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1.
Ocul Surf ; 34: 309-316, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39153598

RESUMO

AIMS: To investigate tear neuropeptide Y (NPY) and substance P concentrations in individuals with type 1 diabetes, comparing those with and without both diabetic retinopathy (DR) and peripheral neuropathy. METHODS: This cross-sectional study involved 41 participants with type 1 diabetes and none to moderate DR, and 22 healthy controls. Assessments included clinical ocular surface parameters, quantification of corneal nerve attributes (based on in vivo confocal microscopy imaging), DR grading, and evaluation for small and large fibre neuropathy. Concentrations of NPY and substance P in tear samples were measured using enzyme-linked immunosorbent assay. RESULTS: Mean (± standard deviation) tear NPY concentrations in participants with type 1 diabetes and length-dependent small fibre neuropathy (SFN) was lower than in controls (10.84 ± 4.10 ng/mL vs 14.72 ± 3.12 ng/mL; p=0.004), but not significantly different from type 1 diabetes participants without SFN (13.39 ± 4.66 ng/mL; p=0.11). Tear NPY levels were lower in individuals with type 1 diabetes and mild/moderate non-proliferative DR (10.44 ± 3.46 ng/mL) compared to none/minimal DR (13.79 ± 4.76 ng/mL; p=0.0005) and controls. In separate linear regression models, both the presence of SFN (ß = -0.75, p=0.02) and the presence of mild/moderate DR (ß = -0.84, p=0.009) were significantly associated with tear NPY levels relative to controls, after adjusting for participant age, sex, and dry eye disease. There were no inter-group differences for tear substance P concentrations. CONCLUSIONS: Tear NPY has potential utility as an indicator of peripheral microvascular complications associated with type 1 diabetes.

2.
Curr Opin Neurol ; 36(5): 382-387, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37639448

RESUMO

PURPOSE OF REVIEW: An increasing number of peripheral neuro(no)pathies are identified as involving other components of the neurological system, particularly those that further impair balance. Here we aim to outline an evidence-based approach to the diagnosis of patients who present with a somatosensory disorder which also involves at least one other area of neurological impairment such as the vestibular, auditory, or cerebellar systems. RECENT FINDINGS: Detailed objective investigation of patients who present with sensory impairment, particularly where the degree of imbalance is greater than would be expected, aids the accurate diagnosis of genetic, autoimmune, metabolic, and toxic neurological disease. SUMMARY: Diagnosis and management of complex somatosensory disorders benefit from investigation which extends beyond the presenting sensory impairment.


Assuntos
Neurologia , Doenças do Sistema Nervoso Periférico , Vestíbulo do Labirinto , Humanos , Ataxia/diagnóstico , Ataxia/terapia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/terapia , Cerebelo
4.
Am J Hum Genet ; 110(1): 105-119, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36493768

RESUMO

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.


Assuntos
Ataxia Cerebelar , Fatores de Crescimento de Fibroblastos , Ataxia de Friedreich , Expansão das Repetições de Trinucleotídeos , Adulto , Humanos , Ataxia/genética , Austrália , Ataxia Cerebelar/genética , Ataxia de Friedreich/genética , Expansão das Repetições de Trinucleotídeos/genética
5.
J Clin Neurophysiol ; 40(1): 86-90, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34038931

RESUMO

PURPOSE: Peripheral neuropathy has been reported commonly in several spinocerebellar ataxia (SCA) types. To date, there is a lack of robust evidence for neuropathy or neuronopathy in SCA type 6 (SCA6). Here, we aim to evaluate the presence of neuropathy or neuronopathy in a cohort of SCA6 patients. METHODS: Twenty-four individuals with genetically confirmed SCA6 underwent detailed neurophysiological assessment. This included nerve conduction studies, and in some, cutaneous silent periods, blink reflexes, tilt table tests, quantitative sudomotor axon reflex tests, and somatosensory (median and tibial) evoked potentials. RESULTS: Mean age was 56.1 years (range, 22-94 years) at the time of testing. Four patients were presymptomatic of SCA6 at recruitment. The mean disease duration of symptomatic patients was 11.9 years (range, 1-40 years). Most patients (79.2%, 19/24) had no neurophysiological evidence of a peripheral neuropathy. One with impaired glucose tolerance had mild, large, and small fiber sensorimotor polyneuropathy. One elderly patient had length-dependent axonal sensorimotor polyneuropathy. Two had minor sensory abnormalities (one had type II diabetes and previous chemotherapy). One other had minor small fiber abnormalities. Ten patients (41.7%) had median neuropathies at the wrist. All somatosensory evoked potential (15/15), and most autonomic function tests (13/14) were normal. CONCLUSIONS: A large proportion of subjects (79.2%) in our cohort had no evidence of large or small fiber neuropathy. This study does not support the presence of neuropathy or neuronopathy as a common finding in SCA6 and confirms the importance of considering comorbidities as the cause of neurophysiological abnormalities.


