RESUMO
Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.
Assuntos
Distrofia Miotônica , Humanos , Feminino , Camundongos , Animais , Distrofia Miotônica/genética , Plexo Corióideo/metabolismo , Plexo Corióideo/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo , RNA/genética , Camundongos Knockout , Expansão das Repetições de TrinucleotídeosRESUMO
INTRODUCTION/AIMS: Remote study visits (RSVs) are emerging as important tools for clinical research. We tested the feasibility of using RSVs to evaluate patients with myotonic dystrophy type 1 (DM1), including remote quantitative assessment of muscle function, and we assessed correlations of remote assessments with patient-reported function. METHODS: Twenty three subjects with DM1 were consented remotely. Toolkits containing a tablet computer, grip dynamometer, and spirometer were shipped to participants. The tablets were loaded with software for video-conferencing and questionnaires about functional impairment, patient experience with technology, and willingness to participate in future remote studies. Grip strength, forced vital capacity, peak cough flow, timed-up-and-go (TUG), and grip myotonia (hand opening time) were determined during RSVs. We assessed correlations of remote assessments with patient-reported outcomes of muscle function and with CTG repeat size. RESULTS: All 23 subjects completed RSVs. 95% of participants were able to complete all components of the remote study. All toolkit components were returned upon completion. Grip strength and TUG demonstrated moderate to strong correlations with self-reported inventories of upper and lower extremity impairment, respectively (ρ = 0.7 and ρ = -0.52). A total of 91% of subjects expressed interest in participating in future RSVs. DISCUSSION: Results of this study support the feasibility of using portable devices and video-conferencing for remote collection of patient-reported outcomes and quantitative assessment of muscle function in DM1.
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Miotonia , Distrofia Miotônica , Estudos de Viabilidade , Força da Mão , Humanos , Músculo Esquelético , Distrofia Miotônica/diagnósticoRESUMO
INTRODUCTION/AIMS: Disease progression in myotonic dystrophy (DM) is marked by milestone events when functional thresholds are crossed. DM type 2 (DM2) is considered less severe than DM type 1 (DM1), but it is unknown whether this applies uniformly to all features. We compared the age-dependent risk for milestone events in DM1 and DM2 and tested for associations with age of onset and sex. METHODS: We studied a large cohort of adult participants in a national registry of DM1 and DM2. Using annual surveys from participants, we ascertained milestone events for motor involvement (use of cane, walker, ankle brace, wheelchair, or ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of employment due to DM, and death. RESULTS: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients) was 7 years. Disability and motor milestones occurred at earlier ages in DM1 than in DM2. In contrast, the risk of diabetes was higher and tended to occur earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events tended to occur earlier, and life expectancy was reduced, when symptoms began at younger ages. In DM1, men were at greater risk for disability (HR, 1.34; P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2; P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68; P = .001) or malignancy (HR, 0.66; P ≤ .01). DISCUSSION: Milestone events recorded through registries can be used to assess long-term impact of DM in large cohorts. Except for diabetes, the age-related risk of milestone events is greater in DM1 than in DM2.
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Diabetes Mellitus Tipo 2 , Distrofia Miotônica , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Distrofia Miotônica/diagnóstico , Sistema de RegistrosRESUMO
INTRODUCTION: Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM variables with muscle structure measured by MRI. METHODS: We evaluated 20 patients with FSHD at two centers, comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHZ) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF). RESULTS: While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (ρ = -0.71, P < .001) and FF (ρ = -0.74, P < .001). DISCUSSION: This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials.
Assuntos
Impedância Elétrica , Músculo Esquelético/fisiopatologia , Distrofia Muscular Facioescapuloumeral/fisiopatologia , Miografia/métodos , Músculo Quadríceps/fisiopatologia , Tecido Adiposo/diagnóstico por imagem , Adulto , Idoso , Eletrodiagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Distrofia Muscular Facioescapuloumeral/diagnóstico por imagem , Tamanho do Órgão , Músculo Quadríceps/diagnóstico por imagem , Gordura Subcutânea/diagnóstico por imagemRESUMO
INTRODUCTION: This study describes clinical, laboratory, and electrodiagnostic features of a severe acute axonal polyneuropathy common to patients with acute nutritional deficiency in the setting of alcoholism, bariatric surgery (BS), or anorexia. METHODS: Retrospective analysis of clinical, electrodiagnostic, and laboratory data of patients with acute axonal neuropathy. RESULTS: Thirteen patients were identified with a severe, painful, sensory or sensorimotor axonal polyneuropathy that developed over 2-12 weeks with sensory ataxia, areflexia, variable muscle weakness, poor nutritional status, and weight loss, often with prolonged vomiting and normal cerebrospinal fluid protein. Vitamin B6 was low in half and thiamine was low in all patients when obtained before supplementation. Patients improved with weight gain and vitamin supplementation, with motor greater than sensory recovery. DISCUSSION: We suggest that acute or subacute axonal neuropathy in patients with weight loss or vomiting associated with alcohol abuse, BS, or dietary deficiency is one syndrome, caused by micronutrient deficiencies. Muscle Nerve 57: 33-39, 2018.
