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Rayaz A Malik - Top 30 Publications

CIDP and other inflammatory neuropathies in diabetes - diagnosis and management.

Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes.

Diabetic Neuropathy and Gait: A Review.

Diabetic peripheral neuropathy (DPN) is a major sequela of diabetes mellitus and may have a detrimental effect on the gait of people with this complication. DPN causes a disruption in the body's sensorimotor system and is believed to affect up to 50% of patients with diabetes mellitus, dependent on the duration of diabetes. It has a major effect on morbidity and mortality. The peripheral nervous system controls the complex series of events in gait through somatic and autonomic functions, careful balancing of eccentric and concentric muscle contractions and a reliance on the sensory information received from the planter surface. In this literature review focussing on kinetics, kinematics and posture during gait in DPN patients, we have identified an intimate link between DPN and abnormalities in gait and demonstrated an increased risk in falls for older patients with diabetes. As such, we have identified a need for further research on the role of gait abnormalities in the development of diabetic foot ulceration and subsequent amputations.

Presence of Peripheral Neuropathy Is Associated With Progressive Thinning of Retinal Nerve Fiber Layer in Type 1 Diabetes.

Reduced retinal nerve fiber layer (RNFL) thickness has been demonstrated in patients with diabetic peripheral neuropathy (DPN) in cross-sectional studies. This prospective study defines longitudinal alterations to the RNFL thickness in individuals with type 1 diabetes without (DPN-ve) and with (DPN+ve) DPN and in relation to risk factors for nerve damage.

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy.

The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagy-related structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy.

Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities.

To assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM).

Corneal Confocal Microscopy: An Imaging Endpoint for Axonal Degeneration in Multiple Sclerosis.

To evaluate whether corneal confocal microscopy (CCM) detects axonal degeneration and whether this is associated with retinal nerve fiber degeneration and clinical disability in patients with multiple sclerosis (MS).

Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy.

Corneal confocal microscopy (CCM) is a rapid, non-invasive, reproducible technique that quantifies small nerve fibres. We have compared the diagnostic capability of CCM against a range of established measures of nerve damage in patients with diabetic neuropathy.

Optical coherence tomography predicts 4-year incident diabetic neuropathy.

To examine the capability of optical coherence tomography-derived retinal thickness measures in detecting 4-year incident diabetic peripheral neuropathy (DPN).

Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus.

Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage.

Use of Corneal Confocal Microscopy to Detect Corneal Nerve Loss and Increased Dendritic Cells in Patients With Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by demyelination, axonal degeneration, and inflammation. Corneal confocal microscopy has been used to identify axonal degeneration in several peripheral neuropathies.

Corneal confocal microscopy best identifies the development and progression of neuropathy in patients with type 1 diabetes.

A sub-set of 38 individuals with type 1 diabetes that fulfilled a strict criterion of "normal" classification for all 7 measures of neuropathy at baseline, were identified and followed. Corneal nerve morphology, as captured with corneal confocal microscopy demonstrated the greatest, and most sustained degeneration over a 4 year period.

Perceptions of Painful Diabetic Peripheral Neuropathy in South-East Asia: Results from Patient and Physician Surveys.

There are no data on physician-patient communication in painful diabetic peripheral neuropathy (pDPN) in the Asia-Pacific region. The objective of this study was to examine patient and physician perceptions of pDPN and clinical practice behaviors in five countries in South-East Asia. Primary care physicians and practitioners, endocrinologists, diabetologists, and patients with pDPN completed separate surveys on pDPN diagnosis, impact, management, and physician-patient interactions in Hong Kong, Malaysia, the Philippines, Taiwan, and Thailand. Data were obtained from 100 physicians and 100 patients in each country. The majority of physicians (range across countries, 30-85%) were primary care physicians and practitioners. Patients were mostly aged 18-55 years and had been diagnosed with diabetes for >5 years. Physicians believed pDPN had a greater impact on quality of life than did patients (ranges 83-92% and 39-72%, respectively), but patients believed pDPN had a greater impact on items such as sleep, anxiety, depression, and work than physicians. Physicians considered the diagnosis and treatment of pDPN a low priority, which may be reflected in the generally low incidence of screening (range 12-65%) and a lack of awareness of pDPN. Barriers to treatment included patients' lack of awareness of pDPN. Both physicians and patients agreed that pain scales and local language descriptions were the most useful tools in helping to describe patients' pain. Most patients were monitored upon diagnosis of pDPN (range 55-97%), but patients reported a shorter duration of monitoring compared with physicians. Both physicians and patients agreed that it was patients who initiated conversations on pDPN. Physicians most commonly referred to guidelines from the American Diabetes Association or local guidelines for the management of pDPN. This study highlights important differences between physician and patient perceptions of pDPN, which may impact on its diagnosis and treatment. For a chronic and debilitating complication like pDPN, the physician-patient dialogue is central to maximizing patient outcomes. Strategies, including education of both groups, need to be developed to improve communication.

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain.

Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43+) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]).

Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome.

Small artery pathophysiology is frequently invoked as a cause of obesity-related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans.

Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study.

The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus.

Spinal Disinhibition in Experimental and Clinical Painful Diabetic Neuropathy.

