ISSN 1473-9348 VOLUME 19 ISSUE 1 AUGUST-OCTOBER 2019

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

In this issue Thanuja Dharmadasa and Neil G Simon – Clinical and research applications of peripheral nerve MRI David Wong and Mike Boggild – Therapeutic plasma exchange in CNS inflammatory demyelinating disorders: time is brain and spine? Rachel Farrell and David Baker – An expert opinion: Optimisation of pharmacological management of multiple sclerosis related spasticity David Veale, A Felix de Carvalho and Jessica Coffin – Safety versus sleep – is a lack of protected sleep time on psychiatry wards bad for mental health? Emma C Argaet, Andrew P Bradshaw and Miriam S Welgampola – Benign Positional Vertigo and its mimics SPECIAL FEATURE JMS Pearce – History of Neurology – Choked disc, optic neuritis, and papilloedema

BOOK REVIEWS > CONFERENCE PREVIEWS AND REPORTS > EVENTS DIARY t an irs d F O e n l h y SALIVARY GLANDS T UK *

B approved a o t e u h l r in r u lo m ia S neu in r otoxin type A

XEOMIN® (botulinum neurotoxin type A) is indicated for the treatment of chronic sialorrhea due to neurological disorders in adults.1

I HAVE GOALS I HAVE ASPIRATIONS HELP ME ACHIEVE THEM

XEOMIN® IS INJECTED DIRECTLY INTO THE SALIVARY GLANDS1 PROVIDING TARGETED TREATMENT OF SIALORRHEA2,3 RECOMMENDED TOTAL DOSE 2* GLAND(S) UNITS PER SIDE TOTAL Parotid gland(s) 30 Units 60 Units

Submandibular 20 Units 40 Units gland(s)

Total 50 Units 100 Units

* The timing for repeat treatment should be determined based on the actual clinical need of the individual patient, and no sooner than every 16 weeks, as per the UK marketing authorisation of XEOMIN®.

References: 1. XEOMIN® Summary of Product Characteristics (SmPC). 2. Jost WH. et al. Neurology. 2019 Apr 23;92(17):e1982-e1991. doi: 10.1212/WNL.0000000000007368. Epub 2019 Mar 27. 3. Restivo D. et al. Toxins (Basel) 2018; 10(2):55.

* As of May 2019

Prescribing information can be found on the facing page. Date of preparation: August 2019 M-XEO-UKI-0499

J000222 A4 Sialorrhea ACNR AD_v3.indd 1 12/08/2019 11:03

CONTENTSAUGUST-OCTOBER 2019

REVIEW ARTICLES 05 Clinical and research applications of BNPA Annual peripheral nerve MRI – Thanuja Dharmadasa and Neil G Simon Meeting 10 Therapeutic plasma exchange in CNS inflammatory demyelinating disorders: time 5th6th March, 2020 is brain and spine? Kings Place, York Way, London – David Wong and Mike Boggild

 Psychedelic drugs in neuropsychiatry 20 Benign Positional Vertigo and its mimics – Emma C Argaet, Andrew P Bradshaw and Miriam S  Neuropsychiatry of PD Welgampola  Psychotic phenomena – hallucinations and beyond REHABILITATION ARTICLE  State of the art neuromodulation 13 An expert opinion: Optimisation of *NEW* Interdisciplinary clinical sessions & discussion of pharmacological management of multiple complex cases through psychiatry & neurology lenses sclerosis related spasticity

– Rachel Farrell and David Baker Registration: www.bnpa.org.uk ESSAY For all other enquiries including sponsors contact 16 Safety versus sleep – is a lack of protected Jackie Ashmenall sleep time on psychiatry wards bad for Telephone: +44 (0)20 898 76111 mental health? Email: [email protected] – David Veale, A Felix de Carvalho and Jessica Coffin SPECIAL FEATURE 18 History of Neurology – Choked disc, optic neuritis, and papilloedema – JMS Pearce REGULARS 09 and 17 Book reviews 24 Events diary Advanced Stroke Imaging 25 Conference previews and reports One Day course Cover image shows papilloedema. See article on page 18. 13th November 2019 This one-day course for healthcare professionals provides an overview of using neuroimaging and mechanical thrombectomy to treat people who have had a stroke. This course is run by the UCL Institute of ACNR Neurology in Queen Square. Published by Whitehouse Publishing, 1 The Lynch, Mere, Wiltshire, BA12 6DQ. Publisher. Rachael Hansford E. [email protected] Course content PUBLISHER AND ADVERTISING • methods for quantifying the impact of a stroke using advanced imaging Rachael Hansford, T. 01747 860168, M. 07989 470278, techniques – from penumbral and core infarct size to methods of E. [email protected] imaging recovery from stroke • using CT and MRI scans to evaluate infarcts and haemorrhages COURSE ADVERTISING Rachael Hansford, E. [email protected] • the benefits nda applications of mechanical thrombectomy EDITORIAL Anna Phelps E. [email protected] Lecture topics will include: Printed by Stephens & George • Evidence basis for thrombectomy Copyright: All rights reserved; no part of this publication may be reproduced, stored in a retrieval • Endovascular services system or transmitted in any form or by any means, electronic, mechanical, photocopying, • Machine learning recording or otherwise without either the prior written permission of the publisher or a license • Foundations of neuroimaging permitting restricted photocopying issued in the UK by the Copyright Licensing Authority. Disclaimer: The publisher, the authors and editors accept no responsibility for loss incurred by any Who this course is for? person acting or refraining from action as a result of material in or omitted from this magazine. Doctors in training / stroke consultants / allied health professionals working Any new methods and techniques described involving drug usage should be followed only in in stroke medicine, You’ll receive a certificate of attendance. There is the conjunction with drug manufacturers’ own published literature. This is an independent publication opportunity for the delegates to submit a case for presentation and panel - none of those contributing are in any way supported or remunerated by any of the companies discussion. The course attracts 8 CPD points by the Federation of the Royal advertising in it, unless otherwise clearly stated. Comments expressed in editorial are those of the Colleges of Physicians of the United Kingdom. The fee for this course is: author(s) and are not necessarily endorsed by the editor, editorial board or publisher. The editor’s decision is final and no correspondence will be entered into. £200 for bookings made from 1 September 2019. ACNR's paper copy is published quarterly, For more information see https://www.ucl.ac.uk/short-courses/ with Online First content and additional email updates. search-courses/advanced-stroke-neuroimaging Sign up at www.acnr.co.uk/subscribe-to-acnrs-e-newsletter For all queries please contact: [email protected] or [email protected] @ACNRJournal /ACNRjournal/

4 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 r e v i e w a r t i c l e Clinical and research applications of peripheral nerve MRI

Thanuja Dharmadasa Abstract MBBS, PhD, FRACP, is a Neurologist and Postdoctoral The non-invasive exploration of the periph- Research Fellow at the Nuffield eral nervous system using magnetic resonance Department of Clinical Neurosciences, imaging (MRI) has recently gained momentum. University of Oxford. Her clinical The use of basic and advanced MRI protocols and research interests are in neuromuscular and neurodegenerative has allowed for both qualitative and quantita- disorders, with particular focus on tive assessment of the peripheral nerves (PN), motor neuron disease (MND). Dr enabling the structural and functional changes Dharmadasa recently completed her of peripheral pathology to be increasingly inves- PhD investigating MND (University of Sydney) and was awarded the tigated. From a clinical perspective, this has Jim Lance Young Investigator's impacted diagnosis, treatment and monitoring Award in 2017. Her post-doctoral across a variety of conditions. This review will research continues in this area, provide an overview of the current MRI protocols Figure 1: Peripheral nerve anatomy. exploring the development of novel Schematic drawing of a large peripheral nerve. The epineurium neurophysiological and neuroimaging used for PN evaluation, the application of this in insheathes a collection of fascicles interspersed with adipose biomarkers for this disorder. the clinical setting, and the expanding techniques tissue. Each fascicle (enlarged) is surrounded by a perineurium within the research field. and contains axons (myelinated and unmyelinated) that are each enclosed by endoneurial connective tissue. Adapted from [4].

Introduction Peripheral nerves (PN) are involved in a myriad of by endoneurial fluid. This fluid is a main deter- pathologies and represent a significant burden of minant of signal characteristics on non-contrast disease. Gold standard evaluation currently relies T2 scans, appearing moderately hyperintense in on both clinical and electrodiagnostic testing, but the absence of pathology. The nerve fascicle is this bestows certain challenges, particularly in the smallest unit that can be visualised on MRI, early stages of disease when signs and symptoms insheathed by the perineurium. This layer acts may be insidious.1 As such, neuromuscular medi- as a blood-nerve-barrier, and thus no gadolinium Neil G Simon MBBS, PhD, cine is not uncommonly marred by diagnostic contrast enhancement should be seen in healthy FRACP, uncertainty, complicating management and treat- nerves.1,3 is an academic Neurologist with ment decisions. MR neurography (MRN) is a specifically clinical and research interests in nerve Although magnetic resonance imaging (MRI) designed PN protocol that delivers a higher level and muscle imaging, neuromuscular disease and clinical neurophysiology. commands a pivotal role in the clinical assess- of anatomic detail. This usually incorporates a Dr Simon is Head of Neurology at ment of neurological disorders, early analysis T1-weighted image that highlights the fascicular Northern Beaches Hospital, Sydney, focused on the central nervous system leaving ultrastructure of the nerve, often combined with Australia and Clinical Senior Lecturer peripheral nerve techniques relatively unsoph- a T2-weighted image that is modified to suppress at the University of Sydney. isticated. Since MR visualisation of the periph- non-neural structures (e.g. fat and vasculature). Correspondence to: eral nerve was eventually pioneered in 1992,2 The latter sequence enhances water-based path- Dr Neil G Simon, developments in this field have now accelerated ology, such as oedema and nerve inflamma- Suite 4101, 834 Pittwater Rd, Dee Why, this tool into the clinical spotlight.3 This review tion.3 High resolution phased-array coils can also Sydney 2099. Email: [email protected] provides an overview of the MRI techniques to be used to increase anatomical detail, making assess peripheral nerves, and will outline current fascicles appear more hyperintense and nerve Conflict of interest statement: clinical applications. Emerging research in this characteristics (including calibre, course and Thanuja Dharmadasa is a recipient of field will also be summarised. size) easier to identify.3 the Australian National Health and Medical Research Council CJ Martin Early Career Fellowship (APP1162075). Peripheral nerve MR techniques Advanced MRI techniques The authors report no relevant Peripheral nerves can now be directly visual- Quantitative assessment of PN pathology is disclosures. ised using basic and advanced MRI protocols, possible through advanced MRI sequences, Provenance and peer review: allowing differentiation of various pathologies at providing valuable pathophysiological informa- Submitted and externally reviewed. a structural and functional level (Table 1). tion regarding the functional integrity of the nerve. Currently, techniques for the PN are largely Date first submitted: 9/7/19 Conventional MRI based on diffusion imaging, which measures a Acceptance date after peer review: 5 7/8/19 MRI provides important information about the wide range of nerve properties. structural integrity of the nerve. Understanding To cite: Dharmadasa T, Simon NG. the microstructural organisation of this pathway Diffusion imaging ACNR 2019;19(1):5-9. is a crucial step for accurate interpretation of MR diffusion imaging is based on the concept that imaging findings (Figure 1).4 Briefly, the axon is water molecules are highly directional (‘aniso- encased by the endoneurium and surrounded tropic’), effectively restricted to move along the

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Table 1: Typical peripheral nerve features using MRI Imaging modality Nerve Normal Abnormal MR Neurography – Size – Distally decrementing, similar to vessel diameter – Enlarged or flattened (diffuse or focal); vessel diameter > – SI – T1: isointense to muscle; T2FS isointense mild → ↑ – T2: hyperintense, similar to adjacent veins – Course – Anatomically consistent, perineural fat outline – Abnormal to anatomical path; focal or diffuse deviations – Fascicular pattern – Present on T1 and T2-weighted images – Loss or disruption of pattern on T2 (esp. T2FS) – Epi- and perineural CT – Hyperintense – Loss of contrast resolution – Post contrast enhancement – T1: no significant enhancement (due to bnb) – T1: moderate contrast enhancement; muscle enhancement – Skeletal muscle changes – No significant changes in muscle size and intensity – Changes seen distally to nerve lesion o Acute ( 48hrs): normal size and morphology, T2 global < hyperintensity, oedema o Subacute (weeks months): some fatty replacement in → tissue, T2 hyperintensity, oedema (usually 10weeks) < o Chronic (months years): Muscle atrophy fat → ± replacement, T1 hyperintensity Diffusion tensor imaging – FA – 0.53 [0.40-0.66] – 0 (lowest level of fibre organisation) – MD (10-3 mm2/s) – 1.14 [0.93-1.45] – or ↓ ↑ -3 – 1.90 [1.40-2.28] – (axonal loss, but can be in some scenarios) – AD (10 mm2/s) ↓ ↑ -3 – 0.76 [0.58-1.07] – (myelin damage) – RD (10 mm2/s) ↑ SI = signal intensity; CT = connective tissue; greater than; increased; decreased; bnb = blood neuronal barrier of the perineurium; T2FS = T2-weighted > ↑ ↓ fat-suppressed imaging; DTI values taken from Kronlage et al [28], with normal values given in mean [range]. The mean is of all nerves tested (sciatic, tibial, ulnar, median, radial).

bility of this technique in healthy peripheral ment decisions. nerves was recently established.5 The common MRI is a particularly useful tool in these DTI parameters are (Figure 2): settings, with techniques increasingly applied (i) fractional anisotropy (FA); indicating to a wide range of PN pathologies including how strongly ‘directional’ water diffusion traumatic nerve injuries, non-traumatic neur- is within the tissue, inferred to reflect the opathies (such as inherited and immune-medi- structural integrity of the pathway; ated disorders) and nerve tumours.7,12-14 (ii) mean diffusivity (MD); reflecting water Practically, PN imaging is usually performed displacement distance independent of on three Tesla (3T) MRI field strength scan- direction; ners. Standard protocols (such as MRN) can (iii) axial diffusivity (AD); representing diffu- be performed with basic MRI facilities, while sion in parallel (axoplasmic) to the nerve DTI protocols often require technical exper- tract. AD is most specific for axonal tise. The growing use of MRI in practice is integrity, and has been reported as an allowing crucial clinical questions to be more indicator of axonal damage;9 accurately addressed, such as (i) localisation (iv) radial diffusivity (RD); representing diffu- of disease pathology, (ii) measurement of Figure 2: Principles of DTI. A. In a normal PN with preserved axonal integrity, water sion in a perpendicular direction to the injury severity and (iii) monitoring of nerve molecules diffuse along one main direction (red arrows) nerve tract. RD probably reflects myelin recovery. and have low perpendicular movement (yellow arrow) integrity and has been related to changes due to the physiological barriers of the intact nerve. B. 9 An injured PN demonstrates a loss of fibre organisation in myelin pathology. (i) Localising pathology (dashed black lines), with subsequent loss of directionality These DTI datasets can also be reconstructed Basic MRI can localise structural pathology, of water molecule movement (red arrows). Loss of perpen- to give a 3D representation of nerve fibre such as focal nerve swelling at sites of conduc- dicular barrier integrity (i.e. myelin sheath) increases move- 15 ment in this direction (yellow arrows). orientation using diffusion tensor tractography tion block in inflammatory polyneuropathies. (DTT) (Figure 3).7,10 Locating the lesion in carpal tunnel syndrome (CTS), the most common form of entrap- Clinical application of peripheral nerve ment neuropathy (caused by median nerve linear nerve pathways, hindered by intact MRI compression at the wrist), may also require cell membranes and macromolecules (Figure Although clinical and electrodiagnostic testing MRI when limited by normal electrophysio- 2A).5-7 Any damage to this microstructural remain at the core of PN evaluation and diag- logical tests in early disease.11,16 In this clinical integrity results in less restriction of water nosis, false negative results can be common, setting, T2-hyperintense signal changes are diffusion along this path and a loss of this particularly during the early phase of disease, seen 24 hours post-injury at (and distal to) directionality (Figure 2B).6 MR diffusion tensor in very proximal nerves, or when nerve injury the site of pathology. Three main signs subse- imaging (DTI) provides metrics to interpret is mild.11 Neurophysiological assessment can quently evolve on imaging to confirm entrap- directionality, creating a numerical approach also be invasive and uncomfortable, and may ment neuropathy: (i) intraneural oedema, to evaluate nerve integrity. Peripheral DTI be impacted by technical issues and hetero- (ii) nerve enlargement, and (iii) gadolinium correlates with neurophysiological and genous disease pathology. Such factors can enhancement (in some instances). MRI can histological nerve changes in a number of lead to a failure to localise pathology to a also explore the specific level and aetiology of studies,5,7,8 and the reliability and reproduci- specific nerve segment and may hinder treat- compression, indirectly aided by the presence

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taneously, neurotmesis requires early surgical intervention. As such, clinical distinction is paramount in order to guide treatment.20

(iii) Monitoring nerve recovery MR modalities can, in theory, also offer a non-invasive alternative for routine monitoring of nerve recovery post-injury, particularly when repeating electrophysiology may not be practical. In some case, early normalisation of MRN changes has been reported prior to neurophysiological evidence of recovery, and may be useful in relapsing inflamma- tory conditions or if infiltrative lesions are of Figure 3: 3D nerve reconstruction using DTT. 15 3D neurography using diffusion tensor tractography (DTT) to visualise nerve fibres surrounding a brachial plexus tumour. concern. MRI measurement of axonal degen- A. Postcontrast T1 image of an enhancing right C4 schwannoma. B,C. Tractography images demonstrate the nerve fibres eration has also been reported in conditions surrounding the tumour. The white arrows (C) show thinning along the anterior face. Reproduced with permission [10]. such as amyotrophic lateral sclerosis (ALS), a rare and progressive terminal disorder, with correlation between disease progres- and distribution of muscle denervation around and adapted by Sunderland (Table 2),18,19 sion and increased brachial plexus signal on the nerve(s) involved (Table 1).16 represent a continuum ranging from mild T2-weighted sequences described.21 The location of PN tumours involving the damage involving focal nerve demyelination Ultimately however, these dynamic nerve nerve sheath can also be identified on basic with no axonal involvement (neuropraxia/ changes can take months to resolve on MRN, MRI by way of a ‘fat-split’ sign, which occurs stage I), to complete nerve tears with a focal and as such this has not been adopted for around the intermuscular space or neuro- loss of axons (neurotmesis/stage V) (Table 2). routine use in clinical practice. vascular bundle. Characteristic MRI features Although electrophysiology remains the main- have also been described to differentiate stay of such assessment, these changes can Future developments between malignant and benign nerve tumour be challenging to resolve in the first six weeks The growth of MRI technology continues to forms, such as a large size and perilesional and MRI may be of additional benefit by iden- promote experimental techniques for PN oedema (causing indistinct margins and tifying early disruption to nerve ultrastructure. imaging, which are currently being developed peripheral enhancement) in the case of the MRI can also facilitate distinction between within the research spectrum. With each former.17 the very severe levels of injury that are iden- technique offering their own strengths and tical on electrophysiological testing, as in the weakness (Table 3), the combined use of (ii) Measuring disease severity case of axonotmesis (i.e. focal loss of axons quantitative and qualitative assessments is Identifying the severity of nerve injury is essen- with preservation of nerve connective tissue) particularly beneficial, providing unique clin- tial to determine the most efficacious treat- versus neurotmesis (i.e. focal loss of axons ical advantages to PN characterisation that ment and the likelihood of recovery.7 Nerve and nerve connective tissue elements) (Table include insights into the dynamics of nerve injury grading systems, established by Seddon 2). Although axonotmesis may recover spon- injury and regeneration.

Table 2: Nerve injury findings Category Neural Structure Affected MRN changes DTI changes Prognosis Sunderland Seddon Myelin Axon Endo Peri Epi FA RD AD May be normal; +/-T2 Full recovery (within ~12 I Neuropraxia – ✓ X X X X hyperintensity, mild nerve weeks) ↑ Good prognosis, As above, plus in II Axonotmesis Δ ? anticipation of recovery ✓/X ✓ X X X fascicular pattern ↓ within months Prognosis dependent on III -- N/A ? degree of endoneurial ✓ ✓ ✓ X X ↓↓ involvement Traumatic neuroma forms Usually requires surgical IV -- between the proximal and ? ✓ ✓ ✓ ✓ X >↓↓ intervention distal nerve gap* Acute: Poor prognosis; Early o complete nerve surgical intervention (if discontinuity; fluid and appropriate) may give granulation tissue seen partial functional recovery; V Neurotmesis Chronic: ? ✓ ✓ ✓ ✓ ✓ Complete loss of function o T2 hypointense soft occurs if intervention tissue in nerve gap, is not early and/or not fibrosis; hyperintense ± indicated terminal neuroma affected; X not affected; Endo = endoneurium; Peri = perineurium; Epi = epineurium; enlargement; change; greater than; N/A = not assessed; ✓ ↑ Δ > FA = functional anisotropy; RD = radial diffusivity; AD = axial diffusivity. *Traumatic neuroma is the non-neoplastic mass of focal nerve enlargement with an effaced fascicular pattern, formed from entangled regenerating Schwann cells and axons, proliferation of fibroblasts and fibrosis. Colour gradients for DTI: darker colour indicates a higher value; a lighter colour indicates a lower value.