Assuntos
Diabetes Mellitus Tipo 2 , Doenças do Sistema Nervoso Periférico , Polineuropatias , Ataxias Espinocerebelares , Humanos , Idoso , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico , Potenciais Somatossensoriais Evocados , Condução Nervosa/fisiologia
6.
Neurol Genet ; 8(5): e200021, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36187726

RESUMO

Increasingly, cerebellar syndromes are recognized as affecting multiple systems. Extracerebellar features include peripheral neuropathies affecting proprioception; cranial neuropathies such as auditory and vestibular; and neuronopathies, for example, dorsal root and vestibular. The presence of such features, which in and of themselves may cause ataxia, likely contribute to key disabilities such as gait instability and falls. Based on the evolving available literature and experience, we outline a clinical approach to the diagnosis of adult-onset ataxia where a combination of cerebellar and peripheral or cranial nerve pathology exists. Objective diagnostic modalities including electrophysiology, oculomotor, and vestibular function testing are invaluable in accurately defining an individual's phenotype. Advances in MRI techniques have led to an increased recognition of disease-specific patterns of cerebellar pathology, including those conditions where neuronopathies may be involved. Depending on availability, a stepwise approach to genetic testing is suggested. This is guided by factors such as pattern of inheritance and age at disease onset, and genetic testing may range from specific genetic panels through to whole-exome and whole-genome sequencing. Management is best performed with the involvement of a multidisciplinary team, aiming at minimization of complications such as falls and aspiration pneumonia and maximizing functional status.

7.
Diabetes ; 70(8): 1794-1806, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33952620

RESUMO

This randomized, double-masked, placebo-controlled trial evaluated the effects of oral omega-3 (n-3) fatty acid supplementation on peripheral nerves in type 1 diabetes. Participants with type 1 diabetes were assigned (1:1) to n-3 (1,800 mg/day fish oil) or placebo (600 mg/day olive oil) supplements for 180 days. The primary outcome was change from baseline in central corneal nerve fiber length (CNFL) at day 180. Secondary outcomes included change in other corneal nerve parameters, corneal sensitivity, peripheral small and large nerve fiber function, and ocular surface measures. Efficacy was analyzed according to the intention-to-treat principle. Safety assessments included diabetic retinopathy grade and adverse events. Between July 2017 and September 2019, 43 participants received n-3 (n = 21) or placebo (n = 22) supplements. All participants, except for two assigned to placebo, completed the trial. At day 180, the estimated increase in CNFL in the n-3 group, compared with placebo, was 2.70 mm/mm2 (95% CI 1.64, 3.75). The Omega-3 Index increased relative to placebo (3.3% [95% CI 2.4, 4.2]). There were no differences in most small or large nerve fiber functional parameters. Adverse events were similar between groups. In conclusion, we found in this randomized controlled trial that long-chain n-3 supplements impart corneal neuroregenerative effects in type 1 diabetes, indicating a role in modulating peripheral nerve health.


