bluuebunny/crossref_metadata_2025 huggingface dataset:
219 First year of the early access to medicines scheme for raxone in duchenne muscular dystrophy
Authors: Lawrence Catherine , Hasham Shabir
Published: March 2023

Raxone (idebenone) received the first positive scientific opinion for a treatment option in DMD for inclusion into the Early Access to Medicines Scheme (EAMS) in June 2017.

EAMS is regulated by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and aims to provide earlier availability of promising new unlicensed medicines to UK patients that have a high unmet clinical need.

The first patient was enrolled 12 weeks after the scheme approval. In the first year of the scheme forty-six patients were able to access Raxone in six centres. Ease of implementation of the scheme across the NHS was variable. In addition to the MHRA positive scientific opinion, and supportive guidance issued by NHS England and Scotland, most clinicians were required to obtain local hospital committee approvals before entering the scheme, which introduced delays in patient enrolment. Local knowledge of EAMS, its objectives and stakeholder responsibilities, was found to be limited and also contributed to delays in implementation and inequality of access.

Under EAMS Raxone is administered under routine clinical practice. In the second year additional data collection has been introduced to obtain information on the effectiveness of the use of Raxone in an environment similar to that which would exist if the medicine receives a future marketing authorisation for DMD.
221 Quality improvement project: updating the muscle biopsy referral form
Authors: Sarkar Pamela , Atton Giles , Urankar Kathryn , Long Nicola , Patel Jennifer , Smart Joanne , Brady Stefen
Published: March 2023

When reconfiguring the muscle biopsy service at our hospital, it became apparent that the referral form used was inadequate. The clinical information acquired was minimal. The form did not comply with National Coding practice.1The absence of good clinical information could negatively affect the neuropathological diagnosis and income generated by the muscle biopsy service. Therefore, in collaboration with Neuropathology and Clinical Coding, we developed a new form to capture relevant clinical and coding information. To determine the impact of the new referral form, we undertook a quality improvement project.

Forty muscle biopsies (2012–2016) were selected at random from the Neuropathology archives. The notes were reviewed and used to complete the new referral form. Using this information, the coding and tariffs were reassessed and compared to those produced using the original referral form. Prospective data from muscle biopsy cases (01–06/2018) were also analysed.

Results demonstrated a significant improvement in quality of documentation supplied to Clinical Coding and increased diagnostic usefulness for Neuropathology. Although the new form has significantly helped the Clinical Coding team, with a simpler and more efficient coding outline that has reached National Coding Standards1, it had little impact on the income generated.

References

‘National Clinical Coding Standards ICD-10 5th Edition 2017 -https://hscic.kahootz.com/gf2.ti/f/762498/27838213.1/PDF/-/NCCSICD102017.pdf
222 Investigating directionality of neurodegeneration in vivo in ALS using multimodal MRI
Authors: Toh Charmaine L , Keslake Andrew , Harding Joseph , Baster Kathleen , Hoggard Nigel , Bigley Julia , McDermott Christopher J , Shaw Pamela J , Wilkinson Iain D , Jenkins Thomas M
Published: March 2023

Background

The anatomical location of the earliest damage in amyotrophic lateral sclerosis (ALS) is still debated. Two main competing hypotheses have been proposed: the dying-forward hypothesis states the damage occurs in the precentral gyrus (PCG) and spreads caudally, which is in contrast with the dying-back hypothesis. This study aims to address this question of directionality of neurodegeneration in vivo using a multimodal neuroimaging approach to derive measures of damage of the motor pathway and analyse them in a common domain.

Methods

MRI was performed on 78 ALS patients and 13 controls. PCG thickness was derived from using FreeSurfer, corticospinal tract (CST) fractional anisotropy (FA) from diffusion tensor imaging using FSL, and axial C3 cord area estimates using Philips online software. Comparisons between patients and controls were reported using unpaired t-tests. Parameter estimates were converted to z-scores, referenced to control data, plotted from PCG through CST to cord and directionality of damage assessed by fitting a mixed-effects linear regression model.

Results

Z-scores were not significantly different between PCG and FA (0.24,[95%CI -0.13,0.61], p=0.208) but were significantly lower in FA compared to cross-sectional cord area (-0.85,[95%CI -1.25,-0.46] p<0.001).

Discussion

This novel multimodal imaging approach supports a dying-forward neurodegenerative process in ALS.
223 Anderson tawil syndrome: expanding the phenotype and assessing cardiac risk
Authors: Vivekanandam Vinojini , Savvitis Konstantinos , Pattni Jatin , Fialho Doreen , Hanna Michael G , Matthews Emma
Published: March 2023

Anderson Tawil Syndrome (ATS) is a rare channelopathy traditionally characterised by periodic paralysis, cardiac arrhythmias and dysmorphic features. Mutations in the KCJN2 gene have been associated with ATS. Accurate and early diagnosis is important in facilitating treatment of episodic paralysis and preventing potentially life-threatening cardiac events.

We aim to fully characterise the phenotype in a carefully stratified cohort including cognitive deficits and cardiac risk.

66 patients were identified with KCJN2 mutations. Comprehensive clinical information was available for 18 of these patients. Cardiac symptoms were prominent. Two thirds (11) had daily or very frequent palpitations. 27% (5) reported shortness of breath. Serious cardiac complications occurred in 4 patients (ICD insertion, left ventricular dysfunction/cardiomyopathy). 39% (7) reported pain which has previously not been appreciated as part of ATS. Interestingly, 4 patients had fasciculations. 4 patients had minimal decrement (<48%) on Long Exercise Tests (LET) despite having episodic weakness. Lower limb Muscle MRI was abnormal in 6 patients. Excess sleepiness was reported. Neuropsychometric testing suggests slowed processing speed. While dysmorphic features exist, these can be subtle. Short stature is not ubiquitous. Heterogeneity within families was commonly seen.