Assuntos
Axônios/patologia , Distúrbios Nutricionais/patologia , Polineuropatias/patologia , Adolescente , Adulto , Neuropatia Alcoólica/patologia , Anorexia/complicações , Cirurgia Bariátrica/efeitos adversos , Suplementos Nutricionais , Eletromiografia , Feminino , Humanos , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Condução Nervosa , Distúrbios Nutricionais/tratamento farmacológico , Distúrbios Nutricionais/etiologia , Estado Nutricional , Polineuropatias/tratamento farmacológico , Deficiência de Vitamina B 6/complicações , Deficiência de Vitamina B 6/patologia , Vitaminas/uso terapêutico , Vômito/complicações , Aumento de Peso , Adulto JovemRESUMO
BACKGROUND: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38ß MAPK) for the treatment of facioscapulohumeral muscular dystrophy. METHODS: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18-65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2-4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. FINDINGS: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI -1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. INTERPRETATION: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. FUNDING: Fulcrum Therapeutics.
Assuntos
Distrofia Muscular Facioescapuloumeral , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ciclopropanos/efeitos adversos , Ciclopropanos/uso terapêutico , Método Duplo-Cego , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: To describe the clinical, micronutrient, and electrophysiologic spectra and prognosis in patients with acute nutritional axonal neuropathy (ANAN). METHODS: Patients with ANAN were identified between 1999 and 2020 by a retrospective review of our EMG database and electronic health records and categorized on clinical and electrodiagnostic grounds, as pure sensory, sensorimotor, or pure motor; and by risk factor (alcohol use disorder, bariatric surgery, or anorexia). Laboratory abnormalities were recorded including thiamine, vitamin B6, B12, and E, folate, and copper. Ambulatory and neuropathic pain status at last follow-up were recorded. RESULTS: Of 40 patients with ANAN, 21 had alcohol use disorder, 10 were anorexic, and 9 had recently undergone bariatric surgery. Their neuropathy was pure sensory in 14 (7 with low thiamine), sensorimotor in 23 (8 with low thiamine), and pure motor in 3 (1 with low thiamine). Vitamin B1 was most commonly low (85%), followed by vitamin B6 (77%) and folate (50%). The risk factor and neuropathy type were not associated with a particular micronutrient deficiency. Of the 37 patients who were seen in follow-up, only 13 (35%) were walking independently, and only 8 (22%) were pain free at the last follow-up visit at a mean of 22 months (range 2-88 months) from onset. DISCUSSION: The spectrum of ANAN is wide, ranging from: (1) a pure sensory neuropathy with areflexia, limb and gait ataxia, neuropathic pain, and unevocable sensory responses to (2) a motor axonal neuropathy with low-amplitude motor responses without conduction slowing, block, or dispersion, and (3) a mixed sensorimotor axonal polyneuropathy. Specific micronutrient deficiencies or risk factors do not predict neuropathy subtype. The subgroup of patients with ANAN with documented thiamine deficiency also range from pure sensory to pure motor, and only a minority have Wernicke encephalopathy. We do not know whether coexistent micronutrient deficiencies may help explain the wide clinical spectrum of thiamine-deficient ANAN. The prognosis of ANAN is guarded due to residual neuropathic pain and slow recovery of independent ambulation. Therefore, early recognition of patients at risk is important.
