Fostering patient engagement through the co-design of seizure detection and monitoring technologies: A roadmap for collaboration between research and development.

The large number of technological developments suggests that patients with epilepsy can be better supported in the management of their seizures, especially when their condition is drug resistant. Patients and their caregivers, who are generally supportive of seizure detection and monitoring technologies, can provide relevant information to improve their effectiveness. We propose a comprehensive co-design approach to support more efficient development of seizure detection and monitoring technologies. Such an approach should follow the steps of the research and development process, take into account the temporal requirements characteristic of seizure management, focus on the themes of autonomy and self-management, and be guided by disease experts. If co-design practices are to continue to contribute to their development, they must also meet the scientific requirements of validity and reproducibility.

Strategy for genetic analysis in hereditary neuropathy.

Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.

Demyelinating Charcot-Marie-Tooth neuropathy associated with FBLN5 mutations.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominantly inherited demyelinating sensorimotor neuropathies. Symptoms usually start in the first to second decade and include distal muscle weakness and wasting, sensory disturbances and foot deformities. The most frequent cause is a duplication of PMP22 whilst point mutations in PMP22 and other genes are rare causes. Recently, FBLN5 mutations have been reported in CMT1 families. METHODS: Individuals with FBLN5-associated CMT1 were compiled from clinical and research genetic testing laboratories. Clinical data were extracted from medical records or obtained during patients' visits at our centres or primary care sites. RESULTS: Nineteen CMT1 families containing 38 carriers of three different FBLN5 missense variants were identified and a mutational hotspot at c.1117C>T (p.Arg373Cys) was confirmed. Compared to patients with the common PMP22 duplication, individuals with FBLN5 variants had a later age of diagnosis (third to fifth decade) and less severely reduced motor median nerve conduction velocities (around 31 m/s). The most frequent clinical presentations were prominent sensory disturbances and painful sensations, often as initial symptom and pronounced in the upper limbs, contrasting with rather mild to moderate motor deficits. CONCLUSIONS: Our study confirms the relevance of FBLN5 mutations in CMT1. It is proposed to include FBLN5 in the genetic work-up of individuals suspected with CMT1, particularly when diagnosis is established beyond the first and second decade and comparably moderate motor deficits contrast with early and marked sensory involvement. FBLN5-associated CMT1 has a recognizable clinical phenotype and should be referred to as CMT1H according to the current classification scheme.

Antineoplastic agents exacerbating Charcot Marie Tooth disease: red flags to avoid permanent disability.

BACKGROUND: Charcot Marie Tooth (CMT) disease is the most common form of hereditary neuropathy. Due to the high prevalence of mild and undiagnosed forms, patients with CMT disease may be exposed to severe neurotoxicity following the administration of neurotoxic chemotherapies. The aim of this report is to alert oncologists to the potential to precipitate severe irreversible peripheral neuropathies when administering neurotoxic compounds to undiagnosed CMT patients. MATERIAL AND METHODS: A retrospective research in the OncoNeuroTox database was performed (2010-2016), searching for patients with the diagnosis of chemotherapy-induced peripheral neuropathy (CIPN) and CMT disease. A comprehensive literature review for previously published cases was performed using the Pubmed and Cochrane databases (1972-2017). RESULTS: Among 428 patients with CIPN, we identified eight patients with concomitant CMT disease. Seven patients out of the eight had no previous diagnosis of CMT disease, although accurate familial history disclosed mild signs of peripheral neuropathy in five cases. Patients themselves had minor stigmata of long-standing peripheral damage. Patients received chemotherapy regimens based on vinca alkaloids, taxanes or a combination of vinca alkaloids and platinum compounds. In two cases, cumulative doses were below or equal to the expected neurotoxic threshold. Following chemotherapy administration, patients developed severe length-dependent sensory-motor deficits. Despite early drug discontinuation, most patients remained severely disabled. CONCLUSION: A brief checklist to disclose long-standing signs of peripheral neuropathy could be helpful to detect patients with undiagnosed hereditary neuropathies who could be at risk of developing severe irreversible neurotoxicity following the administration of neurotoxic agents.

Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP). METHODS: Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. All CMT1A and HNPP patients were recruited at the referral centre for neuromuscular diseases of Pitié-Salpêtrière Hospital. RESULTS: Two phenotypes were identified amongst 18 CMT1C patients: the classical CMT form ('CMT-like', 11 cases) and a predominantly sensory form ('sensory form', seven cases). The mean CMT neuropathy score was 4.45 in CMT1C patients. Motor nerve conduction velocities in the upper limbs were significantly more reduced in CMT1A than in CMT1C patients. On the other hand, the motor nerve conduction velocity of the median nerve was significantly lower in CMT1C compared to the HNPP group. Distal motor latency was significantly more prolonged in CMT1A patients compared to the CMT1C and HNPP groups, the latter two groups having similar distal motor latency values. Molecular analysis revealed five new LITAF/SIMPLE mutations (Ala111Thr, Gly112Ala, Trp116Arg, Pro135Leu, Arg160Cys). CONCLUSIONS: Our study delineates CMT1C as mostly a mild form of neuropathy, and gives clinical and electrophysiological clues differentiating CMT1C from CMT1A and HNPP. Delineating phenotypes in CMT subtypes is important to orient molecular diagnosis and to help to interpret complex molecular findings.

[How I explore Crohn's disease by various imaging modalities]. / Comment j'explore la maladie de Crohn par imagerie.

Crohn's disease is a chronic inflammatory condition characterized by recurrent and/or chronic lesions, leading to cumulative structural bowel damage. It is established that the correlation between symptoms and intestinal lesions is weak. Therefore, monitoring by frequent cross-sectional imaging is proposed to assess the disease activity. There is no consensus about the preferred imaging option. Priority is given to non-radiating modalities, such as ultrasonography and MRI. Tomodensitometry will be reserved for emergency cases. Ultrasonography can be useful, in emergency as well as for the monitoring of lesions of known topography. Entero-MRI is henceforth considered the standard imaging technique for the diagnosis and follow-up of Crohn's disease. Its high contrast resolution allows an accurate assessment of disease activity, therapeutic efficacy, cumulative structural bowel damage and complications.

La maladie de Crohn est une maladie inflammatoire intestinale dont les manifestations récurrentes ou chroniques entraînent des dommages tissulaires cumulatifs. Il est avéré que la corrélation entre la symptomatologie clinique et les lésions intestinales est faible. Par conséquent, des examens d'imagerie fréquents sont nécessaires pour déterminer l'activité de la maladie. Il n'existe pas de consensus quant à l'utilisation de l'une ou l'autre technique. La priorité sera donnée à des examens peu irradiants comme l'échographie et l'IRM. La tomodensitométrie sera réservée aux situations d'urgence ou en cas de contre-indication à l'IRM. L'échographie est un outil à ne pas négliger, tant en urgence que pour le suivi de lésions de topographie connue. L'entéro-IRM est dorénavant l'examen de choix pour le diagnostic et le suivi de la maladie de Crohn. Son excellente résolution en contraste permet d'évaluer l'activité de la maladie, l'efficacité thérapeutique, les dommages tissulaires cumulés et la présence de complications.

