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West of England Seminars in Advanced Neurology (WESAN)

Posted in Courses & Conferences on 22nd Oct 2021

Conference details: 21-22 November 2019. Report by: Dr Ibrahim Imam, Consultant Neurologist, Royal Devon & Exeter Hospital, UK. Conflict of interest statement: None declared.

The West of England Seminars in Advanced Neurology (WESAN) is held annually in Exeter. Each year 13 invited speakers talk on practical and topical neurological issues, and the delegates consist of neurology trainees and consultants, and others. Because of the disruption caused by COVID 19, the conveners deferred the 2020 course to 2021. Below are abstracts of the 13 talks of WESAN 2019.

The first talk at WESAN this year was presented by Kirstie Anderson, Consultant Neurologist with the Paediatric and Adult Regional Sleep Services in Newcastle. Titled ‘Sleep disorders and the neurologist’, the talk began with a review of REM sleep behaviour disorder (RBD), emphasising its relationship to neurodegenerative diseases. The characteristic RBD pattern is progressively increasing frequency over time. Obstructive sleep apnoea is an occasional mimic but, unlike RBD, is associated with sleepiness and snoring. She discussed the need for polysomnography to diagnose. Treatment is melatonin at 2-10mg initially with clonazepam second line if there is no associated obstructive sleep apnoea. She then addressed narcolepsy with a detailed review of the role of hypocretin as a sleep switch for maintaining wakefulness. The newer investigative tests for narcolepsy include CSF hypocretin which has higher sensitivity compared to multiple sleep latency tests (MSLT). Stimulants are effective but so are simple measures including power naps. Her talk also covered restless legs syndrome and slow wave sleep disorders such as sleep walking. Online insomnia CBT is now widely available to primary care.

Dermatological clues to the neurofibromatoses’ was the title of the presentation by Rosalie Ferner, Adult Neurologist and head of the National Neurofibromatosis 1 Centre at Guy’s and St. Thomas’ NHS Foundation Trust. She addressed the molecular biology of neurofibromatosis1, with reference to neurofibromin the gene protein that acts as a tumour suppressor, regulating the ras pathway. She explored the neurological manifestations of NF1 including cognitive impairment, autistic spectrum disorder, brain gliomas, aqueduct stenosis, vasculopathy and epilepsy. She then focused on the skin lesions associated with neurofibromatosis such as café au lait spots, xanthogranulomas, neavus anaemicus, angiomas, and cutaneous neurofibromas. She also discussed plexiform neurofibromas, emphasising that these may enlarge rapidly and dramatically due to haemorrhage. She then reviewed malignant peripheral nerve sheath tumours which usually arise from plexiform neurofibromas and which may develop throughout life, but most commonly in the late 20s and may metastasise widely. She emphasised the differences between schwannomas and neurofibromas, pointing out that the two may be difficult to distinguish clinically. Neurofibromas are the hallmark of NF1 and schwannomas are associated with NF2 and schwannomatosis. She alluded to individuals who had been misdiagnosed as having NF1 with conditions including lipomas, melanocytic naevi, prepatellar bursitis, incontinentia pigmenti, dermatofibrosarcoma protuberans, and Erdheim Chester disease. Her talk also covered NF2, pointing out that meningiomas are a major cause of morbidity and the cardinal feature of NF2 is bilateral vestibular schwannomas. She finally discussed schwannomatosis which is characterised by multiple painful schwannomas and may be confused with mosaic NF2. Her talk was enhanced by many illustrative photographs.

Gordon Plant, Consultant Neurologist to The National Hospital for Neurology and Neurosurgery, presented on ‘bedside eye movement evaluation’. He began with the examination of saccades, pursuits, optokinetic nystagmus, and oculocephalic reflex. He reviewed the mechanisms underlying fixation and tracking, pointing out that disorders of fixation may result in nystagmus in the primary position. He discussed macro-saccadic oscillations which occur in severe cerebellar disorders and, unlike macro-square wave jerks, are symptomatic and cause oscillopsia. He reviewed the interesting phenomenon of seesaw nystagmus which occurs in disorders of the optic chiasm and with bilateral subthalamic lesions. His talk also covered saccadic eye movements, conjugate gaze palsy, optokinetic nystagmus, and broken pursuits or saccadic intrusions. He demonstrated the Halmagyi head thrust test which assesses unilateral canal paresis, and the vestibulo-ocular reflex which assesses supranuclear gaze palsy. His talk was illustrated by many excellent videos.

