Publications by authors named "Rajith de Silva"

27 Publications

  • Page 1 of 1

Diagnosis and management of progressive ataxia in adults.

Pract Neurol 2019 Jun 2;19(3):196-207. Epub 2019 May 2.

Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and University of Sheffield, Sheffield, UK.

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.
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http://dx.doi.org/10.1136/practneurol-2018-002096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585307PMC
June 2019

Guidelines on the diagnosis and management of the progressive ataxias.

Orphanet J Rare Dis 2019 02 20;14(1):51. Epub 2019 Feb 20.

Ataxia Centre, Department of Molecular Neurosciences, UCL Queen Sqaure Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

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.
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http://dx.doi.org/10.1186/s13023-019-1013-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381619PMC
February 2019

Soft tissue plasmacytomas in multiple myeloma.

Lancet 2017 Nov 23;390(10107):2083. Epub 2017 Aug 23.

Department of Haematology, Queen's Hospital, Romford, UK.

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http://dx.doi.org/10.1016/S0140-6736(17)31471-XDOI Listing
November 2017

A hill walker with long chains.

Pract Neurol 2017 Jan 3;17(1):71-73. Epub 2016 Nov 3.

Essex Centre for Neurological Sciences, Queen's Hospital, Romford, UK.

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http://dx.doi.org/10.1136/practneurol-2016-001464DOI Listing
January 2017

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

BMJ Qual Improv Rep 2015 5;4(1). Epub 2015 Nov 5.

See Acknowledgements for author affiliations.

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.
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http://dx.doi.org/10.1136/bmjquality.u209610.w4063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4693104PMC
January 2016

Mutation in Atypical Rett Syndrome with Brain Iron Accumulation.

Mov Disord Clin Pract 2015 Mar 24;2(1):81-83. Epub 2015 Feb 24.

Department of Neurology Essex Center for Neurological Sciences Queen's Hospital Romford Essex United Kingdom.

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http://dx.doi.org/10.1002/mdc3.12120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353382PMC
March 2015

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

Am J Emerg Med 2015 Jun 19;33(6):859.e3-6. Epub 2014 Dec 19.

Department of Neurology, Essex Centre for Neurological Sciences, Queen's Hospital, Romford, Essex, UK.

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.
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http://dx.doi.org/10.1016/j.ajem.2014.12.026DOI Listing
June 2015

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

Behav Neurol 2014 6;2014:584893. Epub 2014 Mar 6.

Dementia Research Centre, UCL Institute of Neurology, University College London, 8-11 Queen Square, London WC1N 3BG, UK.

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.
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http://dx.doi.org/10.1155/2014/584893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006598PMC
December 2014

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

Brain 2013 Oct 11;136(Pt 10):3106-18. Epub 2013 Sep 11.

1 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.

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.
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http://dx.doi.org/10.1093/brain/awt236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784284PMC
October 2013

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

Brain 2013 Jun 17;136(Pt 6):1708-17. Epub 2013 May 17.

Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.

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.
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http://dx.doi.org/10.1093/brain/awt095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673459PMC
June 2013

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

Case Rep Med 2013 3;2013:701264. Epub 2013 Mar 3.

Department of Neurology, Queen's Hospital, Romford RM7 0AG, UK.

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).
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http://dx.doi.org/10.1155/2013/701264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3603422PMC
March 2013

TS or not TS?

Pract Neurol 2013 Aug 13;13(4):268-70. Epub 2013 Mar 13.

Department of Neurology, Essex Centre for Neurological Sciences, Queen's Hospital, Romford, Essex, UK.

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http://dx.doi.org/10.1136/practneurol-2012-000371DOI Listing
August 2013

Review of 'When I die: lessons from the death zone' (YouTube).

BMJ Support Palliat Care 2012 Sep;2(3):287

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http://dx.doi.org/10.1136/bmjspcare-2012-000303DOI Listing
September 2012

An ancient cause of muscle spasm… and an unhelpful magnetic resonance imaging scan.

World Neurosurg 2014 Mar-Apr;81(3-4):e23-5. Epub 2011 Nov 26.

Essex Centre for Neurological Sciences, Queen's Hospital, London, United Kingdom.