The phenotypic spectrum of ATS is broader than currently appreciated, and data analysis is ongoing.
224 Calpainopathy: CAPN compound heterozygosity in a patient with wilson’s disease
Authors: Wong Charis , Fletcher Elaine , Marini-Bettolo Chiara , Barresi Rita , Breen David P
Published: March 2023

A 37 year-old nurse of Czech origin presented with a five year history of progressive, symmetrical limb weakness, myalgia and a tendency to walk on her tip-toes. She had difficulty walking upstairs and lifting her baby. She had a background of Wilson’s disease, diagnosed aged 14 on the basis of liver biopsy. Penicillamine-induced myopathy was initially suspected, but symptoms persisted despite switching to trientine. There was no family history of neurological disease. Examination revealed bilateral scapular winging, wasting of upper arms, tightening of Achilles tendons, weakness of neck extensors and proximal limbs (especially biceps), and Gowers’ sign. Reflexes and sensation were normal. She had fluctuating hyperCKaemia (1000–4000U/L), and myopathic features on electromyogram and lower limb magnetic resonance imaging. Muscle biopsy showed scattered atrophic fibres without evidence of inflammation. Absence of calpain-3 expression was noted on subsequent review, suggestive of Limb Girdle Muscular Dystrophy type 2a (calpainopathy). The diagnosis was confirmed by genetic testing: she was a compound heterozygote for pathogenic variants in the CAPN3 gene (c.598-612del and c.1381C>T). Management included neurophysiotherapy, genetic counselling, and surveillance of respiratory and cardiac function. In summary, recognising her clinical phenotype was essential in guiding appropriate immunohistology and genetic testing to secure the diagnosis.
230 A dog with a bone (marrow biopsy)
Authors: Li Vivien , Kapoor Mahima , Lunn Michael , Cwynarski Kate , Carr Aisling
Published: March 2023

A 71-year-old woman presented with severe painful meningoradiculoneuritis progressing over 6 weeks. She had localised breast cancer treated 13 years prior. Differentials included a vasculitic or infiltrative process.

Neurophysiology showed a patchy, predominantly proximal axonal process with widespread active denervation. MRI revealed asymmetrical enhancement of the brachial plexus, left S1 and multiple cranial nerves. CSFs were lymphocytic (normal T-cells predominant), with elevated protein and negative cytology. FDG-PET was negative for malignancy. BMAT showed no evidence of a lymphoproliferative condition.

Left sural nerve biopsy was non-diagnostic. Right brachial plexus biopsy showed mixed T-/B-cell endoneurial inflammation not fulfilling criteria for vasculitis. She was stabilised with high-dose steroids and cyclophosphamide, followed by mycophenolate for inflammatory myeloradiculoneuritis. However, symptoms recurred when prednisolone was weaned.

Although T-cell receptor gene analysis from the initial BMAT demonstrated clonal rearrangements, it was only when the same clones were identified on two repeat BMATs and CSF that T-cell neurolymphomatosis was diagnosed. Poor performance status precluded chemotherapy. She continued on prednisolone and cyclosporine for 3.5 years, before dying of sepsis.

T-cell neurolymphomatosis is exceedingly rare. Clonality assessment can increase yield when other investigations including histology are non-diagnostic. This case highlights the value of repeated investigations when clinical suspicion is high.
238 Usefulness of concomitant peripheral nerve and muscle biopsy
Authors: Cooper Rebecca , Bunting Eva , Jaunmuktane Zane , Merve Ashirwad , Rosser Alex , Laura Matilde , Manji Hadi , Reilly Mary M , Lunn Mike P , Carr Aisling S
Published: March 2023

A previous evaluation of concomitant nerve and muscle biopsy in the Centre for Neuromuscular Diseases, NHNN suggested that the addition of muscle (vastus lateralis) to nerve (sural) tissue examination did not improve diagnostic yield in suspected vasculitis. Here we assess it may be beneficial in other circumstances.

We reviewed diagnostic yield from combined nerve and muscle biopsies performed between 2013 and 2018. Basic demographic, clinical and histological information was collected retrospectively from the complete list of locally performed biopsies during the study period.

230 nerve and 49 muscle biopsies were performed on 223 patients. 26 superficial peroneal/peroneus brevis, 20 sural/vastus lateralis, and 3 other combinations. Overall nerve biopsy was diagnostic in 38% of individuals; confirming clinical suspicion in 64.5%. The addition of muscle tissue did not provide histological evidence of vasculitic pathology in any case. However, 8 cases provided evidence of co-existent muscle pathology (myopathic changes), with mitochondrial changes in 4/8 and lipid abnormalities in 2/8 informing further genetic tests and leading to diagnosis in 3/8. 5/5 TTR amyloidosis and 2/3 neurolymphomatosis cases showed histopathology in both tissues.

This analysis suggests that in certain clinical situations the addition of muscle biopsy may be helpful in the investigation of neuropathy.
11.27 Late onset multiple sclerosis in north wales
Authors: Karthikeayan Venkatraman , Copeland Yvonne , Fearn Catriona , Whittam Daniel , Elsone Liene , Huda Saif , Jacob Anu
Published: March 2023

Introduction

MS patients who have their first symptom onset after 50 years of age are defined as Late onset Multiple Sclerosis (LOMS). Our study analyses the clinical profile of patients with LOMS in North Wales region of United Kingdom

Methods and materials

A retrospective medical record review of all patients attending regional MS clinic in North Wales, based at Glan Clwyd Hospital (2007–2018) was done.

