The emerging research boosting Parkinson’s disease treatment

Parkinson’s disease (PD) is probably the most iconic neurological disorder. It has diverse manifestations, typical of many neurological diseases. PD is a result of brain dopamine deficiency, and its clinical picture is dominated by motor symptoms- tremor, rigidity and bradykinesia (slowing of movements). It however also manifests with a variety of non-motor symptoms which rival the motor symptoms in their impact. PD is responsive to treatment with several oral medications such as levodopa, infusions such as apomorphine, and interventions such as deep brain stimulation (DBS).

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Regardless of the intervention used, PD is a neurodegenerative disorder that grinds, slowly and steadily, along a chronic progressive course. This often manifests with disabling features such as freezing, hallucinations, and dyskinesias (drug-induced writhing movements). These symptoms creep or barge in unannounced, challenging the wits of the neurologist, and pushing the resolve of patients and their families to the limit. What hope does research offer to smooth the journey for people with PD? Here are my top 7.

1. Increasing evidence for the benefit of exercise

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OK, not every advance has to be groundbreaking. It is self-evident that exercise is beneficial for many chronic disorders, but proving this has been difficult…until now that is. Researchers, publishing in the journal Movement Disorders, looked at the benefits of exercise on cognitive function in PD, and their verdict is-yes, it works! The study, titled Exercise improves cognition in Parkinson’s disease: The PRET-PD randomized, clinical trial, comes with strings attached- you have to keep at the exercise for 2 years! A review  in the same journal indicates that exercise also improves mood and sleep in PD.

2. Lithium for treatment of dyskinesias

By Dnn87 - Self-photographed, CC BY 3.0, Link
By Dnn87Self-photographed, CC BY 3.0, Link

Dyskinesias are abnormal, fidgety movements that develop as side effects of the drugs used to treat PD. Most people with dyskinesias are not overly concerned about the movements because the alternative, disabling freezing and immobility, is worse. Dyskinesias are however energy-sapping, and are distressing for family members. Amantadine is one drug neurologists add-on to improve dyskinesias, but many people do not tolerate or benefit from this. The suggestion that lithium may help dyskinesias is therefore welcome news. The report comes from a study in mice reported in the journal Brain Research titled The combination of lithium and l-Dopa/Carbidopa reduces MPTP-induced abnormal involuntary movements (AIMs). A long way to go yet, but hope.

3. Transcranial magnetic stimulation (TMS)

By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link
By MistyHora at the English language Wikipedia, CC BY-SA 3.0, Link

Transcranial magnetic stimulation (TMS) is playing an increasing role in neurology as I discussed in a previous post titled Are magnets transforming neurology? It is almost inevitable therefore that TMS will crop up in attempts to treat PD. And so it has, going by a meta-analysis and systematic review published in JAMA Neurology. The paper is titled Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease. The reviewers passed the judgement that repetitive TMS improves motor symptoms in PD. Perhaps time to invest in TMS!

4. MRI guided focused ultrasound (MRgFUS)

By Frmir - Own work, CC BY-SA 3.0, Link
By FrmirOwn work, CC BY-SA 3.0, Link

MRI guided ultrasound (MRgFUS) is not new to medicine. It is used, for example, in the treatment of solid tumours and uterine fibroids. It is however innovative in the treatment of tremor and dyskinesia in PD. This came to my attention via a press release from University of Maryland titled Metabolic Imaging Center uses new ultrasound technology to target deep structures of the brain. MRgFUS non-invasively transmits ultrasound waves to the globus pallidus, one of the deep brain structures involved in PD. How this works still remains fuzzy to me, but it is exciting enough to generate a lot of research activity with articles such as MRI guided focused ultrasound thalamotomy for moderate-to-severe tremor in Parkinson’s disease in the journal Parkinson’s Disease; and Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease, published in Neurology. Watch out, deep brain stimulation!