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http://dx.doi.org/10.1016/j.wneu.2011.11.005DOI Listing
June 2014

Do patients wish to 'listen in' when doctors dictate letters to colleagues?

JRSM Short Rep 2010 Nov 2;1(6):47. Epub 2010 Nov 2.

Department of Neurology, Essex Centre for Neurological Sciences, Queen's Hospital , Romford , UK.

Objectives: To evaluate the effects on clinical outcome of dictating correspondence in front of patients and sending them copies of letters.

Design: Observational study of the practices of two consultants, one of whom (RDS) routinely dictated letters in front of his patients and almost always sent them a copy while the other (AM) did neither. Questionnaires were completed anonymously by patients at the end of their consultation.

Setting: Neurology department of a teaching hospital.

Participants: Patients attending neurology outpatient clinics.

Results: Seventy-two percent and 62% of the two consultants' patients were audited, and the demographic features of the two groups were similar. Eighty-six percent and 25% of RDS's and AM's patients, respectively, said that they wished to be present during dictation (p < 0.001). Within AM's group, those who had had some experience of the practice (with other consultants) were more likely to express a desire to be present during dictation (p = 0.023). Ninety-two percent and 77% of RDS's and AM's patients, respectively, felt that having a copy of their letter would be 'very useful' or 'useful' (p < 0.001). The perceived usefulness of receiving a copy letter and the desire to be present during dictation were associated for the total group and for RDS's patients. The two groups of patients were asked to express their degree of understanding at the end of the consultation, and 81% and 93% of RDS's and AM's patients, respectively, thought that their understanding was 'excellent' or 'good'. No trends emerged with regard to patients' preferences (to be present or absent during dictation and to receive or not receive a copy of their letter) and their level of understanding.

Conclusions: Patients appear to like being present when their letters are dictated, and appreciate receiving copies of these, but their overall understanding is seemingly independent of these variables. The success of the clinical consultation is probably influenced by numerous factors, and the elevation of patients' presence during dictation of correspondence and receipt of copy letters above all others seems unjustified.
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http://dx.doi.org/10.1258/shorts.2010.010049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2994352PMC
November 2010

Go now, says NHS chief. Time for debate.

BMJ 2010 Dec 20;341:c7291. Epub 2010 Dec 20.

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http://dx.doi.org/10.1136/bmj.c7291DOI Listing
December 2010

Mitochondrial transfer RNA(Phe) mutation associated with a progressive neurodegenerative disorder characterized by psychiatric disturbance, dementia, and akinesia-rigidity.

Arch Neurol 2010 Nov;67(11):1399-402

Essex Centre for Neurological Sciences, Queen's Hospital, Romford RM7 0AG, United Kingdom.

Background: Mitochondrial diseases are characterized by wide phenotypic and genetic variability, but presentations in adults with akinetic rigidity and hyperkinetic movement disorders are rare.

Objectives: To describe clinically a subject with progressive neurodegeneration characterized by psychosis, dementia, and akinesia-rigidity, and to associate this phenotype with a novel mitochondrial transfer RNA(Phe) (tRNA(Phe)) (MTTF) mutation.

Design, Setting, And Patient: Case description and detailed laboratory investigations of a 57-year-old woman at a university teaching hospital and a specialist mitochondrial diagnostic laboratory.

Results: Histopathological findings indicated that an underlying mitochondrial abnormality was responsible for the subject's progressive neurological disorder, with mitochondrial genome sequencing revealing a novel m.586G>A MTTF mutation.

Conclusions: The clinical phenotypes associated with mitochondrial disorders may include akinesia-rigidity and psychosis. Our findings further broaden the spectrum of neurological disease associated with mitochondrial tRNA(Phe) mutations.
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http://dx.doi.org/10.1001/archneurol.2010.283DOI Listing
November 2010

LRRK2 G2019S in the North African population: a review.

Eur Neurol 2010 23;63(6):321-5. Epub 2010 Apr 23.

Department of Neurology, New Cross Hospital, Wolverhampton, UK.

