Rare genetic movement disorders usually manifest early in life with dystonia, parkinsonism, chorea, or a combination thereof. These are often associated with neurodevelopmental delay, intellectual disability, speech problems, retinal abnormalities, seizures, ataxia, spasticity, or systemic features. Due to their vast number and pheno–genotypic heterogeneity, the diagnosis of these disorders can be challenging. However, recognising their core motor phenomenology as well as clinical, laboratory, and neuroradiological clues can expedite appropriate diagnostic workup, molecular diagnosis, and adequate treatment. In this review, we outline diagnostic clues to rare movement disorders (RMDs), focusing on those that present mainly with dystonia, parkinsonism, or paroxysmal dyskinesia due to genetic causes. Additionally, we provide a decision tree approach linking clinical, genetic, and imaging testing. Finally, we highlight selected RMDs that should not be missed, as they possess established treatments that can hinder their progression, prevent irreversible or life-threatening sequelae and, in certain cases, lead to complete symptom remission.

Brain calcification is often detected incidentally, but basal ganglia calcification has a wide differential diagnosis, including genetic and acquired causes. Primary familial brain calcification (PFBC) (formerly 'Fahr's disease') refers to neurological disorders characterised by bilateral, symmetrical deposition of calcium-hydroxyapatite crystals in the basal ganglia and other encephalic regions, with a presumed genetic basis. Its clinical picture encompasses motor, cognitive and psychiatric manifestations in various combinations. Seven genes have been linked to PFBC since 2012, with either autosomal dominant (SLC20A2, PDGFRB, PDGFB and XPR1) or recessive (MYORG, JAM2 and NAA60) mode of inheritance. Mendelian gene discovery has provided critical insights into the pathogenesis of PFBC. Dyshomeostasis of inorganic phosphate, impaired endothelial functions and disrupted blood-brain barrier integrity has been identified as converging pathomechanisms, which could highlight the targets of potential disease-modifying treatments. We provide a state-of-the-art overview on phenotypic features, diagnosis, aetiopathogenesis and management of PFBC.

Acute Intermittent Porphyria (AIP) can be a challenging diagnosis to make, due to its rarity in actual practice and presenting symptoms often being attributed to more common conditions. This is particularly the case, since many patients will likely present to acute and general hospitals where the diagnosis may often not be considered. However, it remains pivotal to diagnose the condition as early as possible to prevent significant morbidity and even death. Here we present an unexpected case of AIP, illustrating the diagnostic delay that is commonly seen with the condition and yet emphasise the importance of its detection to commence urgent treatment.

The use of methotrexate in clinical practice has expanded significantly in recent years, as an effective chemotherapeutic agent as well as disease-modifying treatment for conditions such as rheumatoid arthritis, psoriasis and Crohn's disease. It is also used as a steroid-sparing agent for a range of inflammatory diseases of the central and peripheral nervous systems. Clinical neurologists must, therefore, know how to start and uptitrate methotrexate, its monitoring requirements and its potential toxicities. This review aims first to explore the evidence base for using methotrexate in various neurological diseases and second to discuss important practicalities around its use, ensuring its safe application and appropriate monitoring.

OBJECTIVES:Leucine-rich glioma-inactivated 1 (LGI1) encephalitis and IgG4-related disease (IgG4RD) have traditionally been regarded as 2 distinct disease entities. METHODS:We detail the presentation, investigations, and management of a patient who showed typical signs and symptoms of LGI1 encephalitis and also found to possess pancreatic changes and a serum profile in keeping with IgG4RD. RESULTS:Serum and CSF analyses at presentation showed a significant hyponatraemia (117 mmol/L), elevated IgG4 concentration (1.73 g/L), and the presence of LGI1 antibodies. MRI revealed symmetrical diffuse T2-weighted hyperintensity and mild swelling throughout both medial temporal lobes. CT of the chest, abdomen and pelvis revealed an edematous, bulky pancreas with loss of lobulation, typical for IgG4RD. A glucocorticoid weaning regimen was commenced, facilitated by 2 rituximab infusions, with the patient showing an effective treatment response. HLA testing confirmed the presence of HLA DRB1 and HLA DQB1 risk alleles. DISCUSSION:This case suggests that there may be shared mechanisms between LGI1 encephalitis and IgG4RD, supported by common risk HLA associations and treatment strategies/responses. To our knowledge, this represents the first instance that LGI1 encephalitis and IgG4RD have been reported in the same patient and emphasizes the continued development of our understanding of the wide range of IgG4-mediated conditions.

Balancing the risks of recurrent ischemia and antithrombotic-associated bleeding, particularly intracranial hemorrhage (ICH), is a key challenge in the secondary prevention of ischemic stroke and transient ischemic attack. In hyperacute ischemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggest CMB presence should not preclude antithrombotic therapy in patients with ischemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomized controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified in most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with the potential to enhance precision medicine in stroke.

