Cerebellar ataxia and sensory ganglionopathy associated with light-chain myeloma.

BACKGROUND: Cerebellar ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. CASE PRESENTATION: A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin ataxia, gait ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. CONCLUSIONS: Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon

Association of biomarkers for human papillomavirus with survival among adults with Barrett high-grade dysplasia and esophageal adenocarcinoma

Importance: The presence of high-risk human papillomavirus (HPV) has been associated with a favorable outcome in Barrett high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Nevertheless, the prognostic significance of other HPV-related biomarkers (ie, retinoblastoma protein [pRb], cyclin D1 [CD1], minichromosome maintenance protein [MCM2] and Ki-67) is unknown. Objective: To examine the association between HPV-related biomarkers and survival in adult patients with Barrett HGD and EAC. Design, Setting, and Participants: This retrospective case-control study examined the hypothesis that the HPV-related cell cycle markers (pRb, CD1, and Ki-67) and the viral surrogate marker (MCM2) may be associated with a favorable prognosis in Barrett HGD and EAC. Pretreatment biopsies were used for HPV DNA determination via polymerase chain reaction and immunohistochemistry for the HPV-related biomarkers. Recruitment of patients occurred in secondary and tertiary referral centers, with 151 patients assessed for eligibility. The study period was from December 1, 2002, to November 28, 2017, and the dates of analysis were from September 9, 2011, to November 28, 2017. Main Outcomes and Measures: Disease-free survival and overall survival. Results: Of 151 patients assessed for eligibility, 9 were excluded. Among the 142 patients with Barrett HGD or EAC (126 [88.7%] men; mean [SD] age, 66.0 [12.1] years; 142 [100%] white), 37 were HPV positive and 105 were HPV negative. No association with disease-free survival was noted for pRb, CD1, Ki-67, and MCM2. In regard to overall survival, only low expression of CD1 had a favorable prognosis (hazard ratio [HR], 0.53; 95% CI, 0.30-0.95; adjusted P = .03). All the biomarkers stratified by HPV status showed significant associations with survival. Patients with HPV-positive, low-expression pRb esophageal tumors were associated with a significantly improved disease-free survival compared with the HPV-negative, high-expression Rb tumors (HR, 0.33; 95% CI, 0.12-0.93; adjusted P = .04). Similarly, HPV-positive, low-expression CD1 was associated with a significantly favorable disease-free survival (HR, 0.26; 95% CI, 0.09-0.76; adjusted P = .01), as was HPV-positive, high-expression MCM2 (HR, 0.27; 95% CI, 0.09-0.78; adjusted P = .02). In regard to overall survival, HPV was significantly associated only with low CD1 (HR, 0.38; 95% CI, 0.15-0.94; adjusted P = .04). Conclusions and Relevance: This study's findings suggest that low expression of CD1 appears to be an independent prognostic marker in Barrett HGD and EAC. Human papillomavirus positivity in combination with pRb, CD1, MCM2, and Ki-67 was associated with a survival benefit in esophageal tumors. These findings suggest the possibility of personalization of therapy for Barrett HGD and EAC based on viral status

Speech treatment for people with cerebellar Multiple System Atrophy (MSA-C) : a pilot randomised controlled trial of two approaches

Speech problems are an early feature of Multiple System Atrophy (MSA). They can lead to social withdrawal and have significant impact on people’s quality of life. There is a considerable lack of clinical trials and clinicians lack guidance on how best to support this population. This project aimed to establish the feasibility and acceptability of a novel treatment approach, ClearSpeechTogether, in patients with the cerebellar variant of MSA (MSA-C), and to pilot an RCT comparing this treatment to standard speech and language therapy (SLT) treatment (ST). We recruited 24 patients with clinically probable MSA-C and dysarthria who were randomised to either treatment arm. Full data were available for 9 participants for ST, and 11 for ClearSpeechTogether. Both interventions lasted 6 weeks, ST offered 1 h of individual therapy a week, ClearSpeechTogether provided four individual therapy sessions over two weeks, followed by four weeks of daily, patient led group practice. Assessment and intervention were provided online via videoconferencing software. Data collection focused on feasibility, acceptability and signal of efficacy. Recruitment, conversion and attrition rates were within or close to target, and neither participants nor clinicians highlighted any acceptability issues. Communication outcomes were mixed, with biggest gains made in communication confidence and participation across both groups. Rapid decline in overall health status appeared to have impacted results. Results were generally positive and support the implementation of larger follow up trials. The study also demonstrated that people with MSA-C can benefit from speech therapy even at more severe stages of their disease progression

Speech treatment for people with cerebellar multiple system atrophy (MSA-C): a pilot randomised controlled trial of two approaches