Long-term evolution and predictive factors of mild inflammatory bowel disease.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are potentially progressive diseases. Few data are available on the prevalence and the factors associated with mild inflammatory bowel diseases (IBD). AIM: Our aim was to assess the natural history of mild CD and mild UC and to identify predictive factors of mild evolution over the long term. METHODS: Retrospective study of IBD patients registered in the database of the university hospital CHU of Liège, Belgium. Mild CD was defined as an inflammatory luminal disease (no stricture, abdominal or perianal fistulae) requiring no immunomodulator (IM), anti-TNF and no surgery. Mild UC was defined as no requirement for IM, anti-TNF and no colectomy. RESULTS: Four hundred and seventy-three CD and 189 UC were included (median follow-up: 13 and 11 years respectively). At 1 year, 147 patients had mild CD. At 5 years and the maximum follow-up, 56% and 13% patients still had mild CD, respectively. At 1 year, 142 patients had mild UC. At 5 years and the maximum follow-up, 72% and 44% still had a mild UC, respectively. Factors associated with long-term mild CD and UC were older age at diagnosis and absence of corticosteroids in the first year. In UC proctitis location was associated with mild UC. CONCLUSIONS: In this cohort, 90% of CD patients and 3/4 of UC with mild disease at 1 year lost their mild disease status over time. An old age at diagnosis was predictive of the persistence of a mild CD and UC.

[FROM EVIDENCE-BASED MEDICINE TO PERSONALIZED MEDICINE IN CROHN'S DISEASE]. / DE L'"EVIDENCE-BASED MEDICINE" À LA MÉDECINE PERSONNALISÉE DANS LA MALADIE DE CROHN.

The therapeutic armamentarium in Crohn's disease includes mesalazine, steroids (including topical drugs), anti-metabolites (purines, methotrexate), anti-TNFα antibodies and, more recently, selective inhibitors of lymphocytes homing (vedolizumab). The efficacy of these drugs has been shown in pivotal phase 3 placebo-controlled trials and meta-analyses. However, the use of these drugs in routine practice still remains ill-defined. Those are rather the cohort studies, natural history data and therapeutic strategy trials that help the clinician to determine, for each individual patient, the treatment leading to an optimal benefit/risk profile, aiming at moving from evidence-based medicine towards personalized medicine.

[Charcot-Marie-Tooth disease associated with periaxin mutations (CMT4F): Clinical, electrophysiological and genetic analysis of 24 patients]. / Maladie de Charcot-Marie-Tooth associée au gène de la périaxine (CMT4F) : description clinique, électrophysiologique et génétique de 24 patients.

Autosomal recessive Charcot-Marie-Tooth disease (AR-CMT) is often characterized by onset in early childhood and severe phenotype compared to the dominant forms. CMT disease associated with periaxin gene (PRX) is rare and characterized by demyelination limited to the major peripheral nerves. Following the discovery of a high frequency of a specific periaxin gene mutation (E1085fsX4 homozygote) in the Reunion Island, we examined all French patients known as carriers of the periaxin gene mutation. There were 24 patients. Eighteen were from the Reunion Island (6 families and 10 sporadic cases). The six remaining patients were in two families, each with two affected individuals, and two sporadic cases. The series included 17 female and seven male patients. Walking was acquired late, on average at 3.4±1.6 years. One patient never learned to walk. The Charcot Marie Tooth Neuropathy Score (CMTNS) averaged 24.5±8.1. Seven patients had been wheelchair-bound since the age of 24±22. Other symptoms were: scoliosis most often observed after the age of 12 years and sometimes complicated by a restrictive respiratory syndrome; foot deformity in 24 patients; strabismus; glaucoma; myopia. When conduction recordings are available, median nerve motor conduction was slow (<10m/s), associated with a major lengthening of distal latencies. Study of the periaxin gene should be considered in patients with severe demyelinating neuropathy associated with early infantile scoliosis. This disease leads to major disability (29% of patients in this series were wheelchair-bound) and to respiratory insufficiency. Genetic counselling is highly recommended for consanguineous families.

[Non-fortuitous dynamin II mutation-related association: neutropenia and Charcot-Marie-Tooth disease]. / Association non fortuite d'une neutropénie chronique et d'une maladie de Charcot-Marie-Tooth en rapport avec une mutation de la dynamine 2.

Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is a genetically and clinically heterogeneous group of disorders of the peripheral nervous system. Mutations in multiple genes are currently known. We report an original case of CMT associated with chronic neutropenia in a patient with a K562del mutation in the dynamin 2 (DNM2) gene in a patient presenting with alterated cognitive function. Associated manifestations may guide molecular study.

