and may be associated emotionalism and Fleischer (1874-1965) said: I have recently had revered in equal measure he dominated certain symptoms of a mental nature. the opportunity to see two more such cases Queen Square Neurology for many years. A It is progressive, and, after a longer and to repeatedly examine them in detail. The fine example of his minutely observed clini- or shorter period, fatal. Pathologically result is in both cases completely consistent copathological observations is still known as it is characterised predominantly by with the Kayser case.11 (Figure 3.) Wilson’s disease. The Kayser Fleischer (K-F) bilateral degeneration of the lenticular Importantly, Fleischer recognised that the ring (Figure 1 below) although a clinical nucleus, and in addition cirrhosis of ring heralded a neurological disorder asso- rarity became recognised as ‘the single most the liver is constantly found, the latter ciated with cirrhosis, shown at autopsy. important diagnostic sign in Wilson’s disease’.1 morbid condition rarely, if ever, giving Fleischer worked at Tübingen, Geneva, and Yet herein lies a paradox. Although it had rise to symptoms during the life of the Berlin, obtaining his doctorate in Tübingen been described a decade earlier, Kinnier patient.6 in 1898 where he became assistant and later Wilson’s famous paper2 Progressive Lenticular associate professor of in 1909. Degeneration did not mention it. With measured disdain, Wilson discounted In 1920 he secured the chair of ophthalmology those instances of pseudosclerosis described at the University of Erlangen. by Westphal and Strümpell that were ‘non specific, with no evidence of liver disease, and heterogeneous’ – a view confirmed later by Greenfield.12 The Kayser-Fleischer ring is a golden to brown annular deposition of copper located in the periphery of the cornea (Descemet’s membrane) in one or both eyes.7 It first appears as a superior crescent, then develops inferiorly and becomes circumferential.8 Usually visible Figure 1: Kayser Fleischer ring. From: Walshe JM, ref. 8 to the naked eye with careful inspection, the Figure 3: Fleischer’s paper 1903. earliest stage is visible only by slit-lamp and Wilson’s disease is a rare autosomal-reces- gonioscopic examination. Corneal rings are The Kayser-Fleischer ring sive disease typically presenting in adoles- almost always present in neurological Wilson The Kayser-Fleischer rings, and less often cence. Fifteen to 20% of patients present with disease but not always in the pre-symptomatic capsular ‘sunflower cataracts’ accompany a liver disease, 70% with neuropsychiatric symp- and hepatic stages of the disease.9 characteristic dysarthria, fixed smile, drooling,

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rigidity and tremor.12 Wilson reported: be due to the accumulation of silver, but the putamen, thalami, and ; and a Gerlach and Rohrschneider13 in 1934 showed characteristic ‘giant panda sign.’ With mouth often held open, and a that they contained copper granules. Many Early treatment by copper chelation stereotyped smile, or, if not laughing or case reports followed, confirming both their using penicillamine, trientine hydrochloride smiling, a vacant or fatuous look, the copper content, and Wilson’s meticulous clin- and zinc is effective but in about 10-30% patient sits and leans to one or the other ical observations. A fundamental discovery causes serious neurological deterioration. side, or back, all four limbs agitated by was Cumings’ proof in 1948 of copper over- Tetrathiomolybdate that inhibits copper tremor, mostly quick and rather fine…5,2 load in both brain and liver.14 In the same absorption from the gut and cellular uptake year Holmberg and Laurell showed a copper of free copper is effective and has fewer side The tremor becomes coarse, irregular, prox- binding globulin, named caeruloplasmin.15 effects. When treatment is started, copper is 16 imal, with a ‘wing beating’ appearance. Low caeruloplasmin levels (<0.20 g/L) allow slowly removed from both the lens capsule 9 Dystonia can be focal or generalised. A trem- the diagnosis of Wilson’s disease. Additional and the corneal rings: a sign useful in evalu- or-rigidity syndrome (‘juvenile Parkinsonism’) tests include raised 24 hour urinary copper ating the efficacy of treatment. should raise suspicion of Wilson’s disease, excretion, and high liver biopsy copper especially in children. content. MR imaging is not diagnostic but * He later said: I have seen the ring only three times. Proc R Initially the K-F rings were thought to typically shows bilateral T2 hyperintensity of Soc Med. 1934 Jan; 27(3):297-298.

REFERENCES

1. Sullivan CA, Chopdar A, Shun-Shin GA. Dense Kayser-Fleischer ring in asymptomatic 9. Scheinberg IH, Sternlieb I. Wilson’s Disease. Vol XXIII Major Problems in Internal Medicine. Wilson’s disease (hepatolenticular degeneration). Br J Ophthalmol 2002;86(1):114. Philadelphia. WB Saunders 1984. 2. Wilson SAK. Progressive Lenticular Degeneration: A familial nervous disease associated with 10. Kayser B. Über einen Fall von angeborener grünlicher Verfärbung des Cornea. Kin.Mbl. cirrhosis of the liver. Brain 1912;34:295-509. Augenheilk. 1902;40(2):22-25. 3. Taly AB, Meenakshi-Sundaram S, Sinha S, Swamy HS, Arunodaya GR. Wilson disease: 11. Fleischer B. Zwei weitere Fälle von grünlicher Verfärbung der Kornea. Klinische Monatsblätter description of 282 patients evaluated over 3 decades Medicine (Baltimore) 2007;86(2):112. für Augenheilkunde, Stuttgart 1903;41(1):489-491. 12. Pearce JMS. Wilson’s disease. J Neurology Neurosurgery Psychiatry 1997;63:174. 4. Mak CM, Lam CW. Diagnosis of Wilson’s disease: a comprehensive review. Critical Reviews in Clinical Laboratory Sciences. 2008;45(3):263-290. 13. Gerlach, W, Rohrschneider W. Besteht das Pigment des Kayser-Fleischerschen Hornhautringes aus Silber? Klin. Wschr 1934;13:48-49. 5. Pearce JMS. Wilson’s Disease. In: Neurological Eponyms. edited by Peter J Koehler, George W Bruyn, John MS Pearce. Oxford, New York. OUP 2000. Pp. 366-371. 14. Cumings JN. The copper and iron content of brain and liver in normal and in hepato-lentic- ular degeneration. Brain 1948;71:410-415. 6. Compston A. Comment on: Progressive lenticular degeneration: a familial nervous disease 15. Holmberg CG, Laurell C-B. Investigations in serum copper. II: Isolation of the copper associated with cirrhosis of the liver, by S. A. Kinnier Wilson. Brain. 2009 Aug;132(Pt containing protein, and a description of some of its properties. Acta chem. scand 8):1997-2001. 1948;2:550-556. 7. Harry J, Tripathi R. Kayser-Fleischer ring A pathological study. Brit J Ophthal 1970;54:794. 16. Walshe JM. Diagnostic significance of reduced serum caeruloplasmin concentration in neuro- 8. Walshe JM. The Eye in Wilson Disease. Q J Med 2011;104: 451-3. logical disease. Mov Disord. 2005;20(12):1658-1661.