Results

Of 648 patients with MS, 60 (9.2%) had LOMS. Mean age at onset was 55.3 years and the M: F ratio was 1:1.85. 63% and 28% of LOMS were progressive and relapsing types respectively.

At a mean of 7.8 years follow up, 31% of relapsing patients converted to SPMS. Majority of LOMS presented with gait difficulties-67% (97% in Progressive MS and 23% in relapsing).Only 15% of the relapsing MS patients were eligible or chose DMT.

Conclusions

LOMS forms at least 9% of this MS cohort with majority presenting with a progressive course at diagnosis. The high proportion of LOMS in this cohort may reflect, delayed reporting of symptoms or slower access to care.
15.33 AVXS-101 in presymptomatic spinal muscular atrophy (SMA)
Authors: Strauss Kevin A , Swoboda Kathryn J , Farrar Michelle A , McMillan Hugh J , Parsons Julie , Krueger Jena M , Iannaccone Susan T , Chiriboga Claudia A , Kwon Jennifer M , Saito Kayoko , Scoto Mariacristina , Kausar Imran , Schultz Meredith , Kernbauer Elaine , Farrow Marcia , Ogrinc Francis G , Kavanagh Sarah , Feltner Douglas E , McGill Bryan E , Spector Sidney A , L’Italien James , Sproule Douglas M , Muntoni Francesco
Published: March 2023

Background

Onasemnogene abeparvovec (AVXS-101) is a gene-replacement therapy that treats the genetic root cause of SMA, biallelic survival motor neuron 1 gene (SMN1) deletion/mutation. In a phase 1 study, AVXS-101 improved survival and motor function of symptomatic SMA type 1 patients. In SPR1NT (NCT03505099), AVXS-101 is being evaluated in presymptomatic newborns with SMA.

Methods

SPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients with 2xSMN2or 3xSMN2. Asymptomatic infants aged ≤6 weeks receive a one-time, intravenous AVXS-101 infusion. Safety and efficacy are assessed through 18 or 24 months for patients with 2x or 3xSMN2, respectively. Primary outcomes are independent sitting ≥30 seconds (2xSMN2) or assisted standing (3xSMN2).

Results

As of 8 March 2019, 18 infants aged 8–40 days received AVXS-101 (11 female; 8 with 2xSMN2; 9 with 3xSMN2; 1 with 4xSMN2). Among patients with 2xSMN2, mean CHOP-INTEND at baseline was 44.0 points, which increased by 14.4 points at 3 months (n=7); 6/8 patients scored ≥60 points; 3/8 reached maximum score. 4/8 patients sat unassisted; all ages of sitting milestone achievements were within the WHO range (1st–99th percentile: 3.8–9.2 months).

Conclusions

Preliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.
250 AVXS-101 phase 3 study in spinal muscular atrophy type 1
Authors: Day John W , Chiriboga Claudia A , Crawford Thomas O , Darras Basil T , Finkel Richard S , Connolly Anne M , Iannaccone Susan T , Kuntz Nancy L , Peña Loren DM , Schultz Meredith , Shieh Perry B , Smith Edward C , Kausar Imran , Feltner Douglas E , Ogrinc Francis G , Ouyang Haojun , Macek Thomas A , Kernbauer Elaine , Muehring Lynlee M , L’Italien James , Sproule Douglas M , Kaspar Brian K , Mendell Jerry R
Published: March 2023

Background

Onasemnogene abeparvovec (AVXS-101), a one-time intravenous gene-replacement therapy, treats the genetic root cause of spinal muscular atrophy (SMA). In the phase 1 study, AVXS-101 dramatically improved survival, motor function, and motor milestone achievement in SMA type 1 (SMA1) patients.

Methods

STR1VE is a phase 3, multicenter, open-label study (NCT03306277) in SMA1 patients <6 months (bi-allelic survival motor neuron 1 gene [SMN1] mutations/deletions, 2SMN2copies). Primary outcomes are independent sitting ≥30 seconds at 18 months of age, and survival (no death/permanent ventilation) at 14 months. Secondary outcomes include ability to thrive and ventilatory support at 18 months. Exploratory outcomes include CHOP-INTEND and Bayley-III.

Results

Enrollment is complete (22 patients dosed). Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support. Mean baseline CHOP-INTEND: 32.6 (17.0–52.0) points; increased by 6.9 (-4.0–16.0), 9.2 (0–18.0), and 11.7 (-3.0–23.0) points at 1, 2, and 3 months; independent sitting: 11/22 patients; survival at 13.6 months: 13/15 (87%) (8 March 2019 datacut).

Conclusions

Preliminary data from the AVXS-101 phase 3 study show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.
256 Thrombectomy in clinical practice, patient selection factors
Authors: Stahl Rose , Littleton Edward , Nader Kurdow
Published: March 2023

Background

Successful stroke treatment with mechanical thrombectomy (MT) involves appropriate patient selection and rapid re-canalisation. Queen Elizabeth Hospital Birmingham provides MT to patients presenting to our own Emergency Department (group A) or transferred from other regional hospitals (group B).

Aims

To assess timelines in MT delivery and patient selection factors which may affect outcomes.

Methods

Data from all stroke patients receiving MT in 2015–2018 were collected retrospectively. Change in NIHSS score (at presentation and at 24 hours) and procedure success (TICI score 2b or 3) were recorded.