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DTI DTI can specify pathophysiological changes affecting nerve fibre integ- rity (such as loss of myelin, presence of oedema, or axonal loss), which is particularly useful in circumstances where structural changes are subtle and difficult to identify using standard MRI. In CTS, a reduction of FA correlates with electrodiagnostic studies and has been reported to hold a diagnostic sensitivity and specificity of 82.2% and 77.8%, respectively.23 Non-invasive localisation and differentiation between benign and malignant nerve tumours may also be facilitated with DTI, with a relatively lower FA and higher MD seen in cases of malignancy.13 3D nerve reconstructions with DTT have been particularly useful for pre-operative planning in this regard, depicting the relationship of the tumour to the remaining nerve fibre (with a mapping sensitivity of 95.7% and specificity of 66.7%). The use of this technique has resulted in a changed surgical strategy in 25% of reported cases.24 The dynamic change of DTI parameters (particularly FA) during the functional stages of recovery has been demonstrated as a marker of PN regeneration and an indicator of treatment efficacy.8,25 This has mainly been evaluated after traumatic nerve injury, with a gradual increase of FA occurring between six weeks to six months in patients who show clinical improvement.12,20 3D nerve reconstruction has also had a role in the post-injury phase and can visualise axonal regeneration.7,12 These findings correlate with electrophysiological studies and probably reflect PN axonal growth and regeneration, restoring the nerve towards a normal (anisotropic) structure. Equally, axonal degeneration can be

Figure 4: Peripheral nerve imaging using 7T MRI. identified by a gradual decline in FA and AD metrics in the lower limb of Tibial nerve fascicles are depicted on high resolution images acquired at 3T and 7T. A and B ALS patients, demonstrated over a six-month period.14 In such conditions show full images at 3T and 7T, respectively. C. Enlarged version within the outlined yellow where robust biomarkers are truly lacking, these parameters may offer an box in A, showing tibial nerve fascicles in detail at 3T. D. Enlarged version within the outlined yellow box in B, showing the same nerve image at 7T. The yellow dotted line (C,D) outlines important indication of disease prognosis. the tibial nerve fascicles, and a single fascicle is seen marked by the linear line in C and D (as highlighted by the blue and green arrow, respectively). Overall, the fascicular structure has a Conclusion clearer definition on 7T (D). Reproduced with permission [22]. The use of non-invasive, novel MRI techniques has enhanced understanding of the structural and functional architecture of PN pathology. The evolution of these techniques for the PN has provided multifaceted information to pilot diagnosis and clinical decision making and has allowed objective 7T MRI monitoring of treatment efficacy. A consensus between the protean MRI 7T MRI imaging of the PN has only recently been attempted in a small protocols are now well poised to be validated in larger cohorts, which pilot study involving three healthy volunteers.22 This demonstrated will hopefully verify robustness and repeatability of technique. This will be much clearer visualisation of nerve fascicules in comparison to 3T essential for successful translation into the routine clinical and diagnostic imaging (Figure 4A-D). Although feasible, the availability of 7T scan- rhetoric of PN assessment, and for reliable interpretation of pathology. ners, a longer scan time, potentially increased sensitivity to side-effects, Ultimately, the current exponential growth of peripheral MRI techniques and the need for different receiver coils have limited the immediate use may soon enable dynamic disease characterisation at an individual patient of this protocol in the clinical setting. level, in-line with a modern era of personalised medicine.

Table 3: Strengths and weaknesses of peripheral nerve MRI Imaging technique Strengths Weakness What clinical questions can be answered? Clinical utility

MR neurography o Provides anatomical o Only provides structural o Location of nerve injury (if structural o Usually 3rd line information information damage is present) investigation (after o May localise nerve o Field of view is limited o The visual extent of structural damage clinical exam and pathology o Expensive, time consuming o In some instances, aetiology electrophysiology if localisation remains o Visualises superficial o Not possible if MRI unclear and deep nerves contraindications o Accessible technique Diffusion tensor o Additionally provides o Technique is not readily o What nerve structures are o Developing research imaging information about accessible (needs expertise) compromised (axon, myelin, collagen tool nerve fibre integrity o Wide range of normal values support etc) o Not yet routinely o Quantitative and make standardisation difficult o Aetiology of nerve pathology implemented in qualitative o Values are subject to o Severity of nerve injury clinical practice o 3D nerve age-related (FA , AD , Δ ↓ ↓ o Recovery of nerve function (e.g. post- reconstructions RD with increasing age) ↑ surgical intervention) provide structural and o Small diameter of PN functional information (2-10mm) makes spatial o Useful for monitoring resolution difficult progression and/or o Proximity of surrounding recovery of the nerve vessels may make contrast resolution poor

8 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 r e v i e w a r t i c l e r e g u l a r s – b o o k r e v i e w s

REFERENCES Rhoton’s Atlas of Head, Neck and Brain 1. Zaidman C, Seelig M, Baker J, Mackinnon S, Pestronk A. Detection of Peripheral Nerve Pathology. Neurology 2013, 80:1634-1640. 2. Howe F, Filler A, Bell B, Griffiths J. Magnetic resonance neurography. Lancet 1992; 341(8846):659-661. 3. Simon N, Talbott J, Chin C, Kliot M. Peripheral Nerve Imaging. Handbook of Clinical Neurology. 2016;136:811- 826. 4. Grinsell D, Keating C. Peripheral Nerve Reconstruction after Injury: A Review of Clinical and Experimental Therapies. BioMed Research International. 2014;2014:1-13. 5. Simon N, Lagopoulos J, Gallagher T, Kliot M, Kiernan M. Authors: Peris-Celda, Martinez-Soriana and Rhoton. Peripheral nerve diffusion tensor imaging is reliable and Published by: Thieme reproducible. J Magn Reson Imaging. 2016;43:962-969. Price: £233.00 6. Beaulieu C. The basis of anisotropic water diffusion in Pages: 648 the nervous system - a technical review. NMR Biomed. ISBN: 9781604069006 2002;15:435-455. Reviewed by: David Lowes, MB ChB MRes, ST2 in 7. Noguerol T, Barousse R, Socolovsky MAL. Quantitative Neurosurgery, University Hospital of Wales, Cardiff. magnetic resonance (MR) neurography for evaluation of peripheral nerves and plexus injuries. Quant Imaging Med Surg. 2017;7(4):398-421. 8. Simon N, Kliot M. Visualising axonal degeneration and regeneration with diffusion weighted MRI. Neural Regen Res. first heard the name Rhoton when larynx and orbits are shown. These 2014;9(24):2122-2124. assisting in an operation to secure are important parts of anatomy for 9. Wheeler-Kingshott C, Cercignani M. About "axial" and "radial" diffusivities. Magn Reson Med. 2009;61:1255- Ia ruptured brain aneurysm as a neurosurgical trainees to be familiar 1260. junior surgical registrar. The instru- with. Minimally invasive approaches 10. Gallagher T, Simon N, Kliot M. Vizualising nerve fibers ments which bear his name are used to the skull base, such as the trans surrounding a brachial plexus tumour using MR diffusion tensor imaging. Neurology. 2016;86(6):582-583. for microsurgical techniques in neuro- orbital, are becoming the mainstay 11. Kimura J. Electrodiagnosis in diseases of nerve and muscle: surgery, helping to carefully dissect of some practice. Although some of principles and practice, 4th edition edn: Oxford University the brain to its deepest structures and this anatomy is daunting to a junior Press. 2013. secrets. After this operation, I decided trainee, the way that the authors lay 12. Simon N, Narvid J, Cage T, Banerjee S, Ralph J, Engstrom neurosurgery was the career I wanted out the dissections help digest the J, Kliot M, Chin C. Visualising axonal regeneration after peripheral nerve injury with magnetic resonance tractog- to follow, and Rhoton was a name I information and understand the func- raphy. Neurology. 2014;83:1382-1384. have heard a lot more of since. tion of their components. 13. Cage T, Yu E, Hou S, Birk H, Simon N, Noss R, Rao A, Chin Known to some as the father of Part four goes into intricate detail of C, Kliot M. Magnetic Resonance Diffusion Tensor Imaging microscopic neurosurgery, Rhoton’s the brain. These dissections help visu- can visualise nerve fibers and their relationship to peripheral nerve tumours. Neurosurg Focus. 2015;39(3). reputation as an anatomist, surgeon alise the approaches used to different 14. Simon N, Lagopoulos J, Paling S, Pfluger C, Park S, and teacher became more apparent areas of the brain, and tie in the Howells J, Gallagher T, Kliot M, Henderson R, Vucic S et when I was learning more about the deficit which would be experienced al. Peripheral nerve diffusion tensor imaging as a measure of brain. This book encompasses not in disease. Understanding of neuro- disease progression in ALS. J Neurol. 2017;264(5):882-890. only the art and scientific detail of anatomy in this detail enables the 15. Ishikawa T, Asakura K, Mizutani Y, Ueda A, Murate K, Hikichi C, Shima S, Kizawa M, Komori M, Murayama K the dissections Rhoton was famous most complex of neurosurgical oper- et al. MR neurography for the evaluation of CIDP. Muscle for, but also the way in which they ations to be undertaken. Dissections Nerve. 2017; 55:483-489. are presented, conducive to learning rather than illustrations or diagram- 16. Bashir W, Connell D. Imaging of entrapment and anatomy, and sharing this knowledge matic figures serve this purpose to a compressive neuropathies. Semin Musculoskelet Radiol. 2008;12:170-182. with others. greater extent when laid out well, as 17. Wasa J, Nishida Y, Tsukushi S, Shido Y, Sugiura H, In 624 figures arranged in 28 they are in this volume. Nakashima H, Ishiguro N. MRI features in the differentiation sections over four parts Dr. Peris-Celda The book is large and heavy, remin- of malignant peripheral nerve sheath tumours and neurofi- and Prof. Martinez-Soriano lay out iscent of coffee table hardbacks, and bromas. AJR Am J Roentgenol. 2010;194:1568-1574. 18. Seddon H, Medaware P, Smith H. Rate of regeneration of the head, neck and brain in stunning is not something to be carried round peripehral nerves in man. J Physiol. 1943;102:191-215. detail, with meticulous labelling by on a day to day basis. The price tag 19. Sunderland S. A classification of peripehral nerve injuries Prof. Valverde and Prof. Martí. is equally hefty, more suitable for a producing loss of function. Brain. 1951;74:491-516. Part one covers the osteolology of departmental purchase than pocket 20. Simon N, Spinner R, Kline D, Kliot M. Advances in the the head and neck. One can spend money. That being said, it is a pleasure neurological and neurosurgical management of peripheral nerve trauma. JNNP 2015;87:198-208. many hours searching for well anno- to use and would be a great addition 21. Gerevini S, Agosta F, Riva N, Spinelli E, Pagani E, Caliendo tated plates such as these. Holding to any neurosurgeon’s library. Perhaps G, Chaabane L, Copetti M, Quattrini A, Comi G et al. a 3D model of a skull in your hand the icing on the cake is that the plates MR imaging of brachial plexus and limb-girdle muscles whilst examining the images can be are also available online. With the in patients with amyotrophic lateral sclerosis. Radiology. 2016;279:553-561. recommended, to fully appreciate the use of the 3D glasses provided, the 22. Yoon D, Biswal S, Rutt B, Lutz A, Hargreaves B. Feasibility grooves, foramina and prominences. dissections come to life. The view of 7T MRI for imaging fasciular structures of peripheral The face and neck is covered in part down the glasses is very similar to that nerves. Muscle & Nerve. 2017;57:494-498. two. The nerves, blood supply and of the operative microscope and helps 23. Lindberg P, Feydy A, Le Viet D, Maier M, Drape J. Diffusion muscles which give humans expres- further appreciate the relationship of tensor imaging of the median nerve in recurrent carpel tunnel syndrome- initial experience. Eur Radiol. 2013;23:3115- sion are beautifully dissected and the structures shown. 3123. displayed layer by layer. This helps This book serves as a worthy tribute 24. Kasprian G, Amann G, Panotopoulos J, Schmidt M, establish a better understanding of the to the work of Rhoton, laying out Dominkus M, Trattnig S, Windhagger R, Prayer D, relationship between these structures, beautifully dissections which help Nobauer-Huhmann I. Peripheral nerve tractography in soft tissue tuomurs: a preliminary 3-Tesla diffusion tensor which leads to their function, but also impart his skills and knowledge to magnetic resonance. Muscle Nerve. 2015;51:338-345. when learning how to turn flaps and the next generation of surgeons, and 25. Gallagher T, Simon N, Kliot M. Diffusion tensor imaging to perform craniotomies. will help them to do the same to the visualize axons in the setting of nerve injury and recovery. following generation. Neurosurg Focus. 2015;39:E10. In part three, the ear, nose, pharynx,

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Therapeutic plasma exchange in CNS inflammatory demyelinating disorders: time is brain and spine?

Key Points weight molecules which have a long half-life of 21 • There is emerging evidence that early TPE in days, TPE is highly efficacious as it allows the rapid NMOSD relapses results in more favourable removal of relevant pathogenic autoantibodies outcomes. involved in the underlying disorder. • Although the optimal timing is unclear, there is One plasma volume of TPE removes David Wong, MBBS, increasing evidence that early TPE within the approximately 65% of intravascular constituents FRACP, first two days may offer the greatest degree of and two plasma volumes about 85%.2 Due to a is a Neurology Trainee based at recovery in NMOSD relapses. potential rebound phenomenon in IgG levels the Royal Brisbane and Women’s Hospital. His interests include • Given underlying shared immunological mech- following 1-2 cycles, most centres typically CNS Inflammatory Demyelinating anisms between NMOSD and other CNS-IDD, perform more procedures (4-5 cycles) to maintain Disorders, Movement Disorders and there may be potential benefit of early TPE lower levels of circulating pathogenic antibodies. Behavioural Neurology. in this spectrum of disorders. This is a further Rapid reduction of immunoglobulins by 60-70% direction of research. of baseline titres following a plasma exchange series has been noted.3 Recovery of levels for most Abstract immunoglobulin subclasses approached baseline TPE has a role in the management of various levels after six weeks post TPE, in line with immune-mediated neurological disorders previous evidence showing a duration of benefit including CNS inflammatory demyelinating of TPE of at least four weeks.4 disorders (CNS-IDD), often as second line treat- There are other mechanisms of action proposed ment following high dose steroids in part due to for plasma exchange in addition to the removal perceived risk, which inevitably result in delays in of antibodies and replacement of deficient Mike Boggild, MBChB, accessing TPE. circulating factors.5 These include a variety of MRCP, MD, FRACP, There has been limited evidence such delays immunomodulatory effects and adaptations is a UK trained Neurologist with a impact long-term outcome, however emerging including the clearance of immune complexes, specialist interest in the diagnosis data suggests that even 10-14 days, typical of when cytokines and upregulation of the complement and management of MS, since 2012 practicing in Townsville, North TPE is reserved for steroid-unresponsive patients, activating system. Queensland having previously worked may adversely affect outcomes. We review TPE as a Consultant at The Walton Centre use in CNS-IDD, focusing on emerging data on Adverse effects of TPE for Neurosciences, Liverpool between timing and implications for clinical practice. Previous estimates of TPE complication rates in 1996 and 2011. the literature range from 15-28%, with serious Correspondence to: The role of TPE – Protocols and Mechanisms complications from 5-22%.6 Dr David Wong, of Action One study6 involved 230 exchanges performed Department of Neurology, Therapeutic plasma exchange (TPE), an apheresis in 134 Myasthenia Gravis (MG) patients, with Royal Brisbane and Women's Hospital, Butterfield St, technique first established in 1952, is a process 44% being inpatients. Over 75% of cases were Herston 4029 which removes plasma from the circulatory performed with a peripheral venous catheter. Australia. system.1 This is offset with physiological fluid Central venous catheters (CVC) were associ- replacement, usually human albumin prepara- ated with more total (68% vs 35%) and serious Conflict of interest statement: None declared. tions or fresh frozen plasma (FFP). The cellular complications (41% vs 4%) compared to periph- components of the plasma initially removed are eral access respectively. However, it should be Provenance and peer review: subsequently returned in this part of the cycle. TPE noted that a significant proportion of TPE via Submitted and externally reviewed. is traditionally performed via central venous cath- CVC’s (38%) were performed in ICU and the total Date first submitted: 20/5/19 eters but can be performed by peripheral access complication rate is high due to events defined Date submitted after peer review: providing the flow is sufficient. as a complication – these included asymptomatic 27/8/19 The purpose of TPE is twofold. It allows the hypotension requiring a fluid bolus. Acceptance date: 28/8/19 replacement of factors deficient in the plasma of In another study7 of 42 moderate to severe MG To cite: Wong D, Boggild M. patients. patients, 45% had mild reactions not requiring ACNR 2019;19(1):10-12. In addition, TPE allows the removal of abnormal termination of the procedure. These included circulating proteins, toxins or antibodies which citrate toxicity and peripheral vascular access are implicated in the clinical and pathological issues. 2.4% had a serious complication where manifestations of an underlying disorder. CNS-IDD, the procedure was abandoned. The majority were which comprises of conditions such as Multiple treated in the outpatient setting (90%) and via Sclerosis (MS), Clinically Isolated Syndrome (CIS) peripheral venous access (83%). and Neuromyelitis Optica Spectrum Disorder Older patients were more likely to have compli- (NMOSD) have an immunological basis for their cations related to TPE. A study8 comparing TPE pathophysiology that makes TPE an attractive between older ( 65 years) and younger (<65 ≥ treatment option. years) groups included a total of 4722 treat- Given antibodies such as IgG are large molecular ment sessions for 581 patients. 31.8% of these