[Genetics and environment in chronic inflammatory bowel diseases]. / Génétique et environnement dans les maladies inflammatoires chroniques de l'intestin.

Inflammatory bowel diseases are both environmental and genetic illnesses. More than one hundred genes or loci involved in the regulation of innate or acquired immune response as well as intestinal mucosa homeostasis have been identified. Environmental studies have been less numerous up to now and only smoking and appendectomy have been validated, as protector for ulcerative colitis, while smoking is clearly associated with an increased risk and more severe forms of Crohn's disease. An important role is also currently suspected for the intestinal flora and the dysbiosis described in inflammatory bowel disease could contribute to the triggering or the persistence of the inflammation. New therapeutic strategies are currently studied, particularly aiming at targeting immune, inflammatory or homeostatic pathways corresponding to the predisposing gene variants.

[Fifteen years of use of anti-TNF antibodies in moderate to severe Crohn's disease: how to make the best of this experience]. / Quinze ans d'anti-TNF dans la maladie de Crohn: comment tirer le meilleur de cette révolution thérapeutique?

After fifteen years of use, the anti-TNF antibodies have become the corner stone of the treatment of moderate and severe Crohn's disease. The skill acquired over the years through experimental trials and clinical experience leads to increased therapeutic efficacy and minimized risks. These antibodies are introduced increasingly earlier in Crohn's disease as well as in a broader range of patients, aiming at changing the natural history of the diseases by avoiding the development of intestinal tissue damage and complications.

Belgian consensus on irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is characterised by recurrent abdominal pain related to defaecation or associated with altered stool frequency or consistency. Despite its prevalence, major uncertainties in the diagnostic and therapeutic management persist in clinical practice. METHODS: A Delphi consensus was conducted by 20 experts from Belgium, and consisted of literature review and voting process on 78 statements. Grading of recommendations, assessment, development and evaluation criteria were applied to evaluate the quality of evidence. Consensus was defined as > 80 % agreement. RESULTS: Consensus was reached for 50 statements. The Belgian consensus agreed as to the multifactorial aetiology of IBS. According to the consensus abdominal discomfort also represents a cardinal symptom, while bloating and abdominal distension often coexist. IBS needs subtyping based on stool pattern. The importance of a positive diagnosis, relying on history and clinical examination is underlined, while additional testing should remain limited, except when alarm features are present. Explanation of IBS represents a crucial part of patient management. Lifestyle modification, spasmolytics and water-solube fibres are considered first-line agents. The low FODMAP diet, selected probiotics, cognitive behavioural therapy and specific treatments targeting diarrhoea and constipation are considered appropriate. There is a consensus to restrict faecal microbiota transplantation and gluten-free diet, while other treatments are strongly discouraged. CONCLUSIONS: A panel of Belgian gastroenterologists summarised the current evidence on the aetiology, symptoms, diagnosis and treatment of IBS with attention for the specificities of the Belgian healthcare system.

Unusual intra-rectal "laterally spreading tumour" in immunosuppressed patient with ulcerative colitis.

Condyloma acuminatum (CA) is a manifestation of Human Papillomavirus (HPV) infection which usually occurs in genital and perianal regions. We report a 46-year-old man with an ulcerative proctitis diagnosed four years earlier, asymptomatic for a long time under azathioprine but without any follow-up for three years. A colonoscopy was performed prior to potential immunosuppressive treatment discontinuation and showed a circumferential "laterally spreading tumour" in the rectum. Surprisingly biopsies revealed a CA with a very focally high-grade intra-epithelial lesion. Azathioprine was stopped and a transanal surgical resection was performed. At guided anamnesis, patient confirmed to be a former active "men who have sex with men". No recurrence of proctitis occurred despite azathioprine discontinuation. A retrospective review of the histological sections suggests that it was, in fact, an intestinal spirochetosis misdiagnosed as inflammatory bowel disease. Involvement of the rectal mucosa by HPV is a rare condition and this may have been promoted by inappropriate immunosuppressive treatment.