Results

102 patients underwent MT (group A=43, group B=59).Mild initial deficit (NIHSS <6) and any pre-existing disability (Modified Rankin >0) were associated with worsening NIHSS scores (+2 and +13.5 respectively). >80% of these patients were in group A, indicating a tendency to select local patients with radiological evidence of proximal MCA thrombus or with dysphasia but mild NIHSS, whereas NIHSS-based patient selection was more strictly applied for group B. We found no differences in outcome dependent on delivery of MT inside/outside the 6-hour window.

Conclusions

In the absence of clinical trial evidence for MT in patients with low NIHSS, caution in selecting these patients for MT is advised.
258 Can clinical experts agree on a diagnosis of TIA?
Authors: Lee Seong Hoon , Aw Kah Long , McVerry Ferghal , McCarron Mark
Published: March 2023

Background

Transient ischaemic attacks (TIAs) are sudden onset focal neurological deficits of vascular pathogenesis that resolve within 24 hours. TIAs remain a diagnostic challenge due to its clinical heterogeneity and lack of biomarkers. Previous studies on the diagnostic accuracy of TIAs by non-specialists have used TIA experts (neurologists or stroke physicians) as the gold standard. However, the inter-rater variability in TIA diagnoses among these experts is not firmly established. Here we conduct a meta-analysis of the inter-rater variability of TIA diagnosis between experts.

Methods

We performed a systematic review of studies from 1988 to present day using MEDLINE, EMBASE, and PubMed. Two reviewers independently screened for eligible studies and extracted inter-rater variability measurements using Cohen’s Kappa scores between expert clinicians.

Results

14 original studies reporting on variability in TIA diagnosis for 15,907 patients were found. Meta-analysis revealed an overall agreement between experts of κ=0.73 (95%CI 0.63–0.84)

Conclusions

Overall agreement between experts is good for TIA diagnosis, but variation still exists for a sizable proportion of cases. Further research into reliability of the accepted gold standard as well as alternative clinical, imaging or blood biomarkers are required given the important clinical implications for making a TIA diagnosis.
259 Use of internet connected cloud devices in stroke rehab-experience with a patient
Authors: Dey K , Das S
Published: March 2023

We provided Alexa devices-Amazon Echo Show and Echo Spot to a 56- year old patient recovering from an ischaemic stroke at home. Amazon Echo device is a WiFi connected device driven by Alexa, a voice assistant. We trained our patient on the use and control of the devices using her voice and provided technical know how. Once set up, she was able to use the voice control to perform several tasks-

listening to news

listening to music and radio

playing sounds for meditation

turning on and off lights

setting up alarms for medications

setting up times for doing scheduled exercise

making hands free phone calls

This was especially useful when her carer was not present by her side. Later on we added Amazon cloud cam to the set up so that family members could remotely monitor her activity.

She was able to make the physiotherapy sessions fun and interesting with the help of apps running on the devices upon voice prompts.

In the emerging economies the joint family structure is breaking down. The relatives working as informal carers are disappearing fast. The main care is often provided by the privately hired nurses or health care assistants provided by local agencies. The cost of such private care is high. In this background, the voice activated cloud devices could play a significant role in the rehabilitation following a stroke.
09.00 Saved by the skin of his teeth: a job well done!
Authors: Jaffer Fatima , Sibtain Naomi , Holmes Paul
Published: March 2023

A 31-year-old former Game Ranger from South Africa presented with subacute onset parieto-occipital headache, photophobia, and vomiting, followed by diplopia, bradykinesia and progressive unsteadiness. There was a history of neonatal eczema, recurrent skin abscesses, osteomyelitis, tuberculosis, hepatitis A, and Rickettsia.

On examination he had meningism, papilloedema, bilateral sixth nerve palsies, left lower motor neurone facial weakness and left upper limb pyramidal weakness. He was areflexic with normal sensation. Mild bilateral extrapyramidal signs, postural instability and gait initiation failure were observed. During admission, he developed acute left lumbar polyradiculopathy. Deep set eyes, coarse facial features, bony deformities, and retention of primary teeth were noted on examination.

MRI showed bilateral globus pallidus necrosis, basal leptomeningeal enhancement, and multilevel lumbar root thickening and enhancement.

CSF culture confirmed Cryptococcus gattii infection and an apical lung opacity seen on chest x-ray was consistent with a cryptococcoma. Twelve months of antifungal therapy was commenced with full symptom resolution.

HIV was negative. Immunological tests revealed elevated IgE levels and IL-17 deficiency. A de novo mutation in the STAT3 gene (c.1241G>C; p.Arg414Thr) confirmed the diagnosis of autosomal dominant Hyperimmunoglobulin E (Job’s) syndrome.

We discuss Job’s syndrome, the challenges in managing cryptococcal infection and immunological testing in non-HIV patients.
267 Motor system biomarkers in amyotrophic lateral sclerosis
Authors: Edmond Evan C , Menke Ricarda , Proudfoot Malcolm , Talbot Kevin , Stagg Charlotte J , Turner Martin R
Published: March 2023

Therapeutic options for the fatal neurodegenerative disorder ALS are urgently needed. Trials rely on blunt outcome measures such as survival because of a lack of objective markers of disease activity and progression. The C9orf72 hexanucleotide repeat expansion (HRE) is associated with 10% of all cases of ALS, bringing the near-future prospect of oligonucleotide therapeutic trials.

The development of biomarkers will reduce trial duration and cost by providing more sensitive measures of disease-slowing and/or evidence of target engagement. ALS is consistently associated with cortical hyperexcitability (CE), based on transcranial magnetic paired stimulation (TMS) to induce short-interval cortical inhibition (SICI). This project builds on the potential shown by non-invasive neuroimaging to provide biomarkers in ALS. We develop functional neuroimaging biomarkers that reflect the phenomenon of CE, including markers of pre-symptomatic pathology.

