A Systematic Review of the Spectrum and Prevalence of Non-motor Symptoms in Multiple System Atrophy.

BACKGROUND: Patients with Multiple System Atrophy (MSA) frequently report non-motor symptoms, and several research groups have highlighted this. OBJECTIVE: We systematically searched for and reviewed papers assessing prevalence of non-motor symptoms (NMS) in MSA patients as reported in the scientific literature. METHODS: We performed a systematic review of studies of subjects with MSA (involving > 10 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947-2022. RESULTS: 23 research papers, with data from 2648 clinically diagnosed and 171 pathologically verified cases of MSA were included, along with 238 controls. Mean age for MSA cases was 61.3 (9.2) years, mean disease duration 3.6 (2.7) years. 57.9% were male. Our analysis showed that the prevalence of cognitive issues in MSA varied widely (between 15-100%); dementia per se was uncommon, but assessment in advanced stages of MSA is impacted by unintelligible speech (which may be noted in a quarter of cases). The prevalence of depressive symptoms in MSA was between 44-88%. Sleep disturbances were reported by 17-89%, with REM-sleep behaviour disorder (RBD) rates as high as 75%. Pain was reported by 40-47% of patients: rheumatic or musculoskeletal sources of pain being commonest. Fatigue was reported by 29-60% of patients. Symptoms of autonomic failure in MSA were seen in 34-96.5% patients at baseline. CONCLUSION: In routine clinical practice, NMS in MSA are under-recognised by clinicians. These impact hugely on patient quality of life and contribute to their overall morbidity. A methodical ascertainment of these complaints will address an unmet need, and lead to a more holistic approach of care for individuals with MSA.

A Systematic Review of the Spectrum and Prevalence of Non-Motor Symptoms in Adults with Hereditary Cerebellar Ataxias.

Background: Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS). Objective: We wanted to ascertain the reported prevalence of NMS in different subtypes of hereditary cerebellar ataxias. Methods: Systematic review of studies of hereditary cerebellar ataxias (involving >5 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947 to 2021. Results: A total of 35 papers, with data from 1311 autosomal dominant spinocerebellar ataxia (SCA), 893 autosomal recessive cerebellar ataxia (ARCA), and 53 X-linked ataxia cases were included with a total of 450 controls. Mean age for SCA cases at diagnosis was 47.6 (SD, 14.9) years, for ARCA cases was 34.6 (SD, 14.7) years and for X-linked ataxia cases was 68.6 (9.1) years. The prevalence of cognitive problems in SCAs was between 23% and 75% (ranging from mild to severe), being least prevalent in SCA6. The prevalence of depression in SCAs was between 13% and 69% and sleep disorders were between 7% and 80%. Pain was reported by 18% to 60% of patients, especially in SCA3, and fatigue by 53% to 70%. The prevalence of reported cognitive dysfunction in ARCA was 12.5% to 100% and depression between 14% and 51%. The prevalence of anxiety in X-linked ataxias (FXTAS) was 17 % and depression 55%. Conclusions: The presence of NMS in hereditary cerebellar ataxias is common. The prevalence and spectrum of NMS in SCAs, ARCAs, and X-linked ataxias vary. In routine clinical practice, NMS in cerebellar ataxias are under-recognized and certainly under-reported. Therefore, they are unlikely to be addressed adequately. Improved ascertainment of NMS in cerebellar ataxias in clinical practice will enable holistic treatment of these patients.

Maternal and fetal outcomes in women with cerebrovascular malformations in pregnancy: A multicentre retrospective cohort study.

OBJECTIVE: To determine maternal, obstetric and neonatal outcomes in a cohort of women with cerebrovascular malformations (CVMs) that include arterial venous malformations (AVMs) and cavernomas. DESIGN: Retrospective cohort study. SETTING: Six specialist centres managing pregnant women with neurological disorders. POPULATION: Sixty-three women with CVMs in 83 pregnancies of ≥20 completed weeks' gestation. METHODS: Retrospective case notes review. MAIN OUTCOME MEASURES: Neurological outcomes including rates of acute cerebral bleeding in pregnancy and reported seizures during pregnancy. Maternal outcomes included number of women with a livebirth and the proportion of women being delivered by caesarean section. RESULTS: Most women had a good pregnancy outcome with high rates of vaginal delivery (73%) at term. There were no maternal deaths. Six women had an acute cerebral bleed, all of whom were delivered by planned caesarean section. In total, ten women had seizures in pregnancy (of whom four also had a bleed). Six (7%) babies were admitted to a neonatal unit. There was no significant difference in outcomes between women with AVMs and those with cavernomas. CONCLUSION: In the majority of cases, pregnancy outcomes were favourable, with most women having a vaginal delivery. All cases of cerebral bleeds that occurred were at a remove from the peripartum period. TWEETABLE ABSTRACT: Women with cerebrovascular malformations have high rates of vaginal delivery.