Assuntos
Alcoolismo , Neuralgia , Humanos , Alcoolismo/complicações , Tiamina , Ácido Fólico , Prognóstico , Vitaminas , Neuralgia/complicações , MicronutrientesRESUMO
PURPOSE OF REVIEW: Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are genetic disorders affecting skeletal and smooth muscle, heart, brain, eyes, and other organs. The multisystem involvement and disease variability of myotonic dystrophy have presented challenges for clinical care and research. This article focuses on the diagnosis and management of the disease. In addition, recent advances in characterizing the diverse clinical manifestations and variability of the disease are discussed. RECENT FINDINGS: Studies of the multisystem involvement of myotonic dystrophy, including the most lethal cardiac and respiratory manifestations and their molecular underpinnings, expand our understanding of the myotonic dystrophy phenotype. Advances have been made in understanding the molecular mechanisms of both types of myotonic dystrophy, providing opportunities for developing targeted therapeutics, some of which have entered clinical trials in DM1. SUMMARY: Continued efforts focus on advancing our molecular and clinical understanding of DM1 and DM2. Accurately measuring and monitoring the diverse and variable clinical manifestations of myotonic dystrophy in clinic and in research is important to provide adequate care, prevent complications, and find treatments that improve symptoms and life quality.
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Distrofia Miotônica , Humanos , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/terapia , Fenótipo , EncéfaloRESUMO
Myotonic dystrophy type 1 (DM1) is a multisystem trinucleotide repeat expansion disorder characterized by the misregulated alternative splicing of critical mRNAs. Previous work in a transgenic mouse model indicated that aerobic exercise effectively improves splicing regulation and function in skeletal muscle. In this issue of the JCI, Mikhail et al. describe the safety and benefits of applying this approach in individuals affected by DM1. A 12-week aerobic exercise program improved aerobic capacity and mobility, but not by the mechanism observed in transgenic mice. Here, we consider the possible reasons for this disparity and review other salient findings of the study in the context of evolving DM1 research.
Assuntos
Distrofia Miotônica , Processamento Alternativo , Animais , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Distrofia Miotônica/terapia , Splicing de RNA , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Facioscapulohumeral muscular dystrophy is the second most common adult muscular dystrophy and is caused by DUX4 protein. DUX4 is expressed when the locus on chromosome 4q35 is hypomethylated. The clinical features can be nearly pathognomonic with facial weakness, scapular winging, and abdominal weakness with a positive Beevor sign. Diagnosis of late-onset or milder disease is often more challenging. Diseases mimicking the facioscapulohumeral muscular dystrophy phenotype should be recognized. We present 6 cases to illustrate both clinical and genetic diagnostic challenges in facioscapulohumeral muscular dystrophy and provide examples on how to navigate the different steps of genetic testing.
Assuntos
Testes Genéticos/métodos , Proteínas de Homeodomínio/genética , Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/genética , Adulto , Pré-Escolar , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Hans Biberstein first described the basaloid follicular hyperplasia overlying dermatofibromas in 1923 and published his extensive observations on the subject in 1931. Part of Josef Jadassohn's department in Breslau, he was forced to leave German by the National Socialist regime and spent the rest of his career in New York. After a hiatus of 30 years, the dermatopathologic literature once again began addressing his seminal finding but never gave him proper credit. We suggest Biberstein's sign as an appropriate term for basaloid follicular hyperplasia overlying a dermatofibroma and as a small tribute to a pioneer dermatopathologist.
Assuntos
Dermatologia/história , Histiocitoma Fibroso Benigno/história , Histiocitoma Fibroso Benigno/patologia , Patologia/história , História do Século XX , Hiperplasia , Neoplasias Cutâneas/patologiaRESUMO
OBJECTIVE: To determine the frequency and relative importance of the most meaningful symptoms in facioscapulohumeral muscular dystrophy (FSHD) and to identify the demographic and clinical features that are associated with the greatest disease burden in this population. METHODS: We performed a cross-sectional study involving 328 participants with FSHD. Collectively, participants reported the prevalence and relative importance of 274 symptoms and 15 symptomatic themes. We assessed the association between symptomatic theme prevalence and participants' age, sex, disease duration, pain level, employment status, and education. RESULTS: Participants answered >48,000 questions regarding their disease burden. The symptomatic themes with the highest prevalence in our sample were problems with shoulders or arms (96.9%), limitations with activities (94.7%), core weakness (93.8%), fatigue (93.8%), limitations with mobility and walking (93.6%), changed body image due to the disease (91.6%), and pain (87.7%). Problems with shoulders and arms and limitations with mobility and walking had the greatest effect on participants' lives. Employment status and the report of pain had the most extensive association with the prevalence of symptoms, with employment being associated with 8 of 15 of the symptomatic themes and pain being associated with 7 of 15 of the symptomatic themes. Men and women with FSHD experienced a similar prevalence of all symptomatic themes. CONCLUSIONS: Adults with FSHD experience a variety of symptoms that play an important role in their disease burden. These symptoms have a variable prevalence and importance in the FSHD population and are associated with disease duration, employment status, and pain level.