Stroke One Day Course: EDINBURGH Advanced Stroke Neuroimaging COURSE 2021 28th October, 2020; London and Online This short course offered by UCL Queen Square Institute of Monday 22nd March to Friday 26th March 2021 Neurology will give an overview of using neuroimaging and Venue: Hilton Edinburgh Carlton, mechanical thrombectomy to treat people who have had a stroke. North Bridge, Edinburgh, EH1 1SD This course will outline methods of quantifying the impact of the This annual course aims to provide up-to-date information on the theory and stroke using advanced imaging techniques – from penumbral and practice of sleep medicine including the technological aspects of measuring core infarct size through to methods of imaging recovery from and monitoring sleep. The course is aimed at all professionals involved in the diagnosis and treatment of sleep disorders. stroke. It will also cover the more familiar aspects of imaging stroke such as using CT and MRI based modalities to evaluate infarcts and Proposed Guest Speakers Dr R Riha - Edinburgh, Dr M Czisch - Munich, Dr I Morrison - Dundee, haemorrhages. Prof J Ellis - Newcastle, Dr A Johal - London, Prof B Kotecha - London, Dr Michelle Ramsay - London, Prof G Mayer - Germany, By the end of this course you should be able to: Prof D Newby - Edinburgh, Prof D Skene - Surrey, • Select the appropriate imaging modality to evaluate a stroke Dr Marisa Bonsignore – Italy, Dr D Urquhart - Edinburgh, case Prof W DeBacker - Antwerpen, Prof Jean-Louis Pepin – France, • Identify the affected artery on the basis of a clinical stroke Prof T Wetter – Ingolstadt, Dr Brian Kent – Ireland, syndrome Dr Dipansu Ghosh – London, Dr E Hill – Edinburgh, • Evaluate the current evidence for endovascular treatment and Prof Winfried Randerath - Germany, Prof Federica Provini – Italy common complications of this treatment CBT-I (Basic) Course Examples of lecture topics: • Ischaemic stroke Saturday 27th March to Sunday 28th March 2021 • Haemorrhagic stroke Speaker: Prof Jason Ellis • Introduction to imaging for stroke The aim of this course is to provide the relevant information on how to identi- • Endovascular treatment fy, assess, and diagnose insomnia, and with peer supervision, manage cases using the principles of Cognitive Behaviour Therapy for Insomnia (CBT-I). Speakers will be experts in their fields from Queen Square and Imperial College London. Further Information and Registration details please contact: https://www.ucl.ac.uk/short-courses/search-courses/ Mrs Lisa Wood, Sleep Consultancy Ltd advanced-stroke-neuroimaging Tel: +44 (0)7555 796272 Early Bird Online Live Stream: £100.00 Email: [email protected] Website: www.sleepconsultancyltd.co.uk Early Bird: £150.00

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BNPA 2020

Conference details: 5-6 March, 2020, King’s Place, London, UK. Report by: Dr Camilla Nord, Department of Psychiatry, University of Cambridge, UK. Conflict of interest statement:None declared.

