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In JoVE (1)
- Corneal Confocal Microscopy: A Novel Non-invasive Technique to Quantify Small Fibre Pathology in Peripheral Neuropathies
Other Publications (51)
- International Review of Neurobiology
- Ostomy/wound Management
- Current Diabetes Reports
- Treatments in Endocrinology
- Investigative Ophthalmology & Visual Science
- Diabetes Care
- Clinical Science (London, England : 1979)
- Diabetes Care
- Current Diabetes Reports
- Diabetes Care
- British Journal of Hospital Medicine (London, England : 2005)
- Diabetes Care
- Diabetes Care
- The Journal of Foot and Ankle Surgery : Official Publication of the American College of Foot and Ankle Surgeons
- Diabetes Care
- Diabetes Care
- Diabetes Care
- Diabetes Care
- Clinical Nuclear Medicine
- Journal of the American Podiatric Medical Association
- Current Pain and Headache Reports
- Pain Medicine (Malden, Mass.)
- Expert Opinion on Pharmacotherapy
- Nature Clinical Practice. Neurology
- Clinical Ophthalmology (Auckland, N.Z.)
- Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
- Diabetes Care
- Clinical Science (London, England : 1979)
- Best Practice & Research. Clinical Endocrinology & Metabolism
- Acta Neuropathologica
- Muscle & Nerve
- Diabetes Care
- Diabetes Care
- Diabetes Care
- Clinical & Experimental Optometry : Journal of the Australian Optometrical Association
- Biological Psychiatry
- Eye & Contact Lens
- Diabetes Care
- Optometry and Vision Science : Official Publication of the American Academy of Optometry
- Experimental Neurology
- Diabetes Care
- Arteriosclerosis, Thrombosis, and Vascular Biology
- The Ocular Surface
- Clinical Science (London, England : 1979)
- Journal of Hypertension
Articles by Rayaz A. Malik in JoVE
Corneal Confocal Microscopy: A Novel Non-invasive Technique to Quantify Small Fibre Pathology in Peripheral Neuropathies
Mitra Tavakoli*, Rayaz A. Malik*
Division of Cardiovascular Medicine, University of Manchester
Corneal Confocal microscopy is a non-invasive clinical technique which may be used to quantify C fibre damage to diagnose and stratify patients with increasing neuropathic severity.
Other articles by Rayaz A. Malik on PubMed
Angiotensin-converting Enzyme Inhibitors: Are There Credible Mechanisms for Beneficial Effects in Diabetic Neuropathy?
International Review of Neurobiology. 2002 | Pubmed ID: 12198819
Ostomy/wound Management. Sep, 2002 | Pubmed ID: 12271734
A retrospective study was conducted to evaluate treatment outcomes associated with the treatment of diabetic foot ulcers using the Scotchcast boot. Data were extracted from the records of 180 patients with diabetes, 150 (83.3%) male, with a mean age of 55.3 +/- 10.9 years undergoing treatment for noninfected, non-ischemic neuropathic diabetic foot wounds at a university teaching hospital's tertiary care outpatient clinic. All patients who met the criteria were treated with the Scotchcast boot as the sole form of pressure relief. The average follow-up for each patient was 85.9 +/- 30.6 months (range 34.2 to 147.7 months). The mean time to healing for all patients was 130.5 +/- 106.7 days. Superficial (Grade 1) wounds healed significantly faster than deep (Grade 3) wounds (111.5 +/- 98.2 versus 180.8 +/- 138.8 days, P = 0.01) and 144 (80%) wounds healed during the follow-up period. Of the 36 (20%) that did not heal with Scotchcast boot therapy, 10 went on to more proximal amputation (5.6% of total population), two required surgical intervention to heal their wounds (0.6% of total population), one patient died with an unhealed wound (0.6% of total population), 23 patients (12.8% of total population) were lost to follow-up, and 47 (26%) died. Experience and the results of this and other studies suggest that this removable modality may be useful in outpatient care of deeper or complex wounds that require frequent inspection, but a device that ensures compliance may be the preferred treatment of superficial wounds.