The fourth talk of the course, ‘The management of MS: beyond the disease modifying drugs’, was presented by Basil Sharrack, Consultant Neurologist at the Sheffield Teaching Hospitals NHS Foundation Trust, and Director of the Sheffield MS Research Clinic. He reviewed the different disease modifying agents and compared their efficacy, cost, and safety to stem cell therapy (SCT). He emphasised the potent effectiveness and toxicity of SCT. He reviewed the different types of stem cell therapies, outlining the processes of stem cell harvest and anti-inflammatory cytotoxic therapy. He pointed out that the best evidence for SCT is for relapsing remitting MS, and that outcomes are better the shorter the disease duration. He discussed recent research into SCT including the multicentre MIST trial which studied subjects with active MS; the interim analysis showed that only three 3 of 55 subjects randomized to SCT progressed, compared with 34 randomized to best standard therapy. He also mentioned the STAR-MS trial which will include patients on alemtuzumab.

Melissa Maguire, Consultant Neurologist and Clinical Associate Professor at Leeds Teaching Hospitals, presented on ‘My approach to the patient with refractory epilepsy’. She began with a challenging case report of a patient with bilateral hippocampal sclerosis who was poorly controlled on trials of anti-epileptic drugs. She re-iterated the definition of refractory epilepsy as the failure of two tolerated and appropriately trialed anti-epileptic drugs (AEDs) adding that this develops in about 30% of people with epilepsy. She cited references showing that additional AEDs may offer a 1 in 11 chance of achieving a seizure remission. She reviewed the risk factors for refractory epilepsy, and its consequences such as depression and SUDEP. She discussed the different approaches to managing refractory epilepsy; the utility of rational poly-therapy using drugs which act via different mechanisms, for example valproate and lamotrigine and reviewed network meta-analysis evidence of add-on AEDs noting a treatment advantage with topiramate and levetiracetam. She explored epilepsy surgery discussing prognostic data which report successful remission in 2 out of 3 patients; in particular those who demonstrate seizure concordance with a unilateral surgical target and undergo gross total resection. She reviewed other beneficial interventions such as vagus nerve stimulation, and those with little evidence in adults such as the ketogenic diet. Her talk also covered the treatment of catamenial seizures and epilepsy in pregnancy.

The neurodegenerative ataxias: prospects for treatment’ was the title of the talk by Alastair Watkins, Reader in Neurology, University of Bristol and Honorary Consultant Neurologist at Southmead Hospital, Bristol. He began by exploring the classification of the genetic ataxias and the spinocerebellar ataxias (SCAs). He discussed the associated non-neurological features of SCA such as retinitis pigmentosa and telangiectasias. He then reviewed ataxia telangiectasia which is characterized by radiation sensitivity, an increased risk of cancer, and high serum alpha fetoprotein. He subsequently addressed Friedreich’s ataxia (FA), the most frequent autosomal recessive ataxia, which is a GAA trinucleotide repeat disorder of the frataxin gene. He detailed the mechanism whereby low frataxin levels result in mitochondrial dysfunction and oxidative stress. He then explored the treatment strategies that are in the pipeline for FA including Omaveloxolone, nicotinamide, and granulocyte colony stimulating factor. He finally reviewed other etiologies of Purkinje cell dysfunction including alcohol, lithium, Creutzfeldt-Jakob disease (CJD), rabies, paraneoplastic antibodies, multiple sclerosis (MS), essential tremor and multiple system atrophy (MSA).