Delayed graft function (DGF) is a common phenomenon following renal transplantation, which can be due to several factors. A rare cause includes invasive fungal infections, which can often be a challenge to diagnose. Nonetheless, prompt identification of such infections particularly within transplant patients is essential as they can lead to severe downstream sequelae, including graft loss and even death. We describe here a challenging case of fungal pyelonephritis complicating and potentially leading to DGF and further dialysis dependence within a renal transplant patient. Notably, we highlight the importance and clinical utility of biopsy to confirm the diagnosis, as investigations may be largely normal otherwise. Furthermore, we emphasise that with early identification of these infections, effective antifungal treatment can be commenced in a timely fashion leading to better patient outcomes and good graft function.

Background: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. Objectives: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. Methods: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. Results: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1negative controls. No phenotypic differences were observed between any of the non-PD groups.Conclusions: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers.

Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases; therefore, existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed 'lesion network mapping' using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuro-imaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed 'coordinate network mapping', which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI data set from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain; however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity) and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.

Objectives Leucine-rich glioma-inactivated 1 (LGI1) encephalitis and IgG4-related disease (IgG4RD) have traditionally been regarded as 2 distinct disease entities. Methods We detail the presentation, investigations, and management of a patient who showed typical signs and symptoms of LGI1 encephalitis and also found to possess pancreatic changes and a serum profile in keeping with IgG4RD. Results Serum and CSF analyses at presentation showed a significant hyponatraemia (117 mmol/L), elevated IgG4 concentration (1.73 g/L), and the presence of LGI1 antibodies. MRI revealed symmetrical diffuse T2-weighted hyperintensity and mild swelling throughout both medial temporal lobes. CT of the chest, abdomen and pelvis revealed an edematous, bulky pancreas with loss of lobulation, typical for IgG4RD. A glucocorticoid weaning regimen was commenced, facilitated by 2 rituximab infusions, with the patient showing an effective treatment response. HLA testing confirmed the presence of HLA DRB1 and HLA DQB1 risk alleles. Discussion This case suggests that there may be shared mechanisms between LGI1 encephalitis and IgG4RD, supported by common risk HLA associations and treatment strategies/responses. To our knowledge, this represents the first instance that LGI1 encephalitis and IgG4RD have been reported in the same patient and emphasizes the continued development of our understanding of the wide range of IgG4-mediated conditions.

IntroductionPatients with clinical features of Parkinson’s Disease (PD), but scans without evidence of dopaminergic deficit are termed SWEDDs. Only a portion of these patients retain their SWEDDs diagnosis later in life and are here regarded as ‘true SWEDDs’. Cognitive symptoms of ‘true SWEDDs’ remain unclear yet important to optimise their management. We used data from the Parkinson’s Progression Markers Initiative to investigate these further.MethodologyBaseline cognitive data of 25 SWEDDs, who retained diagnoses after 2 years of follow up (confirmed by normal 123I-FP-CIT SPECT scans), were compared with that of 62 de novo PD and 195 healthy control (HC) subjects. Data was analysed using SPSS Statistics.ResultsNo significant difference was found when comparing ‘true SWEDDs’ to de novo PD patients and HCs in tests of global cognition, visuospatial function, executive function and attention. However, Hopkins Verbal Learning Test-Revised (HVLT-R) showed a significant difference between the three groups (P=0.004), maintained when specifically analysing ‘true SWEDDs’ versus HCs (P=0.009).ConclusionOur data suggest a significant difference in memory function between ‘true SWEDDs’ and HCs, as demonstrated by the HVLT-R test. This suggests memory-stimulating therapies are important for managing ‘true SWEDDs’, however further work is required to validate these findings.aaronjesuthasan@gmail.com

Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3–25.0%] in women vs 11.9% [7.0–23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9–1.7%] vs 4.5% [1.9–8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p< 0.0001, respectively). Women with diabetes had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women (559.3 ± 32.9 vs 403.2 ± 45.7 mg kg−1 day−1, p = 0.01, and 0.45 [0.26–0.77] vs 0.25 [0.13–0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg−1 day−1, p = 0.34, and 0.72 [0.53–1.15] vs 0.50 [0.32–0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes.

Introduction MRI sensitivity of up to 96% for pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) has previously been reported. However, in 2012, Carswell et al. found that the initial neuroradio- logical report often failed to identify CJD-associated MRI changes (47% sensitivity). These patients were at a more advanced stage of disease when referred to specialist services. Here we assessed whether there has been a change over time. Methods We reviewed MRI scans of 106 patients (sCJD=102, IPD=4) referred to the NPC between 2015- 2019, and compared our findings with the formal reports from referring centres. We recorded the MRC Scale scores at initial patient assessment. Results We found characteristic MRI abnormalities in 101 out of 102 sCJD cases. A differential diagnosis of CJD was documented on the neuroradiological reports of 70 of these cases, giving a significantly improved sensitivity of 69% compared to 2012. There was no association between the location of signal change and reporting accuracy. Patients had less advanced disease compared to 2012. Conclusions MRI reporting of sCJD by referring centres has improved, but further improvement seems possible. We re-emphasize the importance of analysing scans thoroughly for characteristic MRI patterns of sCJD to enable earlier identification of these patients. danielle sequeira@nhs.net|ABN Bursary 26