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patients were in the older cohort accounting tion to onset of relapse10 however it should be considered whilst first line therapies are being for 1289 sessions, reflecting that TPE is not noted that in these studies the delay to TPE administered and then subsequently assessed an uncommon procedure in this age demo- from relapse ranged from 1-3 months. for response. graphic. Indications for TPE were predomin- This is further corroborated by a further antly neurological, haematological and renal Emerging evidence for TPE in NMOSD study20 which found that 40% of patients who related disorders. Effective treatment is particularly important as started apheresis as first line therapy within For patients undergoing TPE for neuro- it is well recognised that NMOSD is an aggres- two days had a complete response to baseline logical conditions, complications with the sive relapsing CNS demyelinating disorder. compared with less than 4% of those who TPE procedure were 14% overall: 18.3% in The mean number of episodes of optic neuritis commenced apheresis after six days. At least the older cohort, compared to 11.4% in the resulting in blindness is less than two and the partial response however, was still observed in younger cohort. These included hypotension, mean number of spinal cord relapses resulting over 80% of patients who had started apheresis coagulopathy, allergies, nausea and flushing. in paraplegia is three.14 after six days. This further supports the notion Complications with access placements were Most studies utilised TPE as a second line of optimal timing being as early as possible 4.2% overall: 7.3% in the older group compared rescue treatment subsequent to unsuccessful following relapse, potentially within the first to 2.3% in the younger group. These included first line therapy, which was predominantly 48 hours. The role of TPE in mild to moderate infection and access clotting. However, 30 day corticosteroids, showing a 50-85% response attacks is less clear as first line therapy. mortality rates did not differ between the two rate.15-19 These typically involved 5 sessions of groups. TPE, although ranged from 2-11 cycles, with Immunoadsorption as an emerging Similar trends of adverse effects were noted 1-1.5 plasma volume exchanges. Replacement alternative for TPE performed for non-neurological indi- fluid was either human albumin 5% or normal Immunoadsorption (IA) has emerged in the cations. saline. An alternate daily or daily regimen 1990s as an alternative to TPE in the treatment were generally adopted in the administration of neurological disorders including CNS-IDD, Evidence of TPE in CNS-IDD protocols with no studies offering a direct although TPE is still the recommended The role of TPE in CNS-IDD was initially estab- comparison between these two in terms of modality. Unlike TPE, IA does not require the lished by a small randomised, sham-controlled, efficacy or tolerability. exchange of blood solutions. IA is a blood puri- double-masked study of plasma exchange in There is a growing body of evidence for fication technique that allows selective removal MS patients with an acute attack refractory to better prognostic outcomes of earlier plasma of potential pathogenic humoral factors such first line parenteral corticosteroid treatment.9 exchange from time of an acute attack.11 One as immunoglobulins from plasma via a high The delay to TPE from symptom onset was study16 showed patients with moderate to affinity adsorbent such as tryptophan.21 between three weeks and three months. In marked improvement compared to minimal There is evidence to support IA having a addition, a delay of two weeks following admin- or none had a median delayed time to TPE of superior safety profile over TPE,22,23 however istration of first line intravenous corticosteroids 14 days versus 51 days respectively. In another a recent larger study showed similar adverse was required prior to TPE commencement. study,19 partial and complete responder rates rates.24 Reasons may include less allergic reac- Seven cycles on alternate days over 14 days for TPE initiated less than three weeks from tions as IA does not require replacement blood were performed, with crossover to the opposite symptom onset was 85.2% compared to 14.8% solutions. It also potentially allows for less group for a further seven cycles if the first treat- when TPE was delayed after this point. plasma volume shifts during exchanges, which ment phase did not result in at least moderate Furthermore, another study involving a may have less haemodynamic implications. improvement. In the first treatment phase, predominant Afro-Caribbean population18 Bleeding risk in IA may be reduced as less the responder rate for such improvement was with severe NMOSD attacks also supported coagulation factors are adsorbed.22,23 45.5% (5/11) and 9% (1/11) for the active versus earlier treatment. The probability of achieving Immunoadsorption may have limited utility sham groups respectively. Including crossover a complete response to TPE when patients in certain neurological conditions, specific- phases, the responder rate was 42.1% (8/19) were treated at day 0-1 from symptom onset ally MuSK Ab Myasthenia Gravis. Tryptophan and 5.9% (1/17) in active versus sham groups. was 50%. This continuously declined with adsorbent ligand has varying affinities for Further studies since then have identified longer delays to TPE, with complete response different IgG subclasses: high for IgG3 (eg. response rates ranging from 44.1-72.2% for rates falling to 5% or less after day 20. However, anti-ganglioside antibody), moderate affinity TPE as second line therapy in CNS-IDD.10-12 the intention of TPE in this study unlike most for IgG1 (eg. Anti-AQP4 Ab, anti-ACHR Ab) and More recent series have also been consistent others was that it was not designed as second low for IgG2 and IgG4 (eg. MuSK Ab).21 with this, including a retrospective cohort line therapy, but rather as first line therapy. In addition, the availability and access to study10 which support the use of TPE in steroid Steroid use concomitantly occurred in 58-81% IA may be limited in many centres compared unresponsive acute MS relapses, showing clin- of cases depending on the site of the lesion, to TPE.23 ical response as evidenced in improvement in however even when these were excluded, EDSS scores. the response rates to TPE showed a similar Use of Immunoadsorption in CNS-IDD The timing of TPE onset from symptom downward trend with increasing delays to There is evidence of similar efficacy of IA and relapse as a predictor of response has had treatment. TPE in NMOSD20 and MS flares.24 mixed findings. Optimal timing of TPE initiation was unable A recent retrospective study24 used either IA In one study,12 the highest responder rate to be determined in this study due to insuffi- or TPE in 140 patients with steroid-refractory was when TPE was commenced before 21 cient patient recruitment, with no significant MS or NMOSD patients where it appeared days. This was corroborated by another study11 difference when commenced by day 1 or equally safe (3.6% vs 3.9% respectively). In where earlier treatment within 16 days since by day 5. However, beyond day 5, there was the MS cohort, IA and TPE were equally effi- relapse, had a responder rate of 83.3%, which a significant decrease in the probability of cacious, although owing to only one NMOSD declined progressively to 42.9% when TPE recovery to baseline. This is an important patient undergoing IA, the comparison in this was commenced more than 60 days following consideration as restricting TPE as second line cohort was limited. symptom onset. therapy in NMOSD attacks may result in delays However, a retrospective study in NMOSD This was not however supported by another to effective treatment if first line therapy is patients20 not only showed equal efficacy in study,13 which showed similar responder rates unsuccessful. Most steroid treatment protocols both apheresis modalities but as previously irrespective of commencement before or after range between 3-5 days and are only associated mentioned, also supported higher recovery 21 days, out to commencement over 60 days. with complete response rates of up to 35%, in rates with shorter delays to treatment, notably In addition, other series have not found any line with previous studies.15 Hence there are when either technique was employed as first correlation between response to TPE in rela- inherent delays to TPE rescue therapy being line therapy.

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Discussion used in an appropriate timeframe. REFERENCES Corticosteroids have been the main Conversely there is also a risk of over- first line therapy for CNS-IDD due to estimating the benefit of TPE where ease of access, administration and institutions offer this mode of therapy relative safety profile. Certain condi- routinely as first line in clinical attacks 1. Bobati SS, Naik KR. Therapeutic plasma exchange - An emerging treatment modality in patients with neurologic and non-neurologic diseases. Journal of tions within CNS-IDD such as NMOSD of all severities. Nevertheless, there Clinical and Diagnostic Research. 2017;11(8):EC35-EC7. 15 are perhaps less steroid responsive. is mounting evidence to support the 2. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A. In addition, NMOSD attacks are gener- timely use of TPE in NMOSD attacks Evidence-based guideline update: Plasmapheresis in neurologic disorders: ally more severe, conferring a poorer that is becoming difficult to disregard. report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76(3):294-300. prognosis, hence effective and timely How translatable this is to other 3. Guptill JT, Juel VC, Massey JM, Anderson AC, Chopra M, Yi JS, et al. treatment is important. TPE has been conditions within the CNS-IDD spec- Effect of therapeutic plasma exchange on immunoglobulins in myasthenia shown to be effective in CNS-IDD with trum is unknown. Many of the CNS-IDD gravis. Autoimmunity. 2016;49(7):472-9. a favourable adverse effect profile. studies involving MS and CIS had TPE 4. Tackenberg B, Kruth J, Bartholomaeus JE, Schlegel K, Oertel WH, Willcox TPE is well tolerated, with commencement 3 weeks after relapse N, et al. Clonal expansions of CD4+ B helper T cells in autoimmune myas- thenia gravis. Eur J Immunol. 2007;37(3):849-63. low serious complication rates. onset, thereby limiting the contribu- 5. Reeves HM, Winters JL. The mechanisms of action of plasma exchange. Br Complication rates vary based on tion of these findings with regards J Haematol. 2014;164(3):342-51. multiple factors including centre to the utility of TPE in the hyper- 6. Guptill JT, Oakley D, Kuchibhatla M, Guidon AC, Hobson-Webb LD, experience, definition of complica- acute period. Given the likelihood Massey JM, et al. A retrospective study of complications of therapeutic tion, but is higher in the older popula- of shared underlying immunological plasma exchange in myasthenia. Muscle & Nerve. 2013;47(2):170-6. tion, central venous catheters and with mechanisms of different CNS-IDD, TPE 7. Ebadi H, Barth D, Bril V. Safety of plasma exchange therapy in patients with myasthenia gravis. Muscle & Nerve. 2013;47(4):510-4. increasing severity of illness. Technical may be similarly effective in the first 8. Abdel-Rahman EM, Hayes J, Balogun RA. Therapeutic plasma exchange factors related to the TPE machine and few days of more disabling attacks in in the elderly: experience at a tertiary center. Journal of Clinical Apheresis. procedural aspects may also play a conditions outside of NMOSD. This is 2012;27(3):108-11. role in reducing adverse rates with a further direction for research. 9. Weinshenker BG, O'Brien PC, Petterson TM, Noseworthy JH, Lucchinetti greater advances in technology and The concept of TPE as first line CF, Dodick DW, et al. A randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease.Ann Neurol. expertise of administration. therapy in NMOSD is gaining trac- 1999;46(6):878-86. Various prognostic factors tion as cumulative evidence supports 10. Correia I, Ribeiro JJ, Isidoro L, Batista S, Nunes C, Macário C, et al. predicting response to TPE have been this approach.18,20 This would not only Plasma exchange in severe acute relapses of multiple sclerosis – Results from a Portuguese cohort. Multiple Sclerosis and Related Disorders. described.12,13 Favourable prognostic have implications on access proto- 2018;19:148-52. factors include early initiation to TPE, cols in TPE capable hospitals but also 11. Llufriu S, Castillo J, Blanco Y, Ramio-Torrenta L, Rio J, Valles M, et al. early response to TPE, ring enhancing on outer district hospitals that they Plasma exchange for acute attacks of CNS demyelination: Predictors of lesions, associated oedema, preserved serve. Once again, the role which TPE improvement at 6 months. Neurology. 2009;73(12):949-53. reflexes and male gender. plays in other CNS-IDD as potentially 12. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG. Plasma exchange for severe attacks of CNS demyelina- Early initiation to TPE is an first line or adjunct therapy, that is tion: predictors of response. Neurology. 2002;58(1):143-6. important consideration, given it is concurrent therapy to corticosteroids 13. Magana SM, Keegan BM, Weinshenker BG, Erickson BJ, Pittock SJ, Lennon a variable that can be controlled to as opposed to rescue therapy, needs VA, et al. Beneficial plasma exchange response in central nervous system a degree allowing for other issues to be better defined. inflammatory demyelination.Archives of Neurology. 2011;68(7):870-8. such as treatment access. There is There is upcoming evidence that IA 14. Cabre P, Gonzalez-Quevedo A, Bonnan M, Saiz A, Olindo S, Graus F, et al. Relapsing neuromyelitis optica: long term history and clinical predictors competing evidence in several may be used as an alternative to TPE of death. J Neurol Neurosurg Psychiatry. 2009;80(10):1162-4. CNS-IDD series with regards to greater in CNS-IDD given it appears to have 15. Abboud H, Petrak A, Mealy M, Sasidharan S, Siddique L, Levy M. benefit in those with TPE commence- similar efficacy. There is conflicting Treatment of acute relapses in neuromyelitis optica: Steroids alone versus ment within 21 days of relapse. There evidence regarding a superior safety steroids plus plasma exchange. Multiple Sclerosis. 2016;22(2):185-92. were other CIS and MS relapse trials profile with IA which needs further 16. Jiao Y, Cui L, Zhang W, Zhang Y, Wang W, Zhang L, et al. Plasma Exchange for Neuromyelitis Optica Spectrum Disorders in Chinese Patients that had found no relation to timing clarification. and Factors Predictive of Short-term Outcome. Clinical Therapeutics. of TPE and responder rates however 2018;40(4):603-12. the initiation period was 1-3 months Conclusions 17. Kumar R, Paul BS, Singh G, Kaur A. Therapeutic efficacy of plasma following relapse. There is emerging evidence that early exchange in neuromyelitis optica. Annals of Indian Academy of Neurology. 2018;21(2):140-3. There is stronger evidence in TPE in NMOSD relapses results in more 18. Bonnan M, Valentino R, Debeugny S, Merle H, Fergé JL, Mehdaoui H, NMOSD that earlier initiation in TPE favourable outcomes, with greater than et al. Short delay to initiate plasma exchange is the strongest predictor confers a more favourable outcome. half of patients accruing disability with of outcome in severe attacks of NMO spectrum disorders. Journal of More recently, there is greater delays in TPE greater than one week Neurology, Neurosurgery and Psychiatry. 2018;89(4):346-51. evidence that early TPE within two post symptom onset. This proportion 19. Hofmann JC, Kiprov DD. Special Issue Abstracts From the American Society for Apheresis 38th Annual Meeting May 3-6, 2017 Fort Lauderdale, Florida. to five days of symptom onset may increases with progressive delays to Journal of Clinical Apheresis. 2017;32(2):71-142. offer the greatest degree of recovery treatment. Practically, timely access to 20. Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Hellwig K, for patients, declining progressively TPE should be considered in NMOSD et al. Apheresis therapies for NMOSD attacks: A retrospective study of subsequently, even with delays of only relapses, potentially concurrently with 207 therapeutic interventions. Neurol Neuroimmunol Neuroinflamm. 2018;5(6):e504. one week.20 IV steroids. In this clinical context 21. Oji S, Nomura K. Immunoadsorption in neurological disorders. Transfus For this reason, incorporating it would appear ‘time is brain and Apher Sci. 2017;56(5):671-6. TPE earlier, or even as part of first spine’. 22. Kohler W, Bucka C, Klingel R. A randomized and controlled study line therapy in NMOSD should be This points to a clear direction for comparing immunoadsorption and plasma exchange in myasthenic crisis. J considered, given the overall poorer research to provide insight into these Clin Apher. 2011;26(6):347-55. prognosis associated with such unanswered questions. How reprodu- 23. Schneider-Gold C, Krenzer M, Klinker E, Mansouri-Thalegani B, Mullges W, Toyka KV, et al. Immunoadsorption versus plasma exchange versus attacks. TPE declines in efficacy with cible this concept is in other CNS combination for treatment of myasthenic deterioration. Ther Adv Neurol time, as seen when implemented late inflammatory demyelinating disorders Disord. 2016;9(4):297-303. as rescue therapy in steroid resistant remains unclear, although there is 24. Lipphardt M, Muhlhausen J, Kitze B, Heigl F, Mauch E, Helms HJ, et al. cases. Retrospectively, this may have some evidence indicating a similar Immunoadsorption or plasma exchange in steroid-refractory multiple scle- rosis and neuromyelitis optica. J Clin Apher. 2019;34(4):381-91. initially confounded the degree of trend. Once again, the void in this benefit from what has now emerged arena provides an impetus for further Acknowledgment - Literature search: Bronia Renison. (2018). The Townsville as a highly efficacious treatment when research. Hospital, Qld, Australia.

12 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 rehabilitation a r t i c l e An expert opinion: Optimisation of pharmacological management of multiple sclerosis

Dr Rachel Farrell related spasticity is a Consultant Neurologist at the National Hospital in Queen Square, and an Honorary Senior Lecturer in the Abstract experiences, diurnal variation, trigger factors department of Neuroinflammation Queen Spasticity is a frequent symptom in people with including infections, bladder and bowel dysfunc- Square, Institute of Neurology, UCL. Dr Multiple Sclerosis. Whilst many respond to first tion, skin breakdown, suitability and fit of splints, Farrell specialises in Neurorehabilitation line therapies it is estimated that 30-40% will and impact on walking and other activities. and complex spasticity management particularly in Multiple Sclerosis (MS). She have suboptimal treatment response requiring Generic and disease specific outcome measures completed a PhD in the department of more specialised management. Such strategies can be used. A combination of objective (hands Neuroimmunology at the UCL Institute include combination of oral medications, botu- on) and patient reported outcome measures is of Neurology, investigating aspects of linum toxin, nabiximols and consideration of essential to understand the degree of spasticity disease modifying treatment for MS. experienced and to monitor response to any Clinically Dr Farrell works in the complex intrathecal therapies; baclofen or phenol. Early spasticity service at the NHNN and leads a expert intervention as outlined in this review can intervention. The most commonly used measure multidisciplinary service to manage walking have a positive impact on functional ability and is the Ashworth or modified Ashworth scales impairment in people with MS. quality of life for people with MS. which are easy to administer in clinical practice.4 There are conflicting reports, however, regarding ultiple sclerosis (MS) is one of the the validity and reliability of these measures. The leading causes of non-traumatic acquired Tardieu scale, commonly used in cerebral palsy Mdisability in young people affecting and stroke, has not been validated for use in MS more than 120,000 people in the UK and about spasticity.5 The MS spasticity scale (MSSS-88) is an 2.5 million people worldwide.1 Significant 88 item patient-based interval level scale which advances have been made in MS disease modi- evaluates the symptoms the patient experiences fying therapies (DMTs) including the progres- and how spasticity affects their daily life.6 The sive phase.2 However, many people live with numerical rating scale for spasticity (NRS) is a David Baker troublesome symptoms related to the disease. 0-10 point scale where the individual will rate is Professor of Neuroimmunology at the The North American Research Committee on the severity of their spasticity over the previous Blizard Institute, Barts and the London 7 School of Medicine & Dentistry, Queen MS (NARCOMS) Registry has identified 11 key 24 hours. There is concern, however, that the Mary University of London. He has symptom domains that are commonly affected individual might rate other symptoms such as been using animal models to investigate in MS: mobility, hand function, tremor/coordina- weakness or pain, rather than spasticity in isola- control of the immune response and tion, vision, pain, fatigue, bowel/bladder function, tion, however this may additionally reflect quality neurodegeneration and symptom control 3 and uncovered the value of cannabinoids sensory, spasticity, cognition, and depression. of life. Other measures which might be useful in for the control of spasticity related to More than 80% of respondents reported spasticity clinical practice include a spasm score or func- multiple sclerosis. during their disease course and spasticity severity tional measures such as timed walking tests (25 Correspondence to: was reported as moderate or high by between 35% foot walk, 10 metre walk) or measures of upper Dr Rachel Farrell, and 54% of respondents. This was associated with limb function (9 hole peg test). Neurorehabilitation, National Hospital of stiffness, spasms, and/or pain, mainly in the lower Neurology and Neurosurgery, limbs. Key aspects of managing MS-related spas- Current pharmacological treatments Queen Square, London WC1N 3BG. Email: [email protected] ticity are understanding the pathophysiology of The basis of pharmacological treatment of spasticity, use of appropriate outcome measures MS spasticity remains with the use of first line Conflict of interest statement: Dr Farrell has received honoraria and hospitality from and a personalised approach to pharmacological agents: Baclofen, Tizanidine and Gabapentin Merck, Canbex pharmaceuticals Ltd, TEVA, treatment in the context of the patient’s activities (pregabalin).8 Whilst many will respond to Novartis, Genzyme, Allergan, Merz, GW and quality of life. such treatment about one third will continue Pharma and Biogen. Spasticity is defined by Lance as “a motor to experience problematic symptoms.9 Addition Acknowledgements: Dr Rachel Farrell is disorder characterised by a velocity dependent of second line agents such as benzodiazepines supported by the UCLH NIHR Biomedical increase in tonic stretch reflexes with exagger- (e.g. diazepam and clonazepam) may be helpful Research Centre. ated tendon jerks, resulting from hyperexcitability but are frequently associated with side effects Provenance and peer review: Submitted and of the stretch reflex, as one component of the including CNS depression, memory impairment externally reviewed. Upper Motor Neuron syndrome”. It is clinically are common as is dependence and withdrawal Date first submitted: 5/8/19 important to differentiate between neural and syndrome if stopped abruptly. Although there are Date submitted after peer review: 17/9/19 non-neural components of stiffness to inform distinct mechanisms of actions, many of these Acceptance date: 21/9/19 management. Optimum management requires agents may serve to hypopolarise neurons, such as To cite: Farrell R, Baker D. ACNR a multidisciplinary team approach including a through opening of chloride channels (benzodi- 2019;19(1):13-15. Neurologist or Rehabilitation Medicine Physician, azepines) or potassium channels and blockage of Physiotherapist, Specialist Nurse and access to calcium channels (baclofen and cannabinoids), occupational therapy and splinting. to block hyperexcitability, to quell the spastic response.10 Dantrolene is unique in its mode Assessment and outcome measures of action impacting the contractile mechanism Thorough assessment of the impact of spasticity of skeletal muscle by decreasing the release of on the individual is key. This involves accurate calcium. Its use is limited by frequent side effects history taking as to the symptoms the individual including gastrointestinal symptoms, weakness,

ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 > 13 rehabilitation a r t i c l e

sedation and dizziness. The risk of hepatotox- Figure 1 MDT spasticity assessment. Does spasticity impact icity is a major limiting factor and requires Spasticity Algorithm function, passive care or cause pain? monitoring of liver function prior and during Yes No therapy. In a Cochrane review of anti-spasticity Optimise self management and agents for MS the conclusions were that there Identify and treat aggravating monitor was in general low quality evidence of the factors and physical strategies. Improved? No efficacy of these agents to treat MS related spas- Is spasticity generalised or focal ticity and that better outcome measures are Yes Generalised required in trials to reflect efficacy and impact Focal Optimise self management on quality of life.11 Introduce 1st line agents: baclofen, tizanidine or and monitor closely gabapentin. Optimise dose Botulinum toxin Improved? Cannabinoids and MS spasticity Loss efficacy, injection No Yes Cannabis has been used recreationally and burden? Yes Optimise dose, self Consider focal nerve block Introduce 2nd line agents: BZPs, medicinally by people with MS for many dantrolene or nabiximols management and monitor years prompting a research programme inves- Improved? tigating utility of cannabis-based medicinal No products (CBMPs) in MS.12-14 Biologically Evaluate suitability for ITB or ITP there is evidence that cannabis-based prod- ucts modulate spasticity via CB1 receptors.15 The whole plant extract contains hundreds of tion, particularly perineal hygiene. It should be tered intrathecally for severe lower limb spas- chemical entities, however the two compon- considered as a useful option for focal problem ticity in people not appropriate for ITB. As a ents of greatest interest are delta9 tetrahydro- areas and avoids the central side effects of focal treatment it may act as a substitute for cannabinol (THC) and cannabidiol (CBD) systemic agents. A recent consensus group BoNT if repeated injections are considered as the major psyochactive and non-psycho- has published the UK National guidelines on detrimental to the patient or not considered active ingredients of cannabis that has been use of botulinum toxin in the management of cost effective. This topic has previously been recently approved for some epilepsy conditions, adult spasticity www.rcplondon.ac.uk/guide- reviewed in ACNR27 {Gaid M, 2012 3291 /id}. respectively. Studies investigating synthetic lines-policy/spasticity-adults-management- Phenol or alcohol mediate their effect through THC, whole plant extracts, smoked cannabis using-botulinum-toxin.23 two different pathways, low dose eg 2% phenol and THC:CBD (Nabiximols) have been for an anaesthetic effect or high dose eg >3% reported.12,16-18 In 2010 THC:CBD (Nabiximols) Intrathecal Baclofen phenol for neurolysis causing denaturation was licensed for moderate to severe MS related Intrathecal baclofen (ITB) is administered via and fibrosis of the nerve which is largely spasticity having shown a significant improve- a programmable, subcutaneously implanted irreversible.28 Similarly low dose alcohol has ment in patient reported spasticity on the NRS as drug delivery system, delivering low doses of an anaesthetic effect and high dose (>50%) is compared with placebo.18 In this pivotal trial the Baclofen directly intradurally around the spinal neurolytic. Following phenol treatment, partial patient cohort was enriched only randomising cord where GABA-B receptors are expressed nerve regeneration and sprouting occurs so responders to ongoing treatment or placebo. in high density. It should be considered in that the clinical effect may ‘wear off’ in about Use of an enriched design is controversial as people with predominantly lower limb spas- 30%. In our experience intrathecal phenol is a is the NRS spasticity as the primary outcome, ticity inadequately managed by 1st and 2nd highly effective treatment in carefully selected thus many regulatory bodies do not accept this line oral agents. In our experience reporting subjects. It will usually impair bowel, bladder as high quality evidence, despite some posi- the impact of ITB in 106 people with MS, the and sexual function and management plans tive evidence of effects on the Ashworth scale benefit of ITB has proved to be sustainable over must be in place in this regard. At the NHNN in small scale academic studies.19,20 However, time with a positive impact on the Ashworth over a 12 year period 2006-2018, 45 people currently THC:CBD is unlicensed by the Food scale, spasm scores and range of movement underwent ITP successfully with a reduction in and Drug Administration (FDA) and variably and has the added benefit of withdrawing oral spasticity on the Ashworth scale, penn spasm reimbursed throughout Europe. In the UK, NICE medications and reduced side effects.24 Early scale and higher levels of comfort. Due to its MS clinical guidelines have recommended series concentrated on people with signifi- destructive and potentially irreversible nature against its use as it is not deemed cost-ef- cant levels of disability but more recently ITB ITP remains a last resort. fective [NICE MS CG 186 2014]. Cannabis based proved to be effective in improving mobility in products are also available in North America, carefully selected individuals; prompting ITB to Discussion Australia and in some European countries and be considered earlier to improve or maintain Spasticity remains a problematic symptom in in November 2018 cannabis based products for walking.25 The main concern in ambulatory people with advanced MS and when sub-opti- medicinal use were moved to Schedule 2 of the individuals is that the therapeutic effect may mally treated leads to significant impairment Misuse of Drugs Regulations 2001 raising the increase weakness and negatively impact on and distress. Unlike the DMT options for MS profile and demand for CBMPs. Many people walking and transfers, as some people with MS there are limited new drugs for spasticity, nabix- with MS are using CBD or whole plant products, are reliant on a degree of hypertonia to be able imols being the only recently licensed option, however there is a lack of clinical trial evidence to transfer and mobilise. In our cohort at the with severely restricted access. People with MS that these treatments are effective and there has NHNN we have found that preserved baseline should be treated with at least two first line yet to become a recognised supply route for walking speed and lower limb muscle strength agents commencing at low doses and escal- medical practitioners.21 predict ambulation after ITB25 {Sammaraiee, ating the dose frequently until effect is gained, 2019 3287 /id}. Another recently published side effects appear or the maximum dose is Botulinum toxin cohort following 47 subjects for up to 1 year, 32 reached. Second line agents should then be BoNT mediates its effect by interfering intra- remained ambulatory for up to 1 year. Efficacy added for additional effect. Botulinum toxin or cellularly with the process of Ca2+ regulated was also noted on modified Ashworth, NRS focal nerve blocks are useful for localised prob- synaptic vesicle exocytosis, and thereby pain and spasm.26 lematic areas. In people, including those who preventing release of their contents into the remain ambulatory, who have failed 1st and synaptic cleft, namely acetylcholine.22 Early Chemical Neurolysis 2nd line systemic agents, intrathecal therapies trials of BoNT in MS addressed hip adductor Chemical neurolysis consists of either a local are reasonable options and they should be tone and showed a significant reduction in injection of ethanol or phenol to manage referred to specialised multidisciplinary service spasticity and an improvement in passive func- an area of focal spasticity or when adminis- for optimal management.

14 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 rehabilitation a r t i c l e

REFERENCES

1. Compston A, Coles A. Multiple sclerosis. Lancet 11. Shakespeare DT, Boggild M, Young C. Anti-spasticity 20. Trojano M, Vila C. Effectiveness and Tolerability of THC/ 2002;359(9313):1221-1231. agents for multiple sclerosis. Cochrane Database Syst CBD Oromucosal Spray for Multiple Sclerosis Spasticity 2. Montalban X, Gold R, Thompson AJ et al. ECTRIMS/ Rev 2003;(4):CD001332. in Italy: First Data from a Large Observational Study. Eur EAN Guideline on the pharmacological treat- 12. Zajicek J, Fox P, Sanders H et al. Cannabinoids for Neurol 2015;74(3-4):178-185. ment of people with multiple sclerosis. Mult Scler treatment of spasticity and other symptoms related to 21. Allan GM, Finley CR, Ton J et al. Systematic review 2018;24(2):96-120. multiple sclerosis (CAMS study): multicentre randomised of systematic reviews for medical cannabinoids: Pain, placebo-controlled trial. Lancet 2003;362(9395):1517- 3. Kister I, Bacon TE, Chamot E et al. Natural history nausea and vomiting, spasticity, and harms. Can Fam 1526. of multiple sclerosis symptoms. Int J MS Care Physician 2018;64(2):e78-e94. 2013;15(3):146-158. 13. Collin C, Davies P, Mutiboko IK, Ratcliffe S. Randomized controlled trial of cannabis-based medicine 22. Schiavo G, Santucci A, Dasgupta BR et al. Botulinum 4. Bohannon RW, Smith MB. Interrater reliability of a in spasticity caused by multiple sclerosis. Eur J Neurol neurotoxins serotypes A and E cleave SNAP-25 at modified Ashworth scale of muscle spasticity.Phys Ther 2007;14(3):290-296. distinct COOH-terminal peptide bonds. FEBS Lett 1987;67(2):206-207. 1993;335(1):99-103. 14. Wade DT, Makela PM, House H, Bateman C, Robson 5. Haugh AB, Pandyan AD, Johnson GR. A systematic P. Long-term use of a cannabis-based medicine in the 23. Royal College of Physicians. Spasticity in adults: review of the Tardieu Scale for the measurement of spas- treatment of spasticity and other symptoms in multiple management using botulinum toxin. National ticity. Disabil Rehabil 2006;28(15):899-907. sclerosis. Mult Scler 2006;12(5):639-645. Guidelines. 20-3-2018. 6. Hobart JC, Riazi A, Thompson AJ et al. Getting the 15. Pryce G, Baker D. Control of spasticity in a multiple scle- 24. Sammaraiee Y, Yardley M, Keenan L, Buchanan K, measure of spasticity in multiple sclerosis: the Multiple rosis model is mediated by CB1, not CB2, cannabinoid Stevenson V, Farrell R. Intrathecal baclofen for multiple Sclerosis Spasticity Scale (MSSS-88). Brain 2006;129(Pt receptors. Br J Pharmacol 2007;150(4):519-525. sclerosis related spasticity: A twenty year experience. 1):224-234. 16. Corey-Bloom J, Wolfson T, Gamst A et al. Mult Scler Relat Disord 2019;27:95-100. Smoked cannabis for spasticity in multiple scle- 7. Farrar JT, Troxel AB, Stott C, Duncombe P, Jensen MP. 25. Sadiq SA, Wang GC. Long-term intrathecal baclofen rosis: a randomized, placebo-controlled trial. CMAJ Validity, reliability, and clinical importance of change in therapy in ambulatory patients with spasticity. J Neurol 2012;184(10):1143-1150. a 0-10 numeric rating scale measure of spasticity: a post 2006;253(5):563-569. hoc analysis of a randomized, double-blind, placebo-con- 17. Vaney C, Heinzel-Gutenbrunner M, Jobin P et al. trolled trial. Clin Ther 2008;30(5):974-985. Efficacy, safety and tolerability of an orally adminis- 26. Lee BS, Jones J, Lang M et al. Early outcomes after tered cannabis extract in the treatment of spasticity in intrathecal baclofen therapy in ambulatory patients with 8. Otero-Romero S, Sastre-Garriga J, Comi G et al. patients with multiple sclerosis: a randomized, double- multiple sclerosis. J Neurosurg 2018;129(4):1056-1062. Pharmacological management of spasticity in multiple blind, placebo-controlled, crossover study. Mult Scler sclerosis: Systematic review and consensus paper. Mult 26. NATHAN PW, Sears TA, Smith MC. Effects of phenol 2004;10(4):417-424. Scler 2016;22(11):1386-1396. solutions on the nerve roots of the cat: an electrophysio- 18. Novotna A, Mares J, Ratcliffe S et al. A randomized, logical and histological study. J Neurol Sci 1965;2(1):7- 9. Pozzilli C. Advances in the management of multiple double-blind, placebo-controlled, parallel-group, 29. sclerosis spasticity: experiences from recent studies enriched-design study of nabiximols* (Sativex((R)) 27. Gaid M. Phenol Nerve Block for Management of Lower and everyday clinical practice. Expert Rev Neurother ), as add-on therapy, in subjects with refractory 2013;13(12 Suppl):49-54. spasticity caused by multiple sclerosis. Eur J Neurol Limb Spasticity. Advances in Neurological Science and Rehabilitation . 11-12-2012. 10. Baker D, Pryce G, Jackson SJ, Bolton C, Giovannoni G. 2011;18(9):1122-1131. The biology that underpins the therapeutic potential of 19. Leocani L, Nuara A, Houdayer E et al. Sativex((R)) 28. Simeoni S, Keenan E, Lee H et al. Intrathecal phenol is a cannabis-based medicines for the control of spasticity in and clinical-neurophysiological measures of spas- safe and effective treatment option for severe lower limb multiple sclerosis. Mult Scler Relat Disord ticity in progressive multiple sclerosis. J Neurol spasticity in advanced multiple sclerosis. Mult.Scler. 24, 2012;1(2):64-75. 2015;262(11):2520-2527. 596. 9-9-2018.

EXPERT TRAINING IN MS MS Foundation MasterClass Module 1: 18-20 March + Module 2: 17-18 Sept 2020 The Essentials of MS Intermediate MasterClass Module 1: 10-12 June + Module 2: 3-4 Dec 2020 Neuropsychiatry MS Advanced MasterClass Module 1: 4-6 Nov 2020 + Module 2: 20-21 May 2021 13th15th December, 2019 BNPA Neurology & Neuropsychiatry Oxford Teaching Weekend This weekend course is aimed at Specialist Registrars in neurology and psychiatry. It is also open to neuropsychologists and will MSLeaders review key areas of neuropsychiatry. : The MS Leadership MasterClass will give you the Registration tools you need to confidently and effictively lead www.bnpa.org.uk cange, so that people with MS in your area get the best possible care and support they can. For all other enquiries including sponsors contact MS Leadership MasterClass Jackie Ashmenall Module 1: 19-21 Feb + Module 2: 30 Sept-2 Oct 2020 Telephone: +44 (0)20 898 76111 Apply now for your fully funded place: Email: [email protected] multiplesclerosisacademy.org/courses

ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 > 15 e s s a y

David Veale, MD, MPhil, BSc, Safety versus sleep FRCPsych, FBPsyS, Hon FBABCP, is a Consultant Psychiatrist – is a lack of protected sleep and Visiting Professor in Cognitive Behavioural Therapies at the Institute of Psychiatry, Psychology time on psychiatry wards bad for and Neurosciences, King’s College London. He leads a national outpatient and inpatient service for mental health? people with severe treat- ment refractory OCD and BDD at the Maudsley Hospital, London and the urveys of psychiatric in-patients find that certain time. Policies usually require the staff Priory Hospital, North London. He was a member the large majority experience insomnia member to clearly see the patient is breathing of the group revising the diagnostic guidelines because of the noise and light on the which can involve either opening the window for ICD11 for Obsessive Compulsive and Related S Disorders for the World Health Organisation. He ward, and from nursing observations.1,2 This hatch in the door or entering the bedroom was a member of the group that wrote the NICE is a bidirectional relationship, as insomnia and shining a torch on the patient’s face or guidelines on OCD and BDD in 2006 and chaired is a symptom of psychiatric disorder and switching on a light or waking the patient by the NICE Evidence Update on OCD in 2013. sleep deprivation also makes most psychi- shaking them. There are many complaints atric disorders worse.3 Importantly, sleep by patients about the practice as it disturbs Dr A Felix de Carvalho, MBBS BSc duration is negatively correlated with subse- their sleep and they are frequently unable to MRPsych, quent length of time in hospital4 and leads get back to sleep. However, the documen- is a specialty doctor to negative changes in the neuroendocrine, tation of a patient’s safety has become the in Psychiatry at South London and Maudsley immune and inflammatory systems, as well only metric of importance to regulators and Trust. He is originally from as hypertension. Furthermore, evidence from managers. No research or discussion has Lisbon and completed his correlational and experimental studies have ever been published into the effectiveness undergraduate training at demonstrated that reduced and/or disturbed for risk management of nursing observations the University of Lisbon and at the Autonoma sleep has a severe effect on emotional regula- at night. Sleep deprivation and worsening University of Barcelona. tion.5 Thus sleep deprived individuals experi- of symptoms for the many might be justified He has a particular ence an increase in anxiety and depression if it significantly reduced the frequency of interest in Psychological which is especially relevant in those who suicide or severe self-harm. However, the Therapies and their importance in various psychi- atric conditions. He aims to become a Child and do not tolerate distress. This article aims to effectiveness of intermittent observations at Adolescent Consultant Psychiatrist and focus on explore the negative impact of routine inter- night in preventing suicide is highly ques- Neurodevelopmental Disorders. mittent nursing observations on the quality of tionable. Only a small number of suicides in patients’ sleep whilst on inpatient units, and mental health patients occur during inpatient Dr Jessica Coffin, MA (Cantab), the subsequent effect this has on their mental stays (114 suicides per annum, compared to MBBS, LGSMD, ATCL, DipABRSM wellbeing and length of stay. 1600 suicides per annum by people known is a Psychiatry Core Psychiatric nursing observation is defined to psychiatric services in the community). Trainee (Year 3) doctor, as ‘...regarding the patient attentively, mini- Furthermore, between 2011 and 2016, only currently working at the mising the extent to which they feel they are 54 of the 338 inpatient suicides of patients National Anxiety Disorders Residential Unit, South under surveillance, encouraging communica- known to mental health services occurred London and the Maudsley tion, listening, and conveying to the patient between the hours of 23:00 and 07:00 (16%).9 NHS Foundation Trust. that they are valued and cared for.’6 National Unfortunately, there are no statistics collected She studied medicine Institute for Health and Care Excellence on the frequency of severe self-harm. at Cambridge University 7 and University College guidelines define various levels of observa- However, it would be surprising if the pattern London, graduating in tion determined by a risk assessment, espe- of self-harm was very different to the reduced 2015. She has a special interest in OCD-related cially for severe self-harm, suicide, violence risk of suicide between 23:00h and 07:00h. disorders and adolescent mental health. and absconding. Despite this, typically in What is also known is that 91% of inpatient Correspondence to: psychiatric hospitals general observations deaths by suicide occur under intermit- David Veale, Centre for Anxiety Disorders and which occur hourly or intermittent observa- tent, rather than constant, observations.10 Trauma, The Maudsley Hospital, London SE5 8AZ. tions which occur up to four times an hour Furthermore, about two out of the 13.7 per Email: [email protected] are still used as standard during the day and 10,000 mental health admissions that result Conflict of interest statement: night times. The importance of ‘engage- in suicide, die at night between 23:00h and None declared. ment’, that is, emotional and psychological 07:00h, and the overwhelming majority of containment of distress and giving of hope is these occur under intermittent observations.11 Provenance and peer review: emphasised as a genuine, not just linguistic However, it is true that, because there are no Submitted and externally reviewed. alternative to observation.8 National guidance randomised control trials, we therefore do not Date first submitted: 12/8/19 and local policies assume that nursing obser- know how many deaths have been prevented Date submitted after peer review: 1/9/19 vation operates over 24 hours. As we believe, (or delayed until the day) by intermittent 9/9/19 Acceptance date: this is where part of the problem lies: ‘engage- observations. This is due to the very low To cite: de Carvalho AF, Coffin J & Veale D. ment’ is not required at night when a patient rate of suicide at night, which would there- ACNR 2019;19(1):16-17. needs to sleep and to be kept safe. fore lead to a requirement of about 250,000 It is up to the nursing staff to determine what patients, to demonstrate non-inferiority fulfils ‘reasonable’ observation when patients between patients on intermittent vs general are sleeping at night. A variety of practices observations at night. and frequency of observations are used at Our impression is that routine intermittent night to document that a patient is safe at a observations at night currently cause sleep

16 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 e s s a y r e g u l a r s – b o o k r e v i e w s

50 Human Brain Ideas You Really deprivation for the majority of inpatients. They also appear to do little to prevent suicide and severe self-harm, and are Need to Know just as likely to increase the risk of this during the day. This is because insomnia increases the severity of mental health conditions, and specifically increases the risk of emotional dysregulation. Furthermore, suicide is far less common at night time, and staff are not expected to engage with the patient during the night, which further reduces the value of intermittent observations during the night. For these reasons, night time observations cannot be justified on the grounds that they keep patients safe.12 Understandably, a policy of placing a patient under inter- mittent observations at night because they are rated at low or medium risk of suicide allows an institution to feel they are doing something to manage risk and protect themselves from criticism, from regulators or negligence claims. However, there is no evidence for differentiating between low, medium and high risk in psychiatric inpatients, and no evidence that intermittent observations prevent suicide, as outlined above.13 It would make more sense to differentiate between those patients at immediate risk of suicide, and place them on Author: Moheb Costandi constant observations, and patients who are not at immediate Published by: Quercus Publishing (2013) risk, and leave them on general observations during the night. Price: £12.99 It also makes more sense for patients to receive individualised Pages: 207 ISBN: 9781780879109 care plans, in which their observations can differ during the Reviewed by: Rhys Davies, Consultant Neurologist, Liverpool. day and night, depending on their risk profiles.14 In conclusion, optimising the sleep of patients on psychi- atric wards should be a priority for staff, in order to prevent his book is not intended for people like us worsening of mental health conditions, improving the well- but, in our busy lives where time is very being of patients and thereby reduce the risk of patients dying Tshort even when funds aren’t, two hundred by suicide whilst an inpatient. pages for £12 can’t be bad. Furthermore, you can give the first quarter on basic Neuroanatomy and Neurophysiology a miss without losing out. That’s unless you want to do some DIY quality

REFERENCES assurance. Of course the 50 short chapters on classical and current subjects in Neuroscience are inad- 1. Horne S, Hay K, Watson S, Anderson KN. An evaluation of sleep disturbance equate. They are not referenced with anything on in-patient psychiatric units in the UK. BJPsych Bulletin 2018; 42(5): 193–7; approaching the rigour we would expect in 2. Muller MJ, Olschinski C, Kundermann B, Cabanel N. Subjective sleep quality our professional reading. The treatment of the and sleep duration of patients in a psychiatric hospital. Sleep Sci 2016; 9(3): subjects that are ‘close to home’ for us neuro-clin- 202–6; icians is inevitably too brief to add very much. 3. Krystal AD. Psychiatric disorders and sleep. Neurol Clin 2012; 30(4): 1389– This includes the chapters on ‘Brain-damaged 413; 4. Langsrud K, Vaaler AE, Kallestad H, Morken G. Sleep patterns as a predictor Patients’ and ‘Consciousness Disorders’ (my least for length of stay in a psychiatric intensive care unit. Psychiatry Res 2016; favourite turn of phrase in the book). 237: 252–6; However, when I picked this up while browsing 5. Talbot LS, McGlinchey EL, Kaplan KA, Dahl RE, Harvey AG. Sleep deprivation I was relieved to find that the text did not gener- in adolescents and adults: changes in affect. Emotion 2010; 10(6): 831–41; ally grate with facile enthusiasm. I also liked the 6. Bowers L, Gournay K, Duffy D. Suicide and self-harm in inpatient psychiatric units: a national survey of observation policies. J Adv Nurs 2000; 32(2): signposting to key Neuroscience names familiar 437–44; to many of us, from their writing and from 7. National Institute for Health and Care Excellence. Violence and Aggression: hearing their keynote lectures. I found this a good Short-Term Management in Mental Health, Health and Community Settings. compromise in a popular volume, where proper NICE, 2015; citations ‘would not do’, for those wishing to read 8. Cutcliffe JR, Barker P. Considering the care of the suicidal client and the case for ‘engagement and inspiring hope’ or ‘observations’. J Psychiatr Ment Health more deeply. Nurs 2002; 9(5): 611–21; I really think that reading three or four pages’ 9. People with Mental Illness. National Confidential Inquiry into Suicide and worth on epigenetics, on the connectome, the Homicide. Health Quality Improvement Partnership, 2017. default mode and on brain-computer interfaces 10. Flynn S, Nyathi T, Tham SG, Williams A, Windfuhr K, Kapur N, et al. Suicide by mental health in-patients under observation. Psychol Med 2017; 47(13): did me good. I might now be able to utter three 2238–45. or four sentences on these subjects, rather just 11. Powell J, Geddes J, Deeks J, Goldacre M, Hawton K. Suicide in psychiatric than three or four words. I think it will enrich my hospital in-patients. Risk factors and their predictive power. Br J Psychiatry ‘proper’ reading over the coming months. 2000; 176: 266–72. I’d recommend this little book as I might a 12. Malik A, Sim LA, Prokop LJ, Wang Z, Benkhadra K, Murad MH. The asso- ciation between sleep disturbance and suicidal behaviours in patients with handbook describing 50 favourite Parisian loca- psychiatric diagnoses: a systematic review and meta-analysis. Syst Rev 2014; tions before going there for a weekend. Not as 3: 18. good as an actual visit, certainly nothing like true 13. Large M, Myles N, Myles H, Corderoy A, Weiser M, Davidson M, et al. familiarity with the place or individual locations. Suicide risk assessment among psychiatric inpatients: a systematic review and meta-analysis of high-risk categories. Psychol Med 2018; 48(7): 1119–27. Remember to visit the Salpêtrière when you go, 14. People with Mental Illness. National Confidential Inquiry into Suicide and by the way... Homicide. Health Quality Improvement Partnership, 2017.