Assuntos
Córnea/patologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ácidos Graxos Ômega-3/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 1/patologia , Suplementos Nutricionais , Método Duplo-Cego , Ácidos Graxos Ômega-3/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/farmacologia
8.
Muscle Nerve ; 61(1): 44-51, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613996

RESUMO

INTRODUCTION: We assess whether improvement in control of type 1 diabetes mellitus (T1DM) with continuous subcutaneous insulin infusion (CSII) can protect peripheral nerve function. METHODS: Twelve patients with T1DM treated with multiple daily insulin injections were assessed with nerve excitability testing prior to and 3 months after initiation of CSII. RESULTS: Although commencing treatment with CSII for 3 months improved mean glycosylated hemoglobin, it did not significantly alter nerve excitability or glycemic variability (GV). In four patients, some deterioration in GV was observed, while eight patients had improvement in SD and mean amplitude of glycemic excursions. For these eight patients, there was normalization of depolarizing and hyperpolarizing threshold electrotonus and recovery cycle superexcitablity. DISCUSSION: When CSII initiation is able to reduce glycemic variability in T1DM, reversal of axonal dysfunction is seen, likely due to normalization of sodium-potassium pump function and restoration of transaxonal membrane potential.


Assuntos
Axônios/patologia , Glicemia/análise , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Sistemas de Infusão de Insulina , Insulina/administração & dosagem , Insulina/uso terapêutico , Adulto , Diabetes Mellitus Tipo 1/patologia , Neuropatias Diabéticas/patologia , Eletrodiagnóstico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neurônios Motores , Exame Neurológico , Fármacos Neuroprotetores , Resultado do Tratamento , Adulto Jovem
9.
Muscle Nerve ; 52(6): 993-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25846267

RESUMO

INTRODUCTION: The compound muscle action potential (CMAP) amplitude of extensor digitorum brevis can show a drop with proximal stimulation in normal fibular nerves. METHODS: We assessed the contribution of the far-field potential recorded by the reference electrode (R-CMAP) to the fibular CMAP. Negative R-CMAP amplitude, peak-to-peak amplitude, and negative area were measured and correlated with the amplitude decrease. Fibular motor nerves from 14 healthy participants were studied. RESULTS: The mean CMAP amplitude drop with proximal stimulation was 14.0 ± 9.3%, including a >30% reduction in 1 study. All measured R-CMAP parameters correlated with the degree of amplitude drop. CONCLUSIONS: A greater R-CMAP contribution to the fibular CMAP leads to greater phase cancellation and temporal dispersion. The resulting amplitude drop seen in the proximal CMAP can be large enough to be classified incorrectly as "probable conduction block" by several different diagnostic criteria.


Assuntos
Potenciais de Ação/fisiologia , Músculo Esquelético/fisiologia , Condução Nervosa/fisiologia , Nervo Fibular/fisiologia , Adulto , Biofísica , Estimulação Elétrica , Eletrodos , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Diabetes Metab Res Rev ; 31(6): 646-50, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25865170

RESUMO

BACKGROUND: This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant. METHODS: Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age-matched and gender-matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness and five healthy control participants without diabetes. All participants underwent (i) a battery of five cardiovascular autonomic function tests, (ii) quantitative sudomotor axonal reflex testing, and (iii) sympathetic skin response testing. RESULTS: Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0- to 3-month post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97 to 69% at 0-3 months (p < 0.001, Fisher's exact test) and to 20% after 12 months (p < 0.0001, Fisher's exact test). This amelioration was maintained at the time of testing (mean time: 4.1 years later, range: 2-6 years). Presence of significant autonomic neuropathy was seen in all five transplanted patients (at least 2/3 above modalities abnormal) but in only one of the patients with diabetes without transplantation. CONCLUSIONS: The long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure.


Assuntos
Doenças do Sistema Nervoso Autônomo/etiologia , Diabetes Mellitus Tipo 1/cirurgia , Neuropatias Diabéticas/etiologia , Autoavaliação Diagnóstica , Hipoglicemia/diagnóstico , Transplante das Ilhotas Pancreáticas/efeitos adversos , Transplante de Pâncreas/efeitos adversos , Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/complicações , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Doenças do Sistema Nervoso Autônomo/prevenção & controle , Sistema Cardiovascular/inervação , Sistema Cardiovascular/fisiopatologia , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Neuropatias Diabéticas/prevenção & controle , Feminino , Humanos , Hipoglicemia/fisiopatologia , Hipoglicemia/prevenção & controle , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Índice de Gravidade de Doença , Pele/inervação , Pele/fisiopatologia , Glândulas Sudoríparas/inervação , Glândulas Sudoríparas/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia
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