Affected ALS patients carrying the C9orf72 HRE and a group of asymptomatic carriers are studied using a combined functional MRI (FMRI and MRS) and neurophysiological (MEG) readout. This study offers novel non-invasive biomarkers based on a consistent neurophysiological mechanism in ALS to advance therapeutic development
269 Prevention of hypertensive injury to the brain by intensive treatment in intracerebral haemorrhage (PROHIBIT-ICH): protocol for a randomised controlled trial of telemetric home BP monitoring
Authors: McGurgan Iain , Butt Shahena , Silver Louise , Werring David , Rothwell Peter
Published: March 2023

Background

Intracerebral haemorrhage (ICH) accounts for about 10% of strokes in the UK and is a major cause of severe disability and death. Sustained post-acute blood pressure (BP) management arguably holds the most potential to improve long-term prognosis, but there have been no trials to guide the optimal strategy for BP lowering after ICH. Telemetric home BP monitoring is a promising intervention to improve control.

Methods

112 adult survivors of hypertension-related ICH across multiple UK sites will be randomised to intensive telemetric home BP monitoring-guided treatment (intervention) to achieve a target of <120/80 mmHg or standard care (control).

Outcomes

Efficacy: the magnitude of difference in BP at 3 months in the intervention arm versus the control arm compared with baseline measures

Feasibility: consent rate; dropout rate from the intervention prior to 1 month; patient approval of the monitoring process

Safety: serious adverse events related to reducing BP in the intervention arm

Conclusion

The BP monitoring component of PROHIBIT-ICH will determine whether a strategy of intensive BP treatment guided by telemetric monitoring for an extended period of time after spontaneous ICH is feasible, safe and effective in reducing BP.
270 Queen square test of auditory cognition (QSTAC): diagnosing dementia with sound
Authors: Johnson Jeremy CS , Hardy Chris JD , Utoomprukporn Nttawan , Rohrer Jonathan D , Bamiou Doris-Eva , Warren Jason D
Published: March 2023

Hearing impairment has emerged as a potent association of cognitive decline in dementia and a promising treatment target. To realise this promise, we need to resolve fundamental questions concerning the roles of peripheral versus central auditory deficits in different dementias, which hearing measures best capture cognitive symptoms and disability and whether hearing measures predict clinical course and brain atrophy.

Using pre-existing and novel stimuli, created at the Dementia Research Centre, University College London, we have designed a unique test battery to assess central auditory function. This will be used to ‘phenotype’ central auditory dysfunction in Alzheimer’s disease (AD) and the primary progressive aphasias (PPA) and compare them with controls as well as across disease groups.

This will provide new tools to determine how auditory measures relate to clinical symptoms and daily-life disability and care burden. Using voxel-based morphometry (VBM) we also aim to correlate test measures with regional brain degeneration and measure how hearing deficits predict longitudinal clinical course.

Here we present the make-up of the battery, explaining the motivation behind component tests and how they probe different stations of the auditory hierarchy. We also make predictions of likely group-specific outcomes, based on neuroanatomical disease predilection.
272 Inherited peripheral neuropathies: analysis of PDXK gene identifies a new treatable disorder
Authors: Chelban Viorica , Wilson Matthew , Zanetti Natalia , Zamba-Papanicolaou Eleni , Conte Maria , Cordivari Carla , Mills Philippa , Wood Nicholas , Clayton Peter , Houlden Henry
Published: March 2023

Polyneuropathies are amongst the most common neurological conditions worldwide affecting over 20 million people. However, 40% of patients with primary polyneuropathies have no disease-causing mutation identified.

We investigated patients with gene-negative primary polyneuropathies using a combination of whole genome sequencing, homozigosity mapping and segregation analysis. Pathogenicity was confirmed via enzymatic assays and mass spectroscopy on recombinant protein and patient-derived fibroblasts, plasma and erythrocytes. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the ATP binding.

We report that biallelic mutations in human PDXK are associated with primary axonal polyneuropathy and optic atrophy. Pyridoxal kinase (PDXK) is involved in converting vitamin B6 to its active form, pyridoxal 5’-phosphate (PLP). We show that PDXK mutations lead to disease via decreased plasma PLP concentrations. Our functional studies revealed conformational rearrangement in the mutant enzyme around the kinase ATP-binding pocket with impaired PDXK ability to bind ATP and leading to reduced erythrocyte PDXK activity. We show that both the human clinical picture and biochemical profile in PDXK mutations are rescued by PLP supplementation. Patients regained their ability to walk independently. Furthermore, treatment-led normalisation of plasma PLP levels, correlated with reduction of neurofilament light chain concentrations, a biomarker of axonal breakdown.

In conclusion, biallelic mutations in human PDXK are associated with a novel disorder leading to treatable primary axonal polyneuropathy and optic atrophy and identifies PLP as therapeutic target.
273 Risk of recurrent stroke in patients with intracranial stenosis: a population based study
Authors: Hurford Robert , Wolters Frank J , Li Linxin , Kuker Wilhelm , Rothwell Peter M
Published: March 2023

Introduction

Intracranial stenosis (ICS) is believed to convey a high risk of recurrent ischaemic stroke, but the SAMMPRIS trial failed to show superiority of ICS stenting over intensive medical management. However, the risk of recurrent stroke in the medical arm was low, leading to questions about generalisability. We studied the long-term risk of recurrent stroke in patients with ICS in a population-based setting.