Ustekinumab in bio-naïve and bio-failure Crohn's disease patients: Results from a « real-life ¼ monocentric cohort.

BACKGROUND: The pivotal clinical trials have largely demonstrated the efficacy and safety of ustekinumab in Crohn's disease. Real-life cohorts published so far only include very few bio-naïve patients. This study assesses effectiveness and safety of ustekinumab in bio-naïve and bio-failure patients treated with ustekinumab in routine practice and look for predictors of response. METHODS: We performed a retrospective monocentric study. Initial response was assessed by maintenance therapy beyond week 16. Sustained response was assessed by the continuation or cessation of therapy over time for another reason than stopping in sustained remission. Treatment persistence was assessed by Kaplan Meier curves and predictors of treatment persistence were studied by univariate and multivariate Cox model. RESULTS: Out of 156 recorded patients, three patients were still in their induction phase at time of analysis and 5 patients were lost to follow-up, leaving 148 patients for clinical effectiveness analyses, including 35 bio-naïve when starting ustekinumab. A maintenance therapy was initiated in 79.7%. At one year, the probability to be still treated with ustekinumab was 73.8%. Treatment cessation increased with smoking in multivariate analysis. Previous biologic failure (as a whole), CRP and fecal calprotectin baseline levels did not influence initial response and treatment persistence. CONCLUSION: A large proportion of CD patients initially respond to ustekinumab and continue this treatment beyond one year. Treatment persistence is as high in bio-failure as in bio-naïve patients.

[Molecular diagnosis of axonal forms of Charcot-Marie-Tooth disease]. / Diagnostic moléculaire des formes axonales de la maladie de Charcot-Marie-Tooth.

Charcot-Marie-Tooth (CMT) disease is the most common cause of inherited peripheral neuropathies with a frequency estimated at 1/2500. Electroneuromyographic examination distinguishes a myelinic form (CMT1) and an axonal form of the disease (CMT2). Significant genetic heterogeneity is found in CMT, with 15 genes or loci for CMT2. To date, a molecular diagnosis has not been established for most CMT2 patients and the distribution of identified mutations is wide spreading over nearly all genes. Simple guidelines for daily practice are difficult to establish from compilation of mutation reports or consultation of databases; little simplification can be expected from future findings. We present our results of molecular diagnosis for 251 CMT2 index cases characterized by their mode of inheritance (217 dominant and 34 recessive cases), and a motor conduction velocity in median nerve equal to or above to 38m/s. For each case, at least one of the genes known to date for CMT2 (MFN2, RAB7, GARS, NF-L, HSPB1, GDAP1, MPZ, HSPB8, GJB1, DNM2, YARS, LMNA, and MED25) was studied. Around 22% of diagnoses were established and efficiency was comparable for dominant or recessive cases. For dominant cases, the first objective was to search for mutations of proteins connexin32, mitofusin2 and P0. For recessive cases, GDAP1 provided the key to molecular diagnosis; lamin A/C mutations were only found for patients with an ethnic background from North Africa. Heat shock proteins HSPB1 and HSPB8 were implicated in a significant proportion of "spinal" (or pure motor) CMT2. NF-L or RAB7 mutations were rare. We did not identify any deleterious mutations in GARS, DNM2, YARS orMED2. We propose a simple decision tree for molecular diagnosis of CMT2.

[Multiple phenotypic manifestations of X-linked spinobulbar muscular atrophy]. / L'amyotrophie bulbospinale liée à l'X ou maladie de Kennedy: variations phénotypiques.