Current Diabetes Reports. Dec, 2002 | Pubmed ID: 12643155
The focal and multifocal neuropathies affect only a minority of patients with diabetes; however, they form a major clinical problem in terms of diagnosis, development of significant symptoms and signs, and often inadequate therapy. Diagnosis requires accurate and detailed clinical history and neurologic examination combined with targeted neurophysiologic tests, which differ considerably from those carried out in day-to-day practice. Because of their relatively infrequent occurrence, treatment is not evidence based.
Treatments in Endocrinology. 2003 | Pubmed ID: 15981943
Diabetic neuropathy is common, related to increased morbidity and mortality, and has no effective treatment at present. Interventions based on putative pathways thought to contribute to damage and repair of nerve fibres have yielded little success to date. Pain is a potentially debilitating manifestation of diabetic neuropathy and has many potential sites of origin and, hence, modulation. Its cause is unclear and it does not respond well to traditional pain therapies, proposed to mediate their benefits via multiple peripheral and central mechanisms. A better understanding of the mechanisms leading to nerve fibre degeneration and regeneration as well as pain has recently resulted in the development of a more targeted approach to the treatment of diabetic neuropathy. Thus, specific NMDA receptor antagonists and more specific neuronal serotonin and norepinephrine (noradrenaline) uptake inhibitors offer promise in the treatment of painful diabetic neuropathy. A number of treatments which include the aldose reductase inhibitors and neurotrophins have failed to reach the clinical arena. However, the antioxidant alpha-lipoic acid, as well as compounds which correct vascular dysfunction and hence neuropathy, such as ACE inhibitors and protein kinase C-beta inhibitors, have demonstrated more success.
Investigative Ophthalmology & Visual Science. Feb, 2004 | Pubmed ID: 14744880
Corneal confocal microscopy is a reiterative, rapid, noninvasive in vivo clinical examination technique capable of imaging corneal nerve fibers. Nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes. The purpose of this study was to define alterations in the tortuosity of corneal nerve fibers in relation to age, duration of diabetes, glycemic control, and neuropathic severity.
Clinical Science (London, England : 1979). Dec, 2004 | Pubmed ID: 15341511
Independent of the severity of coronary artery disease, diabetic patients have an increased risk of developing heart failure. This clinical entity has been considered to be a distinct disease process referred to as 'diabetic cardiomyopathy'. Experimental studies suggest that extensive metabolic perturbations may underlie both functional and structural alterations of the diabetic myocardium. Translational studies are, however, limited and only partly explain why diabetic patients are at increased risk of cardiomyopathy and heart failure. Although a range of diagnostic methods may help to characterize alterations in cardiac function in general, none are specific for the alterations in diabetes. Treatment paradigms are very much limited to interpretation and translation from the results of interventions in non-diabetic patients with heart failure. This suggests that there is an urgent need to conduct pathogenetic, diagnostic and therapeutic studies specifically in diabetic patients with cardiomyopathy to better understand the factors which initiate and progress diabetic cardiomyopathy and to develop more effective treatments.
Effects of Angiotensin Type-1 Receptor Antagonism on Small Artery Function in Patients with Type 2 Diabetes Mellitus
Hypertension. Feb, 2005 | Pubmed ID: 15630048
Endothelial dysfunction has been demonstrated to occur in small arteries from patients with type 2 diabetes and hypertension. The effects of angiotensin II receptor blockade on vessel function were examined using pressure myography in a randomized 12-week double-blind placebo-controlled parallel group study using candesartan cilexitil. The maximal vascular response to acetylcholine (Ach) was impaired at baseline and improved with candesartan. This improvement was primarily caused by an effect in the nitric oxide component of Ach-mediated dilatation. The degree of endothelial dysfunction directly correlated with serum low-density lipoprotein cholesterol levels. Sodium nitroprusside-induced endothelium-independent dilatation was reduced in diabetic patients and intervention with candesartan lead to an improvement in EC50 with no change in maximal response. Vasoconstriction to norepinephrine was normal and did not change with intervention, but responses to angiotensin II were reduced after candesartan in diabetic patients. These results demonstrate that even brief treatment with angiotensin II receptor blockade is associated with a significant improvement in resistance vessel endothelial function.