Methods

Patients with TIA or minor stroke [NIHSS £3] underwent MRA in the Oxford Vascular Study. Stroke risk was determined by face-to-face follow-up out to 7-years with a policy of intensive medical treatment and no stenting.

Results

Of 1026 patients (686-TIA; 340-stroke) who underwent MRA, 210 (20.5%) had >50% ICS (TIA=18.5%; stroke=24.4%). Compared to patients with no ICS, risk of recurrent ischaemic stroke was not increased in those with recently symptomatic ICS (HR=1.36, 95%CI=0.54–3.44) or in those with any ICS (1.28, 0.70–2.35) Moreover, the absolute risk of stroke in those with recently symptomatic ICS was lower than reported in the medical arm of SAMMPRIS (2-year risks: 1.6%, 0–4.7 vs 14.1%, 10.1–19.4)

Conclusion

The ‘real-world’ prognosis of patients with ICS on intensive medical treatment is more benign than supposed, indicating that the findings of SAMMPRIS are generalisable.
09.24 Phone a friend?
Authors: Minton Thomas , Fuller Geraint , Rinaldi Simon , Fehmi Janev , Bosnell Rose , Barton Eleanor
Published: March 2023

A 72-year-old man with type 2 diabetes mellitus was admitted under nephrology with malaise. He was diagnosed with acute kidney injury secondary to urinary retention and hydronephrosis. Over 10 days during this admission he developed progressive symmetrical limb paraesthesia and weakness with areflexia.

Neurophysiological studies demonstrated a severe demyelinating polyneuropathy with widespread motor slowing and prolonged distal motor latencies. CSF was acellular with a protein of 5.9 g/L. He was treated with IV immunoglobulins and stabilised for 2 weeks. He then deteriorated over the next four weeks despite IV methylprednisolone, oral corticosteroids and 5 cycles of plasma exchange. He had profound limb weakness (0/5) and required ventilation. He had hypoalbuminaemia, with 1.5 g proteinuria consistent with a nephrotic syndrome.

We phoned a friend.

IgG4 anti–contactin-1 (CNTN1) antibodies were identified in serum with a CNTN1 at 1:1600.

He received 4 cycles of Rituximab. After 6 weeks he was off ventilation with grade 4 power in both arms.

Recently autoantibodies against node of Ranvier proteins have emerged in a subset of patients with CIDP. These patients have a homogenous clinical phenotype with an aggressive polyneuropathy, proteinuria and poor response to conventional therapy, but seem to respond to other agents, including Rituximab and Cyclophosphamide.
09.36 A tumultuous case of episodic apnoea
Authors: Sun Bo , Mgbachi Victor , Woodhall Mark , Voysey Zanna , Azzopardi Laura , Rajan Prabha , Wroe Stephen , Waters Patrick , Isabel Leite M , Irani Sarosh
Published: March 2023

Glycine-receptor(GlyR) antibodies are well defined in progressive encephalomyelitis with rigidity and myoclonus (PERM), and are associated with a limited spectrum of immunotherapy-responsive syndromes. Whilst paradigms of autoantibody pathogenicity have been proposed, the trigger and propagation of GlyR antibodies remains unclear. We herein describe and define clinical and immunobiological observations of a GlyR antibody positive patient with PERM with the rare association of an ovarian teratoma.

A 36-year-old woman presented with subacute axial and limb rigidity, stimulus-sensitive myoclonus, startle, ataxia, anxiety and episodic apnoea. GlyR antibodies were present in serum and CSF. CT revealed a 53 mm left ovarian teratoma. Despite improvement following immunotherapy, she relapsed with respiratory arrest, therefore removal of the left ovarian teratoma was performed.

The fresh teratoma tissue was cultured in B-cell stimulating and plasma cell maintaining conditions, based on similar work with ovarian teratomas from patients with NMDAR-antibody encephalitis (Makuch et al., Annals of Neurology 2018).This teratoma secreted GlyR antibodies into culture supernatants consistent with intra-tumoral synthesis of glycine-receptor antibodies. Whilst marked post-surgical improvement was observed, relapses persisted in correspondence with persistent glycine-receptor antibodies.

Our case highlights key areas for clinical consideration; GlyR antibody-mediated disease can be paraneoplastic in nature; ovarian teratomas can produce pathogenic autoantibodies; late tumour removal or immunotherapy worsens prognosis.
10.00 An obvious, deceptive, case of immunosuppression
Authors: Kumar Guru , Bodi Istvan , Flores Lorena
Published: March 2023

A 69 year old man developed two month progressive short term memory difficulty and then presented with vomiting and confusion. He had bilateral lung transplants for bronchiectasis, immunosuppressed with tacrolimus and mycophenolate for two years. Examination revealed dry thoracic shingles.

MRI demonstrated two intra-axial frontal lesions with faint peripheral enhancement, diffusion restriction and vasogenic oedema. Additionally, small foci of diffusion restriction were seen in the upper cervical cord and brainstem. Cerebrospinal fluid showed 340/mm3 lymphocytes, protein 1.2 g/L, normal glucose ratio and positive Varicella zoster virus (VZV) PCR.