Background MRI is invaluable for the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), demonstrating characteristic diffusion abnormalities. Previous work showed these changes were often not reported (low sensitivity), leading to eventual diagnosis at a more advanced state. Here, we reviewed the situation a decade later, on the presumption of improved access and awareness over time. Methods We reviewed initial MRI scans of 102 consecutive suspected sCJD patients recruited to the National Prion Monitoring Cohort study between 2015 and 2019, assessing for characteristic signal changes in the striatum, thalamus and cortical ribbon. We compared our findings to formal reports from referring centres. Requesting indications were studied to assess if they were suggestive of CJD. Patients were examined and their MRC Prion Disease Rating Scale scores recorded. Results We identified characteristic MRI abnormalities in 101 cases (99% sensitivity), whilst referring centres reported changes in 70 cases (69% sensitivity), which was a significant improvement in reporting sensitivity from 2012. Reporting sensitivity was associated with signal change in the cerebral cortex, and with the number of regions involved, but not significantly affected by clinical information on request forms, or referring centres being regional neuroscience/non-neuroscience centres. Similar to a previous study, patients with missed abnormalities on initial reporting possessed lower MRC Scale scores when referred to the NPC than those correctly identified. Conclusions Whilst local MRI reporting of sCJD has improved with time, characteristic abnormalities remain significantly under detected on initial scans. Sensitivity is better when the cerebral cortex and multiple regions are involved. We re-emphasize the utility of MRI and encourage further efforts to improve awareness and sensitivity in the assessment of patients with rapidly progressive dementia.

A spectrum of neurological disease associated with COVID-19 is becoming increasingly apparent. However, the mechanisms behind these manifestations remain poorly understood, significantly hindering their management. The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a "cytokine storm". We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident longterm neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.

BACKGROUND:Botulinum toxin A (BoNT-A) is an effective treatment for cervical dystonia. Nevertheless, up to 30% to 40% patients discontinue treatment, often because of poor response. The British Neurotoxin Network (BNN) recently published guidelines on the management of poor response to BoNT-A in cervical dystonia, but adherence to these guidelines has not yet been assessed. OBJECTIVES:To assess adherence to and usefulness of BNN guidelines in clinical practice. METHODS:We undertook a retrospective medical notes audit of adherence to the BNN guidelines in 3 United Kingdom tertiary neurosciences centers. RESULTS:Of 76 patients identified with poor response, 42 (55%) had a suboptimal response and, following BNN recommendations, 25 of them (60%) responded to adjustments in BoNT dose, muscle selection or injection technique. Of the remaining 34 (45%) patients with no BoNT response, 20 (59%) were tested for immune resistance, 8 (40%) of whom showed resistance. Fourteen (18%) of all patients were switched to BoNT-B, and 27 (36%) were referred for deep brain stimulation surgery. In those not immune to BoNT-A, clinical improvement was seen in 5 (41%) after adjusting their dose and injection technique. CONCLUSION:Our audit shows that optimizing BoNT dose or injection strategy largely led to improvements in those with suboptimal response and in those reporting no response without resistance. It would be helpful to standardize investigations of potential resistance in those with no therapeutic response.

It is recommended that developers of Point Of Care Tests (POCTs) assess the care pathway of the patient population of interest in order to understand if the POCT fits within the pathway and has the potential to improve it. If the variation of the pathway across potential hospitals is large, then it is likely that the evaluation of effectiveness is harder and the route towards large-scale takes adoption longer. Evaluating care pathways can be a time-consuming activity when conducted through clinical audits or interviews with healthcare professionals. We have developed a more rapid methodology which extrapolates the care pathway from local hospital guidelines and assesses their variation. Sepsis kills 46,000 people per year in the UK with societal costs of up to £10 billion. Therefore, there is a clinical need for an optimized pathway. By applying our method in this field, we were able to assess the variation in current hospital guidelines for sepsis and infer the potential impact this may have on the evidence development on innovations in this applications. We obtained 15 local sepsis guidelines. Two independent reviewers extracted: use of the national early warning score (NEWS), signs and risk factors informing the decision to prescribe antibiotics, and the number of decisional steps up to this point. Considerable variation was observed in all the variables, which is likely to have an impact on future clinical and economic evaluations and adoption of POCT for the identification of patients with sepsis.

A 35-year-old right-handed man was referred with gradually progressive bilateral shoulder weakness, first noticed at age 16 when he was unable to fully lift his arms above his head. On examination, he had bilateral severe wasting of trapezius muscles, associated marked scapular winging and some