Mentored by a Maverick

When someone lets you down by breaking society’s rule of reciprocity ones natural reaction is for revenge. However, before reaching for the revolver I am using this psychological crisis to reflect on things so that I can hopefully come away with something positive.

At the recent Royal London James Parkinson’s memorial I described myself as an accidental tourist; what I meant was I have found myself ending up being accidental movement disorders researcher. If you know me from seeing or hearing me with my multiple sclerosis hat on you may find this surprising. How I got into movement disorders is a story worth telling. It started back in 1996 when I was asked to apply for the Scarfe Clinical Lecturer post by Ian McDonald at Queen Square. This post was paired with Professor Andrew Lees’ UCLH Senior Registrar post. My ‘PhD mates’ or fellow ‘CRU Club’ dining partners, who knew the English system well, advised me that if I wanted to get the post I would need to woo Andrew Lees. They suggested I work on something related to movement disorders. After thinking about things for a few days I came up with the idea to study the immunology of Sydenham’s chorea. Why Sydenham’s chorea? Although it was by then a rare condition in the UK I had had seen a large number of patients with Sydenham’s in South Africa and as it was autoimmune it had always interested me. As I was working in a immunology laboratory I had the infrastructure at hand to do the research. Andrew Lees liked my proposal and offered to put me contact with a colleague in South America with a similar interest in the condition. Having got the job I now had to deliver on the Sydenham’s chorea project (accident number 1).

Once in post I was tasked by Andrew Lees to help run his Parkinson’s disease and subcutaneous apomorphine pump service. This was based in the old Middlesex Hospital on Mortimer Street. Part of the diagnostic work-up for patients with Parkinson’s disease included a so called L-Dopa challenge. You examine patients and ask them to do a 30 second alternate finger tapping test, by pressing two counters that were spaced approximately 20 cms apart on a board. You then give the test subjects a dose of L-Dopa and repeat the examination and tasks after the L-Dopa has had a chance to work. The first thing I did was to replace the tapping test with the so called BRAIN Test (Bradykinesia Akinesia Incoordination Test), which was a simple bit of software that I had originally written using the PASCAL programming language back in South Africa. The programme ran on top of the DOS operating system. As PASCAL was not suited for collecting accurate timing data from the keyboard a very good friend of mine re-coded the test using more responsive interrupts in Assembler language, a very low level programming language for computer geeks. For me the BRAIN test was quite an innovation as it collected much more interesting data than the simple manual tapping test. For example, it could differentiate between cerebellar dysfunction and Parkinson’s disease. The data collected eventually led to a publication, one of many, with Andrew Lees as the senior author. Andrew had officially become my movement disorder collaborator and mentor (accident number 2).

Andrew Lees was a very insightful neurologist and realised that micromanaging his trainees was not the best way to get the best out them. Apart from the biweekly ward rounds and advice during and after clinics Andrew trusted us to get on with things and to come to him if we had any problems. Andrew would let us make most of the treatment decisions about his patients and would only occasionally tweak things. Andrew felt that too many cooks spoil the broth and let us learn from our mistakes when it came to dealing with these extremely complex cases. Kirsten his PD specialist nurse knew more about managing the apomorphine patients than any of us trainees and soon got me up to speed with the complexities of this highly specialised area of Parkinson’s disease. It was during my time on the ward that I soon realised that a large number of our patients were addicted to apomorphine and were overdosing on it to treat the inevitable low that came when they were off. One of the cases, who we subsequently wrote-up, was consuming about 50% of our time managing his psychiatric and behavioural problems. I spent many hours observing and documenting his problems and on reading the literature I realised we were dealing with a new syndrome that had not been described. Kirsten helped us identify several other ‘Apomorphine addicts’, who I was introduced to and we wrote them up in a seminal paper. We deliberately avoided using the term addiction when describing these patients because of the associated stigma of being labelled an addict and because they needed their apomorphine to be on, i.e. to function. After some debate we settled on using the term ‘hedonistic homeostatic dysregulation’, which summarised what we were describing very well and had already been used in the psychiatric literature. Subsequently this term was dropped and substituted with the easier to use name of the ‘dopamine dysregulation syndrome’ (accident number 3).