Diabetes Care. Apr, 2005 | Pubmed ID: 15793206
Lancet. Oct 15-21, 2005 | Pubmed ID: 16226599
Current Diabetes Reports. Dec, 2005 | Pubmed ID: 16316591
A large number of measures may be employed in clinical practice and for epidemiologic studies to quantify and risk stratify diabetic patients with neuropathy. However, not all measures are suitable for assessing the benefits of therapeutic intervention. Therefore, for the purpose of this review we focus on measures that may be employed to define the efficacy of interventions in clinical trials of human diabetic neuropathy. Two major types of end points are used: 1) those that assess symptoms for defining efficacy in painful diabetic neuropathy, and 2) those that assess neurologic deficits that assess the effects of treatments that may prevent further degeneration or promote repair.
The Biogun: A Novel Way of Eradicating Methicillin-resistant Staphylococcus Aureus Colonization in Diabetic Foot Ulcers
Diabetes Care. May, 2006 | Pubmed ID: 16644661
British Journal of Hospital Medicine (London, England : 2005). Oct, 2006 | Pubmed ID: 17069121
Diabetes Care. Feb, 2007 | Pubmed ID: 17259529
Diabetes Care. Mar, 2007 | Pubmed ID: 17327336
The pathogenesis of painful diabetic neuropathy (PDN) is not clear. Following our in vivo observations of increased sural nerve epineurial blood flow in patients with PDN, we investigated the cutaneous microcirculation of the foot by laser Doppler flowmetry to determine if the epineurial findings were just confined to the nerve or more widespread in other vascular beds.
The Journal of Foot and Ankle Surgery : Official Publication of the American College of Foot and Ankle Surgeons. Mar-Apr, 2007 | Pubmed ID: 17331876
A sural nerve biopsy may be useful to enable the clinician to diagnose the etiology and underlying pathology of patients presenting with symptoms of a peripheral neuropathy, when no clear underlying cause has been determined with conventional assessment such as electrophysiology or quantitative sensory testing. Given the prevalence of lower extremity neurological pathology, it is surprising that few descriptions in the peer-reviewed medical literature exist on the rationale and technique for biopsy of the sural nerve. We review the usefulness of this procedure, describe the technique, and discuss the potential complications.
Diabetes Care. Jul, 2007 | Pubmed ID: 17372147
Diabetes. Aug, 2007 | Pubmed ID: 17513704
Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.
Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients with Type 1 Diabetes
Diabetes Care. Oct, 2007 | Pubmed ID: 17623821
Corneal confocal microscopy (CCM) is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber pathology. We have used it to assess the neurological benefits of pancreas transplantation in type 1 diabetic patients.
Diabetes Care. Dec, 2007 | Pubmed ID: 17898089
Delayed wound healing in diabetic patients without large-vessel disease has been attributed to microvascular dysfunction, neuropathy, and abnormal cellular and inflammatory responses. The role of these abnormalities has mainly been examined in animal models. Few studies have been undertaken in diabetic patients, and those that have are limited due to analysis in wounds from chronic ulcers. In this study, we quantified the rate of wound healing in relation to skin neurovascular function and structure following a dorsal foot skin biopsy in type 2 diabetes.
Reduced Vascular Endothelial Growth Factor Expression and Intra-epidermal Nerve Fiber Loss in Human Diabetic Neuropathy
Diabetes Care. Jan, 2008 | Pubmed ID: 17934147
To assess the relevance of vascular endothelial growth factor (VEGF) in the maintenance of peripheral nerve integrity in diabetic neuropathy we have assessed the expression of VEGF and intra-epidermal nerve fiber density (IENFD) in skin biopsy samples from diabetic patients.