his year’s BNPA Annual Meeting took Next, we heard about psychotic day was Professor Essi Viding (UCL), who place on March 5th and 6th, at King’s phenomena from three very different view- walked us through a comprehensive over- TPlace in London. It was one of our points, in a session chaired by Tim Nicholson view of developmental psychopathy, and largest meetings to date, made up of dele- and Vaughan Bell. Professor Paul Fletcher in particular the genetic and neural basis gates ranging from young trainees to esteemed (Cambridge) began with an introduction of conduct disorder traits. Professor Viding BNPA members. to predictive coding models of psychosis, showed compelling evidence for neural differ- a hugely influential perspective that places ences in the processing of both negative Day 1: Psychedelics, psychosis, psychosis in the Bayesian brain framework, and positive affective and social information psychopathy— and prizes theorising that disruptions in the balance of in children with heightened symptoms of The meeting began with a moving BNPA prior expectations and sensory evidence can conduct disorder, including the interesting Medal Lecture, delivered by Professor Andrew manifest as hallucinations and delusions. Dr finding of reduced laughter contagion in boys Lees (Professor of Neurology at University Dominic Ffytche (King’s/SLaM) continued this at risk for psychopathy. College London and the National Hospital session by asking us to begin to examine for Neurology and Neurosurgery, Queen ‘perceptual phenomena at the margins of The BNPA evening reception then took Square). Professor Lees spoke about ‘Soulful hallucination’ in neurodegenerative disease; place at the October Gallery, surrounded by Neurology’, walking us through his training his work demonstrates that visual hallucina- beautiful art representing the trans-cultural as a young neurologist who found unlikely tion phenomena are an important marker of avant-garde, including a piece by none other inspiration in William S. Burroughs. This was clinical prognosis, and should be tracked as than William S. Burroughs, with whom we ‘altamirage’: his unusual interest in Burroughs the disease progresses. Lastly, we heard about had started our day via Prof. Lees’ talk. At the spurred him to explore clinical ideas that were the applied work of Professor Dan Freeman reception, we awarded the first-ever BNPA (at the time) off-the-beaten-path, ideas which (Oxford), with whom we got to experience Lifetime Achievement Award to our second became part of his enormous contribution to some of his group’s virtual reality applications, BNPA president, Professor Maria Ron, the first neurology and Parkinson’s disease. an exciting prospect for psychosis treatment, female neuropsychiatrist in the UK (and likely The first session of the day was on psyche- and which also seems effective for other internationally!). delic drugs and neuropsychiatry: then and mental health conditions, such as phobias: now, chaired by David Okai and Camilla in a game context, patients are much more Day 2: Pleasure, Parkinson’s, and Nord. The session began with an historical willing to directly encounter their fears, greatly perturbing the brain with overview of psychedelics in psychiatry, given helping exposure therapy. neuromodulation by author and cultural historian Mike Jay, Following some excellent poster pres- The second day of the BNPA meeting began who upended the notion that psychedelics entations by members, we gathered back to with a talk by Professor Morten Kringelbach for psychiatry began with LSD in the mid-20th hear the three Lishman Prize lectures by Drs. (delivered virtually as the speaker was self-iso- century. Instead, the story he recounted began Akshay Nair (UCL), Susannah Pick (King’s), lating), chaired by our President, Valerie with a much earlier history of mescaline use and Jonathan Rogers (UCL), chaired by Boyd Voon. Professor Kringelbach (Oxford) told around the world. Professor Valerie Curran Ghosh and Thomas Cope. First, Dr Rogers us his about his extensive work on the neuro- (UCL), world-renowned for her psycho- comprehensively reviewed catatonia in a biology of pleasure, and its subtypes, including pharmacology research, spoke next about large demographic, clinical, and laboratory hedonia and eudaimonia. His more recent some of her most recent work on the cogni- dataset, finding no evidence for a systemic work takes a network approach, creating a tive and neural mechanisms of cannabis. A inflammatory response in catatonia, though dynamical systems model to better understand powerful message was that the two subcom- interestingly catatonia was associated with specific brain states. ponents of cannabis (THC and cannabidiol) low iron levels. Next, Dr Nair won the prize for Next, we had a highly participatory clinical may have opposing properties when it comes his work in Huntington’s disease, finding aber- case discussion, chaired by Annette Schrag to addiction: THC potentially increasing, and rant striatal value representation in HD gene and Marco Mula, on legal issues associated cannabidiol decreasing the addictiveness of carriers, which he showed 25 years before with impulse control disorders in Parkinson’s cannabis. Over the past few decades, the ratios disease onset. Lastly, Dr Pick presented work disease: Andrew Lees and David Okai of these two subcomponents have changed in on interoception and state dissociative experi- recounted some of the recent cases in legal street cannabis; today, cannabis contains a far ences in functional neurological disorders, history concerning whether or not Parkinson’s higher proportion of THC. Following on from applying an experimental model of dissoci- disease (or treatment) could explain particular this highly topical research, our final speaker ation (10 minutes of mirror gazing) for the criminal behaviours. of the session was a scientist at the forefront of first time in FND, and finding that increased Dr Rimona Weil (UCL) completed the psychedelic treatment development, Dr Robin dissociation was associated with lower intero- session, presenting her extraordinary research Carhart-Harris (Imperial). Dr Carhart-Harris ceptive accuracy. on visual disturbances in Parkinson’s disease, spoke about his recent empirical and theor- The interdisciplinary clinical case discus- including the finding that measuring the iron etical advances in treating major depression sion, chaired by Thomas Cope, was presented content of brain tissue can track dementia with psychedelics (in particular psilocybin). by Drs. Esther Coutinho and Tom Pollak, who progression in patients with Parkinson’s; this He put forward a theory that single transform- presented fascinating examples of two quite finding has now been widely reported by the ative experiences like psychedelics can alter distinct cases of autoimmune psychosis from media. expectations of the world, causing universal their jointly-run autoimmune neuropsychiatry Professor Peter Brown began our session on changes in the cognitive processes altered by clinic, highlighting the variety of ways auto- neuromodulation (chaired by Dr Voon and mental health disorders. An upcoming study immune psychosis can present and progress, former President of the BNPA Chris Butler) of his will put this theory to the test in a head- with recommendations for improved diag- with updates on closed-loop deep brain stimu- to-head trial comparing psilocybin and SSRIs nostic and screening criteria. lation in Parkinson’s disease: that is, brain for depression treatment. The final and keynote speaker of the stimulation that ‘listens and responds’ to the

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surrounding area, rather than delivering a the cortex. Finally, Professor Tim Denison even amongst those of us with mental imagery, static level of stimulation to the brain at all (Oxford) gave us a preview of what to expect there exists a long continuum for ease and times. Dr Butler (Oxford) next told us the in the future for neuromodulation from the specificity of visual imagination). exciting story of focused ultrasound stimu- perspective of an engineer, including how The BNPA Annual Meeting 2020 was lation, which he and his team have been best to translate these exciting techniques to absolutely a success, and we thank all our developing in healthy subjects. A key message real-world patients. wonderful members and delegates for such was that the potential applications of this Our final speaker of the conference was an excellent conference. We were lucky to be extraordinarily focused, non-invasive tech- Professor Adam Zeman (Exeter), who told us one of the last scientific meetings to go ahead nique are astounding – but we must first better about his discovery (or rather, re-discovery before social distancing measures were put in understand its neural and cognitive effects. Dr after Galton in 1880) of aphantasia: that in Nir Grossman (Imperial) then told us about a the population, there exist people who do place as a result of the COVID-19 pandemic second non-invasive deep brain stimulation not possess a ‘mind’s eye’ – who cannot – so this year we feel particularly grateful to technique that he has developed, temporal voluntarily evoke mental imagery. Initially, this have heard our incredible line-up of speakers interference, which exploits the properties of condition was thought to be quite rare, but it is and facilitate the meeting of so many scientists electric fields to drive activity now known that many members of the popula- and clinicians who represent the future of in deep brain structures without effects on tion have varying degrees of aphantasia (and neuropsychiatry.

These dates are correct as we go to press. Please see www.acnr.com/event, or check with the organisers for any changes due to the COVID-19 pandemic. Please send diary listings for our website and next issue to [email protected]