The last presentation of the first day was by Jonathan Rohrer, MRC Clinician Scientist at the UCL Institute of Neurology and Honorary Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. His talk was titled ‘Frontotemporal dementia: diagnostic and therapeutic prospects’. He began by exploring the complex pathology and genetics of FTD. He then reviewed the different FTD variants with emphasis on the most frequent, the behavioural variant (bvFTD). He reviewed the differential diagnoses of bvFTD such as executive dysfunction due to other causes including depression, and late-onset psychosis. He explored primary progressive aphasia (PPA) which is subclassified into a number of variants which are semantic, non-fluent, logopenic, and a fourth group of people not fitting criteria for any specific form. He discussed the investigative tests of FTD, emphasising the value of volumetric MRI in detecting frontal and temporal lobe atrophy, and pointing out that it is as good as (if not better than) FDG PET. He argued that a raised cerebrospinal fluid tau level is not a marker of tau pathology, but in combination with amyloid levels it may help to exclude Alzheimer’s disease. He finally reviewed investigational FTD therapeutics such as tau monoclonal antibodies and antisense oligonucleotides for C9orf72 and MAPT mutations.

The second day of talks was started by Elizabeth Warburton, Consultant in Stroke Medicine in Cambridge, whose topic was ‘Resolving the uncertainties in acute stroke care’. She began with the differential diagnosis of TIAs pointing out that there is a 30-60% rate of mimics in a typical TIA clinic, and warning that the ABCD score is no longer considered a good discriminating tool for TIA. In cases of TIAs which are recurring on antiplatelets, she suggested that differential diagnoses such as amyloid and intracranial stenosis should be considered. In the initial imaging of TIA, she emphasised that routine CT head is not helpful except to exclude alternative diagnoses such as subarachnoid haemorrhage. In discussing the initial management of suspected and confirmed TIAs, she said aspirin 300mg is indicated; she pointed out that the addition of Clopidogrel to aspirin prevents 15 more disabling strokes per every 1,000 cases, but it also results in an additional 5 bleeds per 1,000 cases. She advocated that suspected atrial fibrillation should be confirmed by tests, such as implantable devices, before starting anticoagulants. She highlighted the benefit of thrombectomy in the treatment of acute stroke, and she recommended acute imaging with a CT angiogram to look for proximal occlusions. For patients presenting 6-24 hours after anterior circulation stroke, she said CT perfusion imaging is helpful to guide patient selection for thrombectomy. She reviewed the eligibility criteria for inclusion in future thrombectomy trials, such as an mRS score of <3, and an NIHSS of >5.

Karen Morrison, Consultant Neurologist at Queen’s University Belfast, presented on ‘MND: making the diagnosis and managing the patient’. She started her talk with a historical account of her early research work in the genetics of spinal muscular atrophy (SMA). She traced the remarkable progress that has taken place since then with the identification of the SMN gene, and more recent treatment with Nusinersen, an antisense oligonucleotide. She emphasised the significant impact Nusinersen has had on SMA survival and function. She then addressed motor neurone disease (MND) with emphasis on its early red flag symptoms such as painless dysarthria and dysphagia, and pointed out that prominent behavioural symptoms are rare at disease onset. She also reviewed the atypical presentations of MND including dropped head, monomelic MND, and respiratory failure. She discussed the close mimics of MND such as benign fasciculations, multifocal motor neuropathy (MMN), Kennedy disease, chronic inflammatory demyelinating polyneuropathy (CIDP), inclusion body myositis (IBM), myeloradiculopathy, and hereditary spastic paraparesis (HSP). She subsequently reviewed the genetic forms of MND with emphasis on the c9orf72 hexanucleotide variant which accounts for 8% of sporadic MND. She detailed the processes and essential stages of genetic counselling and testing, recommending initial testing for SOD1 and C9orf72, and proceeding to genetic panel testing if these are negative.

How I manage the complex stages of Parkinson’s disease’ was the title of the presentation by David Nicholl, Consultant Neurologist at City and University Hospitals, Birmingham. He started his talk with an exploration of the complex presentations of PD. He focused on patients presenting with prominent autonomic features, emphasising that absent uptake on cardiac MIBG scans may help to differentiate PD from multiple system atrophy (MSA) which does not affect the cardiac autonomic system. He addressed the complex situation where PD patients are not responding to treatment, in which case he recommended investigating for co-morbid disorders such as cervical myelopathy. Similarly, he said patients whose symptoms are not progressing should be assessed for PD mimics such as dopa-responsive dystonia, SCA3, and functional disorders. In his discussion of the treatment of the complex stages of PD, he said dopamine agonists are superior to Rasagiline and Entacapone, but they are associated with more side effects such as impulse control disorders and dopamine dysregulation syndrome. He reviewed other interventions for the complex stages including apomorphine, deep brain stimulation, and duodopa. He also advocated the use of amantadine for patients with dyskinesias, and he emphasised the importance of planning early for palliative and end-of-life care. He illustrated his talk with several descriptive videos.