For possible VZV vasculopathy, he received steroids and acyclovir but unfortunately died of multi organ failure approximately two weeks from admission. Post mortem examination demonstrated necrotic frontal lesions with angiodestructive neoplastic B cell proliferation and EBV positivity. An infarct within the upper cervical cord was also seen with arteritis of one of the posterior spinal arteries. There was widespread perivenular inflammatory cell infiltrate. These findings were consistent with lymphomatoid granulomatosis with vasculitic changes; a rare EBV-driven lymphoproliferative disorder that affects the lungs, skin and central nervous system. Aetiology in this case is felt to be secondary to immunosuppression. However, the role of varicella is unclear and the native lungs have not been examined.
11.30 Comparison of fixed high dose with variable low dose rituximab in neuromyelitis optica spectrum disorders
Authors: Kelly Patricia , Whittam Daniel , Linaker Samantha , Mutch Kerry , Karthikeayan Venkatraman , Huda Saif , Jacob Anu
Published: March 2023

Introduction

Rituximab is an effective treatment for neuromyelitis optica spectrum disorders (NMOSD) but the ideal dosing regimen is unknown. This study compares a standard fixed dosing regimen (2 g 6-monthly) with a lower variable dosing regimen (2 g induction, then 1–2 g on repopulation of CD19+ B-cells to ≥1% of circulating lymphocytes, tested monthly).

Method

Retrospective review of all rituximab-treated adult NMOSD patients who had at least 6months relapse-free follow-up from treatment initiation (n=52). Rituximab dosing fell into four groups: Purely fixed dosing (n=13), purely variable dosing (n=18), fixed then variable dosing (n=18), other (n=3).

Results

Median annualized relapse rate (ARR) was not significantly different between these groups. Pooled analysis of all fixed dosing (n=31, median duration 25 months) versus all variable dosing (n=36, median duration 38 months) showed median and mean ARRs of 0.00 and 0.10 in both groups. Patients on fixed dosing received a median 3.9 infusions/year; those on variable doing received only 1.5 infusions/year.

Conclusion

Variable dosing of rituximab with B-cell monitoring appears as effective as fixed dosing with lower cumulative drug doses. This approach led to reduced costs, increased patient convenience and has the potential for reducing side effects.
12.18 Neurology led, outpatient plasma exchange: the wessex experience
Authors: Jennings Rachel , Osman Chinar , Hill Katie , Kitley Joanna , Pinto Ashwin
Published: March 2023

Introduction

Plasma Exchange (PLEX) is a proven treatment for many antibody-mediated neurological diseases, appearing equally efficacious as intravenous immunoglobulins (IVIG) in the majority of conditions. In Wessex, PLEX was previously only available using a membrane-filtration device, requiring central venous access and a high care environment. Increasing restrictions on IVIG alongside bed capacity constraints prompted us to develop a neurology-led, outpatient, centrifuge PLEX service. To our knowledge, this is the first service of its kind in the U.K. We describe our experience over the first eighteen months and compare pre- and post-service development audit data.

Results

Prior to the outpatient service, mean length of stay for elective patients was 10.7 days. The new service has facilitated outpatient PLEX for all elective patients. For inpatient (emergency) PLEX, mean delay from referral to first exchange reduced from 3.7 days to 1.8 days.

Overall, 59% of all plasma exchanges were performed via peripheral access with no major complications in this group.

Conclusion

The new service has facilitated delivery of outpatient PLEX, reduced demand for neurology inpatient beds and reduced treatment delay. Use of peripheral access has also reduced complication rates. Given the national shortage of IVIG, investment in PLEX is essential for neurology services.
11.30 Mutations in the glycosyltransferase domain of GLT8D1 cause ALS
Authors: Cooper-Knock Johnathan , Moll Tobias , Ramesh Tennore , Castelli Lydia , Shaw Christopher , Al-Chalabi Ammar , McDermott Christopher , Hautbergue Guillaume , Shaw Pamela
Published: March 2023

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder without effective neuroprotective therapy. Known genetic variants impair pathways including RNA processing, axonal transport and protein homeostasis. Here we report mutations in a new ALS gene encoding the glycosyltransferase GLT8D1; this class of proteins has not previously been associated with neurodegeneration. Exome sequencing in an autosomal dominant ALS pedigree identified p.R92C mutations in GLT8D1 which co-segregate with disease. Sequencing of local and international cohorts demonstrated significant ALS-association in the same exon, including additional rare deleterious mutations in conserved amino acids. Mutations are associated with the substrate binding site and both R92C and G78W changes impair GLT8D1 enzyme activity. Mutated GLT8D1 exhibits in vitro cytotoxicity and induces motor deficits in zebrafish consistent with ALS. Relative toxicity of mutations in model systems mirrors clinical severity. In conclusion, we have discovered a previously uncharacterised pathophysiological pathway for ALS caused by inherited mutations within a glycosyltransferase enzyme.
11.48 The misdiagnosis of functional disorders as neurological disease
Authors: Walzl Dennis , Carson Alan , Stone Jon
Published: March 2023

Background

When patients with functional neurological disorders are followed up, another neurological disease rarely better explains the initial symptoms in hindsight. No study has examined the reverse, studying patients with various neurological diseases to assess how often a new functional disorder is found which better explains their original symptoms.

Methods

We conducted a prospective multi-centre cohort study of 2637 new neurology outpatient referrals from primary care. Neurologists provided initial diagnoses and a rating of the extent to which their symptoms were explained by an ‘organic’ neurological disease. Patients were followed up 19 months later, via primary care physician questionnaire.

Results

Valid responses were obtained for 2378 patients (90% follow up). Ten patients (0.4%) had acquired an unexpected new functional disorder at follow-up which better explained their original symptoms, and 38 patients (1.6%) had acquired an unexpected new ‘organic’ disease.

Conclusion

Patients diagnosed with neurological disease sometimes have a new functional disorder diagnosis at follow-up which better explains the original symptoms. This occurs at a frequency similar to the misdiagnosis of ‘organic’ neurological disease as functional disorder. Misdiagnosis can harm patients in either direction, which is especially relevant in an era of evidence-based treatment for functional neurological disorders.
001 Risperidone induced seizures after cessation of clozapine
Authors: Kanani Muhammad-Kazim
Published: March 2023

Introduction

Antipsychotic drugs are known to reduce the seizure threshold. clozapine, a second-generation antipsychotic is most associated with causing convulsions.