Clinical Nuclear Medicine. May, 2008 | Pubmed ID: 18431145
A medullary thyroid cancer (MTC)/multiple endocrine neoplasia syndrome was suspected in a patient having an metaiodobenzylguanidine (MIBG) scan while she was being investigated for pheochromocytoma. After surgery, this was confirmed histologically. Although MIBG scanning cannot be used as a screening tool for MTC because of its poor sensitivity for detection of MTC, this case report highlights that one should always scrutinize the thyroid gland while interpreting MIBG scans.
Journal of the American Podiatric Medical Association. Jul-Aug, 2008 | Pubmed ID: 18685055
Neuropathic symptoms in patients with diabetes occur commonly and are most often a consequence of the diabetes. Up to 10% of patients with diabetes and neuropathy have an etiology other than diabetes as a cause of their nerve dysfunction. Herein we present a case of vasculitic neuropathy initially misdiagnosed as diabetic neuropathy that led to separate amputations of two toes. This case emphasizes the importance of considering alternative, potentially treatable, causes of peripheral neuropathy in patients with diabetes.
Current Pain and Headache Reports. Jun, 2008 | Pubmed ID: 18796269
Diabetes is the most common cause of peripheral neuropathy, and painful diabetic neuropathy (PDN) affects approximately 30% of diabetic patients with neuropathy. It is extremely distressing for the patient and poses significant management difficulties because no treatment provides total relief, and side effects of therapy are a major limiting factor for titrating therapy. Understanding the pathogenesis of diabetic neuropathy may lead to the development of new treatments to prevent nerve damage, and a better understanding of the mechanisms that modulate pain may lead to more effective relief of painful symptoms. We provide an update on the pathogenesis, diagnosis, and treatment of PDN.
Pain Medicine (Malden, Mass.). Sep, 2008 | Pubmed ID: 18828198
To facilitate the clinician's understanding of the basis and treatment of painful diabetic neuropathy (PDN).
Expert Opinion on Pharmacotherapy. Dec, 2008 | Pubmed ID: 19006473
The commonest cause of peripheral neuropathy is diabetes and pain occurs in approximately 30% of diabetic patients with neuropathy. It is extremely distressing for the patient and poses significant difficulties in management, as no treatment to date provides total relief and the side effects of therapy limit dose titration. Understanding the pathogenesis of diabetic neuropathy may lead to the development of new treatments for preventing nerve damage. Furthermore, a better understanding of the mechanisms that modulate pain may lead to more effective relief of painful symptoms. This review provides an update on the assessment and treatment of painful diabetic neuropathy.
Nature Clinical Practice. Neurology. Dec, 2008 | Pubmed ID: 19015659
This Practice Point commentary discusses the results of a study that employed thermal threshold testing and quantification of intraepidermal nerve fiber (IENF) density in patients with diabetes who had normal electrophysiology findings. The study showed that a significant proportion of these patients had abnormalities in small-fiber function, as quantified by thermal thresholds, and structure, as quantified by IENF density. Interestingly, patients who showed symptoms of diabetic neuropathy had reduced IENF densities but no difference in thermal thresholds compared with diabetic patients lacking these symptoms. This study highlights the importance of establishing which tests should be used to detect the earliest nerve damage in diabetic neuropathy, and which tests should be used as end points in clinical trials relating to this condition.
Clinical Ophthalmology (Auckland, N.Z.). Jun, 2008 | Pubmed ID: 19668734
Corneal confocal microscopy is a novel clinical technique for the study of corneal cellular structure. It provides images which are comparable to in-vitro histochemical techniques delineating corneal epithelium, Bowman's layer, stroma, Descemet's membrane and the corneal endothelium. Because, corneal confocal microscopy is a non invasive technique for in vivo imaging of the living cornea it has huge clinical potential to investigate numerous corneal diseases. Thus far it has been used in the detection and management of pathologic and infectious conditions, corneal dystrophies and ecstasies, monitoring contact lens induced corneal changes and for pre and post surgical evaluation (PRK, LASIK and LASEK, flap evaluations and Radial Keratotomy), and penetrating keratoplasty. Most recently it has been used as a surrogate for peripheral nerve damage in a variety of peripheral neuropathies and may have potential in acting as a surrogate marker for endothelial abnormalities.
Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association. Feb, 2009 | Pubmed ID: 19028754
Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy
Diabetes Care. Mar, 2009 | Pubmed ID: 19074993
Abnormal small nerve fiber function may be an early feature of diabetic neuropathy and may also underlie painful symptoms. Methods for assessing small-fiber damage include quantitative sensory testing (QST) and determining intraepidermal nerve fiber density. We recently described a reproducible physiological technique, the LDIflare, which assesses small-fiber function and thus may reflect early dysfunction before structural damage. The value of this technique in painful neuropathy was assessed by comparing it with QST and dermal nerve fiber density (NFD).
Local Inflammation and Hypoxia Abolish the Protective Anticontractile Properties of Perivascular Fat in Obese Patients
Circulation. Mar, 2009 | Pubmed ID: 19289637
Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown.
Clinical Science (London, England : 1979). May, 2009 | Pubmed ID: 19364331
Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazolidinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.
Eutrophic Remodeling of Small Arteries in Type 1 Diabetes Mellitus is Enabled by Metabolic Control: a 10-year Follow-up Study
Hypertension. Jul, 2009 | Pubmed ID: 19470882
Type 2 diabetes mellitus profoundly changes small artery remodeling in response to hypertension. Abnormal increases of both wall thickness and lumen diameter are associated with an increased mortality. Changes to small artery structure in response to blood pressure (BP) in patients with type 1 diabetes mellitus have never been examined. In 1997, 17 patients with type 1 diabetes mellitus and 9 control subjects underwent in vitro assessment of gluteal-fat small arteries using pressure myography. Patients with BP <140/90 mm Hg (systolic BP: 119+/-3 mm Hg; n=12) had normal-resistance artery structure. However, patients with BP >140/90 mm Hg (systolic BP: 152+/-5 mm Hg; n=5) demonstrated vascular hypertrophic remodeling with a significant increase in the medial cross-sectional area and wall thickness. In 2008, 8 of the original 17 diabetic patients returned for a repeat assessment. All 8 of the patients had significantly improved cholesterol (2008: 154+/-9 mg/dL versus 1997: 191+/-9 mg/dL; P=0.01) and low-density lipoprotein cholesterol (2008: 79+/-8 mg/dL versus 1997: 122+/-9 mg/dL; P=0.003) but higher BPs (systolic BP: 2008: 136+/-3 mm Hg versus 1997: 119+/-6 mm Hg; P=0.03). Glycemia was improved (2008: 7.9+/-0.3% versus 1997: 8.9+/-0.6%; P=0.17), but not significantly so. In the small arteries studied, there were significant increases in medial wall thickness and wall:lumen ratio, but cross-sectional area was unchanged, indicating eutrophic remodeling. Collectively, these findings suggest that, with poor metabolic control, small arteries from patients with type 1 diabetes mellitus show hypertrophic growth in response to elevated BP, similar to that seen in type 2 diabetes mellitus. However, metabolic improvements enable eutrophic remodeling to occur in response to an increase in BP. This has only been observed previously in patients without diabetes mellitus.
Best Practice & Research. Clinical Endocrinology & Metabolism. Jun, 2009 | Pubmed ID: 19520308
Diabetic individuals have a significantly increased likelihood of developing cardiovascular disease. Whilst part of this association is explained by the presence of concomitant risk factors, large epidemiological studies have consistently reported diabetes as a strong risk factor for the development of heart failure after adjusting for such covariates. This has resulted in the notion that there is a distinct cardiomyopathy specific to diabetes, termed 'diabetic cardiomyopathy'. The natural history is characterized by a latent subclinical period, during which there is evidence of diastolic dysfunction and left ventricular hypertrophy, before overt clinical deterioration and systolic failure ensue. These clinical findings have been supported by a growing body of experimental data which support the notion that diabetes inflicts a direct insult to the myocardium, with cellular, structural and functional changes manifest as the diabetic myocardial phenotype. Several of these mechanisms appear to work in unison, forming complicated reciprocal pathways of disease. Reactive oxygen species and alterations in intracellular calcium homeostasis appear to play significant roles in many of these mechanisms. Determining the hierarchy of this cascade of disease will allow identification of the pathological trigger most responsible for disease. Translational research in this field is currently hindered by a lack of clinical studies and intervention trials specifically in patients with diabetic cardiomyopathy. Future clinical and experimental studies of accurate models of diabetic cardiomyopathy should help to define the true aetiology and lead to the development of specific pharmacotherapies for this condition, ultimately reducing the increased cardiovascular morbidity and mortality in diabetic patients.