Speech problems are an early feature of Multiple System Atrophy (MSA). They can lead to social withdrawal and have significant impact on people’s quality of life. There is a considerable lack of clinical trials and clinicians lack guidance on how best to support this population. This project aimed to establish the feasibility and acceptability of a novel treatment approach, ClearSpeechTogether, in patients with the cerebellar variant of MSA (MSA-C), and to pilot an RCT comparing this treatment to standard speech and language therapy (SLT) treatment (ST). We recruited 24 patients with clinically probable MSA-C and dysarthria who were randomised to either treatment arm. Full data were available for 9 participants for ST, and 11 for ClearSpeechTogether. Both interventions lasted 6 weeks, ST offered 1 h of individual therapy a week, ClearSpeechTogether provided four individual therapy sessions over two weeks, followed by four weeks of daily, patient led group practice. Assessment and intervention were provided online via videoconferencing software. Data collection focused on feasibility, acceptability and signal of efficacy. Recruitment, conversion and attrition rates were within or close to target, and neither participants nor clinicians highlighted any acceptability issues. Communication outcomes were mixed, with biggest gains made in communication confidence and participation across both groups. Rapid decline in overall health status appeared to have impacted results. Results were generally positive and support the implementation of larger follow up trials. The study also demonstrated that people with MSA-C can benefit from speech therapy even at more severe stages of their disease progression

Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics

Purpose Phenytoin is an effective anticonvulsant for focal epilepsy. Its use can be associated with long-term adverse effects including cerebellar ataxia. Whilst phenytoin is toxic to Purkinje cells in vitro; the clinical and radiological phenotype and mechanism of cerebellar degeneration in vivo remain unclear. We describe the prevalence, clinical and radiological characteristics of phenytoin-related ataxia. Methods Patients with epilepsy receiving treatment with phenytoin were recruited from the Epilepsy clinics at Royal Hallamshire Hospital, Sheffield, UK. Neurological examination was performed on all patients after recruitment. Patients were categorised into those with and without ataxia. We determined the severity of ataxia clinically (SARA score) and the pattern of cerebellar involvement by neuroimaging (MRI volumetry and MR spectroscopy). Results Forty-seven patients were recruited. Median duration of epilepsy was 24 years, median duration of phenytoin treatment was 15 years and current median phenytoin daily dose was 325 mg. Fifty-five percent of patients complained of poor balance. Clinical evidence of ataxia was seen in 40% patients. Gait, stance and heel-shin slide were the predominant features of cerebellar dysfunction. MRI demonstrated structural, volumetric and functional deficits of the cerebellum. Only one patient with ataxia had phenytoin levels above the normal range. Conclusions Cerebellar ataxia is present in 40% of patients with epilepsy and chronic exposure to phenytoin. Patients on long-term phenytoin have reduced cerebellar volume even if they have no clinical evidence of ataxia. Evidence of structural deficits on imaging suggests a predilection for vermian involvement

Clinical characteristics, cerebellar MR spectroscopy and response to 3,4-diaminopyridine in spinocerebellar ataxia 27B: the Sheffield Ataxia Centre experience

Background The clinical and genetic heterogeneity of hereditary ataxias presents a significant diagnostic challenge, particularly in sporadic adult-onset cases. Spinocerebellar ataxia type 27B (SCA27B) is caused by an intronic GAA·TTC repeat expansion in the fibroblast growth factor 14 (FGF14) gene and is inherited in an autosomal dominant manner, although with reduced penetrance. This novel ataxia is emerging as a frequent yet underdiagnosed cause of late-onset often sporadic cerebellar ataxia. Method In this study, we describe our experience in clinical presentation, neuroimaging characteristics (including MR spectroscopy of the cerebellum), tremor analysis, and therapeutic response to 3,4-diaminopyridine in a cohort of 50 patients with SCA27B. Results The mean age at onset was 61.8 years. Episodic symptoms were reported in 28% of cases, while downbeat nystagmus and oscillopsia were observed in 50% and 28% individuals, respectively. Tremor was also present in 22% of patients. Tremor analysis demonstrated bilateral, intermediate-frequency (~ 6 Hz) tremor with both action and resting components, occasionally involving, apart from arms, the lower limbs and head. MRI findings revealed involvement of the superior cerebellar peduncle, and MR spectroscopy of the cerebellum (MRS) demonstrated a progressive decline in NAA/Cr area ratios in the cerebellar hemisphere over time. Notably, treatment with 3,4-diaminopyridine was associated with subjective symptom improvement in most patients and objective stabilization and/or improvement on MRS. Conclusion Our findings expand the clinical, neuroimaging and tremor phenotype of SCA27B and support the use of 3,4-diaminopyridine as a potentially effective therapy

Simultaneous ALS and SCA2 associated with an intermediate-length ATXN2 CAG-repeat expansion

Spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) share a common molecular basis: both are associated with CAG-repeat expansion of ATXN2 and TDP-43-positive neuronal cytoplasmic inclusions. To date, the two disorders are viewed as clinically distinct with ALS resulting from 30-33 CAG-repeats and SCA2 from >34 CAG-repeats. We describe a 67-year old with a 32 CAG-repeat expansion of ATXN2 who presented with simultaneous symptoms of ALS and SCA2. Our case demonstrates that the clinical dichotomy between SCA2 and ATXN2-ALS is false. We suggest instead that CAG-repeat expansion length determines the timing of SCA2 clinical symptoms relative to onset of ALS; consistent with this age of onset of SCA2 but not ATXN2-ALS, is dependent upon expansion length. Review of the literature and our local cohort provides evidence for occurrence of ALS in late stage SCA2, which may be under-recognised by clinicians who think of the two diseases as distinct

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified