European Journal of Neurology

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding of the epidemiology, genetics, pathology and pathogenesis of Alzheimer's disease is outlined, before its clinical presentation and current treatment strategies are discussed. Finally, the review discusses how our enhanced understanding of Alzheimer pathogenesis, including the recognition of a protracted preclinical phase, is informing new therapeutic strategies with the aim of moving from treatment to prevention.

Multiple sclerosis (MS) is the commonest non‐traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene–environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein–Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of ‘pre‐symptomatic MS’ being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.

Background:  Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System.

Objectives:  To revise these guidelines.

Methods:  Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion.

Recommendations:  The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).

Background:  Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate owing to publication of more relevant articles. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN.

Methods:  Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30th, 2009. All pertinent articles were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy.

Results and Conclusions:  Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (Recommendation Level A). Normative reference values are available for bright‐field immunohistochemistry (Recommendation Level A) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright‐field or immunofluorescence microscopy, should always refer to normative values matched for age (Recommendation Level A). Newly established laboratories should undergo adequate training in a well‐established skin biopsy laboratory and provide their own stratified for age and gender normative values, intra‐ and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels, are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (Recommendation Level B).A reduced IENF density is associated with the risk of developing neuropathic pain (Recommendation Level B), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (Recommendation Level C). However, further studies are warranted to confirm its potential usefulness as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3‐mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35 000 biopsies and a mere 0.19% incidence of non‐serious side effects in about 15 years of practice (Good Practice Point).

Background and purpose:  Headache disorders are very common, but their monetary costs in Europe are unknown. We performed the first comprehensive estimation of how economic resources are lost to headache in Europe.

Methods:  From November 2008 to August 2009, a cross‐sectional survey was conducted in eight countries representing 55% of the adult EU population. Participation rates varied between 11% and 59%. In total, 8412 questionnaires contributed to this analysis. Using bottom‐up methodology, we estimated direct (medications, outpatient health care, hospitalization and investigations) and indirect (work absenteeism and reduced productivity at work) annual per‐person costs. Prevalence data, simultaneously collected and, for migraine, also derived from a systematic review, were used to impute national costs.

Results:  Mean per‐person annual costs were €1222 for migraine (95% CI 1055–1389; indirect costs 93%), €303 for tension‐type headache (TTH, 95% CI 230–376; indirect costs 92%), €3561 for medication‐overuse headache (MOH, 95% CI 2487–4635; indirect costs 92%), and €253 for other headaches (95% CI 99–407; indirect costs 82%). In the EU, the total annual cost of headache amongst adults aged 18–65 years was calculated, according to our prevalence estimates, at €173 billion, apportioned to migraine (€111 billion; 64%), TTH (€21 billion; 12%), MOH (€37 billion; 21%) and other headaches (€3 billion; 2%). Using the 15% systematic review prevalence of migraine, calculated costs were somewhat lower (migraine €50 billion, all headache €112 billion annually).

Conclusions:  Headache disorders are prominent health‐related drivers of immense economic losses for the EU. This has immediate implications for healthcare policy. Health care for headache can be both improved and cost saving.

The aim of this international guideline on dementia was to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta‐analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.

Background:  Although Wernicke encephalopathy (WE) is a preventable and treatable disease it still often remains undiagnosed during life.

Objectives:  To create practical guidelines for diagnosis, management and prevention of the disease.

Methods:  We searched MEDLINE, EMBASE, LILACS, Cochrane Library.

Conclusions and recommendations:   

 The clinical diagnosis of WE should take into account the different presentations of clinical signs between alcoholics and non alcoholics (Recommendation Level C); although prevalence is higher in alcoholics, WE should be suspected in all clinical conditions which could lead to thiamine deficiency (good practice point – GPP).

Background:  Paraneoplastic neurological syndromes (PNS) almost invariably predate detection of the malignancy. Screening for tumours is important in PNS as the tumour directly affects prognosis and treatment and should be performed as soon as possible.

Objectives:  An overview of the screening of tumours related to classical PNS is given. Small cell lung cancer, thymoma, breast cancer, ovarian carcinoma and teratoma and testicular tumours are described in relation to paraneoplastic limbic encephalitis, subacute sensory neuronopathy, subacute autonomic neuropathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus‐myoclonus, Lambert‐Eaton myasthenic syndrome (LEMS), myasthenia gravis and paraneoplastic peripheral nerve hyperexcitability.

Methods:  Many studies with class IV evidence were available; one study reached level III evidence. No evidence‐based recommendations grade A–C were possible, but good practice points were agreed by consensus.

Recommendations:  The nature of antibody, and to a lesser extent the clinical syndrome, determines the risk and type of an underlying malignancy. For screening of the thoracic region, a CT‐thorax is recommended, which if negative is followed by fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Breast cancer is screened for by mammography, followed by MRI. For the pelvic region, ultrasound (US) is the investigation of first choice followed by CT. Dermatomyositis patients should have CT‐thorax/abdomen, US of the pelvic region and mammography in women, US of testes in men under 50 years and colonoscopy in men and women over 50. If primary screening is negative, repeat screening after 3–6 months and screen every 6 months up till 4 years. In LEMS, screening for 2 years is sufficient. In syndromes where only a subgroup of patients have a malignancy, tumour markers have additional value to predict a probable malignancy.

Background:  Diffuse infiltrative low‐grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management.

Methods:  The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly.

Results and conclusions:  WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression‐free and overall survival, whilst reducing the risk of malignant transformation. Early post‐operative radiotherapy improves progression‐free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large‐field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor‐related epilepsy, treatments and psychological distress.

Đặt vấn đề và mục đích:  Bệnh thần kinh tủy sống (NMO) hay bệnh Devic là một rối loạn tự miễn viêm và mất myelin hiếm gặp của hệ thần kinh trung ương (CNS), được đặc trưng bởi các đợt tấn công lặp lại của viêm gai thị (ON) và viêm tủy ngang kéo dài (LETM), khác biệt với bệnh đa xơ cứng (MS). Các hướng dẫn này được thiết lập nhằm cung cấp hướng dẫn cho thực hành lâm sàng tốt nhất dựa trên tình trạng hiện tại của tri thức lâm sàng và khoa học.

Chiến lược tìm kiếm:  Bằng chứng cho hướng dẫn này được thu thập thông qua việc tìm kiếm các bài báo gốc, báo cáo ca và phân tích tổng hợp trong các cơ sở dữ liệu MEDLINE và Cochrane. Ngoài ra, các hướng dẫn thực hành lâm sàng của các tổ chức thần kinh và thấp khớp chuyên nghiệp cũng đã được nghiên cứu.

Kết quả:  Các tiêu chí chẩn đoán khác nhau cho chẩn đoán NMO [Wingerchuk et al. Tiêu chí NMO đã được chỉnh sửa, 2006 và Miller et al. Tiêu chí nhóm công tác của Hiệp hội Đa xơ cứng Quốc gia (NMSS), 2008] và các đặc điểm có thể gợi ý về NMO hỗ trợ cho chẩn đoán. Bên cạnh đó, nhóm công tác đã cung cấp hướng dẫn cho việc đánh giá và chẩn đoán các rối loạn quang phổ NMO có hạn chế về không gian. Do thiếu các nghiên cứu đáp ứng yêu cầu cho các mức độ bằng chứng cao nhất, nhóm công tác đề xuất các khái niệm điều trị cho các cơn bùng phát cấp tính và phòng ngừa các đợt tấn công dựa trên ý kiến chuyên gia.