Diagnosis and management of progressive ataxia in adults.

Progressive ataxia in adults can be difficult to diagnose, owing to its heterogeneity and the rarity of individual causes. Many patients remain undiagnosed ('idiopathic' ataxia). This paper provides suggested diagnostic pathways for the general neurologist, based on Ataxia UK's guidelines for professionals. MR brain scanning can provide diagnostic clues, as well as identify 'structural' causes such as tumours and multiple sclerosis. Advances in molecular genetics, including the wider and cheaper availability of 'next-generation sequencing', have enabled clinicians to identify many more cases with a genetic cause. Finally, autoimmunity is probably an under-recognised cause of progressive ataxia: as well as patients with antigliadin antibodies there are smaller numbers with various antibodies, including some associated with cancer. There are a few treatable ataxias, but also symptomatic treatments to help people with the spectrum of complications that might accompany progressive ataxias. Multidisciplinary team involvement and allied health professionals' input are critical to excellent patient care, including in the palliative phase. We can no longer justify a nihilistic approach to the management of ataxia.

Guidelines on the diagnosis and management of the progressive ataxias.

The progressive ataxias are a group of rare and complicated neurological disorders, knowledge of which is often poor among healthcare professionals (HCPs). The patient support group Ataxia UK, recognising the lack of awareness of this group of conditions, has developed medical guidelines for the diagnosis and management of ataxia. Although ataxia can be a symptom of many common conditions, the focus here is on the progressive ataxias, and include hereditary ataxia (e.g. spinocerebellar ataxia (SCA), Friedreich's ataxia (FRDA)), idiopathic sporadic cerebellar ataxia, and specific neurodegenerative disorders in which ataxia is the dominant symptom (e.g. cerebellar variant of multiple systems atrophy (MSA-C)). Over 100 different disorders can lead to ataxia, so diagnosis can be challenging. Although there are no disease-modifying treatments for most of these entities, many aspects of the conditions are treatable, and their identification by HCPs is vital. The early diagnosis and management of the (currently) few reversible causes are also of paramount importance. More than 30 UK health professionals with experience in the field contributed to the guidelines, their input reflecting their respective clinical expertise in various aspects of ataxia diagnosis and management. They reviewed the published literature in their fields, and provided summaries on "best" practice, including the grading of evidence available for interventions, using the Guideline International Network (GIN) criteria, in the relevant sections.A Guideline Development Group, consisting of ataxia specialist neurologists and representatives of Ataxia UK (including patients and carers), reviewed all sections, produced recommendations with levels of evidence, and discussed modifications (where necessary) with contributors until consensus was reached. Where no specific published data existed, recommendations were based on data related to similar conditions (e.g. multiple sclerosis) and/or expert opinion. The guidelines aim to assist HCPs when caring for patients with progressive ataxia, indicate evidence-based (where it exists) and best practice, and act overall as a useful resource for clinicians involved in managing ataxic patients. They do, however, also highlight the urgent need to develop effective disease-modifying treatments, and, given the large number of recommendations based on "good practice points", emphasise the need for further research to provide evidence for effective symptomatic therapies.These guidelines are aimed predominantly at HCPs in secondary care (such as general neurologists, clinical geneticists, physiotherapists, speech and language therapists, occupational therapists, etc.) who provide care for individuals with progressive ataxia and their families, and not ataxia specialists. It is a useful, practical tool to forward to HCPs at the time referrals are made for on-going care, for example in the community.

Reversible cerebral vasoconstriction syndrome as a cause of thunderclap headache: a retrospective case series study.

Thunderclap headache is a common emergency department presentation. Although subarachnoid hemorrhage (SAH) should be the first diagnosis to exclude, reversible cerebral vasoconstriction syndrome (RCVS) is an important alternative cause, which may be commoner than appreciated. Reversible cerebral vasoconstriction syndrome is characterized by multifocal narrowing of cerebral arteries, typically manifested by acute, severe headache with or without neurologic deficits. To compare and discuss the clinical and radiologic characteristics of patients with RCVS. We report 4 cases of RCVS, presenting at a single unit in 1 year. All presented with thunderclap headache, whereas half of them had additional neurologic symptoms such as right homonymous hemianopia, right-sided weakness, and slurred speech. Brain computed tomography was normal in 2 of our patients, but subsequent cerebrospinal fluid analysis revealed xanthochromia consistent with SAH. The remaining 2 patients demonstrated intracerebral hemorrhage on computed tomography. All of our patients underwent digital subtraction angiography that showed segmental narrowing and dilatation of one or more cerebral arteries without any signs of aneurysm. Repeat digital subtraction angiography after 3 months was entirely normal prompting the diagnosis of RCVS. Thunderclap headache requires urgent workup to identify the underlying cause. Although SAH is the most important diagnosis to exclude in the first instance, emergency physicians should be aware of other causes and how they present, such as RCVS. Early recognition of this condition is important in order to remove precipitants, avoid unnecessary investigations, and inform patients about their prognosis.