5. Nasal mucosal grafting

Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471
Big Nose Strikes Again. Bazusa on Flikr. https://www.flickr.com/photos/bazusa/260401471

What a great thing, the blood-brain barrier, protecting the brain from all the bugs and toxins running amok in the bloodstream. This iron-clad fence unfortunately also effectively keeps out, or limits the entrance of, many beneficial drugs which need to get to the brain to act. As with all borders however, there are always people ready to break through, without leaving any tracks behind. And the people in this case are neurosurgeons who have successfully bypassed the blood brain barrier, and safely ‘transported’ PD drugs in to the brain. They did this by removing a portion of the blood brain barrier of mice, and replaced it with a piece of the tissue which lines the inside of the nose, a procedure called nasal mucosal grafting. They then delivered glial derived neurotrophic factor (GDNF), a protein that treats PD in mice, across the graft. The neurosurgeons explained all this in their paper titled Heterotopic mucosal grafting enables the delivery of therapeutic neuropeptides across the blood brain barrier. You may however prefer the simpler version from the Boston Business Journal (can you believe it!) titled A new way to treat Parkinson’s disease may be through your nose. It will however take time before human trials of nasal mucosal grafting…this is science after all, not science fiction!

6. Fetal stem cell transplantation

Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806
Marmoset embryonic stem cells forming neurons. NIH Image gallery on Flikr. https://www.flickr.com/photos/nihgov/27406746806

It doesn’t seem too long ago when all ethical hell broke loose because some scientists were transplanting fetal tissue into human brains. I thought the clamour had put this procedure into the locker, never to be resurrected. Apparently not; fetal stem cell transplantation (SCT) is back, reminiscent of Arnold Schwarzenegger in the Terminator films. Learn more of this comeback in this piece from New Scientist titled Fetal cells injected into a man’s brain to cure his Parkinson’s. The work is from Roger Barker‘s team at the University of Cambridge, and they are planning a big study into this named TRANSNEURO. Watch this space

7. Pluripotent stem cell transplantation

By Judyta Dulnik - Own work, CC BY-SA 4.0, Link
By Judyta DulnikOwn work, CC BY-SA 4.0, Link

The future of stem cell transplantation probably lies with pluripotent, rather than fetal cells. The idea is to induce skin cells, called fibroblasts, to transform into dopamine-producing cells. Fibroblasts can do this because they are pluripotent cells; that is they are capable of becoming whatever type of cells you want, so long as you know the magic words. In this case, the words are likely to be the transcription factors Mash1, Nurr1 and Lmx1a. Beatsopen sesame‘, and surely less controversial than fetal cells. Researchers are taking this procedure very seriously indeed, setting out ground rules in articles such as Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. This was published in the journal Nature, but you may prefer the easier read in New Scientist titled Brain cells made from skin could treat Parkinson’s. But don’t get too excited…pluripotent stem cell transplantation is barely at the starting line yet.

 

Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595
Eu Sou. jeronimo sanz on Flikr. https://www.flickr.com/photos/jeronimooo/12069638595

There is so much more going on in the field of Parkinson’s disease to cover in one blog post. I will review neuroprotection in Parkinson’s disease in a coming post. In the meantime, here are links to 12 interesting articles and reviews on the future of PD:

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A short history of WESAN

This is a follow up to my last blog post titled What has the Exeter neurology course accomplished in the last decade? There I discussed the achievements of the West of England Seminars in Advanced Neurology (WESAN). In this post, the focus is on the history of WESAN, and who better to tell the story than Christopher Gardner-Thorpe, who spent the bulk of his neurology career at the Royal Devon and Exeter Hospital, where I now work. His own story needs a different blog post to relate. For now, here is Chris’s brief look-back at the history of WESAN. In a way, this also happens to be the first Neurology Lounge guest blog!

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A Short History of WESAN

By Christopher Gardner-Thorpe

The Bath Course that David Bateman started in 1993/4 was very successful and the first general neurology course in the south of the country (the Edinburgh Course which had started before 1993 was a little different but equally enjoyable and useful), concentrating on everyday issues. The participants were drawn from consultant and trainee doctors who enjoyed a couple of days in Bath with accommodation and good fraternity intermingled with significant learning opportunities. The slide projection apparatus in those days left a lot to be desired and often the slide projector would jam or the laptop computer would not recognise the projector or vice versa. It usually took up to half a dozen persons clustered round the apparatus in order to get it going again.

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Pharmaceutical sponsorship was available and widespread in those days and the Course rightly counted for study leave. Audit had barely started and discussions between colleagues enabled us all to keep roughly in-line with current practice throughout the country.

David Bateman moved from Bath to Carlisle to start a new neurology unit, in the north of England where he knew the territory well, having trained partly in Newcastle. This provided a good opportunity for Exeter to take over the course. Colleagues in Bath did not wish to run the course nor was there a competitive venue to continue the course there. So we set up West of England Seminars in Advanced Neurology and the acronym WESAN was the obvious shortcut term. Nick Gutowski and Christopher Gardner-Thorpe were pleased to take on the course.

By Equestenebrarum - File:Topographic Map of the UK - Blank.png, CC BY 3.0, Link
By EquestenebrarumFile:Topographic Map of the UK – Blank.png, CC BY 3.0, Link

In order to continue to ensure the conviviality that surrounded the Bath meetings, a clear choice of venue was Bovey Castle in Moretonhampstead. This hotel, previously a British Railway hotel of mediocre reputation, had been greatly improved and was a fine venue. We were made most welcome and the course content went from strength to strength. The one drawback was that the hotel was a taxi ride across half of Dartmoor from Exeter, but this did not deter participants – and the isolation might have been an advantage. Again, pharmaceutical support allowed the cost for participants to be kept reasonable. This continued for a few years until the squeeze came – three golf courses was the nail in the coffin.

Bovey Castle. © Copyright Martin Bodman http://www.geograph.org.uk/photo/2475196
Bovey Castle. © Copyright Martin Bodman http://www.geograph.org.uk/photo/2475196

A new venue had to be found. This took the form of the Rougemont Hotel in Exeter, the old hotel opposite the Southern Railway Station of Exeter Central, the name reflecting the red earth of Devon and the mound upon which in 1068 the castle had been built nearby. The venue was not exactly the similar to Bovey Castle but access within Exeter was much easier. Furthermore, just before Christmas (for we had changed the timing from June to November) the hotel was within easy walking distance of the High Street shops. The dinner has been held at one of two sites, the Cathedral Chapter House and the Guildhall. The latter has become the venue of preference and is only a couple of hundred yards from the hotel. The hotel became the Thistle and is now the (second) Mercure in Exeter.

The Rougemont Hotel, Exeter. Robert Cutts on Flikr https://www.flickr.com/photos/panr/5542700403
The Rougemont Hotel, Exeter. Robert Cutts on Flikr https://www.flickr.com/photos/panr/5542700403

We have enjoyed running the course and the speakers have increased from about ten to a regular and lucky number of thirteen, over the two days, Thursday and Friday, with the option of staying to enjoy Devon over the ensuing weekend. Joe Gormley and Ibrahim Imam have joined the team to provide new stimulus, continuity and a long future for this Course.

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 Why not click to register for WESAN now!

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What has the Exeter neurology course accomplished in the last decade?

The West of England Seminars in Advanced Neurology (WESAN) is a neurology course which holds annually in Exeter, the historic English city in the scenic county of Devon. It is a highly-regarded, even if a little bit unassuming, neurology meeting. Over the last decade I have attended several WESAN conferences, always going back to base buzzing with neurological enthusiasm, and brimming with fresh insights into knotty problems. I was therefore very pleased when, along with my colleague Joe Gormley, I was invited to join the long-running conveners of this distinguished course, Christopher Gardner-Thorpe and Nick Gutowski.  And I am talking about this now because the next WESAN is on the 24-25 November 2016.

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What has WESAN achieved over the last ten years to earn the accolades I have poured all over it? Who are the neurology masters who have graced the WESAN podium over the years? Who are the unsung but bright stars who have cast their spell on generations of neurology consultants and trainees? Which subjects did WESAN tackle, and what topics did the speakers conjure up to regale and enthuse? And what will delegates be served this year?

By Dietmar Rabich - Own work, CC BY-SA 4.0, Link
By Dietmar RabichOwn work, CC BY-SA 4.0, Link

To find out, I collated all WESAN programmes since 2005, and I have reproduced them below. The range of topics addresses all the core neurology subspecialties, but keep an eye out for sprinkling of intriguing titles such as Quoi de neuf? Rien de neuf! by Alan Emery, The neuropathologist in court by Waney SquierMagic but treatable? by Oliver Hanemann, Gratiolet’s torque and the evolution of language by Tim CrowEffective whistle-blowing skills for neurologists by David Nicholl, and Therapeutic gardening by Richard Thompson.