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Choked disc, optic neuritis, and papilloedema

‘optic neuritis’, ‘choked disc’ and ‘papillitis’,4 although it is clear he was simply renaming JMS Pearce MD, FRCP the appearance of the optic disc already Emeritus Consultant Neurologist, Department of recognised for over 50 years. Neurology, Hull Royal Infirmary, UK. The German term Stauungspapille or Correspondence to: strangled papilla had been employed by the J.M.S. Pearce, 304 Beverley Road Anlaby, ophthalmologist, Albrecht von Gräfe [Graefe] East Yorks, HU10 7BG, UK. Email: [email protected] [*] (1828–1870) (Figure 3). He reported in 1860: Conflict of Interest statement: None declared Date first submitted: 7/11/18 Acceptance date: 10/7/19 a state due to increased pressure within Published online first: 30/7/19 the cranium from the extension of a To cite: Pearce JMS, ACNR 2019;19(1);18-19. proliferating process at the base of the brain along the connective elements of the optic nerve eye (‘descending neur- itis’).5

Abstract He gave a lucid description: Before the invention of the ophthalmoscope in 1851, doctors were neither able to recognise …the papilla very considerably and papilloedema nor to diagnose accurately irregularly swollen; it rose abruptly on intracranial hypertension, malignant hyperten- the one side, to return on the opposite sion and inflammatory and systemic disorders to its proper level. The otherwise trans- affecting the optic fundus. This paper seeks to parent substance appeared turbid with uncover early descriptions and experiments an unusually strong admixture of red, that tried to unravel the causes of the swollen Figure 2. Sir John Herbert Parsons. From Biogr. Mems Fell. R. as did the adjacent retina, whereby the Soc. 1958 4, 204-214. optic disc, its mechanism and its clinical choroidal boundary of the optic nerve significance. Papilloedema is a purely descrip- was completely effaced. The retinal veins tive name that requires the underlying cause and Parsons.3 The word ‘papilloedema’ was were dilated, unusually tortuous, very to be specified. first used in 1908 by Sir John Herbert Parsons dark in streaks, stood out irregularly in (1868–1957) (Figure 2) to replace von Gräfe’s the opaque substance, the arteries were term, ‘choked disc’ (Stauungspapille), caused proportionally slight. (cited by Koster)6 by raised intracranial pressure. Papillitis, a word used in 1879 by Gowers, is derived In this paper I have no new light to shed from the Latin papilla, a nipple. Parsons tried upon the controversial mechanisms of the to distinguish the terms then in use, such as swollen optic disc, but refer to selected histor- ical descriptions, views and experiments (reviewed by Hayreh),7 which tried to unravel them and their causes. Ludwig Türck (1810-68) in 1853 first described retinal haemorrhages, due to stasis in the cavernous sinus caused by the raised intracranial pressure in intracranial tumours.8 But it was von Gräfe, who in four cases of ‘sarcoma cerebri’ observed a:

high–grade swelling of the optic nerve Figure 1. Papilloedema head was determined by ophthalmos- copy,…which was pathologically– apilloedema is perhaps the most important anatomically examined.’ He said that Pphysical signs that the aspiring neurol- pressure of the tumours on the cavernous ogist has to recognise. (Figure 1.) The sinus led to a congestion of the blood in advent of non-invasive imaging techniques the retinal veins, and to the tumefaction is no substitute for its clinical recognition. of the papilla, which gradually led to Before Helmholtz’s (1821–1894) invention of hypertrophy of the connective tissue.5 the ophthalmoscope in 1851,1 doctors were unable clearly to distinguish optic neuritis Hughlings Jackson (1835-1911) in 1871 from uveitis, glaucoma, orbital tumours, and recognised optic neuritis in brain tumours — other ocular and systemic disorders.2 and even described four stages; but wisely At the end of the nineteenth century cautioned that the appearances were not British ophthalmology enjoyed an array of specific and demanded a search for other internationally esteemed exponents, who causes.9 included: Jonathan Hutchinson, Nettleship, Figure 3. Friedrich Wilhelm Ernst Albrecht von Gräfe. From The nomenclature was bewilderingly http://www.mrcophth.com/ophthalmologyhalloffame/ 10 Doyne, Marcus Gunn, Treacher Collins, Paton vongraef.html varied. Harvey Cushing (1869-1939), prefer-

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ring the term choked disc coined by von the accumulation of extracellular fluid in the Choked disc, optic neuritis, and papilloedema Gräfe, wrote: lamina cribrosa.7 …papilledema,…actually conveys Conclusion nothing more of the process than does Many arguments based on nomenclature can choked disc, and its adoption would only be resolved by the view that papilloedema add confusion. can variously result from raised intracranial pressure, malignant hypertension, and from This view was supported in the minutely ischaemic optic neuropathy, demyelination, argued text of Thomas Clifford Allbutt (Figure inflammatory and infiltrative diseases of the 4) (1836-1925), physician to the General optic nerve. Papilloedema is therefore best Infirmary at Leeds. The ophthalmoscope11 was understood as a purely descriptive name that at first underused, causing Allbutt to warn: requires the underlying cause to be specified.

No observer of nervous diseases can now dispense with the use of the ophthalmo- scope; and the reports of cases in which the instrument was not frequently used must henceforth be regarded as defective in an important particular.12 Figure 4. Sir Thomas Clifford Allbutt. From – National Portrait Gallery by Walter Stoneman, circa 1916. NPG Ax46129 Allbutt preferred the term ‘choked disc’,12 though both Hughlings Jackson and William REFERENCES Gowers (1845–1915) in 1879 called it ‘optic ‘‘spot’’ which covers the object looked at neuritis’. Supporting von Gräfe, Allbutt and gives an unnatural colour, the hand 1. Helmholtz H. Beschreibung eines Augenspiegels. Berlin, described: looking, for example, as if covered by a Germany: A Förstner’sche Verlagsbuchhandlung; 1851. brown glove.15 2. Pearce JMS. The Ophthalmoscope: Helmholtz’s Augenspiegel. Eur Neurol 2009;61:244–258. The disc is prominent, its outlines are 3. Duke-Elder S. John Herbert Parsons, 1868-1957. Biogr. dimmed, and the retinal veins are Thomas Buzzard (1831-1919), close friend Mems Fell. R. Soc. 1958;4,:204-214. distended, dark and tortuous. This state both of Hughlings Jackson and Sir David 4. Parsons JH. Pathology of the Eye. London, Hodder & we call choked, swollen, or congested Ferrier, in 1893 reported the association of Stoughton.1908;4:1249 et seq. disc. [with von Gräfe, this he attributed to optic neuritis with disseminated (multiple) 5. von Gräfe A. Über Komplikation von increased pressure within the cranium] sclerosis.16 Sehnervenentzündung mit Gehirnkrankheiten. Arch. f. Ophth. VII, 2. 1860. See: https://archive.org/stream/ At other times we see rather a prolif- Leslie Paton and Gordon Holmes reported b21287429/b21287429_djvu.txt erative than a dropsical process… vessels 60 brain tumour patients and by histological 6. Koster W. Two cases of tumour of the brain, with are now less distended…concealed by examinations explored theories of its patho- remarks on the connexion between cerebral tumours new elements, which also extend over genesis.17 They established that papilloedema and affections of the retina and of the optic nerve. 13 Translated from the Nederlandsch Archief voor Genesen and conceal a wide belt of surrounding was a result of intracranial hypertension and Natuurkunde, le Deel, 4e Aflevering, Utrecht, 1865. retina. To this state the term optic neur- not, as then commonly thought, an inflam- (Continued from page 68C.) Medical Press and Circular. itis, neuroretinitis or descending neuritis matory process. They also observed: ‘as the https://archive.org/stream/…/medicalpresscirc02lon- duoft_djvu.txt is applied disc swells lateralwards, it displaces the retina 7. Hayreh SS. Pathogenesis of optic disc edema in raised … throwing it into series of folds which run intracranial pressure. Prog Retin Eye Res. 2016 However, confusion persisted13 in both nomen- concentric with the edge of the disc.’ (Paton’s Jan;50:108–44. clature and cause, since not all papilloedema folds: now well shown on spectral-domain 8. Türck L. Ein Fall von Hämorrhagie der Netzhaut beider was due to raised intracranial pressure. optical coherence tomography). Augen. Zeit. Ges. Wien. Ärzte. 1853;9:214–218. Cited by Garrison and Morton’s Medical Bibliography [5870]: Edward Nettleship, (1845-1913) who 2nd edn. Andre Deutsch, 1954. removed a cataract from William Gladstone, Pathogenesis 9. Jackson H. Med Times and Gazette 1871;1: 241,341, and attended Queen Victoria for the same Cushing with Bordley experimentally investi- 581. cited in: Lecture on optic neuritis from intracranial condition, was according to Sir John Parsons: gated mechanisms and found that when fluid disease. In: Taylor J, ed. Selected writings of JH Jackson, 2 volumes. 1931. Reprinted: London: Staples Press the most scientific teacher of his time. In 1884 was forced under pressure into the subdural 1958;2:251–64. Nettleship gave a comprehensive account space, there was engorgement of the retinal 10. Lenore FE. Toward a definition of papilledema: a of ‘retro-ocular [syn. retrobulbar] neuritis’, veins and the development of papilloedema. historical review, 1851–1911. Surgical Neurology almost certainly demyelinating, emphasising (Figure 1) They showed that when the fluid 1982;17(3):178 – 180. pain on eye movement, abnormal disc appear- pressure was greater than venous pressure 11. Allbutt TC. On the Use of the Ophthalmoscope in Diseases of the Nervous System, Kidneys, etc. Macmillan: I871. ances and impaired colour vision.14 Eleven there was engorgement of the retinal veins, 12. Allbutt TC. On The Causation And Significance Of of his 16 patients had a central scotoma. He and when it approached the arterial pressure The Choked Disc In Intracranial Diseases. Brit med J accurately characterised its features: a high grade choked disc resulted.18 1872;1:443–5. A swollen disc caused by raised intra- 13. Horsley V. Optic Neuritis,’ ‘Choked Disc,’ Or Failure of sight limited to one eye, often cranial pressure affects visual acuity late in its ‘Papilloedema. Br Med J. 1910;1:553–558. accompanied by neuralgic pain about the course, whereas inflammatory, demyelinating, 14. Pearce JMS. Edward Nettleship and Optic neuritis. Advances in Clinical Neuroscience and Rehabilitation. temple and orbit and by pain in moving ischaemic, and proliferative optic neuritis 2017;17(1);15–16. the eye; many recover but permanent results in early loss of acuity, an enlarged blind 15. Nettleship E. On cases of retro–ocular neuritis. Trans damage and even total blindness may spot, central or paracentral scotoma, and Ophthal Soc UK 1884;4:186–226. ensue; there is at first little, sometimes impaired colour vision. When papilloedema 16. Buzzard T. Atrophy of the optic nerve as a symptom of no, ophthalmoscopic change, but the is caused by raised cerebrospinal fluid pres- chronic disease of the central nervous system. Br Med J 1893;2:779-784. disc often becomes more or less atrophic sure, the pressure in the optic nerve sheath in a few weeks… The defect in vision is slows axoplasmic flow causing swelling of [*] Perhaps better known for von Gräfe’s sign in hyper- thyroidism: a failure of the upper lid to follow a down- often described at first as a ‘‘gauze’’ or optic nerve fibres and the optic disc. This ward movement of the eyeball when the patient looks a ‘‘yellow mist’’ or a ‘‘dark patch’’ or a oedema induces secondary venous stasis and downward.

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Emma C Argaet, BHlthSc Benign Positional MClinAud, is an Audiologist at Royal Prince Alfred Hospital, Sydney, and a Research Affiliate of the University Vertigo and its mimics of Sydney. Her clinical work entails compre- hensive audio-vestibular function assessments of Abstract latency of seconds, rapidly rises in velocity to patients with vertigo or Benign positional vertigo (BPV) is well known a peak, and decays within one minute as the balance disturbance. Her to produce brief episodes of vertigo triggered otoconia reach the lowest gravitational point translational research focuses on the differential diagnosis of benign by head movements in the plane of the and the cupula returns to a neutral position positional nystagmus and central positional affected semicircular canal. The character- (Figure 1).4 In our sample of 100 subjects with nystagmus. istics of the positional nystagmus reflect the posterior canalithiasis, the median nystagmus location of the otoconia within the semi- onset latency was 1.4s (range 0-14.2s), Andrew P Bradshaw, BE BSc PhD, circular canal. Here we review the nystagmus duration was 12.5s (range 2.5-34.5s) and peak is an engineer at Royal profiles of common BPV subtypes and present slow-phase velocity (SPV) was 37.3°/s (range Prince Alfred Hospital, Sydney, and a postdoc- three mimics that could be misdiagnosed as 3.1-218.6°/s). The peak SPV was reached at toral researcher with the BPV. 2.9s (range 0-19.2s) after onset and declined University of Sydney. by half within 3.4s (range 1.1-16.4s). He completed his PhD Introduction In posterior cupulolithiasis, the nystagmus in three-dimensional reconstruction tech- Vertigo brought on by head movement is direction is the same however there may niques of the temporal the hallmark of benign positional vertigo be no latency, the nystagmus is less intense bone anatomy in 2013. (BPV) in which displaced otoconia from the and persists for more than one minute as the His current work focuses otolith maculae stimulate the semicircular heavy cupula deflects downwards, providing on the development of new approaches for the 5 analysis of spatio-temporal profiles of nystagmus canal afferents in response to changes in head sustained stimulation. and the characteristics of the vestibulo-ocular position. Positional nystagmus with an axis reflex. orthogonal to the affected semicircular canal is a reliable physical sign that dispenses with Figure 1. Nystagmus profile of a subject with right Miriam S Welgampola, BSc Med the need for any other diagnostic tests. Less posterior canalithiasis. There was no nystagmus in the upright position. In the right Dix-Hallpike (Hon) FRACP PhD, commonly, positional vertigo and nystagmus position there was upbeating rightward torsional is an Associate Professor can arise from other peripheral and central nystagmus which began 2s after reaching the of Neurology at the vestibular disorders. provocative position, quickly rose to a peak Central Clinical School, slow-phase velocity (SPV) of 39°/s and decayed There are two theorised mechanisms of University of Sydney, and completely within 20s. a Consultant Neurologist BPV: In canalithiasis, the gravitational move- at Royal Prince Alfred ment of free-floating otoconia within the Upright Position Hospital, Sydney. Her canal-duct is thought to cause abnormal research and clinical inter- endolymph flow;1 In cupulolithiasis, otoconia ests include ictal assess- ment of acute vestibular attached to the cupula are presumed to alter syndromes presenting to its density relative to the surrounding endo- the emergency room, early diagnosis of vestibular lymph and generate gravity-dependent deflec- disorders by event monitoring and the manage- tions of the cupula.2 The stimulus is transient in ment of intractable positional vertigo.

canalithiasis and sustained in cupulolithiasis. °) Correspondence to: This is reflected in the temporal pattern of 20 Miriam S Welgampola, Institute of Clinical

benign positional nystagmus which may be ositio n( Neurosciences, Royal Prince Alfred Hospital,

paroxysmal or persistent. The nystagmus eP Central Clinical School, University of Sydney, 0 NSW Australia. direction reflects stimulation of the involved Ey Email: [email protected] semicircular canal. BPV is treated with repo- sitioning manoeuvres which use knowledge RightRight DDix-Hallpikeix-Hallpike Conflicts of interest: of the orientation of the canals within the None declared.. head to direct the otoconia back to the utricle Provenance and peer review: through a sequence of head movements. Submitted and externally reviewed. Posterior Canal BPV Date first submitted: 14/6/19 Date submitted after peer review: 4/8/19 Patients with posterior canal BPV (PC-BPV) ) °) Acceptance date: 5/8/19 experience brief episodes of vertigo brought ° ( First published on-line: 22/8/19 on by head movements such as sitting up, 20 lying down, bending forward or looking up. Acknowledgements: ositio n(

Miriam Welgampola is supported by grants from Episode duration is typically less than one eP 0 the National Health and Medical Research Council minute however residual symptoms may Ey (APP1126976) and Garnett Passe and Rodney persist for hours.3 The Dix-Hallpike test causes Williams Memorial Foundation. free-floating otoconia in the posterior canal to -20

To cite: Argaet EC, Bradshaw AP, Welgampola MS. gravitate away from the ampulla, producing (°/s ) ACNR 2019;19(1):20-24. excitatory nystagmus. The fast-phase of the

SPV 0 nystagmus is upbeating and torsional with 01020 the upper pole of the eye beating towards Time (s) the affected ear. Nystagmus begins after a

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It is very rare for lesions other than BPV to present with nystagmus ment of BPV, with a preliminary diagnosis of right posterior cupulo- similar to posterior canalithiasis. Vestibular migraine (VM) can present lithiasis. After three treatments, she reported some improvement in her with positional vertigo and nystagmus, however it is more likely to positional vertigo but continued to experience migraines and disequi- resemble cupulolithiasis as the nystagmus is generally without latency, librium. Her follow up assessments revealed spontaneous diagonal persistent and lower velocity.6 The direction is most often horizontal but up/right beating nystagmus which was enhanced during Dix-Hallpike may be vertical or torsional.6 Unlike BPV, nystagmus in VM is not neces- testing (Figure 2). Her imaging and audio-vestibular tests were normal. sarily consistent with a single semicircular canal plane. The presence of VM was considered the dominant pathology and she commenced migraine features such as headache, photophobia, phonophobia and migraine preventative therapy with good effect. She continued to visual aura, support the diagnosis of VM, however there is also a high experience intermittent episodes of positional vertigo with some relief prevalence of migraine amongst patients with BPV and the two condi- with repositioning manoeuvres. The final diagnosis was VM with co-oc- tions may co-occur.7 curring BPV.