Parkinson's disease (PD) is a common neurodegenerative disorder, for which environmental and/or genetic factors are postulated as possible causes. Over the past decade there has been a substantial increase in the knowledge of the genetics of PD. Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic causes of PD, and the common G2019S mutation has been identified in various ethnic groups with variable frequency. The aim of this article is to review the literature relating to LRRK2 G2019S in the North African population, which is composed of two main ethnic groups - the Berbers and the Arabs. The frequency of LRRK2 G2019S is 30-41% in familial PD and 30-39% in apparently sporadic PD in North Africa. Within healthy controls, Moroccan Berbers appear to have the highest carrier frequency at 3.3%. The majority of the available studies do not draw a clear distinction between the two ethnic groups, despite the distinct possibility that their ancestral origins are different. Further research looking at the respective prevalences of LRRK2 G2019S in Berbers and Arabs, and in different Arab populations, seems justified.
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http://dx.doi.org/10.1159/000279653DOI Listing
October 2010

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

Cortex 2011 Apr 17;47(4):451-9. Epub 2010 Feb 17.

Essex Neurosciences Centre, Queen's Hospital, Romford, Essex, UK.

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.
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http://dx.doi.org/10.1016/j.cortex.2010.01.009DOI Listing
April 2011

Parkinson's disease in Arabs: a systematic review.

Mov Disord 2008 Jul;23(9):1205-10

Department of Neurology, Queen Elizabeth Neuroscience Centre, Queen Elizabeth University Hospital, Birmingham, United Kingdom.

Studies of specific populations have provided invaluable knowledge about Parkinson's disease (PD), especially in the field of genetics. The present report systematically reviews the medical literature on PD in Arabs. Medline and Embase were searched, and 24 article were identified: genetic (n = 17), epidemiological (n = 3), and clinical series (n = 5). Both autosomal dominant and recessive forms of inherited PD are described, associated with four genes (Parkin, PINK1, LRRK2, and PARK9). The G2019S LRRK2 mutation is more common in both familial (37-42%) and apparently sporadic PD (41%) in North African Arabs than in Europeans and North Americans (2-3%). The incidence of PD is reported at 4.5 per 100,000 person-years and reported prevalence at 27 to 43 per 100,000 persons. Hospital-based clinical series suggest that parkinsonism is the commonest movement disorder. Clinical features of PD in Arabs are not significantly different from those reported elsewhere. PD was reported as the cause of dementia in around 7% of Arabs. The majority of studies relate to the role of genes in the etiology of PD in North African Arabs. Further genetic, epidemiological and clinical studies from the majority of Arabic countries may enhance our understanding of PD.
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http://dx.doi.org/10.1002/mds.22041DOI Listing
July 2008

POLG1 mutations manifesting as autosomal recessive axonal Charcot-Marie-Tooth disease.

Arch Neurol 2008 Jan;65(1):133-6

Department of Neurology, Essex Center for Neurological Sciences, Queen's Hospital, Romford, England.

Background: Although a molecular diagnosis is possible in most patients having Charcot-Marie-Tooth disease (CMT), recessively inherited and axonal neuropathies still present a diagnostic challenge.

Objective: To determine the cause of axonal CMT type 2 in 3 siblings.

Design: Case report.

Setting: Academic research.

Participants: Three siblings who subsequently developed profound cerebellar ataxia.

Main Outcome Measures: Muscle biopsy specimen molecular genetic analysis of the POLG1 (polymerase gamma-1) gene, as well as screening of control subjects for POLG1 sequence variants.

Results: Cytochrome c oxidase deficient fibers and multiple deletions of mitochondrial DNA were detected in skeletal muscle. Three compound heterozygous substitutions were detected in POLG1.

Conclusion: Even in the absence of classic features of mitochondrial disease, POLG1 should be considered in patients having axonal CMT that may be associated with tremor or ataxia.
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http://dx.doi.org/10.1001/archneurol.2007.4DOI Listing
January 2008

Diagnostic DNA testing and consent.

Authors:
Rajith de Silva

Pract Neurol 2007 Feb;7(1):62; author reply 62-3

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February 2007

A case of voltage-gated potassium channel antibody-related limbic encephalitis.

Nat Clin Pract Neurol 2006 Jun;2(6):339-43; quiz following 343

Addenbrooke's Hospital, Cambridge, UK.