Reunion of neurologists at the Salpêtrière hospital. Photograph, 1926 http://wellcomeimages.org/indexplus/obf_images/03/de/5ebbbcfa56d021dda69b21761b96.jpgGallery: http://wellcomeimages.org/indexplus/image/M0005197.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36322408
Reunion of neurologists at the Salpêtrière hospital, 1926. http://wellcomeimages.org/indexplus/obf_images/03/de/5ebbbcfa56d021dda69b21761b96.jpgGallery: http://wellcomeimages.org/indexplus/image/M0005197.html, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=36322408

WESAN 2005

  • Jeremy Hobart (Plymouth) Who rates scales? How to sell yourself short
  • Vaughan Pearce (Exeter) On being a medical director
  • Waney Squier (Oxford) The neuropathologist in court
  • Jonathan Schott (London) Limbic encephalitis-the autoimmune connection
  • Chris Clough (London) The JCHMT
  • Alan Emery (Exeter) Quoi de neuf? Rien de neuf!
  • Stephen Brown (Bodmin) Epilepsy and psychiatry
  • Adam Zeman (Exeter) Syndromes of global amnesia
  • Roger Barker (Cambridge) Huntington’s disease
  • Peter Newman (Middlesborough) IVIG in neurology
  • Pam Shaw (Sheffield) Diseases of the motor neurone
  • Giles Elrington (London) Commercial neurology

WESAN 2006

  • Christopher Weatherley (Exeter) Understanding spinal surgery
  • Mike Boggild (Liverpool) Multiple sclerosis
  • Brendan Davis (Stoke-on-Trent) Headache
  • David Nicholl (Birmingham) Ethics for neurologists
  • Graham Hughes (London) Lupus
  • Peter Harper (Cardiff) Neurology and the beginnings of genetics
  • Adrian Wills (Nottingham) Ventilatory failure for the neurologist
  • David Hilton-Jones (Oxford) Muscles
  • John Winer (Birmingham) Peripheral nerves
  • Tim Lewis  (Bristol)Neuroradiology
  • Pam Crawford (York) Epilepsy-do the facts fit?
  • Geraint Fuller (Gloucester) Training

WESAN 2007

  • Brendan McLean (Truro) Epilepsy
  • Nick Kane (Bristol) Problems and pitfalls in clinical use of EEG
  • Mark Wiles (Cardiff) Education in neurology
  • Mark Edwards (Queen Square) Movement disorders
  • Michael Hutchinson (Dublin) Multiple sclerosis and pregnancy
  • Richard Thompson (Royal College of Physicians) Therapeutic Gardening
  • Vik Devaraj (Exeter) Peripheral nerve surgery for neurologists
  • Oliver Hanemann (Plymouth) Magic but treatable? Tumours due to the loss of merlin
  • Peter Nestor (Cambridge) Mild cognitive impairment-use and abuse of a new construct
  • Rustam Al-Shahi Salman (Edinburgh) Dilemmas in the management of cavernous malformations
  • Paul Davies (Northampton) Headache
  • Peter Bliss (Exeter) Neuro-oncology
Exeter High Street, GuildhallBy Franzfoto - Own work, CC BY-SA 3.0, Link
Exeter High Street, GuildhallBy FranzfotoOwn work, CC BY-SA 3.0, Link

WESAN 2008

  • Neil Scolding (Bristol) Stem cell therapy and MS
  • Robin Howard (Queen Square) Neuromuscular complications on the ITU
  • Russell Lane (Queen Square) Understanding headache
  • Andrew Larner (Liverpool) Practical cognitive neurology
  • Mark Manford (Cambridge) When is a fit not a fit?
  • Ian Barker (Medical Defence Union) Medicolegal matters
  • Hadi Manji (Queen Square) Tropical neurology in central London
  • Tim Crow (Oxford) Gratiolet’s torque and the evolution of language
  • Hardev Pall (Birmingham) Tremor – changes in classification and treatment
  • Malcolm Hilton (Exeter) BPPV: Five-minute miracle cure guaranteed
  • Charles Clarke (Queen Square) The neurology of high altitude, the problems of chronic hypoxia
  • Peter Whitfield (Plymouth) Question time with a neurosurgeon (in the hot seat)