Recessive X-linked amyotrophic spinobulbar muscular atrophy (SBMA) or Kennedy disease is a neuroendocrine disorder with a slowly progressive phenotype, caused by an expansion of a polymorphic tandem CAG repeat of the androgen receptor gene. Classical clinical hallmarks include onset in the third decade of life, weakness and wasting predominantly in proximal extremity muscles, variable weakness of bulbar muscles, abundant muscle fasciculations, sensory nerve action potential abnormalities and signs of androgen insensitivity such as gynecomastia and testicular atrophy. The diagnosis has been recently made easier by the availability of genetic testing but Kennedy disease is probably still underdiagnosed because of phenotypic variability. We report 11 new cases, of which seven had atypical initial manifestations presenting respectively with myasthenia, cramps and fasciculation syndrome, polyneuropathy, post-trauma monomelic neuronopathy, effort-dependent muscle intolerance and/or muscular dystrophy, with the aim to enlarge the phenotypic spectrum of the published series.

Human dendritic cells pulsed with specific lipopeptides stimulate autologous antigen-specific T cells without the addition of exogenous maturation factors.

SUMMARY: Serum-free culture conditions to generate immature human monocyte-derived DC (Mo-DC) were optimized, and the parameters that influence their maturation after exposure to lipopeptides containing CD4(+) and CD8(+) T-cell epitopes were examined. The lipopeptides contained a single CD4(+) helper T-cell epitopes, one of a number of human leucocyte antigen (HLA)-A2-restricted cytotoxic T-cell epitope and the lipid Pam2Cys. To ensure complete maturation of the Mo-DC, we examined (i) the optimal lipopeptide concentration, (ii) the optimal Mo-DC density and (iii) the appropriate period of exposure of the Mo-DC to the lipopeptides. The results showed that a high dose of lipopeptide (30 microm) was no more efficient at upregulating maturation markers on Mo-DC than a low dose (6 microm). There was an inverse relationship between Mo-DC concentration and the mean fluorescence intensity of maturation markers. In addition, at the higher cell concentrations, the chemotactic capacity of the Mo-DC towards a cognate ligand, CCL21, was reduced. Thus, high cell concentrations during lipopeptide exposure were detrimental to Mo-DC maturation and function. The duration of exposure of Mo-DC to the lipopeptides had little effect on phenotype, although Mo-DC exposed to lipopeptides for 48 rather than 4 h showed an increased ability to stimulate autologous peripheral blood mononuclear cells to release interferon-gamma in the absence of exogenous maturation factors. These findings reveal conditions for generating mature antigen-loaded DC suitable for targeted immunotherapy.

Relapsing demyelinating disease affecting both the central and peripheral nervous systems.

BACKGROUND: Clinical and electromyographic findings of chronic inflammatory demyelinating polyradiculopathy (CIDP) are occasionally observed in patients with multiple sclerosis (MS). OBJECTIVE: To define a new inflammatory demyelinating disease unlike MS or CIDP. RESULTS: This study reports on five patients with a demyelinating disease affecting the central nervous system (CNS) and peripheral nervous system (PNS). Each case presented a relapsing-remitting course in which CNS involvement preceded PNS involvement. All patients fulfilled Barkhof's criteria on MRI and the McDonald criteria for MS. Two patients had grey matter lesions with typical white matter changes. No systemic inflammatory disease and no metabolic or inflammatory factor for peripheral neuropathy were found. In all cases electromyography showed a demyelinating peripheral neuropathy without conduction block. Four patients fulfilled the European Federation of Neurological Societies/PNS guideline for CIDP and Nicolas et al's criteria for CIDP, one of whom also fulfilled the Ad Hoc Subcommittee criteria for CIDP. Nerve biopsy, performed in two patients, showed histological evidence of CIDP. An improvement in clinical status and neurophysiological parameters was observed in three patients after treatment with either intravenous immunoglobulin (n = 1) or cyclophosphamide (n = 2). CONCLUSION: The CNS and PNS demyelination, the absence of oligoclonal bands and the peripheral demyelination without conduction block indicate pathogenic mechanisms different from MS and CIDP. The chronology of events suggests an entity unlike that involved in acute demyelinating encephalomyelitis. Immunological reactivity against antigens common to peripheral and central myelin may explain why the demyelinating disease affected both the CNS and PNS.