Reduced Myelinated Nerve Fibre and Endoneurial Capillary Densities in the Forearm of Diabetic and Non-diabetic Patients with Carpal Tunnel Syndrome
Acta Neuropathologica. Dec, 2009 | Pubmed ID: 19641929
The underlying basis of carpal tunnel syndrome (CTS) and the basis of its increased incidence in diabetes are unknown. We have quantified pathology in an uncompressed nerve (posterior interosseous nerve, PIN) in the forearm between diabetic and non-diabetic patients with CTS and control subjects. In an age- and gender-matched series, 26 diabetic patients with CTS and 20 non-diabetic patients with CTS underwent biopsy of the PIN at the time of surgical carpal tunnel release. Control subjects consisted of ten PIN biopsies taken postmortem and three biopsies taken at the time of wrist surgery. We found PIN myelinated nerve fibre density significantly reduced in diabetic (mean 5,373/mm2 [95% confidence interval, 4,835–5,911]) and non-diabetic (6,617/mm2 [5,697–7,537]) patients with CTS compared to control subjects (9,109/mm2 [7,967–10,250], P < 0.001). Furthermore, diabetic patients had a significantly lower density than non-diabetic patients (P < 0.03). Endoneurial capillary density was also reduced in diabetic (58/mm2 [50–66]) and non-diabetic (67/mm2 [55–78]) patients compared to control subjects (86/mm2 [72–101], P < 0.02) with no difference between diabetic and non-diabetic patients with CTS. Our results suggest that a reduction in myelinated nerve fibre and capillary densities may predispose patients, particularly those with diabetes, to develop CTS.
Corneal Confocal Microscopy: a Novel Noninvasive Means to Diagnose Neuropathy in Patients with Fabry Disease
Muscle & Nerve. Dec, 2009 | Pubmed ID: 19902546
Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal aesthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS) and heat-induced pain (HIP) were only significantly increased in males on ERT (P < 0.01). However, corneal sensation assessed with NCCA was significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QST and CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.
Diabetes Care. Jan, 2010 | Pubmed ID: 20040677
Diabetes Care. Jun, 2010 | Pubmed ID: 20215455
Risks of diabetes and cardiovascular disease are elevated worldwide in Indian Asians. However, risks of other diabetes-related complications, i.e., foot ulceration and amputation, also with a vascular basis, are substantially lower in Asians than in white Europeans in the U.K., possibly due to less neuropathy. We therefore compared signs, symptoms, and objective quantitative measures of diabetic neuropathy and their risk factors in Indian Asians and Europeans.
Corneal Confocal Microscopy: a Novel Noninvasive Test to Diagnose and Stratify the Severity of Human Diabetic Neuropathy
Diabetes Care. Aug, 2010 | Pubmed ID: 20435796
The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.
Clinical & Experimental Optometry : Journal of the Australian Optometrical Association. Sep, 2010 | Pubmed ID: 20579078
Diabetic peripheral neuropathy (DPN) is one of the most debilitating complications of diabetes. DPN is a major cause of foot ulceration and lower limb amputation. Early diagnosis and management are key factors in reducing morbidity and mortality. Current techniques for clinical assessment of DPN are relatively insensitive for detecting early disease or involve invasive procedures such as skin biopsies. There is a need for less painful, non-invasive, safe evaluation methods. Eye-care professionals already play an important role in the management of diabetic retinopathy but recent studies have indicated that the eye may also be an important site for the diagnosis and monitoring of neuropathy. Corneal nerve morphology is a promising marker of diabetic neuropathy occurring elsewhere in the body. Emerging evidence tentatively suggests that retinal anatomical markers and a range of functional visual indicators could similarly provide useful information regarding neural damage in diabetes, although this line of research is less well established. This review outlines the growing body of evidence supporting a potential diagnostic role for retinal structure and visual functional markers in the diagnosis and monitoring of peripheral neuropathy in diabetes.