Case 1 Anterior Canal BPV A 48-year-old female presented with a 13 year history of recurrent Anterior canal BPV (AC-BPV) can produce paroxysmal predominately positional vertigo and right-sided throbbing headaches with nausea. She downbeat nystagmus in the supine straight heading-hanging position had a history of motion sensitivity. Her initial examination revealed spon- or during the Dix-Hallpike test. The side of the Dix-Hallpike test cannot taneous diagonal up/right beating nystagmus. In the right Dix-Hallpike be used to lateralise AC-BPV as one or both ears down may result position she had vigorous upbeating rightward torsional nystagmus in mobilisation of otoconia within the anterior canal.8 If there is a which persisted for more than two minutes. She underwent backward visible torsional component, this should beat towards the affected ear, rotations on the Epley Omniax rotator, a motorised chair for the treat- however it is not always apparent as the anterior canals are positioned closer to the sagittal plane than the posterior canals.8 Nystagmus onset is immediate or within a few seconds of reaching the provocative Figure 2. Nystagmus profile of a subject with vestibular migraine. The subject had low 9 velocity diagonal up/right beating nystagmus in the upright position. This nystagmus position, should last less than one minute and exhibit a rapid increase was enhanced in both Dix-Hallpike positions and showed a flat slow-phase velocity to a peak velocity followed by a more gradual decay (Figure 3). In (SPV) profile. our sample of three subjects with anterior canalithiasis, the nystagmus onset ranged from 0-2.8s upon reaching the Dix-Hallpike position. The Upright Position duration was 13.4-23.1s, the peak SPV was reached within 3.0-5.4s and decayed by half within 6.4-10.5s. Paroxysmal positional downbeat nystagmus may also be attributed to atypical PC-BPV, in which otoconia positioned near the common crus evoke an inhibitory response upon Dix-Hallpike testing.10 AC-BPV accounts for less than two percent of BPV cases and ) °) ° 11

( should be diagnosed with caution. Paroxysmal positional downbeat 20 n

o nystagmus, closely resembling AC-BPV, has been documented in central 12 ositio n( lesions involving the inferior cerebellar vermis. The co-occurrence of 0 eP Ey

Upright Position Right Dix-Hallpike °) 20

°) 20 ositio n(

eP 0 Ey ositio n(

eP 0

-20 Ey

(°/s ) 0 SPV 01020304050 Left Dix-HallpikeDix-Hallpike Time (s) Left Dix-Hallpike

Figure 3. Nystagmus profile of a subject

) with right anterior °) ° ( 20 canalithiasis. There was

°) no nystagmus in the 20 upright position. In the ositio n( left Dix-Hallpike position eP ositio n( there was downbeating Ey eP 0 0 rightward torsional

Ey nystagmus with an onset latency of 3s, a peak 20 -20 °/s) slow-phase velocity

(°/s ) (SPV) of 21°/s, and a 0 total duration of less SP V(

SPV 0 01020304050 0102030 than 30s. Time (s) Time (s)

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different types of nystagmus depending on 4.5-61.9°/s) with the affected ear lowermost. away from the affected ear for the geotropic the positioning manoeuvre and the presence The time taken to reach the peak SPV was variant, although this may vary depending of other oculomotor abnormalities may help prolonged compared to canalithiasis (median on the starting position of the otoconia.13,14 to differentiate central positional vertigo from peak latency with unaffected ear down 18.6s, BPV. A small number of patients with VM may range 5.7-27.8s). present with positional downbeat nystagmus Due to the 30-degree incline of the hori- which may be separated from AC-BPV by its zontal canals with respect to earth-horizontal, Figure 5. Nystagmus profile of a subject with left sustained nature and low intensity.6 Imaging is pseudo-spontaneous nystagmus may be seen horizontal canalithiasis. There was no nystagmus in the upright position. Both roll tests showed an 13 always warranted in the presence of additional in some patients with HC-BPV. Pseudo- immediate onset of horizontal geotropic nystagmus neurological signs or when the symptoms fail spontaneous nystagmus beats towards the which lasted less than 30s. With the affected (left) to resolve with repositioning. affected ear for the apogeotropic variant and ear down, the nystagmus quickly rose to a high peak slow-phase velocity (SPV) of 173°/s and then more slowly decayed. With the unaffected (right) ear down Case 2 a visibly lower peak SPV of 14°/s was recorded. A 66-year-old male presented with a 2-3 year Figure 4. Nystagmus profile of a subject with a history of episodic vertigo, mainly when rolling left superior cerebellar haemangioblastoma. This Upright Positionition over in bed. He reported a gradual decline in subject had low velocity left beating nystagmus hearing bilaterally, a recent onset of pulsatile in the upright position. Both Dix-Hallpike tests revealed paroxysmal downbeating nystagmus with tinnitus and non-throbbing bilateral occipital a short duration of less than 20s. The rise and fall headaches associated with nausea. He had slow-phase velocity (SPV) profile resembled anterior subtle left beat spontaneous nystagmus. Both canalithiasis. Dix-Hallpike tests showed paroxysmal down- beat nystagmus lasting less than 20 seconds Upright Position °) (Figure 4). He was treated for presumed AC-BPV, 20

without improvement. MRI with MRA/MRV ositio n(

revealed a lesion in the left superior cerebellar eP 0 hemisphere extending into the left superior Ey cerebellar peduncle. He underwent a complete resection of the lesion, which was confirmed to °) Left Rolloll TestTest be a haemangioblastoma. The pulsatile tinnitus 20 and unresponsiveness to repositioning were red flags pointing to a central cause. ositio n( eP 0 Ey Horizontal Canal BPV Patients with horizontal canal BPV (HC-BPV) Right Dix-Hallpike typically report short episodes of vertigo induced by rolling over in bed or head move- °) 20 ments in the yaw plane. Horizontal nystagmus is elicited during the supine roll test and is ositio n( paroxysmal geotropic (beating towards the eP 0 ground) in the case of typical canalithiasis or Ey °) persistent apogeotropic (beating away from 20 the ground) in the case of cupulolithiasis. In the geotropic variant, rolling onto the ositio n( eP 0

affected side produces an intense excitatory Ey nystagmus while rolling onto the unaffected side produces a less intense inhibitory nystagmus (Figure 5). 20 50 °/s) The reverse is true for apogeotropic variants, °/s)

SP V( 0 in which the affected side is identified as the SP V( 01020 0 side with the weaker response (Figure 6). In 0102030 Time (s) a sample of 30 subjects with horizontal cana- Time (s) lithiasis, nystagmus onset was typically instan- Left Dix-Hallpike Right RollRoll TestTest taneous after rolling onto the affected side (median onset latency 0s, range 0-4.4s) and lasted less than one minute (median duration 26.1s, range 9.9-48.5s). The median peak SPV was 52.2°/s (range 9.1-241.2°/s). The peak SPV was reached after 3.6s (median, range °) 0.3-24.4s) and declined by half at 7s (median, °) 20 20 range 2.8-24.6s). With the unaffected ear ositio n( down, a less intense paroxysm (median peak ositio n(

eP 0 SPV 17.2°/s, range 3.6-96.7°/s) with similar 0 eP Ey temporal characteristics was seen. Ey In a sample of 10 subjects with hori- -50 20

zontal cupulolithiasis, nystagmus onset was (°/s ) mostly immediate (median 0s, range 0-3.0s) SPV(°/s)

SPV 0 0 during the roll test. The median peak SPV 01020 0102030 was 69.6°/s (range 9.9-105.4°/s) when lying Time (s) Time (s) on the unaffected side and 13.5°/s (range

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Leaning the head back or lying down in a supine position further elevates and differential diagnosis may rely on the presence of other neurological the ampulla and should produce nystagmus in the same direction as the or aural signs and the response to repositioning manoeuvres. Choi et al.19 pseudo-spontaneous nystagmus, while bowing the head forward should suggested comparing the intensity of sitting and supine nystagmus. They produce nystagmus in the opposite direction.15 found that a more intense nystagmus when supine compared to sitting Horizontal geotropic positional nystagmus has been described in acute is consistent with HC-BPV while a symmetrical response between sitting VM and central lesions of the cerebellar peduncle and lateral medulla. and supine is more indicative of a central lesion. This nystagmus is persistent rather than paroxysmal, making it easy to separate from canalithiasis.16-18 Horizontal apogeotropic nystagmus has Case 3 been reported in central lesions typically of the cerebellar vermis and A 41-year-old female presented with a two-month history of episodic nodulus,16-19 VM, and more rarely in Ménière's Disease and vestibular unsteadiness and left lateropulsion when walking, accompanied by schwannomas.18 The nystagmus can closely resemble cupulolithiasis nausea and occipital pressure. Separately, she reported episodes of spontaneous and positional vertigo lasting seconds. She had no auditory symptoms. She had a history of migraine and motion sensitivity. She had no spontaneous or gaze evoked nystagmus. Head shaking provoked up Figure 6. Nystagmus profile of a subject with left horizontal cupulolithiasis. There was no nystagmus in the upright position. Both roll tests showed an immediate onset of beating nystagmus. In either Hallpike position, she had persistent low persistent horizontal apogeotropic nystagmus. The peak slow-phase velocity (SPV) was velocity up beating nystagmus. In either roll position she had persistent visibly higher with the unaffected (right) ear down (85°/s) than with the affected (left) horizontal geotropic nystagmus (Figure 7). ear down (24°/s). Her audiogram and vestibular function tests were normal. Her MRI Upright Positionsto

Figure 7. Nystagmus profile of a subject with vestibular migraine. There was no nystagmus in the upright position. In the right roll position, right beating nystagmus was recorded. In the left roll position, left beating nystagmus was recorded. The nystagmus was persistent, low velocity and did not have a rise and fall (SPV) profile typical of canalithiasis.

°) Upright Position 20 ositio n(

eP 0 Ey °) Left Rolll TeTestst 20 ositio n(

eP 0 Ey

Right Roll Test °) 20 ositio n(

eP 0 Ey °) -50 20 (°/s ) ositio n( SPV 0 eP 0

01020304050 Ey Time (s) Right Rolloll Test -20 (°/s ) 0 SPV 010203040 Time (s) Left Roll Test °) 20 ositio n(

eP 0 °) Ey 20 ositio n( 0 eP Ey

50 20 °/s)

SPV(°/s) 0 0 SP V( 01020304050 010203040 Time (s) Time (s)

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REFERENCES scan showed diffuse white matter hyperintensities. The patient was 1. Hall S, Ruby R, McClure J. The mechanics of benign paroxysmal vertigo. J Otolaryngol 1979;8(2):151-158. diagnosed with VM and treated 2. Schuknecht HF. Cupulolithiasis. Arch Otolaryngol 1969;90(6):765-778. with migraine preventative therapy. 3. von Brevern M, Bertholon P, Brandt T, Fife T, Imai T, Nuti D, Newman-Toker D. Benign paroxysmal positional vertigo: Diagnostic Repeat MRI scan one year later criteria. J Vestib Res 2015;25:105-117. doi:10.3233/VES-150553 showed white matter hyperintensi- 4. Parnes LS, Agrawal SK, Atlas J. Diagnosis and management of benign paroxysmal positional vertigo (BPPV). Can Med Assoc J ties were stable. 2003;169(7):681-693. 5. Hain TC, Squires TM, Stone HA. Clinical implications of a mathematical model of benign paroxysmal positional vertigo. Ann N Y Acad Sci 2005;1039(1):384-394. doi:10.1196/annals.1325.036 Conclusion 6. Polensek SH, Tusa RJ. Nystagmus during attacks of vestibular migraine: An aid in diagnosis. Audiol Neurotol 2010;15(4):241-246. A history of brief episodes of doi:10.1159/000255440 positional vertigo and characteristic 7. von Brevern M, Radtke A, Lezius F, Feldmann M, Ziese T, Lempert T, Neuhauser H. Epidemiology of benign paroxysmal positional nystagmus upon positional testing vertigo: A population based study. J Neurol Neurosurg Psychiatry 2007;78(7):710-715. doi:10.1136/jnnp.2006.100420 are fundamental to the diagnosis of 8. Bertholon P, Bronstein AM, Davies RA, Rudge P, Thilo KV. Positional down beating nystagmus in 50 patients: Cerebellar disorders and possible anterior semicircular canalithiasis. J Neurol Neurosurg Psychiatry 2002;72(3):366-372. doi:10.1136/jnnp.72.3.366 BPV. Alternative diagnoses must be 9. Lopez-Escamez JA, Molina MI, Gamiz MJ. Anterior semicircular canal benign paroxysmal positional vertigo and positional downbeating investigated when the nystagmus nystagmus. Am J Otolaryngol 2006;27(3):173-178. doi:10.1016/j.amjoto.2005.09.010 is atypical, unresponsive to repo- 10. Vannucchi P, Pecci R, Giannoni B. Posterior semicircular canal benign paroxysmal positional vertigo presenting with torsional down- sitioning manoeuvres or when there beating nystagmus: An apogeotropic variant. Int J Otolaryngol 2012:1-9. doi:10.1155/2012/413603 are additional otologic or neuro- 11. Korres S, Balatsouras DG, Kaberos A, Economou C, Kandiloros D, Ferekidis E. Occurrence of semicircular canal involvement in benign logical signs incompatible with a paroxysmal positional vertigo. Otol Neurotol 2002;23(6):926-932. diagnosis of BPV.3 12. Choi J-Y, Kim JH, Kim HJ, Glasauer S, Kim J-S. Central paroxysmal positional nystagmus: Characteristics and possible mechanisms. Neurology 2015;84(22):2238-2246. doi:10.1212/WNL.0000000000001640 13. Asprella-Libonati G. Pseudo-spontaneous nystagmus: A new sign to diagnose the affected side in lateral semicircular canal benign parox- Videos are available on the ACNR ysmal positional vertigo. Acta Otorhinolaryngol Ital 2008;28(2):73-78. website to accompany the figures 14. Lee S-U, Kim H-J, Kim J-S. Pseudo-spontaneous and head-shaking nystagmus in horizontal canal benign paroxysmal positional vertigo. in this article. visit using the links Otol Neurotol 2014;35(3):495-500. doi:10.1097/MAO.0000000000000250 below: 15. Choung YH, Shin YR, Kahng H, Park K, Choi SJ. ‘Bow and lean test’ to determine the affected ear of horizontal canal benign paroxysmal positional vertigo. Laryngoscope 2006;116(10):1776-1781. doi:10.1097/01.mlg.0000231291.44818.be https://is.gd/vertigo_video1 16. Lee HJ, Kim ES, Kim M, Chu H, Ma HI, Lee JS, Koo JW, Kim HJ, Hong SK. Isolated horizontal positional nystagmus from a posterior https://is.gd/vertigo_video2 fossa lesion. Ann Neurol 2014;76(6):905-910. doi:10.1002/ana.24292 https://is.gd/vertigo_video3 17. von Brevern M, Radtke A, Clarke AH, Lempert T. Migrainous vertigo presenting as episodic positional vertigo. Neurology https://is.gd/vertigo_video4 2004;62(3):469-472. doi:10.1212/01.wnl.0000106949.55346.cd https://is.gd/vertigo_video5 18. Lechner C, Taylor RL, Todd C, Macdougall H, Yavor R, Halmagyi GM, Welgampola MS. Causes and characteristics of horizontal posi- https://is.gd/vertigo_video6 tional nystagmus. J Neurol 2014;261(5):1009-1017. doi:10.1007/s00415-013-7223-5 19. Choi J-Y, Glasauer S, Kim JH, Zee DS, Kim J-S. Characteristics and mechanism of apogeotropic central positional nystagmus. Brain https://is.gd/vertigo_video7 2018;141(3):762-775. doi:10.1093/brain/awx381 r e g u l a r s – e v e n t s d i a r y

Dementia MasterClass To list your event in this diary email [email protected] by 29th November 2019 28-29 November, 2019; Halifax Hall, Sheffield University Campus, UK https://dementiaacademy.co/events/ 2019 Alzheimer’s Research UK Clinical Conference dementia-masterclass-6/ Tuesday 12 November; Royal Society of Medicine, London, UK T. 0114 327 0230 SEPTEMBER www.alzheimersresearchuk.org/about-us/our-influence/ for-clinicians/clinical-conference-2019/ DECEMBER 41st Edinburgh Clinical Neurology Course E. [email protected] 30 September - 1 October, 2019; Edinburgh, UK Encephalitis Conference 2019 Advanced Stroke Imaging One Day Course https://www.ed.ac.uk/clinical-brain-sciences/ 13 November, 2019; Queen Square, London, UK 2 December, 2019; RCP, London, UK postgraduate-training/edinburgh-clinical-neurology-course https://www.ucl.ac.uk/short-courses/search-courses/ https://www.encephalitis.info/event/ E. [email protected] advanced-stroke-neuroimaging encephalitis-conference-2019 E. [email protected] E. [email protected] OCTOBER Vegetative and minimally conscious states: diagnosis, Liverpool Paediatric Neurosurgery Masterclass Joint meeting of the Society for Research in Rehabilitation management and end-of-life decisions to inform clinical and Thursday 5 - Friday 6 December, 2019; Liverpool, UK legal practice and the British Society of Rehabilitation Medicine www.aesculap-academia.co.uk 14-15 October, 2019; Warwick, UK 18 November, 2019; RCP London, UK E. [email protected] E. [email protected] https://www.bsrm.org.uk/events/bsrm-events/profile/ The Birmingham Afferent Course bsrm-srr-2019-joint-scientific-meeting Complex Epilepsy Study Day for Specialist Nurses 19 November, 2019; Crowne Plaza Stephenson Quarter, Wednesday 11 December, 2019 E. [email protected] Newcastle, UK E. [email protected] Prolonged Disorders of Consciousness: From scientific E. [email protected] discovery to clinical practice: How the discovery that some Recent advances in young onset dementia 2020 vegetative patients are aware has changed our practice 20 November, 2019; St Georges University of London, UK JANUARY FREE EVENT Thursday 17 October, 2019; London, UK https://shop.sgul.ac.uk/short-courses/professional-educa- E. [email protected] tion/neuro/recent-advances-in-young-onset-dementia The Birmingham Afferent Course E. [email protected] Wednesday 8 January, 2020; Birmingham, UK NOVEMBER Neurobehavioural Disability after Acquired Brain Injury: E. [email protected] Selective Topics Demonstrating Innovation in Practice and Neurology Symposium The 18th annual King’s Neuromuscular Disease Symposium Delivery Tuesday 5 November, 2019; Royal College of Physicians of 25 November, 2019; Swansea Marriott Hotel, Swansea, UK Friday 31 January, 2020; London, UK Edinburgh, UK E. [email protected] E. [email protected] E. [email protected] Complex Epilepsy Study Day Neurology 2020 MSologists MasterClass 26 November, 2019; Crowne Plaza Congress Road, Glasgow, UK 6 March, 2020; RCP Glasgow, UK Module 1: 6-8 November, 2019 E. [email protected] https://rcpsg.ac.uk/events/NEURO Module 2: 21 & 22 May, 2020; Sheffield, UK Expert to Expert: Epilepsy E. [email protected] multiplesclerosisacademy.org For paediatric neurologists and other seeing children with VasCog 2020 epilepsy at tertiary level The British Neurosurgical Research Group Meeting 28-29 November, 2019; Manchester, UK 9-12 September, 2020; Newcastle University, UK Thursday 7 and Friday 8 November, 2019; Edinburgh, UK https://courses.bpna.org.uk/ https://www.vas-cog.com/vascog-2020/ E. [email protected] ecomm_product_view.p­­­­hp?courseid=393 E. [email protected]

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The ABN Annual Meeting 2019

Conference details: 20-23 May 2019, Edinburgh, Scotland. Report by: Sian K Alexander, Department of Neurology, Addenbrooke’s hospital, Cambridge and Richard N Rees, Department of Clinical and Movement Neuroscience, Queen Square Institute of Neurology, UCL, (both pictured below) on behalf of the ABNT. Conflict of interest statement: SKA and RR are members of the ABN Trainees.