The furore that arose from the hedonistic homeostatic dysregulation paper was quite unbelievable; we received abusive criticisms of the paper with many movement disorder experts ridiculing us for daring to describe what we saw. I only later became aware of Arthur Schopenhauer’s dictum, ‘All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.’ How true! When I was contacted by a US law firm to give evidence in a class-action lawsuit against the Pharma industry, in relation to impulse control disorders on dopamine agonists, Andrew wisely recommended that I should say no.

Once I started working for Andrew I helped set-up an anti-basal ganglia antibody assay, received our first shipment of serum samples from Brazilian patients with Sydenham’s chorea and started to get results. The Sydenham’s research project happened to coincide with the description of PANDAS (paediatric neuropsychiatric disorders associated with streptococcal infection), which has a very similar clinical presentation to Tourette’s Syndrome. I still consider PANDAS to be a forme fruste of Sydenham’s chorea. Once we had identified potential autoantigens common to both Sydenham’s chorea and PANDAS we stared screening clinical cohorts of patients with complex neuropsychiatric and movement disorders and found a small proportion having these autoantibodies. As the anti-basal ganglia phenotype spread the test lost specificity. Either the test was at fault or these other conditions had an immune component to them. I suspect the latter. Basal ganglia disorders are renowned for having variable clinical presentations with a lot of overlap. Why should autoimmune disorders of the basal ganglia not have a variable phenotype? Shortly after leaving Queen Square to take-up the Chair of Neurology at Barts and The London I made a strategic decision to give-up working on movement disorders and to focus my efforts on multiple sclerosis. However, this didn’t last very long.

Interestingly, the BRAIN Test has survived and has subsequently been re-coded in Javascript to allow it run inside a web browser. I yearn to have time, in particular quality time, to learn how to code in Javascript. Being able to do your own coding gives such an advantage in the digital era. However, the BRAIN Test has proven to be resilient and has become a core part of my recent foray as a movement disorder researcher. On taking up my post at Barts and The London I had the pleasure of supervising Alastair Noyce an incredibly bright academic trainee. Alastair had done a medical school project on taste and smell in Parkinson’s disease. People with Parkinson’s disease have a prodromal or premotor phase before they are diagnosed as having the disease. One of the prodromal manifestations of Parkinson’s disease is loss of smell or anosmia. This led to the idea of developing an online platform to recruit subjects from the general population and to screen them for prodromal symptoms and signs so that we can predict who will go onto develop Parkinson’s disease. Alastair developed the platform, which includes the Brain Test, and went onto study it as part of a PhD at UCL. Andrew Lees was kind enough to take Alastair under his wing and supervise his PhD. The preliminary evidence from the Predict PD platform is that it works and has opened my mind to the possibility of doing a remote neurological assessment on the web (accident 4).

On arriving at Barts and The London I was astounded by the history of the Royal London and St Bartholomew’s Hospitals and their respective medical schools. I therefore started the Lord Brain Memorial Lecture and Medal to celebrate this legacy. As Andrew Lees was an alumnus of The London it seemed natural for Andrew to be the first recipient of the Lord Brain Memorial medal to give the first Lord Brain Memorial lecture. His talk ‘Brainwashed by the Black Stuff’ still reverberates around the hallowed halls of The London.

Across my accidental research career in movement disorders Andrew Lees has been a soft influence, a hidden hand on my shoulder, guiding and helping me. I was truly touched to get a mention in Andrew’s brilliant book ‘Mentored by a Madman: The William Burroughs Experiment’. The book is an interesting insight into Andrew’s mind and modus operandi and explains why he is one of the most cited researchers in field of Parkinson’s disease. His creativity as a thinker and writer in Parkinson’s disease is unrivalled and sets him apart from the pack. He is clearly a maverick.

I am privileged to have being mentored by Andrew Lees; his sage counsel across my career is much appreciated. I assume he is going to talk me down from needing to use the revolver.

Thank you.

The following are the papers that Andrew Lees and I have published as co-authors in the movement disorder field. Not bad for an accidental tourist?

Noyce AJ, Dickson J, Rees RN, Bestwick JP, Isaias IU, Politis M, Giovannoni G, Warner TT, Lees AJ, Schrag A. Dopamine reuptake transporter-single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson’s disease. Mov Disord. 2018 Mar;33(3):478–482.