Background: A 56-year-old man presented to hospital with a 6-month history of recurrent episodes of altered behavior and 'odd' episodes. He had become apathetic and uninterested in his family. He had no relevant past medical or family history. General and physical neurological examinations were unremarkable, as was bedside cognitive testing.

Investigations: Brain MRI scan, 24-h electroencephalogram, serum and cerebrospinal fluid testing for voltage-gated potassium channel antibodies, blood screening for tumors, CT scans of the chest, abdomen and pelvis, whole-body PET scan, neuropsychological examination, brain 18F-fluorodeoxyglucose-PET scan.

Diagnosis: Voltage-gated potassium channel antibody-related limbic encephalitis.

Management: Antiepileptic drugs, immunomodulatory therapy, oral steroids, plasma exchange.
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http://dx.doi.org/10.1038/ncpneuro0194DOI Listing
June 2006

LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation.

Eur J Hum Genet 2005 May;13(5):623-7

Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, University of Newcastle upon Tyne, UK.

Pathogenic point mutations in the mitochondrial MTND1 gene have previously been described in association with two distinct clinical phenotypes -- Leber hereditary optic neuropathy (LHON) and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Here we report the first heteroplasmic mitochondrial DNA (mtDNA) point mutation (3376G>A) in the MTND1 gene associated with an overlap syndrome comprising the clinical features of both LHON and MELAS. Muscle histochemistry revealed subtle mitochondrial abnormalities, while biochemical analysis showed an isolated complex I deficiency. Our findings serve to highlight the growing importance of mutations in mitochondrial complex I structural genes in MELAS and its associated overlap syndromes.
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http://dx.doi.org/10.1038/sj.ejhg.5201363DOI Listing
May 2005

Frontal lobe dysfunction in sporadic hyperekplexia--case study and literature review.

J Neurol 2004 Jan;251(1):91-8

Department of Neurology, Essex Centre for Neurology & Neurosurgery, Oldchurch Hospital, Oldchurch Road, Romford, Essex RM7 0BE, UK.

Hyperekplexia (HE), or startle disease, is usually a familial disorder associated with mutations in the glycine receptor alpha1 subunit gene (GLRA1), characterised by exaggerated startle reactions to unexpected auditory, somaesthetic and visual stimuli. Non-familial cases may be idiopathic, or associated with pathology usually in the brainstem or rarely in the supratentorial compartment. The pathophysiological basis of HE is unclear. We report the case of a 40-year-old woman presenting with excessive startle response to unexpected stimuli and falls since the age of 16 years. There was no family history. She was initially diagnosed with epilepsy and started on phenytoin with no resolution of her symptoms. Clinical examination revealed hyperreflexia and an insecure broad-based gait but no other abnormalities. Routine comprehensive neuropsychological assessment revealed below average intelligence with signs of frontal lobe dysfunction. EEG showed non-specific abnormalities in the right frontal and central regions. A (99m)Tc-HMPAO SPET scan revealed hypoperfusion in the frontal (worse on the right) and temporal lobes and to a lesser extent in the basal ganglia. MRI was normal, as well as blood and CSF tests. No mutations were found in a genetic analysis of GLRA1. The patient improved partially with treatment by clonazepam. The localisation of the clinical and neuropsychological findings accord with the EEG and SPET scan abnormalities in our patient and corroborates previous reports. Appropriate neuropsychological testing and functional imaging enable more accurate delineation of the clinical phenotype of this rare disorder.
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http://dx.doi.org/10.1007/s00415-004-0288-4DOI Listing
January 2004

Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation.

Neurology 2003 Aug;61(4):537-40

Department of Respiratory Medicine, Aberdeen Royal Infirmary, Grampian University Hospital Trust, Aberdeen, Scotland, UK.

The authors report the case of a 60-year-old man with acromegaly, who developed narcolepsy 2 weeks after completing radiotherapy for a pituitary adenoma. Cataplexy and sleepiness were predominant symptoms. Onset of narcolepsy is unusual at this age and the temporal relationship following radiotherapy suggests this treatment was implicated. His CSF hypocretin levels were normal, indicating other factors may be important in his narcolepsy.
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http://dx.doi.org/10.1212/01.wnl.0000078191.19709.c0DOI Listing
August 2003