Biological Psychiatry. Jul, 2010 | Pubmed ID: 20609838
Cerebrovascular disease plays an important role in depressive disorder, especially in older adults. An understanding of vascular function in depression is important etiologically and to develop innovative treatments that may improve prognosis by ameliorating vascular damage.
Cerebrovascular Damage in Late-life Depression is Associated with Structural and Functional Abnormalities of Subcutaneous Small Arteries
Hypertension. Oct, 2010 | Pubmed ID: 20713917
Late-life depression is increasingly viewed as a vascular illness because of patients exhibiting characteristic white matter brain lesions and in vivo large artery endothelial dysfunction. However, the "vascular depression" hypothesis pertains to the microvasculature, and this circulation has not been studied in this context. Our objective was to examine structure and function of small subcutaneous arteries in patients with late-life depression. Thus, 16 patients aged 71.8±4.0 years with late-life depression were compared with 15 control participants aged 72.1±5.9 years. There were similar cardiovascular profiles between the 2 groups. All of the participants underwent MRI brain scans and subcutaneous gluteal fat biopsy from which small arteries were isolated and studied using pressure myography. Cerebral microvascular damage in depressed patients was confirmed by assessment of basal ganglia Virchow-Robin space scores (depressed patients 3.9±1.7 versus controls: 2.5±1.6; P=0.01). Contractility to norepinephrine was equivalent in both groups, but relaxation of the small arteries to acetylcholine was significantly reduced in depressed patients (84.0±4.0%) compared with control participants (96.0±1.4%; P=0.012). This difference in arterial relaxation was reduced but not entirely eliminated when NO synthase was inhibited. Depressed patients also exhibited hypertrophic wall growth with an increase in medial cross-sectional area (P=0.035, multiple ANOVA and wall thickness; P=0.04, multiple ANOVA). In conclusion, despite similar cardiovascular profiles, depressed patients with cerebral microvascular damage show abnormalities of subcutaneous small artery structure and function.
Eye & Contact Lens. Sep, 2010 | Pubmed ID: 20724854
To analyze the repeatability of measuring nerve fiber length (NFL) from images of the human corneal subbasal nerve plexus using semiautomated software.
Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments
Diabetes Care. Oct, 2010 | Pubmed ID: 20876709
Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.
Optometry and Vision Science : Official Publication of the American Academy of Optometry. Dec, 2010 | Pubmed ID: 21037498
The objective of this study was to explore the discriminative capacity of non-contact corneal esthesiometry (NCCE) when compared with the neuropathy disability score (NDS) score-a validated, standard method of diagnosing clinically significant diabetic neuropathy.
Corneal Confocal Microscopy: a Novel Means to Detect Nerve Fibre Damage in Idiopathic Small Fibre Neuropathy
Experimental Neurology. May, 2010 | Pubmed ID: 19748505
Patients with idiopathic small fibre neuropathy (ISFN) have been shown to have significant intraepidermal nerve fibre loss and an increased prevalence of impaired glucose tolerance (IGT). It has been suggested that the dysglycemia of IGT and additional metabolic risk factors may contribute to small nerve fibre damage in these patients. Twenty-five patients with ISFN and 12 aged-matched control subjects underwent a detailed evaluation of neuropathic symptoms, neurological deficits (Neuropathy deficit score (NDS); Nerve Conduction Studies (NCS); Quantitative Sensory Testing (QST) and Corneal Confocal Microscopy (CCM)) to quantify small nerve fibre pathology. Eight (32%) patients had IGT. Whilst all patients with ISFN had significant neuropathic symptoms, NDS, NCS and QST except for warm thresholds were normal. Corneal sensitivity was reduced and CCM demonstrated a significant reduction in corneal nerve fibre density (NFD) (P<0.0001), nerve branch density (NBD) (P<0.0001), nerve fibre length (NFL) (P<0.0001) and an increase in nerve fibre tortuosity (NFT) (P<0.0001). However these parameters did not differ between ISFN patients with and without IGT, nor did they correlate with BMI, lipids and blood pressure. Corneal confocal microscopy provides a sensitive non-invasive means to detect small nerve fibre damage in patients with ISFN and metabolic abnormalities do not relate to nerve damage.