Improving the likelihood of neurology patients being examined using patient feedback.

We aimed to establish whether recall of elements of the neurological examination can be improved by use of a simple patient assessment score. In a previous study we demonstrated that in-patients referred to neurology at two United Kingdom (UK) hospitals were not fully examined prior to referral; we therefore designed a larger quality improvement report with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a four month period (in hospitals in the UK (10), Jordan (1), Sweden (2), and the United Arab Emirates (1)) were asked whether they recalled being examined with a tendon hammer (T), ophthalmoscope (O), and stethoscope (S) since admission. The results were disseminated to local medical teams using various techniques (including Grand Round presentations, email, posters, discounted equipment). Data were then collected for a further four month period post-intervention. Pre-intervention and post-intervention data were available for 11 centres with 407 & 391 patients in each arm respectively. Median age of patients was 51 (range 13-100) and 49 (range 16-95) years respectively, with 44.72% and 44.76% being male in each group. 264 patients (64.86%) recalled being examined with a tendon hammer in the pre-intervention arm, which significantly improved to 298 (76.21%) (p<0.001). Only 119 patients (29.24%) recollected examination with an ophthalmoscope pre-intervention, which significantly improved to 149 (38.11%)(p=0.009). The majority of patients (321 (78.87%)) pre-intervention recalled examination with a stethoscope, which significantly improved to 330 (84.4%) to a lesser extent (p=0.045). Results indicate that most patients are not fully examined prior to neurology referral yet a simple assessment score and educational intervention can improve recall of elements of the neurological examination and thus the likelihood of patients being examined neurologically. This is the largest and - to our knowledge - only study to assess this issue. This has implications for national neurological educators.

"The mind is its own place": amelioration of claustrophobia in semantic dementia.

Phobias are among the few intensely fearful experiences we regularly have in our everyday lives, yet the brain basis of phobic responses remains incompletely understood. Here we describe the case of a 71-year-old patient with a typical clinicoanatomical syndrome of semantic dementia led by selective (predominantly right-sided) temporal lobe atrophy, who showed striking amelioration of previously disabling claustrophobia following onset of her cognitive syndrome. We interpret our patient's newfound fearlessness as an interaction of damaged limbic and autonomic responsivity with loss of the cognitive meaning of previously threatening situations. This case has implications for our understanding of brain network disintegration in semantic dementia and the neurocognitive basis of phobias more generally.

Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1-3, 6, 7 and Friedrich's ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost was ∼£400 (€460 or US$620). Our pathogenicity interpretation pathway predicted 13 different mutations in eight different genes: PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3 and DARS2 of which nine were novel including one causing a newly described recessive ataxia syndrome. Genetic testing using targeted capture followed by next-generation sequencing was efficient, cost-effective, and enabled a molecular diagnosis in many refractory cases. A specific challenge of next-generation sequencing data is pathogenicity interpretation, but functional analysis confirmed the pathogenicity of novel variants showing that the pipeline was robust. Our results have broad implications for clinical neurology practice and the approach to diagnostic testing.

ß-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Peripartum isolated cortical vein thrombosis in a mother with postdural puncture headache treated with an epidural blood patch.

A 32-year-old woman presented with low pressure headache 3 days after delivery of her baby. An assessment of postdural puncture headache was made. This was initially treated with analgesia, caffeine, and fluids for the presumed cerebrospinal fluid (CSF) leak. The woman was readmitted two days after her hospital discharge with generalised seizures. A brain scan showed features of intracranial hypotension, and she was treated for CSF leak using an epidural blood patch. Her symptoms worsened and three days later, she developed a left homonymous quadrantanopia. An MRI scan confirmed a right parietal haematoma with evidence of isolated cortical vein thrombosis (ICVT).

Unusual amnesia in a patient with VGKC-Ab limbic encephalitis: a case study.

We describe the case of a patient with confirmed voltage-gated potassium channel antibody-associated encephalitis (VGKC-Ab). MRI studies revealed bilateral hyper-intensity in the hippocampi, with their volumes preserved. At presentation, the patient's anterograde and retrograde memory skills were found to be impaired and he showed fluctuation in his ability to recall familiar information. Following treatment with immunotherapy, his condition improved considerably and, in a series of follow up assessments, he performed satisfactorily (i.e., within the average range or above) on formal tests of memory, as well as on a range of other cognitive tests, including tests of executive function. By contrast, in the context of contemporaneous unstructured interviews, he showed a strong tendency to confabulate. We argue that the reported case broadens the phenomenology of VGKC-Ab limbic encephalitis and raises important theoretical questions about the aetiology of this patient's most unusual memory disorder.