SEPTEMBER ONLINE Effective multidisciplinary working – free online Unravelling Strength and Conditioning for Therapists course from the MNDA 17-18 October, 2020; Whittington Hospital, London ONLINE Research for clinicians: Making clinical work your 28 September, 2020 T. 01332 254679 research With Professor Barbara A. Wilson, OBE https://www.open.edu/openlearncreate/course/view. E. [email protected] 4 September, 2020 php?id=4358 https://www.ncore.org.uk/Website_Event_List https://assbi.com.au/ASSBI-Webinars/ ONLINE Sleep Medicine: Sleep-disordered breathing and Neurological Upper Limb for Occupational Therapists ONLINE Clinical of Vision - Virtual sleep-related movement disorders (CPD) 19 October & 16 November, 2020; Derby, UK 7 September, 2020 29 September – 3 November, 2020; Oxford University T. 01332 254679 https://checkout.moorfields.nhs.uk/product? E. [email protected] E. [email protected] catalog=CR809-2002STEV https://www.conted.ox.ac.uk/about/sleep-medicine https://www.ncore.org.uk/Website_Event_List ONLINE Explain Pain Parkinson's Advanced MasterClass 38A – Module 1 MS Basecamp – in person 8-9 September, 2020 29-30 September, 2020; Halifax Hall, Sheffield University 19-20 October, 2020; Sheffield, UK T. 01332 254679 Campus, UK https://multiplesclerosisacademy.org/events/ E. [email protected] https://parkinsonsacademy.co/courses/ ms-basecamp-1/ https://www.ncore.org.uk/Website_Event_List advanced-masterclass-course/ ONLINE & IN PERSON Advanced Stroke Imaging Course Where innovation meets evidence: The cutting edge of MS Leadership MasterClass – Module 2 28 October, 2020; London, UK Neurologic Music Therapy and evidence-based practice in 30 September-3 October, 2020 E. [email protected] https://onlinestore.ucl.ac.uk/conferences-and-events/ clinical settings https://multiplesclerosisacademy.org/ faculty-of-brain-sciences-c07/ucl-institute-of- September 10, 2020; 9-5pm; London, UK ONLINE International Virtual Cerebral Amyloid Angiopathy neurology-d07/d07-stroke-one-day-course-advanced-stroke- https://chilternmusictherapy.co.uk/events/conference Conference neuroimaging-28102020 ONLINE MS Virtual 2020 – 8th Joint ACTRIMS-ECTRIMS 30 September-1 October, 2020 meeting https://icaaconference.org/ NOVEMBER 11-13 September, 2020 OCTOBER ONLINE Cognitive Behavioural Therapy for Insomnia https://msvirtual2020.org/ Masterclass ONLINE Controversies in Neurology 2-3 November, 2020; Oxford, UK Epilepsy in the elderly: tracing the origins, treating the 29 October-1 November, 2020 www.ndcn.ox.ac.uk/study-with-us/online-programme-in- disease. webinar led by Heather Angus-Leppan, with global http://cony.comtecmed.com/ sleep-medicine/short-courses/masterclass-in-cbt-i, E. sleep- faculty MS Intermediate MasterClass 11 – Module 1 [email protected] 16 September,2020; 6-7pm 7-9 October, 2020; Sheffield,UK www.exploring-connections.com MS Advanced MasterClass 12 – Module 1 https://multiplesclerosisacademy.org/events/ 4-6 November, 2020; Sheffield, UK ONLINE Neuropsychiatry 2020: Joint International ms-intermediate-masterclass-11-module-1/ https://multiplesclerosisacademy.org/events/advanced- Conference of Faculty of Neuropsychiatry and International 4th ILAE British Branch Epilepsy Neuroimaging Course masterclass-12-module-1/ Neuropsychiatry Association 8-10 October, 2020; Chalfont Centre for Epilepsy, UK ONLINE Neurology Symposium 17-18 September, 2020 E. [email protected] 5 November, 2020, Virtual www.rcpsych.ac.uk https://bit.ly/32s6PAx https://events.rcpe.ac.uk/neurology-0 Mobilisation of the Neuroimmune System Posture and Balance as it relates to Selective Control of the Naidex 46 15-16 September, 2020; Derby, UK Upper Limb 9-10 November, 2020; Birmingham, UK T. 01332 254679 10-11 October, 2020; Dublin, Ireland www.naidex.co.uk/?PtnACNR E. [email protected] T. 01332 254679 MS Service Provision in the UK 2020: Raising the Bar E. [email protected] https://www.ncore.org.uk/Website_Event_List 12-13 November, 2020; Birmingham, UK https://www.ncore.org.uk/Website_Event_List Parkinson's Foundation MasterClass https://multiplesclerosisacademy.org/events/ 17-19 September, 2020; Halifax Hall, Sheffield University Skill Acquisition in Stroke Rehabilitation ms-service-provision-in-the-uk-2020-raising-the-bar/ 10 October, 2020; Leamington Hospital, Warwick, UK Campus, UK ONLINE Virtual NECTAR 2020: The Network for European T. 01332 254679 https://parkinsonsacademy.co/courses/ CNS Transplantation and Restoration foundation-masterclass-course/ E. [email protected] 19-20 November, 2020 https://www.ncore.org.uk/Website_Event_List ONLINE Sleep Medicine: The Physiological Basis of Sleep https://nectar-eu.com/ Management of Spasticity in the Upper Limb following (CPD) ONLINE ‘How to’ evaluate mainstream and emerging tech- Stroke 23-25 September, 2020; Oxford University nologies used for executive function support after brain 12 October, 2020; Derby, UK E. [email protected] injury T. 01332 254679 www.conted.ox.ac.uk/about/sleep-medicine With A/Professor Libby Callaway and Professor Grahame E. [email protected] Simpson ONLINE Parkinson's UK Research Virtual Conference 2020 https://www.ncore.org.uk/Website_Event_List 27 November, 2020 24-25 September, 2020 ABN Annual Meeting https://assbi.com.au/ASSBI-Webinars/ https://www.parkinsons.org.uk/events/ 16 October, 2020, preceded and succeeded by 4 Thursday Diary dates continue on page 53 research-conference-2020 night sessions ONLINE British Neurotoxin Network 2020 Virtual Annual https://www.theabn.org/page/virtual_meeting_2020 DECEMBER Meeting 5th Clinical update Sleep: International Conference 2020 Alzheimer’s Advanced Masterclass – Module 1 Friday 25 September, 2020 16 October, 2020, London, UK 3-4 December, 2020; Sheffield, UK https://mondale-events.co.uk/event/ https://www.sleepsociety.org.uk/event/5th-clinical-up- https://dementiaacademy.co/events/ british-neurotoxin-network-2020-annual-meeting/ date-sleep-international-conference-2020/ alzheimers-masterclass-1-module-1/

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6th congress of the European Academy of Neurology (EAN)

Conference details: 23-26 May, 2020. Conference streamed virtually. Report by: Nicole Lichtblau, Neurology Department, St George’s University Hospital, London and Angelika Zarkali, Dementia Research Centre, University College London, London. Conflict of interest statement:None declared.

rom 23rd to 26th May 2020 the European showing that the use of fMRI, EMG and ERP in but also preventing progressive disabilities for Academy of Neurology (EAN) held its 6th patients with disorders of consciousness was patients suffering from long-term conditions F congress, for the first time fully streamed able to help distinguish minimally conscious- such as epilepsy and migraine. online. Originally planned to take place in ness states from vegetative state and that The EAN issued a statement this year Paris, the planning committee chose to go their use can facilitate basic communica- which addresses the need to identify and virtual rather than cancelling the congress in tion and interaction with aphasic, non-com- treat Obstructive Sleep Apnoea early as it light of the ongoing COVID-19 pandemic – a municating minimally conscious patients. He comes with an increased risk for stroke, and decision they can only be congratulated on. further emphasised that professionals should concludes that CPAP might offer some benefit With over 2500 presentations and posters and no longer use the term vegetative state due in primary and secondary prevention in those a record-breaking 42,500 participants from to its negative perceptions and associations patients. Furthermore, stroke survivors are around the world this had been a huge organi- in the public, and rather speak of a state at higher risk of developing sleep disorder sational and technical effort that was mastered of unresponsive wakefulness. The EAN also breathing and sleep-wake-disorders in general, exceptionally well. Symposia were held in issued updated guidelines which reflect these which if not diagnosed can cause increased combination with pre-recorded lectures and recommendations.1 disability and future stroke risk.2 live “question and answer” sections. As in In the field of neurodegenerative disor- The congress also saw multiple presenta- previous years there was a large number of ders, many presentations focused on new tions addressing the positive effects of sleep-ac- workshops and teaching courses as well which diagnostic approaches and use of biomarkers tivity regulation in preventing and ameliorating had to be re-conceptualised to fit the virtual to facilitate early diagnosis and risk stratifica- symptom progression of dementia, ranging congress format but nevertheless have been tion. This includes skin biopsies investigating from presentations explaining the presumed a great source of education throughout this for α-synuclein depositions in small nerve molecular mechanism behind that effect, e.g. congress, despite no direct hands-on-experi- fibres in early stages of suspected Parkinson’s the role of the glymphatic pathway clearing ence. We saw excellent courses on caring for disease, wider use of CSF amyloid and tau the interstitial space from amyloid, to presenta- pregnant women with neurological diseases, analysis as well as neuroimaging biomarkers tions providing evidence that improved sleep- examination of vertigo, acute neurology and in the early diagnosis of Alzheimer Dementia, wake-cycles and increased daytime activities many others. Participants were able to further which in the long view will also require health- can result in better cognitive performance in test their knowledge in the Brain challenge care systems to adapt to facilitate those diag- standard neuro-psychometric testing just by quiz, socialise through the virtual hub or try nostic pathways. using specific lighting systems in care homes, out the yoga classes. Focus was also placed on the need for for example. Throughout the conference the unifying trandiagnostic research in neurodegeneration; Besides sleep disorders we have known spirit of the neurology community during lock- many patients with dementia have more than for many years that multiple modifiable risk down has been one of inspiration, flexibility, one pathology on brain biopsy (for example factors, such as weight, hypertension and optimism and collaboration and all presenters vascular or Lewy body pathology frequently smoking, contribute largely to a person’s stroke took the challenge of preparing their talks at occurs in patients with sporadic Alzheimer’s risk. Reviewing multiple large studies such as high standards and mastered the technical disease). This multi-pathology comorbidity in the INTERSTROKE study and Framingham hurdles. dementia along with newly defined syndromes study, David Tanne concluded that up to 90% The overarching theme this year “Time such as Primary Age Related Tauopathy of strokes are preventable by targeting those for Action. Predict – Prevent – Repair” was and Limbic predominant age-related TDP-43 modifiable risk factors early, and since stroke reflected in a huge number of brilliant talks encephalopathy, pose an additional challenge is a major risk factor for subsequent develop- covering all areas of neurology. Given the in the accurate diagnosis of dementia. More ment of dementia, up to a third of dementia enormous amount of presentations and topics accurate, multi-source biomarkers and deep cases could be likewise prevented. covered during the congress we can only clinical phenotyping as well as research into On a more experimental, still pre-clinical give a brief and incomplete summary. But for differential diagnosis of different dementia note, Hugues Chabriat presented results from interested EAN members webcasts can still be syndromes is needed to address this and other research groups who made some prom- viewed on demand on the EAN webpage. facilitate the development of effective disease- ising advances in the field of immunisation specific treatments. to prevent small vessel damage in transgenic “Predict” A very interesting teaching course on mice expressing mutant Notch3, which Right at the start of the conference, Yann “Neurology by night” highlighted the import- could in future be of relevance in preventing LeCun – computer scientist by background – ance of adequate diagnosis of idiopathic REM brain damage and disability in patients with gave an inspiring overview during his opening sleep behavioural disorders (iRBD) as they CADASIL. Chabriat received the Brain Prize lecture on how artificial intelligence and in have a highly predictive value of affected this year for his and his team’s efforts in particular deep learning has revolutionised individuals developing synucleinopathy in the researching the genetic causes of CADASIL. the way machines can learn, and could be future, up to 90% after 14 years, making iRBD Multiple studies thematising adequate and used hopefully more widely in the future to a possibly better and more specific prodromal timely epilepsy management were presented. support clinicians making early diagnoses and symptom than depression, hyposmia or consti- Some of the take-home-messages were that in predictions – for example by more accurate pation. status epilepticus early treatment is crucial, imaging reporting augmented by artificial benzodiazepines at adequate doses should intelligence. “Prevent” be used first-line followed by anti-epileptic A further hot topic of this year’s congress Prevention, very often in the form of secondary drugs (AED) such as Levetiracetam, Sodium focused on predicting outcomes of patients prevention, plays a major role in caring for Valproate or Phenytoin, which have been in a prolonged disorder of consciousness. patients with neurological conditions. So not found to be equally effective in status treat- Steven Laureys presented results from his surprisingly many of this year’s talks focused ment (Concept, EcLIPSE, ESETT-trial 2019); research group in the Brown-Séquard lecture on better prevention of stroke and dementia, seizures related to auto-immune encephalitis

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respond poorly to AED but warrant early and contralateral cathodal transcranial and handing over the EAN presidency offi- immunosuppressant treatment; and in treat- magnetic stimulation, which achieved remark- cially to Claudio Bassetti, who has been acting ment refractory epilepsy surgical treatment able improvement in verbal semantic associ- President since 2019, following Franz Fazekas, should be considered as early as 5 to 7 years ation and fluency. who has been EAN President since 2018. after first diagnosis, as this is associated with better outcomes in terms of seizure-freedom Further congress highlights and less complication rates from surgery. This year’s congress also addressed the chal- The next EAN congress will be held from Two studies have investigated the positive lenges in caring for patients with severe neuro- 19-22 June, 2021 in Vienna. effect of the complement inhibitor Ecilizumab logical disorder and long-term disability and in treatment of generalised Myasthenia stressed the importance of implementing Gravis (REGAIN study) and on relapse rate collaborations with associated specialties of in Neuromyelitis optica spectrum disorders psychiatry and palliative care medicine to (PREVENT study). allow our patients best possible care where we References: cannot cure them. 1. Kondziella D, Bender A, Diserens K, van Erp W, “Repair” Preliminary data of the European registries Estraneo A, Formisano R, Laureys S, Naccache L, Ozturk S, Rohaut B, Sitt JD, Stender J, Tiainen M, Rossetti Frustratingly, in the third category of the over- collating prevalence of neurological compli- AO, Gosseries O, Chatelle C. European Academy of arching theme – repair – not many advances cations in patients with COVID-19: Main neuro- Neurology guideline on the diagnosis of coma and other have been made and neurological disorders logical manifestations that have been reported disorders of consciousness. Eur J Neurol, 2020;27: 741-756. doi:10.1111/ene.14151. remain widely untreatable and neuronal are anosmia, headaches and delirium, but 2. Bassetti CLA, Randerath W, Vignatelli L, Ferini‐Strambi damage irreversible. also increased stroke risk due to hyperthrom- L, Brill AK, Bonsignore MR, Grote L, Jennum P, Leys D, There have been some studies addressing botic state, and some rarer cases of encephal- Minnerup J, Nobili L, Tonia T, Morgan R, Kerry J, Riha advances in neuro-rehabilitation including itis and neuropathy. R, McNicholas WT and Papavasileiou V. EAN/ERS/ESO/ ESRS statement on the impact of sleep disorders on risk one remarkable study by Mehanna and The conference closed with congress high- and outcome of stroke. Eur J Neurol. 2020. doi:10.1111/ colleagues on Primary Progressive Aphasia lights, announcement of tournament winners ene.14201.

Encephalitis Conference Edinburgh Sleep Medicine Course 2nd International Conference on Neuro-Rehabilitation 8 December, 2020; Royal College of Physicians, London, UK 22-25 March, 2021, Edinburgh, UK (NEURAM 2021) www.encephalitis.info/conference https://www.sleepconsultancyltd.co.uk/courses/ 27-28 May, 2021; Balaclava, Mauritius Dizziness and Balance Workshop edinburgh-sleep-medicine/ T. 0203 238 8683 8 December, 2020; London, UK Parkinson’s Advanced MasterClass 40.1A E. [email protected] www.dizzinessandbalanceworkshop.co.uk 23-24 March, 2021; Sheffield, UK https://zibrant.eventsair.com/neuram-2020/neuram ONLINE Virtual 31st International ALS/MNDSymposium https://parkinsonsacademy.co/events/ 9-11 December, 2020 UK Neuro-Ophthalmology Society (UKNOS) Annual JUNE https://symposium.mndassociation.org/ Meeting Alzheimer’s Mod 2 25 March, 2021; London, UK 8 June, 2021; Sheffield, UK JANUARY Festschrift for Dr Gordon Plant https://dementiaacademy.co/events/ Queen Square Multidisciplinary Neuro-oncology Teaching 26 March, 2021; London, UK Course: Benign & Malignant Tumours www.UKNOS.com MS Foundation MasterClass 13.1 13 January, 2021, London, UK 9-11 June, 2021; Sheffield, UK https://www.ucl.ac.uk/ion/study/queen-square-courses/ APRIL https://multiplesclerosisacademy.org/events/ queen-square-multidisciplinary-neuro-oncology 2021 Spine Society of Australia 32nd Annual Scientific 8th EAN Congress 2021 -teaching-course Meeting June 19-22, 2021; Vienna, Austria 9-11 April, 2021; International Convention Centre, Sydney Recognising Post Traumatic Stress Disorder www.ean.org/ www.dcconferences.com.au/ssa2021 18 January, 2021; Derby, UK E. [email protected] T. 01332 254679 MS Intermediate MasterClass 11.2 E. [email protected] 21-22 April, 2021; Sheffield, UK 6th Pacific Rim Conference: #headstogether2021, combined https://www.ncore.org.uk/Website_Event_List https://multiplesclerosisacademy.org/events/ INS, ASSBI, CCN Hybrid Conference ms-intermediate-masterclass-11-module-2/ 30 June-3 July, 2021, Melbourne, VIC, Australia FEBRUARY https://www.mersevents.com/6th-pacific-rim-conf Neuropharmacy 2 - Mod 2 Exploring Functional Patterns of Movement 23-24 April, 2021; Sheffield, UK 1 February, 2021; Derby, UK https://neurologyacademy.org/events/ JULY T. 01332 254679 neuropharmacy-masterclass-2-module-2/ NR-SIG-WFNR Conference E. [email protected] 5-6 July, 2021; VIC, Australia https://www.ncore.org.uk/Website_Event_List 2nd Academic and Clinical Symposium in Cognitive- Communication Disorders (CCDs) https://www.mersevents.com/18th-nr-sg-wfnr Balance Rehabilitation 29-30 April, 2021, Manchester, UK 23-24 February, 2021; Derby, UK https://m.mersevents.com/2nd-CCD-Symposium.html SEPTEMBER T. 01332 254679 E. [email protected] MAY VasCog 2021 7-11 September, 2021; Newcastle University, UK https://www.ncore.org.uk/Website_Event_List British Neurotoxin Network Paediatric Workshop on E. [email protected] Assessment and Ideas for the Treatment of Thorax in Adults Ultrasound Guided Injection with Neurological Damage 8 May, 2021; London, UK www.vas-cog.com/vascog-2020/ 26 February, 2021; Derby, UK https://mondale-events.co.uk/event/british-neuro- MS Intermediate MasterClass 14.1 T. 01332 254679 toxin-network-paediatrics-ultrasound-workshop/ 15-17 September, 2021; Sheffield, UK E. [email protected] MS Advanced 12 - Mod 2 https://multiplesclerosisacademy.org/events/ https://www.ncore.org.uk/Website_Event_List 13-14 May, 2021; Sheffield, UK ILAE British 2021 Annual Scientific Meeting https://multiplesclerosisacademy.org/events/ MARCH 28-30 September, 2021; Cardiff, UK advanced-masterclass-12-module-2/ Palliative Care 2021 http://ilaebritish.org.uk/ Dementia MasterClass 7 11-12 March, 2021; Sheffield, UK OCTOBER https://neurologyacademy.org/courses/palliative-care/ 18-19 May, 2021; Sheffield, UK https://dementiaacademy.co/events/ World Congress of Neurology WCN 2021 Management of Spasticity in the Upper Limb following dementia-masterclass-7/ 3-7 October, 2021; Rome, Italy Stroke https://2021.wcn-neurology.com 15 March, 2021; Derby, UK MS Advanced MasterClass 12 – Module 2 – PREVIOUS T. 01332 254679 MODULE 1 REQUIRED EAN Regional Teaching Course E. [email protected] 20-21 May, 2021; Sheffield, UK 4 - 6 October 2021, Liverpool, UK https://www.ncore.org.uk/Website_Event_List https://multiplesclerosisacademy.org/events/advanced- https://www.ean.org/learn/educational-events/region- masterclass-12-module-2/ al-teaching-courses/rtc-in-liverpool-uk MS Foundation MasterClass 10.2 18-19 March, 2021; Sheffield, UK KetoCollege 2021 Parkinson’s Foundation MasterClass 41F https://multiplesclerosisacademy.org/events/ 25-27 May, 2021; West Sussex, UK 12 – 13 October, 2021; Sheffield, UK ms-foundation-10-module-2/ www.mfclinics.com/keto-college/ketocollege-uk-2020/ https://parkinsonsacademy.co/events/