WESAN 2009

  • Marguerite Hill (Swansea) Myasthenia
  • Simon Hammans (Southampton) Muscle disorders and their genetics
  • Graham Venables (Sheffield) Stroke
  • Kirstie Anderson (Newcastle) Sleep
  • Angus Kennedy (Charring Cross) Cognitive problems
  • Caroline Hahn (Edinburgh) Veterinary neurology
  • Susan Duncan (Edinburgh) Epilepsy
  • Peter Harvey (London)
  • Siobhan Leary (Queen Square) Multiple sclerosis
  • Karen Morrison (Birmingham) Motor neurone disease
  • Guy Sawle (Nottingham) Movement disorders
  • Nick Silver (Liverpool) Headache

WESAN 2010

  • Mark Roberts (Manchester) Muscle disorders
  • Peter Simcock (Exeter) Neuro-ophthalmology and optic nerve disorders
  • Bridget MacDonald (St George’s) Epilepsy-practical points in the ordinary neurology clinic
  • Mike Lunn (Queen Square) The diagnosis, pathogenesis and therapy of inflammatory peripheral neuropathies
  • Fady Joseph (Gwent) Behcet’s disease
  • Ian Gilmore (Liverpool) Alcohol-the good, the bad and the ugly
  • Richard White (Liverpool) Headache and stroke in clinical practice
  • Stanley Hawkins (Belfast) Multiple sclerosis
  • Mike Alexander (Dublin) Neurophysiology
  • Ralph Gregory (Poole)
    • When the Parkinson Disease honeymoon is over
  • Gerry Saldanha (London) On Education
  • Kathryn Peall (Cardiff) Myoclonus-dystonia syndromes and familial tremor

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WESAN 2011

  • Lionel Ginsberg (Royal Free) Fabry Disease and peripheral neuropathies
  • Ray Murphy (Dublin) Interesting clinical cases
  • Lina Nashef (Kings) SUDEP-an update
  • Markus Reuber (Sheffield) Managing patients with non-epileptic attacks
  • Chris Turner (UCL) Which is the most important organ involved in myotonic dystrophy?
  • David Bates (Newcastle) The Future of treatments in multiple sclerosis
  • Alastair Compston (Cambridge) Brain: a journal of neurology, 133 years on
  • Ed Fathers (Taunton) How to give a talk
  • Paul Maddison (Nottingham) Paraneoplastic disorders and related antibodies
  • Mark Jackson (Exeter) 1922: stress and the origins of neuro-endocrinology
  • Richard Davenport (Edinburgh) The cervical spine
  • Sam Chong (Medway and Kings) Neuropathic pain-just amitriptyline deficiency?
  • Paul Worth (Norwich) Movement disorders

WESAN 2012

  • Luke Bennetto (Bristol) Intracranial tension-highs and lows
  • Manish Gandhi (Exeter) When the heart rules the brain
  • Richard Jacoby (Exeter) Rheumatology for neurologists
  • David Gow (Manchester) Peripheral nerves
  • Desmond Kidd (Royal Free) Neurosarcoidosis
  • Yvonne Hart (Newcastle) Epilepsy
  • David Nicholl (Birmingham) Effective Whistle-blowing skills for neurologists
  • Tom Hughes (Cardiff) Stroke: trials and tribulations
  • Nigel Leigh (Brighton) Motor neurone disease as a syndrome-lumping, splitting or just mixed up?
  • Simon Mead (Queen Square) Prions and dementia: an update, new diagnostic techniques and clinical trials
  • Philip Buttery (Cambridge) Gene therapy and Parkinsonism
  • Nick Davies (Hereford and Birmingham) Metabolic muscle disorders
  • Diane Playford (Queen Square) Vocational rehabilitation and MS