Assuntos
Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Fadiga/complicações , Fadiga/diagnóstico , Fadiga/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular Facioescapuloumeral/complicações , Dor/complicações , Dor/diagnóstico , Dor/fisiopatologia , Adulto JovemRESUMO
A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.
Assuntos
Ensaios Clínicos como Assunto/métodos , Distrofia Muscular Facioescapuloumeral , Animais , Proteínas Cromossômicas não Histona/genética , Metilação de DNA , Epigênese Genética , Proteínas de Homeodomínio/genética , Humanos , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/patologia , Distrofia Muscular Facioescapuloumeral/terapiaRESUMO
Myasthenia gravis presents a risk factor for pregnancy and delivery, and can affect the newborn. In return, pregnancy can affect the course of myasthenia and worsen the disease during pregnancy requiring treatment modifications. Treatment optimization and drug safety should be addressed before conception. Delivery is complicated by prolonged labor. Newborns can develop neonatal myasthenia gravis, a treatable and transient disease. Patients should not be discouraged to become pregnant, but provided with supportive counseling, planning, and monitoring in a multidisciplinary team involving obstetrician, anesthesiologist, pediatrician, and neurologist. Pregnancy outcome is favorable in women who receive treatment and expert care.
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Miastenia Gravis , Complicações na Gravidez , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Fatores de RiscoRESUMO
BACKGROUND: Non-antiretroviral (ART) drug exposures and poor nutrition may be important modifiable risk factors for distal symmetric polyneuropathies (DSP) in sub-Saharan Africa. METHODS: We conducted a cross-sectional study of DSP prevalence and factors associated with DSP among clinic attendees in urban and rural Zambia. All participants underwent neurologist-performed examination. Laboratory investigations seeking comorbid risk factors for DSP were performed for DSP cases. RESULTS: We identified 31/137 (22.6%) HIV+ and 21/177 (11.9%) HIV- DSP cases. DSP prevalence did not differ by urbanicity, although rural participants were significantly more likely to have one asymptomatic DSP sign. Low dietary diversity, history of syphilis, history of tuberculosis, and prior metronidazole and ciprofloxacin use were associated with DSP amongst HIV+ cases, while age and education were associated with DSP in HIV- participants (all p-valuesâ¯<â¯0·05). In a multivariate logistic regression model, HIV (pâ¯=â¯0·0001) and age (pâ¯<â¯0·0001), and ciprofloxacin exposure (pâ¯=â¯0·01) remained independently associated with DSP. While diabetes was rare, supoptimal micronutrients levels were common among DSP cases regardless of HIV status. CONCLUSIONS: While HIV infection is strongly associated with DSP in Zambia, history of non-ART drug exposures and low dietary diversity are also important determinants of DSP in HIV+ individuals. Treatable micronutrient deficiencies were common.
Assuntos
Polineuropatias/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fármacos Anti-HIV/uso terapêutico , Estudos Transversais , Complicações do Diabetes/epidemiologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Desnutrição/complicações , Desnutrição/epidemiologia , Pessoa de Meia-Idade , Estado Nutricional , Polineuropatias/complicações , Polineuropatias/diagnóstico , Prevalência , Fatores de Risco , Adulto Jovem , Zâmbia/epidemiologiaRESUMO
Homonymous hemianopia (HH) is a frequent deficit resulting from lesions to post-chiasmal brain structures with a significant negative impact on activities of daily living. To address the question how patients with HH may compensate their visual field defect in a naturalistic environment, we performed a driving simulation experiment and quantitatively analyzed both eye and head movements using a head-mounted pupil camera. 14 patients with HH and 14 matched healthy control subjects participated in the study. Based on the detection performance of dynamically moving obstacles, which appeared unexpectedly along the sides of the road track, we divided the patient group into a high- and a low-performance group. Then, we compared parameters of eye and head movements between the two patient groups and the matched healthy control group to identify those which mediate successful detection of potentially hazardous objects. Differences in detection rates could not be explained by demographic variables or the extent of the visual field defect. Instead, high performance of patients with HH in the naturalistic setting of our driving simulation depended on an adapted visual exploratory behavior characterized by a relative increase in the amplitude and a corresponding increase in the peak velocity of saccades, widening horizontally the distribution of eye movements, and by a shift of the overall distribution of saccades into the blind hemifield. The result of the group comparison analyses was confirmed by a subsequent stepwise regression analysis which identified the horizontal spread of eye movements as single factor predicting the detection of hazardous objects.