Prevalence and Characteristics of Painful Diabetic Neuropathy in a Large Community-based Diabetic Population in the U.K
Diabetes Care. Oct, 2011 | Pubmed ID: 21852677
To assess, in the general diabetic population, 1) the prevalence of painful neuropathic symptoms; 2) the relationship between symptoms and clinical severity of neuropathy; and 3) the role of diabetes type, sex, and ethnicity in painful neuropathy.
Macrophage Activation is Responsible for Loss of Anticontractile Function in Inflamed Perivascular Fat
Arteriosclerosis, Thrombosis, and Vascular Biology. Apr, 2011 | Pubmed ID: 21273560
The aim of this study was to determine whether macrophages dispersed throughout perivascular fat are crucial to the loss of anticontractile function when healthy adipose tissue becomes inflamed and to gain an understanding of the mechanisms involved.
The Ocular Surface. Jan, 2011 | Pubmed ID: 21338566
Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies. This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new noninvasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and noncontact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.
Small Artery Function 2 Years Postpartum in Women with Altered Glycaemic Distributions in Their Preceding Pregnancy
Clinical Science (London, England : 1979). Jan, 2012 | Pubmed ID: 21745185
GDM (gestational diabetes mellitus) is associated with later adverse cardiovascular risk. The present study examined the relationship between glycaemia during pregnancy and small artery function and structures approx. 2 years postpartum. Women were originally enrolled in the HAPO (Hyperglycaemia and Adverse Pregnancy Outcome) study from which they were classified by their glycaemic distribution during pregnancy as controls (in the lower half of the distribution), UQ (upper quartile; in the UQ of the glycaemic distribution) or having had overt GDM. Subcutaneous arteries from a gluteal fat biopsy taken at follow-up 2 years later were examined using wire myography. Small artery structure, stiffness and vasoconstrictor responses were similar across groups. Maximal endothelium-dependent dilation in response to carbachol was impaired in arteries from both GDM (43.3%, n=8 and P=0.01) and UQ (51.7%, n=13 and P=0.04) women despite generally 'normal' current glycaemia (controls, 72.7% and n=8). Inhibition of NOS (nitric oxide synthase) significantly reduced maximum endothelium-dependent dilation in controls but had no effect on arteries from UQ and GDM women, suggesting impaired NOS activity in these groups. Endothelium-independent dilation was unaffected in arteries from previous GDM and UQ women when compared with the control group. Multiple regression analysis suggested that BMI (body mass index) at biopsy was the most potent factor independently associated with small artery function, with no effect of current glycaemia. Overweight women with either GDM or marginally raised glycaemia during pregnancy (our UQ group) had normal vascular structure and stiffness, but clearly detectable progressively impaired endothelium-dependent function at 2 years follow-up. These results suggest that vascular pathology, which may still be reversible, is detectable very early in women at risk of decline into Type 2 diabetes mellitus.
Effects of Diabetes and Hypertension on Structure and Distensibilty of Human Small Coronary Arteries
Journal of Hypertension. Feb, 2012 | Pubmed ID: 22124179
Previous studies have demonstrated that hypertension and diabetes induce significant structural remodelling of resistance arteries from various vascular beds. The hypothesis of this study is that structural alterations of small coronary arteries may occur during hypertension and diabetes. This study is the first to compare human coronary small resistance artery structure from normotensive and hypertensive patients, with and without diabetes undergoing coronary arterial bypass graft surgery.