WESAN 2013

  • Simon Hickman (Sheffield) Optic neuritis and multiple sclerosis
  • Paul Hughes (Brighton) Medicine in the Armed Forces
  • Anu Jacob (Liverpool) What’s new in neuromyelitis optica?
  • Mark McCarron (Derry) Have advances in our understanding of cerebral amyloid angiopathy helped the patient?
  • Stuart Weatherby (Plymouth) Rare headache syndromes
  • Andrea E Cavanna (Birmingham) Crossroads in neurology and psychiatry: Tourette syndrome
  • Tim Lewis (Bristol) Neuroradiology
  • Martin Prevett (Southampton) Chronic neurological disease in Africa
  • Angus Kennedy (Chelsea and Westminster) An approach to neurology in the Intensive Care Unit and in obstetrics
  • Nick Davies (Chelsea and Westminster) The neurology of HIV in the combined anti-retroviral era
  • David Bennett (Oxford) Advances in understanding sensory neuropathies and channelopathies
  • John Duncan (Queen Square) Imaging the brain in epilepsy
  • Romi A Saha (Brighton) Movement disorders

WESAN 2014

  • Jonathan Knibb (Brighton) Progressive aphasia
  • Graham Flint (Birmingham) Syringomyelia
  • Tony Warner (Queen Square) Dystonia and dystonia Parkinsonism syndromes
  • Robin Lachman (Queen Square) Metabolic encephalopathy
  • Martin Turner (Oxford) Making a diagnosis of motor neurone disease
  • Tim Lynch (Dublin) I have learned from my patients
  • Michael Pelly (Chelsea and Westminster) Managing a humanitarian disaster
  • Tony Marson (Liverpool) Seizures, epilepsy and driving
  • Peter Brex (King’s College, London) A NICE update of multiple sclerosis
  • Raanan Gillon (Queen Square) Minimally conscious state, medical ethics and English Law
  • Robert Guiloff (Queen Square) Recent developments in neuropathic pain
  • Barry Seemungal (Charring Cross) A clinical and scientific approach to acute dizziness
  • Andrew Larner (Liverpool) Which screening tool should I use in a patient complaining of poor memory

WESAN 2015

  • Kerry Mills (King’s College, London) EMG and NCV-use and misuse in neurology
  • Melissa Maguire (Leeds) Music and its associations with epileptic disorders
  • Guy Leschziner (London) Differential diagnosis of parasomnias
  • Matt Craner (Oxford) Neuroprotection in MS-old drugs, new tricks
  • Gareth Llewelyn (Cardiff) Recognising and treating peripheral nervous system vasculitis
  • Steve Sturman (Birmingham) Assessment of consciousness and prognosis after acute brain injury
  • Paul Lewis (London) Brain tumour history
  • Justin Pearson (Bristol) Hyperacute stroke units
  • James Miller(Newcastle) Myositis-rashes, inclusions and drugs
  • Raanan Gillon (London) Minimally conscious state, medical ethics and English Law
  • Heather Angus-Leppan (London) Migraine and headache
  • Jeff Kimber (London) Autonomic disorders
  • Alan Whone (Bristol) Current and future advanced treatments for Parkinsonism

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And this year, WESAN 2016 offers:

  • Charlotte Dougan (Liverpool) Muscle disorders
  • Hadi Manji (London) Drug-related neuropathies
  • Simon Farmer (London) Superficial siderosis
  • Martin Sadler (Plymouth)  Epilepsy
  • Kate Petheram (Sunderland) Multiple sclerosis
  • David Werring (London) Microbleeds and cerbral amyloid
  • Chris Allen (Cambridge) A Lifetime in neurology
  • John Stein Dyslexia
  • Andrew Brown (DVLA) Neurologists and driving
  • Thomasin Andrews(London) Huntington’s Disease and movement disorders
  • Mark Wardle (Cambridge) Ataxias: an overview and diagnostic strategy
  • Diego Kaski (London) Diagnosis and management of acute vertigo-central or peripheral?
  • Ibrahim Imam (Exeter) Neurology in Nigeria

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Was WESAN really called The Bath Course, in the distance past? Was David Bateman associated with WESAN in any way? Keep an eye out for the answers in follow-up post on A Short History of WESAN by Chris Gardener-Thorpe.

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