Case report

A 70-year old gentleman with a diagnosis of Paranoid Schizophrenia had been stable on a daily dose of clozapine 150 mg. The patient wished to stop clozapine for a number of reasons. His clozapine was stopped and he was titrated on to risperidone 3 mg daily. Two weeks after being on risperidone monotherapy the patient attended the emergency department following a fall. Within the department he had two witnessed seizures. Following normal investigations a diagnosis of risperidone induced seizures was made and the medication stopped.

Discussion

The incidence of seizures in non-epileptic patients attributed to the use of risperidone has been reported as 0.3%. The mechanism is unclear but it is interesting to note that a moderate risk of EEG abnormalities has been associated with it. Other risk factors such as old age and hypertension can also influence EEG changes. In contrast seizures with clozapine are dose-dependent (5% at doses above 600 mg/day) and associated with rapid titration. These effects are consistent with the process of kindling.

Conclusion

A reminder that all antipsychotics can cause seizures. Clozapine is most commonly associated but has specific risk factors. Consideration of patient specific pro-convulsive factors is required before prescribing antipsychotics.
002 Management of idiopathic intracranial hypertension: an audit of the 2018 ABN guidelines
Authors: McWilliam Matthew , Broad Rebecca , Cousins Oliver , Flores Lorena , Harikrishnan Sreedharan
Published: March 2023

The annual incidence of idiopathic intracranial hypertension (IIH) has increased from 1.0 per 100000 (1990–2001) to 2.4 per 100000 (2002–2014). Strong correlation exists with rising levels of obesity. We conducted an audit within East Kent Hospitals NHS Trust utilising the 2018 ABN guidelines. A retrospective analysis was performed on 33 patients diagnosed with IIH, from September 2017 to September 2018.

The results demonstrated that all patients had CSF opening pressure recorded. However, only 42% had MRI brain and 24% had MR-venogram within 24 hours, while just 27% completed all neuroimaging within 48 hours. Formal visual field testing at identification of papilloedema was performed in 27% and ongoing ophthalmology assessment was arranged in 82%. BMI was recorded in only 3% and weight management discussion was recorded in 27%. Headache management was initiated in 91%. Discussion regarding drug side effects (e.g. Acetazolamide and Topiramate) were documented in just 15% and teratogenicity in 3%.

These findings demonstrate clear areas for improvement. Working alongside acute physicians and ophthalmologists to formalise neuroimaging pathways and visual field assessments is paramount. Information leaflets including drug side effects and teratogenicity, as well as weight loss advice, should be given at diagnosis. BMI should be recorded at each appointment.
003 Diagnostic workup in suspected viral encephalitis-a single centre audit
Authors: Aslam Faizan , Patel Helee , Garcia-Reitboeck Pablo
Published: March 2023

The British Infection Society and Association of British Neurologists published joint guidelines in 2012 for the management of encephalitis. We wanted to audit our practice. We analysed data from discharge summaries of 150 patients admitted to St George’s Hospital who underwent a lumbar puncture (LP) between March-December 2017. We identified 30 patients with suspected encephalitis. Time to LP was 30.47 ± 6.98 hours. Opening pressure was documented in 14/30(46.6%) whereas paired serum glucose was sent in 6/30(20%) cases. Neuroimaging was performed prior to lumbar puncture with a mean time of 7.68 ± 3.93 hours in 26/30 (86.6%) cases, 16 (61.5%) of whom had a clear indication with focal neurological signs and/or low Glasgow coma score (GCS) (no documentation of ophthalmoscopy was found). Time to acyclovir administration was 10.43 ± 4.01 hours. Repeat LP after 24 hours was performed in 3/30(10%) cases. Viral PCR was performed in 27/30(90%) cases; 3/30(10%) cases were HSV-1 positive. MRI scan done in 12/30(40%) cases.

We recommend a clear protocol for clinicians to improve timeliness and completeness of the workup of suspected viral encephalitis.
004 A triaging blood test for neurology? Serum neurofilament levels in a cohort of GP referrals
Authors: Robertson Josephine , Gray Elizabeth , Thompson Alexander , Feneberg Emily , Talbot Kevin , Turner Martin
Published: March 2023

Increased serum neurofilament is associated with CNS axonal loss from a range of causes. We assessed its potential as a minimally-invasive indicator of active CNS pathology in those with neurological symptoms.

GP referrals to the Neurology Rapid Access Clinic (RAC) at the John Radcliffe Hospital, Oxford were approached to take part. Informed consent was taken under a local Research Ethics Committee-approved protocol. Serum was taken prior to clinical assessment and tested for phosphorylated neurofilament heavy chain (pNFH) using a commercial ELISA (Euroimmun, Germany). Participants were followed up for final diagnosis.

The 62 participants had a range of symptoms, with final diagnoses including migraine, functional, neurodegenerative and inflammatory conditions. Receiver Operating Curve analysis defined cut-off levels based on serum pNfH levels in healthy controls and patients with motor neurone disease measured as part of an independent local biomarker study. pNFH levels in the ‘pathological’ range were associated with serious underlying pathology in several RAC referrals. Ongoing analysis of the cohort will be presented.

Alongside clinical reasoning, serum pNFH may have significant value for the improved triage of those presenting to primary care with neurological symptoms. Further study in larger populations, including healthy individuals, is now warranted.