‘Negotiating the evolving landscape of migraine therapeutics’ was the title of the talk by Brendan Davies, Consultant Neurologist at the University of Hospital of North Staffordshire, Stoke-on-Trent and Clinical Lead for the North Midlands Regional Headache Clinic. He started by discussing the conventional treatments of migraine, pointing out that there is no evidence for the value of gabapentin in episodic migraine. He then reviewed the role of the potent vasodilator, calcitonin gene related peptide (CGRP), in the pathogenesis of migraine. Pointing out that the level of CGRP is elevated in people with migraine, he explored the different treatments that reverse this. He focused on the anti CGRP monoclonal antibodies, pointing out that Erenumab acts on the CGRP receptor whilst the other antibodies act on the CGRP ligand. He noted that the different antibodies are all well-tolerated, have similar responder rates, and do not trigger immunological side effects. He said treatment response is expected within 3 months of treatment, and he advised that responders should be treated for one year. He recommended using the monoclonal antibodies before considering botulinum toxin even though they have similar treatment responses. He then reviewed the GEPANTS, small molecule inhibitors of CGRP, which are effective and well-tolerated for acute migraine. His talk also covered the serotonin receptor agonist Lasmiditan, transcranial magnetic stimulation (TMS), external vagus nerve stimulation (VNS), supraorbital transcutaneous stimulation, occipital nerve stimulation, and cervical cord neurostimulation.

Alzheimer’s disease: prospects and challenges of definitive treatment’ was the title of the talk by Andrew Larner, Consultant Neurologist at the Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool. He reviewed the potential of disease modifying treatments in AD, pointing out that several approaches based on the amyloid hypothesis have so far failed; these include amyloid vaccines, monoclonal antibodies, and secretase inhibitors. He noted that Aducanumab is awaiting FDA approval for use in early Alzheimer’s disease. He then reviewed the prospects of identifying asymptomatic at-risk subjects, noting that this is limited by the restricted availability of investigations for biomarkers such as amyloid PET and CSF proteins. He then reviewed the insensitivity of current AD assessment tools for early AD, arguing that better screening instruments are needed for future trials. He speculated whether measures of accelerated long-term forgetting might be a useful pre-symptomatic marker for AD. In the current absence of disease modifying therapies for AD, he favoured a proactive preventive approach paradigm over the traditional reactive therapeutic response paradigm. The importance of simple preventative strategies such as increased physical activity, control of blood pressure, tobacco cessation, and nutritional interventions was emphasised; the current insufficiency of evidence supporting the preventative value of interventions such as social activity, treatment of depression, and treating hearing loss was noted. He went on to discuss individual risk stratifying or banding strategies, for example polygenic hazard scores based on the findings of genome wide association studies (GWAS), and the potential application of “deep phenotyping” to risk identification.

The last talk of the course was by James Taylor, Consultant Radiologist at the Royal Devon and Exeter Hospital, and it was titled Gadolinium toxicity: what does the neurologist need to know. He began with a discussion of nephrogenic systemic fibrosis, the first recognised disorder associated with gadolinium toxicity which was associated with the use of the linear forms of gadolinium. He pointed out that, although the macrocyclic forms of gadolinium have not been associated with nephrogenic systemic sclerosis, they also deposit in the dentate nuclei and the globus pallidum where they show as T1 hyperintensity. He explained that gadolinium deposition is dose-dependent, and it also occurs in soft tissues and bones. He however emphasised that there are no proven clinical correlates of gadolinium deposition in the brain. He then reviewed alternatives to contrast imaging such as inversion, double inversion, time of flight (TOF)/phase contrast, and extended DWI techniques. He subsequently reviewed the potential applications of arterial spin labelling, a technique that serves as an endogenous contrast. He also listed potential alternatives to gadolinium such as manganese and nanoparticles.

WESAN 2021 is scheduled to hold on 25-26 November. To register, please visit the WESAN website https://wesanmeeting.org.uk/