Assuntos
Condução de Veículo , Movimentos Oculares/fisiologia , Movimentos da Cabeça/fisiologia , Hemianopsia/complicações , Desempenho Psicomotor/fisiologia , Atividades Cotidianas , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação/fisiologiaRESUMO
Diverse cognitive functions decline with increasing age, including the ability to process central and peripheral visual information in a laboratory testing situation (useful visual field of view). To investigate whether and how this influences activities of daily life, we studied age-related changes in visual exploratory behavior in a natural scene setting: a driving simulator paradigm of variable complexity was tested in subjects of varying ages with simultaneous eye- and head-movement recordings via a head-mounted camera. Detection and reaction times were also measured by visual fixation and manual reaction. We considered video computer game experience as a possible influence on performance. Data of 73 participants of varying ages were analyzed, driving two different courses. We analyzed the influence of route difficulty level, age, and eccentricity of test stimuli on oculomotor and driving behavior parameters. No significant age effects were found regarding saccadic parameters. In the older subjects head-movements increasingly contributed to gaze amplitude. More demanding courses and more peripheral stimuli locations induced longer reaction times in all age groups. Deterioration of the functionally useful visual field of view with increasing age was not suggested in our study group. However, video game-experienced subjects revealed larger saccade amplitudes and a broader distribution of fixations on the screen. They reacted faster to peripheral objects suggesting the notion of a general detection task rather than perceiving driving as a central task. As the video game-experienced population consisted of younger subjects, our study indicates that effects due to video game experience can easily be misinterpreted as age effects if not accounted for. We therefore view it as essential to consider video game experience in all testing methods using virtual media.
RESUMO
Patients suffering from homonymous hemianopia after infarction of the posterior cerebral artery (PCA) report different degrees of constraint in daily life, despite similar visual deficits. We assume this could be due to variable development of compensatory strategies such as altered visual scanning behavior. Scanning compensatory therapy (SCT) is studied as part of the visual training after infarction next to vision restoration therapy. SCT consists of learning to make larger eye movements into the blind field enlarging the visual field of search, which has been proven to be the most useful strategy(1), not only in natural search tasks but also in mastering daily life activities(2). Nevertheless, in clinical routine it is difficult to identify individual levels and training effects of compensatory behavior, since it requires measurement of eye movements in a head unrestrained condition. Studies demonstrated that unrestrained head movements alter the visual exploratory behavior compared to a head-restrained laboratory condition(3). Martin et al.(4) and Hayhoe et al.(5) showed that behavior demonstrated in a laboratory setting cannot be assigned easily to a natural condition. Hence, our goal was to develop a study set-up which uncovers different compensatory oculomotor strategies quickly in a realistic testing situation: Patients are tested in the clinical environment in a driving simulator. SILAB software (Wuerzburg Institute for Traffic Sciences GmbH (WIVW)) was used to program driving scenarios of varying complexity and recording the driver's performance. The software was combined with a head mounted infrared video pupil tracker, recording head- and eye-movements (EyeSeeCam, University of Munich Hospital, Clinical Neurosciences). The positioning of the patient in the driving simulator and the positioning, adjustment and calibration of the camera is demonstrated. Typical performances of a patient with and without compensatory strategy and a healthy control are illustrated in this pilot study. Different oculomotor behaviors (frequency and amplitude of eye- and head-movements) are evaluated very quickly during the drive itself by dynamic overlay pictures indicating where the subjects gaze is located on the screen, and by analyzing the data. Compensatory gaze behavior in a patient leads to a driving performance comparable to a healthy control, while the performance of a patient without compensatory behavior is significantly worse. The data of eye- and head-movement-behavior as well as driving performance are discussed with respect to different oculomotor strategies and in a broader context with respect to possible training effects throughout the testing session and implications on rehabilitation potential.