he ABN annual meeting 2019 was in tive disorder leading to vasculitis of multiple Edinburgh this year and featured a organs and ultimately death. Tbagpipe-accompanied reception, excel- The clinico-pathological case always fills me lent Scottish hospitality and speakers from with delight, not least because I am glad not to across the UK, as well as that rarest of clinical and investigation of these critically unwell be the discussant! This year Ed Newman was entities – Scottish sunshine. Whilst the Gala patients and it presents an interesting growth the brave person to discuss the case, and kept dinner, with accompanying auction of rare area for collaboration. the audience riveted as he worked through books and ceilidh were fantastic – and they the problem with elegant ease. Seeing the were – the entire programme showcased the Motor neurone disease diagnostic process laid bare is always impres- best of UK neurology. MND featured prominently this year. In sive, even more so when accompanied by Over three days plus one day pre-meeting Professor Dame Pamela Shaw’s ABN medal- Scottish neurovocabulary (Bonkle,Tyndrum, with separate sessions for neurology registrars, list lecture, she demonstrated the huge Kells anyone?) and the correct diagnosis. GP and acute medical physicians and pre-ST3 value of involving the public and patients in We also want to mention a debate that has doctors, the audience was treated to a series of neurological research. She cited examples been initiated (but by no means concluded) stellar talks. There was so much on offer that of the sizeable financial donations made by regarding whether or not the ABN should we will focus on a few highlights. prominent individuals towards establishing adopt a formal position on medical assisted SiTRAN, Sheffield translational neuroscience. dying. Jaquie Palace and Uma Nath clearly An era of new treatments These collaborations have also driven thera- and dispassionately summarised the current Professor Matthew Walker discussed the peutic innovations such as the HeadUp state of affairs. They focused on the various rapidly-evolving area of epilepsy treatments, Collar, a supportive technology meeting a definitions and legal nuances of the debate which include virus-derived vectors for focal common patient-identified need in MND. as well as the recent change in position of delivery of specific ion channel DNA that can Professor Siddhartan Chandran’s talk on the Royal College of Physicians (London) integrate and potently reduce focal seizures. inducible pluripotent stem cells in human from a state of opposition to neutrality. They He discussed the potential for this to be used disease modelling highlighted the particular also presented data on the voting patterns of in an epilepsy surgery pathway with recourse utility of this technology for diseases affecting different physician groups in the RCP survey. to resection of the dysfunctional and vector- cells of the brain and spine. There were also This was followed by a brief but lively discus- treated tissue if refractory, thereby containing several talks on current research, including sion from the floor. The ABN will be drawing the potential treatment risks. Building on by Dr Jonathan Cooper-Knock and data from more attention to the work that they are excitement about antisense oligonucleo- the Scottish CARE-MND platform on geno- doing surrounding this important topic in the tide treatment in spinal muscular atrophy, type-phenotype correlations of long-survivors coming months. Professor Charles Thornton from Rochester with MND, giving opportunity for optimism Congratulations and thank you to Jon gave the Gordon Holmes lecture on devel- about this challenging disease. Sussman and committee who organised the oping treatments for myotonic dystrophy. meeting. Although not truly a neurological treatment, Neurological cases The next ABN meeting is in Bournemouth, CAR-T therapies for acute leukaemias and The case presentations are always of excep- 13-15th May 2020. So why go? The calibre lymphomas have been licensed for use in tional quality, and this year was no exception and breadth of talks is high, and they are seven specific Haematology units across with a range of challenging and thought-pro- consistently practical, relevant and inspira- England (https://www.england.nhs.uk/ voking cases, with a neuroimmunological tional in equal measure. There are always cancer/cdf/car-t-therapy/). They can cause flavour overall. For us, take-home messages plenty of opportunities to catch up with old prominent, usually self-limiting neurological were (i) the growing utility of paranodal anti- friends and colleagues and to make new ones. symptoms as a direct toxicity related to their body assays from Dr Simon Rinaldi’s lab in Finally, the opportunity to appreciate the neur- anti-CD19 properties, but have the potential Oxford (research domain at present); (ii) ology Zeitgeist is, we think, unparalleled: to to transform outcomes in acute leukaemias rare but potentially under-recognised paran- hear and contribute to discussions on Assisted (as recently featured in BBC documentary eoplastic myelitis mimicking neuromyelitis Dying, Shape of Training, and neurological War in the Blood). These centres will need optica; (iii) an ongoing note of caution of the services is as important as the exciting new dedicated neurologists as a named member potential risks of immunosuppression with science and treatments discussed in sessions of the team, to help guide management a case of EBV-associated lymphoprolifera- on either side.

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European Society for the Study of Tourette Syndrome (ESSTS)

Conference details: 15-17 May 2019, Hannover, Germany. Report by: Jeremy Stern, Consultant Neurologist, St George’s Hospital. Conflict of interest statement: None declared.

onference organising committees diagnosed children. EMTICS is a significant and can’t be reproduced here but the quality usually aspire to a freshness in their achievement which will yield other data and of the existing data does lead to some anom- Cprogramme that will be different to the analyses. For now, whilst there remain contro- alies. RCTs, obviously, are King so that the last few annual meetings, with big breaking versial aspects to PANS which can exert a category of ‘low confidence in the evidence’ is news and novel ideas for sessions. They aren’t Lyme-like attraction to some parents and older shared by unused drugs like metoclopramide always entirely successful but for this European patients, streptococcus does not appear to be with an older option like pimozide which Tourette Syndrome meeting the ESSTS officers relevant to typical TS and remains of doubtful anecdotally may well have equal effective- and local organiser Kirsten Müller-Vahl did relevance to most adult onset presentations. ness to some in the ‘moderate confidence’ better than most. This will be a rather selective A new idea was a session on “Is it time group (eg aripiprazole an often favoured first summary from that perspective. There are to rename Tourette’s”, a debate chaired by line drug, haloperidol, risperidone, clonidine). many published reviews covering progress Andrea Cavanna who did not hesitate to Only Comprehensive Behavioural Intervention in complex genetics and uncertain neuro- launch into ‘…a rose by any other name’ at for Tics (CBIT) was in the ‘high confidence’ biology, which were also covered. the first opportunity. There is a growing feeling group but is sadly underprovided. The Around 1% of children have Tourette that despite our attachment to the eponym and Professor Mary Robertson prize for research Syndrome (TS) with higher rates in SEN educa- Gilles de la Tourette’s Salpêtrière pedigree (a contribution was this year won by Per Andrén tion. Tics are more commonly seen in the definitive biography by Olivier Walusinski has for his published paper on a controlled trial context of transient tic disorders in up to recently been published) the name ‘Tourette’ of internet delivered behaviour therapy which 15-20% of boys, and in persisting chronic is potentially an unhelpful distraction and is part of a wider data-driven movement to multiple tics. TS is defined by chronic multiple a term like ‘tic spectrum disorder’ may be improve access to treatment. motor and at least one vocal tic which can more appropriate both scientifically and in Other clinical highlights included the first be simple or complex. It is highly associated terms of reducing stigma. I favour this but controlled trial by Dr Müller-Vahl of thalamic with other comorbidities including OCD and we can think of examples of name changes ADHD. Severity varies, many children improve in medicine not successfully destigmatising versus GPi deep brain stimulation (DBS) in 9 but others have a lifelong intrusive condition. a condition. More interestingly there were patients with bilateral dual stimulation with Firstly, big news. 25 years ago Susan Swedo people with TS at the meeting who spoke GPi seeming superior. There remains much presented a hypothesis of immune mechan- powerfully of ‘owning’ their condition and not uncertainty over patient and target selection isms responding to Group A Streptococcal wanting the label they had lived with through and DBS is effectively not currently available (GAS) infection causing a neuropsychiatric life to be taken away. This was also seen for TS in the UK due to an NHSE commis- syndrome with movement disorders in chil- when the American Psychiatric Association sioning decision. dren (PANDAS), analogous to Sydenham’s left Asperger’s syndrome behind in the clas- The meeting included an interactive session chorea, in association with anti-basal ganglia sification of autism (before it became known on functional movement disorders. The explo- antibodies. PANDAS (now reclassified as Asperger was a Nazi eugenicist). However, sion of interest in this area has perhaps come a PANS) is distinct from TS but since then in adult it is fair to consider whether this view is also little late to the TS clinical community and can practice when dealing with apparently late or representative of a family being given the diag- be challenging as psychogenic movements explosive onset TS we have tested ASO titres nosis for the first time. The vote in favour of a share some characteristics of tics (suggest- and anti-basal ganglia antibodies without the name change was narrowly lost, the debate ibility, distractibility) with important differ- data to understand their clinical significance. may continue. ences (lack of premonitory urge, usually less Antibodies are seen in about 25% of children A problem for adult neurologists is that suppressibility). Our adult explosive-onset with TS. Streptococcal carriage is common in drugs for tics are variable in efficacy although cases commonly appear to have varying the population- is there a relationship between can be very useful – not unlike our medication degrees of functional components even when infection and the onset or exacerbation of options for essential tremor, dystonia or, for there also seem to be typical tics or a history TS in a more typical setting? Many strands of that matter, chronic migraine. The data for of tics in childhood. “Tic attacks”, a category evidence have pointed to this question which TS is generally poor and usually short term often made by the patients themselves can has now been addressed by a major pan-Euro- with clinical translation often disappointing resemble dissociative seizures. This area will pean EU funded study, EMTICS. Children with for many patients. There has previously been grow but may be reliant on opinion as much TS (n=715) were followed prospectively and a NIHR HTA assessment with meta-analysis of as objective signs. a group at risk of new onset, their siblings treatments in children, and now the AAN has (n=260). The preliminary results gave a valu- published a comprehensive systematic review The next ESSTS meeting will be held able negative result; there were 200 new GAS for children and adults including treatment 3rd -5th June 2020 in Lausanne which also exposures but no indication these were prefer- and adverse effects and a practice guideline. happens to be the place of Gilles de la entially associated with the new onset of tics The lead author Tamara Pringsheim presented Tourette’s death in 1904 from neurosyphilis. in 60 cases, nor with exacerbations in already these at the meeting. Both are worth reading

There is a growing feeling that despite our attachment to the eponym and Gilles de la Tourette’s Salpêtrière pedigree...the name ‘Tourette’ is potentially an unhelpful distraction and a term like ‘tic spectrum disorder’ may be more appropriate both scientifically and in terms of reducing stigma.

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1st International Keto Live Event 2019

Conference details: 10-14 June 2019, Kurhaus Hotel, Bergün, Switzerland. Report by: Dr Ana Iacob, Psychiatrist at Valais Hospital, Switzerland. Conflict of interest: None declared.

he Keto Live Event in Bergün, Switzerland, sistant epilepsy. Later on, Sybille Kraft from “Could migraines act as an energy-conserving was the first medical conference in France presented the use of a KD as a first-line behaviour in an energy deficient brain?” and TSwitzerland with an entire focus on treatment for Angelman Syndrome. showed the potential use of exogenous ketones Non-Communicable Diseases (NCD) and the The 2nd day was dedicated to cardio- for migraines. Dr Georgia Ede spoke about use of a Ketogenic Diet (KD) as a prevention, vascular diseases and we had lecturers like nutritional psychiatry, metabolic disturbances but also as a powerful treatment tool. Dr Aseem Malhotra, Ivor Cumming and Dr in psychiatric conditions and important blood It brought together scientists from all Schoonbee. Dr Malhotra spoke about the role work psychiatrists should ask for their patients. around the world who presented the latest of lifestyle choices, cholesterol and statins in She also presented the similarities between research in their field. The conference was heart diseases while Ivor Cumming developed Alzheimer’s and Parkinson’s disease and open to healthcare professionals, but also to the topics of hyperinsulinemia, its role in explained why a nutritional intervention could the general public interested in health and atherosclerosis and the use of a Coronary be beneficial for both diseases. The conference the KD. The presentations were divided into Calcium Score in cardiovascular risk assess- ended with a panel discussion about future four main topics: heart and cardiovascular ment. Lastly, Dr Schoonbee held an interesting projects and an introduction to the 2020 event. diseases, cancer, diabetes and neurology - talk on why insurance companies should care Overall, the first edition of the Keto Live Event neuropsychiatry. Each topic had one whole about nutrition and who would benefit from highlighted the existing science behind the role day of presentations and discussions dedicated better nutrition guidelines. that food holds in NCD, a role that is often to it, which made attending easy as one could On the day dedicated to cancer, we had overlooked or unclear among many conflicting choose to attend only on certain days, although world-known cancer researcher Professor Dr studies. It brought together researchers, clin- I would definitely recommend attending to it Thomas Seyfriend who held two amazing pres- icians and people interested in health from entirely. entations. He talked about cancer develop- around the world to discuss and promote The conference was recognised as a ment, cancer metabolism, mitochondrial further collaboration in the beautiful town of Continuing Medical Education (CME) tool for dysfunction and metabolic therapies (Press Bergün, right in the centre of Europe. healthcare professionals and accredited with – Pulse Therapies) for cancer, their use and What will the second conference bring? 35 CME credits. It was free of any pharmaceut- results. The conflicting question of nutrition While the first event was amazing, the second ical advertising, which is something we rarely in cancer patients and the inconsistent and one looks even more promising. It will have get to see at a medical conference nowadays, changing information that patients receive was international world-known lecturers like and all lecturers had to provide their conflict the main topic of Patricia Daly and Domini Professor Stephen Cunnane and Dr Georgia of interest. The participants also had the possi- Kemp talks. We also listened to Michel Lundell Ede from the USA, Dr David Unwin from the bility of attending three workshops and every explaining the potential use of ketones and UK, Dr Jean-Pierre Spinosa from Switzerland, evening a different documentary movie on the Julia Tulipan who presented the factors that Prof Dr Markus Seämann from Austria, Prof Dr topic was playing at the cinema room of the may influence the feasibility and implementa- Helene von Bibra from Germany and many hotel. The delicious meals, all matching a KD, tion of a KD in cancer patients. more. Themes like brain development, multiple were made from local organic products and The 4th day was focused on diabetes with sclerosis, psychotropics, autoimmune diseases, were included in the conference fee. Dr Ian Lake from the UK who spoke about type cardiovascular diseases, kidney diseases and Dr John Schoonbee from SwissRe, 1 diabetes and the use of a KD in managing cancer will be discussed, while answering Switzerland opened the conference with his the disease, while Amy McKenzie from Virta talk "Why we have to rethink" referring to Health, USA covered the topic of type 2 diabetes questions like: Is it possible to reverse cardio- strategies for NCD. Supported by the Charlie (T2D). She presented the results of their 2 years’ vascular diseases, what are the ketogenic meta- Foundation, he introduced the first topic in prospective study, which demonstrates that bolic therapies and what are they used for? neurology, epilepsy and KD. Michel Lundell, T2D biomarkers can be reversed using a KD. from Sweden, the inventor of a Ketone Lastly, Prof Jörg Spitz from Germany evidenced Save the Date for the 2nd International breath-monitoring device who also suffers from the importance of vitamin D for health. Keto Live Conference in Switzerland from epilepsy, spoke about the use of KD as a treat- On the last day, Elena Gross and Dr Georgia 8th - 12th of June 2020. You can find more ment for children and adults suffering from this Ede carried on the topic of neuropsychiatric details including the new program on the disease. Unfortunately, nowadays, the diet is and neurodegenerative diseases. Elena Gross official website - www.keto-live.com recommended as a last-resort, only in drug-re- started the day with a puzzling question:

Physioroom.com extends range of services with new online treatment

PhysioRoom.com, a jargon-explained, sports injury, rehab and fitness app helps to monitor progress. website, has partnered with PhysioFast Online (PFO), who offer inter- Lee Bannister, Head of Customer Experience, said: “Leading research active videocall appointments with qualified physiotherapists to extend has found that video consultations are as effective as face-to-face its range of services. Launched in 2000, the site offers a wide range of appointments and that three in four people can be triaged, assessed content, empowering users with the knowledge of their own sports and supported online without any need for physical treatment. This injuries in order to supplement treatment and advice given by their collaboration with PFO gives our customers quick and easy access to a doctor. team of qualified physios.” Customers will be able to book an appointment with a quali- Katie Knapton, Founder of PFO, said: “Our service will help to fied physio via www.Physioroom.com or www.physiofastonline.co.uk. guide patients quickly to the correct rehabilitation treatment and is Appointments will normally be available same day to swiftly help accessible to anyone with a screen and an internet connection from reduce suffering and concern and, in many cases, promote a quicker recovery time. the comfort of their home, workplace or even overseas. We also offer a complete A screen share facility ensures that sessions are interactive and personal, whilst 3D package of care including referral to imaging if required and a personalised rehab human anatomy diagrams help to educate, empower and inform. A downloadable programme.”

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Raising the bar for MS services – how we propose to tackle service variance together

Conference details: 1-2 November, Birmingham, UK. Report by: Charlotte Peel, Health Writer, Neurology Academy. Conflict of interest statement: Report supplied by event organiser. Published online: 22/8/19.

ovember 2018 saw the first in a series of of whom attended two of five practical work- to MS services, reminding the conference events set to tackle MS service variation stream groups, and left the two-day confer- that improving services is not a destination to Nin the NHS. The event highlighted a ence with actionable ‘to-do’ lists (Figure 1) reach but a continual cycle of imagining, plan- number of challenges to improving health which fitted into an overarching three-year ning, designing and building. Jerry Clough and social care, to deliver more equitable and plan (Table 1). encouraged the room to see challenges as optimised MS services in the UK. The workstream sessions were practical difficulties to overcome together rather than A poll, posed at the opening of the event, set workshops where delegates were equipped as unsolvable problem to abandon, and to the tone thereafter, when 85% either agreed or with tools and information to effect change locate their ‘why’, so that they could work strongly agreed that ‘Those of us in the room through embracing data, audit, patients as with purpose. have the power we need to fundamentally partners, social determinants, and wellness After the first event it was clear that improve the quality of MS care in the UK, and lifestyle. some ‘enablers’ were needed to give this reduce variation and offer consistent care Alongside these, interactive presentations programme of work traction. Leadership, and at the level we want everywhere, in the next encouraged clinicians to think in new ways, sharing of best practice were two of those three years’. and to work in new ways. Sue Thomas and identified. In response, Professor Gabriele de This July, the follow up event inspired, then Martin Fischer gave a fresh perspective as Luca and Barbara Hoese examined what it galvanised activity amongst its delegates, all they asked whether we can improve access means to ‘lead for change’ and announced

Key aim Information Outputs

Year 1: by 31st July 2020

Quality audit rollout. All centres actively engage in a national quality audit (see audit Set the 4+4 ambition, test it and get adopted as a workstream). target across the community (at least 20 centres). adopt the vision of 4+4 and aspire to meet the associated Socialise with key policymakers, support/interest timeframes. groups, industry and healthcare leaders. Further information and guidelines: NHSE algorithm. Create a business case with the costs and benefits International Brain Health standards: an optimal target to aim for. of achieving the 4+4 vision and how it will reduce variation.

Year 2: by 31st July 2021

Patient partner All centres have tested a nationally-developed patient partner Determine how to collect data to meet the ambition. programme rollout. programme to upskill pwMS on navigating local services, Articulate the KPIs and reporting methodology. self-monitoring and self-managing (see patients as partners workstream). Get policy makers to adopt the KPIs within a national framework (NHSE). Alternatively, this programme will offer opportunities for pwMS to make local connections, being developed in partnership with Seek funding support and NHSE backing. patient organisations and dependant on local professionals to Centres to produce plans to remodel services to engage disempowered patients soon after diagnosis and enable achieve the vision. pwMS to lead the programme’s delivery.

Year 3: by 31st July 2022

Holistic management of All centres are working differently and managing MS holistically, Rollout the use of the KPI to all centres with national MS and ‘no patient left adopting the ‘no patient left behind’ ethos, and including reporting. behind’ ethos. programmes to screen and manage comorbidities and promote Centres change services with a determined ambition lifestyle interventions (see wellness and lifestyle workstream). to achieve standards across the UK by the end of Centres collect data on these new activities (audit & data year 3. workstreams). Centres have systems in place to make sure that all people with MS covered by a particular service have access to that service (see social determinants workstream).

Enablers

Leadership. The leadership programme will be small and selective, focus Leadership education programme, delivered by Pr on ‘doing’, with the programme involving participation and Gabriele de Luca and facilitated by the MS Academy. Sharing practice. completion of a national project. The MS Academy will support and enable this sharing Centres commit to share their successes and failures so that others through online platforms and its existing infrastructure can learn from them, and to share their materials and experiences and educational courses. with other centres, creating peer support and raising the bar for everyone.