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4th Frontiers in Traumatic Brain Injury (TBI) Conference

Conference details: 16 June, 2020. Conference streamed virtually. Report by: Juliet Reid, ST6 Rehabilitation, Leeds. Conflict of interest statement:None declared. Published online: 5/8/20.

n the 16th June, over 1000 people biomarkers to understand severity of injury Molero Plaza, a researcher at the Karolinska gathered online for the 4th Frontiers to the brain. Henrik Zetterburg, Professor Institute, discussed her team’s work using Oin Traumatic Brain Injury (TBI) of at the University of registries of the entire Swedish population, Conference. Although COVID-19 necessitated Gothenburg and University College London which demonstrated that, compared to the move online from the conference’s usual highlighted serum neurofilament light (NfL) controls, individuals experiencing TBI were base with the host Imperial College London, as a promising biomarker for neuronal injury, more likely to be receiving medication, this facilitated the participation of a truly and demonstrated its association with concus- including psychotropic and pain medication, global collection of speakers and attendees. sive symptoms in players of high-risk sports. not only after but also before their injury, The philosophy of the conference, as shared The use of biomarker S100 calcium binding raising important questions about the reasons by David Sharp, Professor of Neurology at protein B (S100B) has already been incor- for this correlation. Imperial College London, in his introduc- porated into Scandinavian guidelines for Another challenge is how the adverse tion, is to try and bring together the exciting management of head trauma, as explained by effects of TBI can be mitigated. Mark Wilson, science in TBI which has been developing Eric Thelin, a post-doctoral researcher at the Clinical Professor at Imperial College London, over a number of years with the clinical Karolinska Institut, who also noted the import- spoke on the importance of early manage- aspects. ance of correct patient selection to avoid risk ment of head trauma to prevent secondary The day itself was split into two streams, of high numbers of false positives. brain injury. To this end, he has co-founded resulting in a total of around 20 hours of Another key theme was the importance GoodSAM, enabling rapid video assessment speaker content, some of which is being of considering not only isolated lesions, of emergency situations to improve triage, made available after the event through the but also the impact on associated white in accordance with his mantra that if you’re Frontiers in TBI YouTube channel. The bulk matter tracts. Michel Thiebaut de Schotten, not dead when the ambulance arrives, you of this was dedicated to the vast variety of a tenured research director at the French shouldn’t die. Management of longer term research which is advancing understanding National Centre for Scientific Research, impacts of TBI is also crucial, and Jennie in traumatic brain injury, and included rapid- presented his pioneering work establishing Ponsford, Professor of fire presentations and online posters as well the Disconnectome map of white matter at Monash University, presented research as more detailed dives into specific subject tracts, enabling researchers to understand suggesting light therapy as a possible interven- areas. There were also two teaching sessions, these impacts on an individual patient level. tion for the commonly seen issues of fatigue in which experienced clinicians discussed Furthermore, Celia Demarchi, a clinical and sleep disturbance after TBI. current management of patients with TBI, as psychologist from Imperial College London, The conference was concluded by David well as an extended session around the legal demonstrated how using diffusion tensor Sharp, starting with the awarding of prizes aspects of TBI. MRI in combination with neuropsychological for rapid-fire presentations to Nick Parsons One key theme emerging from the confer- testing had enabled her team to establish and Alexandre Trottier, and for poster pres- ence was the importance of neuroinflam- correlations between damage to particular entation to Marie Hanscom. He reflected that mation in damage to the brain following white matter tracts and specific neuropsycho- the conference had helped to bring to light trauma. Soyon Hong, group leader at the logical deficits in adolescents with TBI. tremendous insights into the neuroscience UK Dementia Research Institute, University One important challenge considered by the of TBI, as well as highlighting the need for College London, detailed her team’s research conference was the prevention of TBI. Risk further experimental studies to bridge the gap into the role play in neuroinflam- of TBI in sport is well recognised, and Stefan between the basic science and clinical trials. mation, with particular consideration of their Duma, Henry Wyatt Professor of Engineering Although deprived of a traditional round of importance in synapse loss and dysfunction. at Virginia Tech, presented evidence chal- applause by the online nature of the confer- The role of microglia in neuroinflamma- lenging preconceptions about the lack of ence, the chat log was awash with comments tion was further developed by David Loane, protection afforded by helmets in sport, and expressing gratitude to the team for a fantastic Associate Professor at the Shock, Trauma and instead encouraged consideration of the conference, and no doubt many of the partici- Anaesthiology Research Center, University role they may play within reducing risk of pants will already be looking forward to the of Maryland, who reported evidence that TBI. However, brain injury in sport is a rela- planned 2021 conference. delayed microglial depletion can avoid the tively well studied field compared to the risk presence of chronically activated microglia presented by intimate partner violence, as and improve motor and cognitive recovery Jonathan Lifshitz, Professor of Child Health To see the talks please visit: after TBI in animal models. at the University of Arizona, highlighted, also https://www.youtube.com/channel/ Neuroinflammation after TBI can also noting that symptoms are often dismissed UCy4feuSEdFNj9vufJmuVergr be exploited clinically through the use of as being psychogenic. In addition, Yasmina