Noyce AJ, R’Bibo L, Peress L, Bestwick JP, Adams-Carr KL, Mencacci NE, Hawkes CH, Masters JM, Wood N, Hardy J, Giovannoni G, Lees AJ, Schrag A. PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson’s disease. Mov Disord. 2017 Feb;32(2):219–226.

Noyce AJ, Schrag A, Masters JM, Bestwick JP, Giovannoni G, Lees AJ. Subtle motor disturbances in PREDICT-PD participants. J Neurol Neurosurg Psychiatry. 2017 Mar;88(3):212–217.

Noyce AJ, Mencacci NE, Schrag A, Bestwick JP, Giovannoni G, Lees AJ, Hardy J. Web-based assessment of Parkinson’s prodromal markers identifies GBA variants. Mov Disord. 2015 Jun;30(7):1002–3.

Noyce AJ, Nagy A, Acharya S, Hadavi S, Bestwick JP, Fearnley J, Lees AJ, Giovannoni G. Bradykinesia-akinesia incoordination test: validating an online keyboard test of upper limb function. PLoS One. 2014 Apr 29;9(4):e96260.

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Knowles CH, Hardy J, Giovannoni G, Nageshwaran S, Osborne C, Lees AJ, Schrag A. PREDICT-PD: identifying risk of Parkinson’s disease in the community: methods and baseline results. J Neurol Neurosurg Psychiatry. 2014 Jan;85(1):31–7.

Noyce AJ, Bestwick JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G, Lees AJ, Schrag A. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol. 2012 Dec;72(6):893–901.

Noyce AJ, Treacy C, Budu C, Fearnley J, Lees AJ, Giovannoni G. The new Bradykinesia Akinesia Incoordination (BRAIN) test: preliminary data from an online test of upper limb movement. Mov Disord. 2012 Jan;27(1):157–8.

Luk C, Giovannoni G, Williams DR, Lees AJ, de Silva R. Development of a sensitive ELISA for quantification of three- and four-repeat tau isoforms in tauopathies. J Neurosci Methods. 2009 May 30;180(1):34–42.

Edwards MJ, Dale RC, Church AJ, Trikouli E, Quinn NP, Lees AJ, Giovannoni G, Bhatia KP. Adult-onset tic disorder, motor stereotypies, and behavioural disturbance associated with antibasal ganglia antibodies. Mov Disord. 2004 Oct;19(10):1190–6.

Edwards MJ, Trikouli E, Martino D, Bozi M, Dale RC, Church AJ, Schrag A, Lees AJ, Quinn NP, Giovannoni G, Bhatia KP. Anti-basal ganglia antibodies in patients with atypical dystonia and tics: a prospective study. Neurology. 2004 Jul 13;63(1):156–8.

Dale RC, Church AJ, Surtees RA, Lees AJ, Adcock JE, Harding B, Neville BG, Giovannoni G. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain. 2004 Jan;127(Pt 1):21–33.

Church AJ, Dale RC, Lees AJ, Giovannoni G, Robertson MM. Tourette’s syndrome: a cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatry. 2003 May;74(5):602–7.

Church AJ, Dale RC, Cardoso F, Candler PM, Chapman MD, Allen ML, Klein NJ, Lees AJ, Giovannoni G. CSF and serum immune parameters in Sydenham’s chorea: evidence of an autoimmune syndrome? J Neuroimmunol. 2003 Mar;136(1–2):149–53.

Dale RC, Church AJ, Benton S, Surtees RA, Lees A, Thompson EJ, Giovannoni G, Neville BG. Post-streptococcal autoimmune dystonia with isolated bilateral striatal necrosis. Dev Med Child Neurol. 2002 Jul;44(7):485–9.

Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G. Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology. 2002 Jul 23;59(2):227–31.

Giovannoni G, O’Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry. 2000 Apr;68(4):423–8.

Giovannoni G, van Schalkwyk J, Fritz VU, Lees AJ. Bradykinesia akinesia inco-ordination test (BRAIN TEST): an objective computerised assessment of upper limb motor function. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):624–9.

Neurologist, researcher, avid reader, ms & preventive neurology thinker, blogger, runner, gardener, husband, father, dog-owner, cook and wine & food lover.