28 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 r e g u l a r s – c o n f e r e n c e n e w s the MS Academy’s new leadership programme individual workstreams feed in and interlink find our ‘why’ as a community of people to enable clinical leaders to do just this. within the plan. committing to improving the lives of those with Meanwhile, around the conference, posters With clinical leaders emerging to spear- MS was throughout the event. That community – all now available online – were sectioned head change, and every healthcare profes- must feature those living with MS as equal into the workstream themes and provided an sional embracing the workstream that they partners in this journey to raise the bar across opportunity to showcase innovative ways that are passionate about, whilst sharing their prac- MS services – in review, design and delivery. teams across the country have already begun tical learning and supporting their peers, it is CEO of Altogether Better, Alyson McGregor ‘raising the bar’ in their local service. achievable. summed up well, saying ‘we need to agree a In order to give some structure and unity to The take home message last year was ‘we new purpose – for clinicians only to decide this national programme, an ambitious time- need to do things differently.’ This year, that won’t cut it, we need to work together, in real frame has been drawn up, and was presented message was deepened into ‘we need to collaboration.’ to all at the conference (Table 1). Whilst it think differently, work differently, and deliver may appear daunting at first glance, all of the services differently.’ The encouragement to

WORKSTREAMS: Raising the Bar Practical actions to take this year

Social Data Patients as Audit determinants Wellness and partners of health lifestyle 1. Compile a list of all 1. Volunteer to be a pilot 1. St.g. to define 1. Understand how many 1. Scope your area: what’s your MS patients centre! parameters for audit patients have dropped available already? and disseminate out of the MS specialist Can you tap into it? 2. Identify a friendly 2. Develop the programme system IT colleague at and with pilot centres 2. Prepare to use data 2. Swap 1 monthly clinic sources e.g. Blueteq 2. Develop a screening tool for a wellness and 3. Ask them to link your 3. Begin to deliver the ready for audit to identify people for lifestyle clinic for 6 list to the Patient programme at pilot (see ‘data’) inclusion on a high risk months Administration System centres register (PAS) and to create a 3. Access DMT calculator 3. Monitor the results dashboard (RDC), HES data (ST), 3. Develop a standard letter from that swap... service component for newly diagnosed 4. Supplement and link online form (JH) patients describing 4. Get to know the needs with any bespoke MS the importance of and motivations of information 4. Access MS brain health maintaining a healthy your patients and tailor quality standards lifestyle your info, advice & 5. Identify any gaps or suggestions errors and update 5. Participate in rolling 4. Design a pragmatic audit (100% agreed) social prescribing study

MS Leadership MasterClass clinically-led national programme to ‘Leadership is, simply put, influencing tackle variance in MS services has someone for the common good’. If you are an Acreated a bespoke leadership course MS specialist or a clinician with an interest in to equip healthcare professionals to affect MS and you want to see change in your area, change from the ground up. you have the ability to lead that change. The The programme, ‘Raising the bar for MS’ fully-funded Leadership MasterClass is avail- has outlined a three-year plan ‘to improve Neurology Academy, who is supporting able to help show you how. MS services for all people with MS and their the programme, has just launched its first families, and to make delivering these services Leadership MasterClass specifically to equip for all involved a rich and rewarding experi- clinicians to lead for change. The selective To find out more or to submit an applica- ence.’ course, led by Professor Gabriele de Luca and tion, visit www.multiplesclerosisacademy. org and select ‘Courses’. Professor Gavin Giovannoni, chair of the Barbara Hoese, will equip delegates to confi- programme’s steering group, said, ‘It was clear dently and effectively lead change, so that https://multiplesclerosisacademy.org/ to us at last year’s meeting that for our vision people living with MS across the UK can access courses/leadership to be realised we need a new generation of the best possible care and support they can - to leaders to make things happen.’ lead the lives they want to live.

ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 > 29 r e g u l a r s – c o n f e r e n c e n e w s

SPECS: Seeing brain injury clearly A psychosocial training for professionals working with children and young people with acquired brain injury

Report by: Dr Jenny Jim, Principal Clinical Psychologist, Birgitta Norton, Senior Specialist Educational Psychologist and Dr Gemma Costello, Psychology Lead, Specialist Educational Psychologist in Paediatric Neurodisability at the The Children’s Trust.

PECS is an acronym for core psycho- Advanced day Reported key benefits to professionals social factors that should be addressed • What does ‘culture’ mean? include: enhanced awareness, knowledge, Sin successful neurorehabilitation: Social, • Working with families to support their confidence and skills to work effectively with Physical, Emotional, Cognitive and Spiritual. cultural needs children/young people and families affected Few training packages exist that specifically • Insight of the child/young person and by ABI. In turn families have reflected on the address the unique psychosocial needs of parents/families abilities of staff to support them in increasing children and young people (CYP) with severe • Risks of Insight their knowledge of acquired brain injury, acquired brain injury (ABI), as well as, their • Self-Care enhancing coping, adjustment and adaptation families and staff looking after them. In line • Adjustment, grief and loss and reducing a sense of isolation. with the core principles behind the inter- • Managing expectations and transitions Developing the SPECS model has included national classification of functioning: disability • Managing social situations incorporating it into everyday clinical prac- and health, children and youth version (ICF- • Responding to looks, stares and comments tice. SPECS now contributes a range of CY; WHO, 2007); SPECS is a training package • Coping with difficult questions “what shall perspectives when exploring formulation with that aims to increase the skills and confidence I say?” teams and families (see Figure 1 below). of professionals working directly with children • Complex presentations and situations that It enables teams and families to reflect on and young people with ABI and their families. challenge us the strengths, resources and needs of our SPECS is designed to promote psychosocial • Managing difficult questions and feelings children, young people and families in order rehabilitation, reflective practice and self-care • Active listening and communication skills to support the goals and inform the most in teams. • Non-verbal communication effective approaches to neurorehabilitation. The importance of addressing the holistic • Working with parents effectively In summary, SPECS supports the notion that needs of children and young people with • Lots of practice examples, group reflective comprehensive paediatric neurorehabilitation long-term neurological conditions through tasks and discussion involves a holistic approach inclusive of cogni- specialist rehabilitation is a major motivator • Top tips tive, physical and psychosocial rehabilitation. of the Annual Report of the Chief Medical Officer (2012) “Our Children Deserve Better”. The training is currently provided to inter- Psychosocial factors are major predictors of disciplinary groups at The Children’s Trust in If you’re interested in learning more about long-term outcomes in this population (Ross et order to support shared learning and explore the support The Children’s Trust can offer to children and young people you al, 2011). If psychosocial stressors are buffered multiple perspectives and is accessible to may be working with, come to our FREE staff with both clinical and non-clinical back- and resiliencies increased, those living with Professional Showcase event which takes ABI can achieve a high quality of life. It is grounds in ABI. The delivery includes multi- place on Friday 8 November 2019. To book imperative that professionals are trained to model learning methods (didactic approach, or for further information, visit work to rehabilitate not only the cognitive films, reflective exercises, TED talks, parent www.thechildrenstrust.org.uk/showcase and physical deficits but understand the intri- and children/young people pieces, self- cate interplay between psychosocial support, directed learning, group learning). cognitive recovery and long-term life course outcomes. SPECS was made collaboratively with staff and parents of the children and young people supported by The Children’s Trust, the UK’s leading charity for children with brain injury. SPECS comprises an introductory (day 1) and advanced day (day 2) training programme each concentrating on different aspects of psychosocial care, including:

Introductory day • Thinking more deeply about children/ young people and their context • Maintaining personhood/individuality • Understanding children/young people and family in the context of ABI • Family habits and values • Preparing to meet a new child/young person and family: practice examples • Beginnings and endings • “Seeing yourself in a new light” • Siblings and relationships • Insight • Top tips

30 > ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 r e g u l a r s – c o n f e r e n c e n e w s

International Lewy Body Dementia Conference 2019

Conference details: 22-26 June 2019, Caesars Palace, Las Vegas, Nevada, USA. Report by: Dr Angelika Zarkali, Alzheimer’s Research UK Fellow, Institute of Neurology, University College London. Conflict of interest statement: None declared.

he International Lewy Body Dementia reduced prevalence of resting tremor in LBD Genetics and Epidemiology. These are too Conference closed its doors having compared to PD and the emergence of wear- many to do them justice in this report but they Tbrought together researchers and clin- able technologies for quantifying and object- covered the breadth and depth of LBD at the icians in the field from across the world, as ively monitoring motor symptoms. Finally she highest of standards. Highlights included the well as people living with Lewy Body Disease reported the results of a recent randomised emerging importance of visual dysfunction (LBD) and their carers. I have to admit that controlled trial of zonisamide in LBD which as a predictor of cognitive decline, novel I was initially sceptical about the choice of showed improvement in UPDRS Part III with neuroimaging techniques such as network venue in Las Vegas, but the weather was 50mg dose (compared to placebo, addition to lesion mapping and thalamic nuclei segmenta- pleasant (less than 40 degrees), and the facili- levodopa) without worsening cognition. tions, and the development of new biomarkers ties luxurious and surprisingly quiet; despite Simon Lewis, University of Sydney, gave the such as neurofilament light and EEG. having to pass through the noisy and smoky last talk of the day on Sleep and Autonomic The conference ended with another lively casino to reach it, the conference centre was symptoms in LBD. He walked us through debate on Controversies. Firstly on whether calm and organised. the phenomenology and diagnosis of REM patients with Dementia with Lewy Bodies The conference itself more than lived up sleep behaviour disorder (RBD) as well as and PD dementia should be included in the to our expectations. The first day opened by the significant role of idiopathic RBD as same clinical trials where John Paul Taylor, James Leverenz, Cleveland clinic who high- a prodromal stage to synucleopathies. He Newcastle argued against and Dag Aarsland, lighted the exciting developments in LBD since highlighted the predictors of conversion to Kings College London arguing for. Then the last conference was held in 2017: the publi- synucleopathy from iRBD: abnormal quanti- followed a debate on whether protein aggre- cation of new diagnostic criteria, the inclusion tative motor testing, objective motor examin- gates should be the primary focus for disease of LBD in the National Alzheimer’s Project, ation, olfactory deficit, MCI, erectile dysfunc- modifying therapies; Alberto Espay, University the DIAMOND Lewy programme and many tion, abnormal DAT and abnormal colour of Cincinnati, argued against and David Irwin, others. Susan Schneider-Williams followed vision. University of Pennsylvania, argued for this. with a touching, personal account of the After coffee and pastries, we continued our All speakers made their arguments well and a impact of the disease on her husband Robin update on all things LBD with Kejal Kantarci, thoughtful and interesting discussion followed Williams and herself as carer. She concluded Mayo Clinic, talking about imaging. She high- with the audience with opinions remaining by highlighting the areas of LBD where she felt lighted the value of surrogate neuroimaging relatively divided until the end. more research is needed: improving accuracy markers of synuclein pathology including DAT Overall, the ILBD meeting this year high- of diagnosis, better symptom management and SPECT and pointed out the importance of lighted the extraordinary advancements in this and preventing suicide in people with LBD. better quantifying and recognising mixed AD field of neurodegeneration which has been Following this inspirational opening was and LBD pathology. Next, Douglas Galasko, for so long overlooked. Most importantly, it a series of plenary sessions that provided a University of California, discussed other brought together clinicians and patients from thorough update on all aspects of LBD. Ian biomarkers of LBD, including CSF and blood across the globe in a beautiful venue, promo- McKeith, Newcastle University, updated us a-synuclein. Although these biomarkers have ting further discussion and collaborations. on the diagnostic criteria for LBD. These were significantly improved and exciting develop- The next ILBD meeting will not be for published in 2017 and have received 281 ments like RTQuick are in the pipeline, there another 2 years, but everyone in the field citations so far, being amongst the top 1% of is need for standardisation before these can should watch out for it! papers in Neurodegeneration; this highlights be used in practice. Debby Tsuang, University the increased importance of LBD in neuro- of Washington, then updated us on genetics degeneration research. However, challenges focusing on the significant genetic correlation still exist. Although both DSM V and ICD 11 between AD and PD with Dementia with recognise LBD separately from Parkinson’s Lewy Bodies but the very small correlation Top 5 highlights from ILBD 2019 disease (PD) they still include inconsistencies between AD and PD; this provides further 1 The 2017 Revision of LBD criteria: regarding the presentation and diagnosis of evidence for the importance of AD pathology Lumbar punctures are back in diag- LDB. In DSM V for example, patients can meet in LBD. Dennis Dickson, Mayo Clinic, further nosis of MS the criteria for diagnosis for both DLB and PD expanded on this topic, including how the 2 The DIAMOND Lewy programme: dementia. Rectifying these inconsistencies in pathological criteria for LBD have changed Assessment toolkit available to the next DSM and ICD will be an important and the recognition of new forms such as download for free: https://research. challenge. amygdala predominant LBD. Last but not ncl.ac.uk/ Taris Ferman, Mayo Clinic, followed least in this session, Jordan Gladman, NINDS diamondlewy/toolkitsvideos/ giving a thorough update on cognition in and Angela Taylor, LBD Association, gave an 3 Zonisamide can be a useful add-on LBD including predicting progression to LBD update on the ADRD Summit giving us hopeful to levodopa for motor symptoms in from Mild Cognitive Impairment and key news of increased funding for research in LBD. LBD without cognitive side effects. differences in neuropsychology and imaging Following lunch, we proceeded to an 4 Prodromal LBD is a growing field between LBD and Alzheimer’s disease engaging debate on Consensus criteria for including not only RBD but also (AD). Next, Daniel Weintraub, University of Prodromal Dementia with Lewy Bodies. This MCI, late onset psychosis and Pennsylvania, highlighted the importance of included lively discussion on Biomarkers, Mild possibly delirium. psychiatric symptoms in both LBD and PD Cognitive Impairment, Delirium, Psychiatric 5 New neuroimaging techniques and dementia which is reflected in the updated presentations and RBD which will inform the biomarkers are likely to improve diagnostic criteria and updated us on avail- work of the committee in the months to come. diagnosis and patient stratification able treatment options. Jennifer Goldman, The rest of the conference included 30 in LBD. University of Chicago, then, updated us on selected presentations on Clinical aspects, motor symptoms in LBD; she highlighted the Imaging, Therapeutics, Biomarkers, Pathology,

ACNR > VOLUME 19 NUMBER 1 > AUGUST-OCTOBER 2019 > 31 YOUR CHOICE FOR ELDERLY NVAF PATIENTS LIXIANA® can be used across a broad range of elderly patients.1–3 By offering a combination of clinical1,2,4 and practical3,5 benefi ts, LIXIANA® may help reduce the complexity in managing stroke prevention in your elderly NVAF patients.

KEEPING THE ELDERLY IN MIND

LIXIANA® is a once-daily direct oral anticoagulant (DOAC) indicated for: In NVAF patients with high CrCl, there is a trend towards decreasing ef­ cacy with increasing CrCl for edoxaban vs well-managed warfarin, therefore careful evaluation of thromboembolic and • Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial ­ brillation bleeding risk is necessary before initiation. (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) References: 1. Giuliano RP et al. N Engl J Med 2013;369(22):2093–2104; and supplementary appendix. 2. Kato ET et al. J Am Heart Assoc 2016;5(5). pii: e003432. 3. LIXIANA® Summary of • Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of Product Characteristics. 4. Ruff CT et al. Lancet 2015;385(9984):2288–95. 5. Steffel J et al. Eur recurrent DVT and PE in adults Heart J 2018;39:1330–1393.

LIXIANA (edoxaban) 60 mg / 30 mg / 15 mg fi lm-coated tablets recent gastrointestinal (GI) ulceration, presence of malignant neoplasms at P-gp inhibitors ciclosporin, dronedarone, erythromycin, or ketoconazole prescribing information high risk of bleeding, recent brain or spinal injury, recent brain, spinal or requires edoxaban dose reduction to 30 mg. Edoxaban should be used Refer to the Lixiana Summary of Product Characteristics (SmPC) prior to ophthalmic surgery, recent intracranial haemorrhage, known or suspected with caution with concomitant P-gp inducers (e.g. rifampicin, phenytoin, prescribing oesophageal varices, arteriovenous malformations, vascular aneurysms carbamazepine, phenobarbital, St John’s Wort). Concomitant high dose or major intraspinal or intracerebral vascular abnormalities. Uncontrolled ASA (325 mg) or chronic NSAIDs is not recommended. Concomitant Presentation: 60 mg (yellow) / 30 mg (pink) / 15 mg (orange) edoxaban severe hypertension. Concomitant treatment with any other anticoagulants ASA at doses > 100 mg and < 325 mg should be under medical (as tosilate) fi lm-coated tablets. Indications: Prevention of stroke and e.g. UFH, low molecular weight heparins, heparin derivatives (fondaparinux, supervision only. Very limited experience with dual antiplatelet therapy systemic embolism in adult patients with non-valvular atrial fi brillation etc.), VKA or DOACs except under specifi c circumstances of switching oral or fi brinolytics. Possibility of increased bleeding risk with concomitant (NVAF) with one or more risk factors, such as congestive heart failure, anticoagulant therapy or when UFH is given at doses necessary to maintain SSRIs or SNRIs. Adverse reactions: Common: anaemia, dizziness, headache, epistaxis, abdominal pain, lower GI haemorrhage, upper GI hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient an open central venous or arterial catheter. Pregnancy and breast-feeding. haemorrhage, oral/pharyngeal haemorrhage, nausea, blood bilirubin ischaemic attack (TIA). Treatment of deep vein thrombosis (DVT) and Special warnings and precautions for use: Haemorrhagic risk: Caution increased, gamma GT increased, cutaneous soft tissue haemorrhage, pulmonary embolism (PE), and prevention of recurrent DVT and PE in in patients with increased risk of bleeding such as elderly on ASA. rash, pruritus, macroscopic haematuria/urethral haemorrhage, vaginal adults. Posology and method of administration: Recommended Discontinue if severe haemorrhage occurs. The anticoagulant effect of NVAF: haemorrhage, puncture site haemorrhage, liver function test abnormal. dose is 60 mg edoxaban once daily with or without food. Continue therapy edoxaban cannot be reliably monitored with standard laboratory testing. thrombocytopaenia, hypersensitivity, intracranial long term. Recommended dose is 60 mg edoxaban once daily with A specifi c anticoagulant reversal agent for edoxaban is not available. Serious uncommon: VTE: haemorrhage (ICH), intraocular haemorrhage, other haemorrhage, or without food following initial use of parenteral anticoagulant for at least Haemodialysis does not signifi cantly clear edoxaban. Renal impairment: haemoptysis, surgical site haemorrhage. Serious rare: anaphylactic 5 days. Duration of therapy (at least 3 months) should be based on risk CrCl should be monitored at the initiation of edoxaban and afterwards reaction, allergic oedema, subarachnoid haemorrhage, pericardial profi le of the patient. For NVAF and VTE the recommended dose is 30 mg when clinically indicated. Not recommended in patients with end stage haemorrhage, retroperitoneal haemorrhage, intramuscular haemorrhage edoxaban once daily in patients with one or more of the following: moderate renal disease or on dialysis. Renal function and NVAF: A trend towards decreasing effi cacy with increasing CrCl was observed for edoxaban (no compartment syndrome), intra-articular haemorrhage, subdural or severe renal impairment (creatinine clearance (CrCL) 15 - 50 mL/min); haemorrhage, procedural haemorrhage. Legal classifi cation: POM. low body weight ≤ 60 kg; concomitant use of the P-glycoprotein (P-gp) compared to well-managed warfarin. Edoxaban should only be used in patients with NVAF and high CrCl after a careful benefi t risk evaluation. Package quantities, marketing authorisation (MA) numbers and inhibitors, ciclosporin, dronedarone, erythromycin, or ketoconazole. The basic NHS costs: 60 mg – 28 tablets – EU/1/15/993/018 - £49.00. 15 mg dose of edoxaban is not indicated as monotherapy, and should only Hepatic impairment: Not recommended in severe hepatic impairment. Caution in mild or moderate hepatic impairment. Caution in patients with 30 mg – 28 tablets – EU/1/15/993/005 - £49.00. 15 mg – 10 tablets be used during a switch from edoxaban to VKA in certain patients (see - EU/1/15/993/001 - £17.50. MA holder: Daiichi Sankyo Europe GmbH, elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN. SmPC for full details). Edoxaban can be initiated or continued in patients Zielstattstrasse 48, 81379 Munich, Germany. Date of preparation of Perform liver function testing prior to initiation and then periodically monitor who may require cardioversion. For transoesophageal echocardiogram Prescribing Information: May 2019 EDX/19/0141 guided cardioversion in patients not previously treated with anticoagulants, for treatment beyond 1 year. Surgery or other interventions: discontinue edoxaban should be started at least 2 hours before cardioversion to ensure edoxaban as soon as possible and preferably at least 24 hours before the adequate anticoagulation. Cardioversion should be performed no later than procedure. If procedure cannot be delayed, the increased risk of bleeding 12 hours after the dose of edoxaban on the day of the procedure. Confi rm should be weighed against urgency of the procedure. Restart edoxaban Adverse events should be reported. prior to cardioversion that the patient has taken edoxaban as prescribed. as soon as haemostasis achieved. Prosthetic heart valves and moderate to Reporting forms and information can be found If a dose of edoxaban is missed, the dose should be taken immediately severe mitral stenosis: Not recommended. Haemodynamically unstable PE at www.mhra.gov.uk/yellowcard. and then continued once daily on the following day. Contraindications: patients or patients who require thrombolysis or pulmonary embolectomy: Adverse events should also be reported to Hypersensitivity to the active substance or to any of the excipients. Not recommended. Patients with active cancer: Not recommended in Daiichi Sankyo UK Pharmacovigilance on 0800 028 5122, Clinically signifi cant active bleeding. Hepatic disease associated with treatment and/or prevention of VTE. Patients with a history of thrombosis coagulopathy and clinically relevant bleeding risk. Lesion or condition, if diagnosed with antiphospholipid syndrome: DOACs including edoxaban [email protected] considered to be a signifi cant risk for major bleeding including current or are not recommended. Drug interactions: Concomitant use of the www.lixiana.co.uk Date of preparation: June 2019 | Job code: EDX/19/0350