Academic Study for a PhD in Neurorehabilitation at the UCL Queen Square Institute of Neurology, while working at the Wellington Hospital Neurorehabilitation PhD Candidates can apply throughout the year until all posts are programme filled. Enquiries to Prof Sven Bestmann, s.bestmann at. ucl.ac.uk https://www.ucl.ac.uk/ion/working-institute/vacancies-and New fellowship scheme for junior doctors -careers/academic-neurorehabilitation-phd-programme

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CONFERENCE PREVIEW: ABN Annual Conference 2020 s with everything else around the globe, platform and poster sessions online, even Specialist COVID-19 has wreaked its havoc with the ABN Interest Groups, whilst maintaining links with our Ameetings. We had been looking forwards to ever generous sponsors. Appropriately, the Virtual a sunny three days in Bournemouth followed by a meeting encompasses sessions on viruses and emer- more autumnal day in London in October. Early in gency neurology, as well as the two most popular March we cancelled Bournemouth and set our sights clinical sessions, the trainee case competition and on two days in London in October….until it became the CPC. The virtual world struggles to mirror the joy clear that mass meetings anywhere in 2020 were just of human interaction (surely the main reason most us not feasible and our Meetings secretary began to attend such meetings?), but we have plans for some wonder if he might just be the first in office never virtual extra-curricular activity...dust off those yoga to actually stage a meeting. But the virus cannot mats and running shoes and sharpen your musical suppress human ingenuity or force of will, thus we brains, all shall become clear. We hope to see you all welcome you to the ABN’s first ever Virtual meeting. very soon; what was once an unimaginable proposal Or rather, series, as we have eight one-hour evening has become reality and so very 2020, we hope you symposia starting on Thursday 17th September, with can enjoy it live, but there’s always catch up. the Virtual meeting nestling in the middle (Friday 16th October), the symposia culminating with an exciting battle of the platform and poster sessions. Despite the Richard Davenport, ABN Meeting Secretary limitations of a curtailed online programme, we have 2019-21 crow barred all the best bits from the abandoned https://www.theabn.org/page/virtual_ two real life meetings, as well as accommodating the meeting_2020

ANNUAL MEETING 2020: THE VIRTUAL EXPERIENCE

As noted above, the meeting will be spread over nine weeks with a main meeting day on Friday 16 October, preceded and succeeded by four Thursday night sessions. All live sessions will be recorded and available to delegates until 16 November. Platform and posters presentations have been replaced by recorded narrated PowerPoint presentations which will be available to delegates from 7 September via the ABN confer- ence and, for ABN members, via the ABN website. Sponsored symposia will also be available as on demand recordings via the conference app and the ABN website.

EVENING SESSIONS. 7pm, Thursday evenings • 22.10.20: Lessons from the Experts history: Hadi Manji, London from 17 September o Update on Tremor: Classification, diagnosis o COVID-19 and the nervous system: and modern management: Sundus Ali, Rustam Al-Shahi Salman, Edinburgh • 17.09.20: Expert Updates in Therapeutics Liverpool o Neurology and the COVID-19 pandemic: o Complications of MS Therapies and the o Mini symposium (5 minutes): Sanofi what have we learned and what’s the effect of COVID: Victoria Williams, London o Sorting out the adult onset Ataxias for the future: Catherine Mummery, London and o Mini symposium (5 minutes): Teva generalist: Mark Wardle, Cardiff Christopher Kipps, Southampton o New therapies for Headache: • 29.10.20: The Eyes Have It Brendan Davies, Staffordshire • 10:30am: Case Presentation Competition o Vision 1 Pre-chiasmatic: The optic o Confused and tetraplegic: examine your • 24.09.20: Video session neuropathies: Zhaleh Khaleeli, London ICU patient: Aram Aslanyan o Epilepsy: Khalid Hamandi, Cardiff o Mini symposium (5 minutes): Biogen o Bad altitude: Sabrina Kalam o Mini symposium (5 minutes): Novartis o Vision 2 Post-chiasmatic: Hallucinosis, o Genes, legs and ham: Josh King-Robson what's it all about?: Rimona Weil, London o Movement Disorders: o Coincidence? We think not…: John Franklin Christopher Kobylecki, Manchester • 05.11.20: Battle of the Platforms o A wolf in sheep’s clothing: Emily Gibbons o Live presentations of top 5 Platforms • 01.10.20: Cerebral Palsy • 11:15am: selected from recorded presentations o Neurological Art and Music (10 minutes) o Mini symposium (5 minutes): o Mini symposium (5 minutes): o Novartis Symposium (10 minutes) Jazz Pharmaceuticals GW Pharmaceuticals o Common problems in adult cerebral o GW Pharmaceutical Symposium palsy: Red and other colour flags: Valerie • 12.11.20: Battle of the Posters; (10 minutes) Stevenson, London and Diane Playford, Top 5 Posters Live • 11:45am: Session 2 – Emergency Neurology Warwick o Live presentations of top 5 Posters selected from recorded presentations o Movement Disorders: Kathryn Peall, Cardiff • 08.10.20: Neurotech o Mini symposium (5 minutes): Celgene o Acute Respiratory Neurology: Mark Roberts, o Whole genome sequencing for Manchester Neurologists: Big genetic data in future: MAIN MEETING DAY 16 October 2020 o Status Epilepticus: Definitions, identification Getting signal from noise: Andrea Németh, and management: Hannah Cock, London Oxford • 9:00am: Opening and Welcome: David Burn, ABN President • 1:15pm: Clinicopathological Conference: o Mini symposium (5 minutes): AveXis Discussant: Lucy Kinton, Southampton o Remote monitoring in Neurology: • 9:15am: Session 1 – Going Viral David Sharp, London o Viruses and the nervous system; a potted • 2pm: Close

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