Impaired rate-dependent depression (RDD) of the Hoffman reflex is associated with reduced dorsal spinal cord potassium chloride cotransporter expression and impaired spinal γ-aminobutyric acid type A receptor function, indicative of spinal inhibitory dysfunction. We have investigated the pathogenesis of impaired RDD in diabetic rodents exhibiting features of painful neuropathy and the translational potential of this marker of spinal inhibitory dysfunction in human painful diabetic neuropathy. Impaired RDD and allodynia were present in type 1 and type 2 diabetic rats but not in rats with type 1 diabetes receiving insulin supplementation that did not restore normoglycemia. Impaired RDD in diabetic rats was rapidly normalized by spinal delivery of duloxetine acting via 5-hydroxytryptamine type 2A receptors and temporally coincident with the alleviation of allodynia. Deficits in RDD and corneal nerve density were demonstrated in patients with painful diabetic neuropathy compared with healthy control subjects and patients with painless diabetic neuropathy. Spinal inhibitory dysfunction and peripheral small fiber pathology may contribute to the clinical phenotype in painful diabetic neuropathy. Deficits in RDD may help identify patients with spinally mediated painful diabetic neuropathy who may respond optimally to therapies such as duloxetine.

Effects of panretinal laser photocoagulation on the corneal nerve plexus and retinal nerve fiber layer in retinal vein occlusion.

To determine the effects of panretinal photocoagulation (PRP) on corneal sub-basal nerve plexus (SBNP) and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with unilateral central retinal vein occlusion (CRVO) who had previously undergone PRP treatment.

Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy.

Oxaliplatin, an organoplatinum compound, is used in the treatment of colorectal cancer, but its clinical use can be limited due to the development of peripheral neuropathy. Whilst mitochondrial dysfunction has been implicated as a major pathomechanism for oxaliplatin-induced neurotoxicity, the prevention of autophagy may also aggravate neuronal cell death. Melatonin, a well-known mitoprotectant and autophagy inducer, was used to examine its neuroprotective role in oxaliplatin-induced peripheral neuropathy (OIPN). Melatonin prevented the loss of mitochondrial membrane potential (Ψm) and promoted neuritogenesis in oxaliplatin-challenged neuro-2a cells. It did not interfere with the cytotoxic activity of oxaliplatin in human colon cancer cell line, HT-29. Melatonin treatment significantly alleviated oxaliplatin-induced pain behavior and neuropathic deficits in rats. It also ameliorated nitro-oxidative stress mediated by oxaliplatin, thus prevented nitrosylation of proteins and loss of antioxidant enzymes, and therefore, it improved mitochondrial electron transport chain function and maintained cellular bioenergetics by improving the ATP levels. The protective effects of melatonin were attributed to preventing oxaliplatin-induced neuronal apoptosis by increasing the autophagy pathway (via LC3A/3B) in peripheral nerves and dorsal root ganglion (DRG). Hence, it preserved the epidermal nerve fiber density in oxaliplatin-induced neuropathic rats. Taken together, we provide detailed molecular mechanisms for the neuroprotective effect of melatonin and suggest it has translational potential for oxaliplatin-induced neuropathy.

Assessment of Corneal Sensation, Innervation and Retinal Nerve Fiber Layer in Patients Treated with Multiple Intravitreal Ranibizumab Injections.

To evaluate the effects of repeated intravitreal ranibizumab injections on corneal sensitivity, corneal sub-basal nerve plexus (SBNP) and peripapillary retinal nerve fiber layer (RNFL) thickness in patients with neovascular age-related macular degeneration (AMD).

COL6A5 variants in familial neuropathic chronic itch.

Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.

Diabetic Neuropathy: A Position Statement by the American Diabetes Association.

NerveCheck for the Detection of Sensory Loss and Neuropathic Pain in Diabetes.

Accurate and economic detection of nerve damage in diabetes is key to more widespread diagnosis of patients with diabetic peripheral neuropathy (DPN) and painful diabetic neuropathy. This study examined the diagnostic performance of NerveCheck, an inexpensive ($500) quantitative sensory testing (QST) device.

Iodine-123 metaiodobenzylguanidine scintigraphy for the assessment of cardiac sympathetic innervation and the relationship with cardiac autonomic function in healthy adults using standardized methods.

Global iodine-123 metaiodobenzylguanidine (I-MIBG) uptake is predictive of cardiovascular events and mortality in patients with heart failure. Normal variations in global and regional uptake, however, are not well defined and few studies have addressed the functional relevance of I-MIBG uptake and distribution in healthy individuals.

The perception of affective touch in Parkinson's disease and its relation to small fibre neuropathy.

Affective touch sensation is conducted by a sub-class of C-fibres in hairy skin known as C-Tactile (CT) afferents. CT afferents respond maximally to gentle skin stroking at velocities between 1 and 10 cm/s. Parkinson's disease (PD) is characterised by markedly reduced cutaneous C-fibres. It is not known if affective touch perception is influenced by C-fibre density and if affective touch is impaired in PD compared to healthy controls. We predicted that perceived pleasantness to gentle stroking in PD would correlate with C-afferent density and that affective touch perception would be impaired in PD compared to healthy controls. Twenty-four PD patients and 27 control subjects rated the pleasantness of brush stroking at an optimum CT stimulation velocity (3 cm/s) and two sub-optimal velocities (0.3 and 30 cm/s). PD patients underwent quantification of C-fibre density using skin biopsies and corneal confocal microscopy. All participants rated a stroking velocity of 3 cm/s as the most pleasant with significantly lower ratings for 0.3 and 30 cm/s. There was a significant positive correlation between C-fibre density and pleasantness ratings at 3 and 30 cm/s but not 0.3 cm/s. Mean pleasantness ratings were consistently higher in PD patients compared to control subjects across all three velocities. This study shows that perceived pleasantness to gentle touch correlates significantly with C-fibre density in PD. The higher perceived pleasantness in PD patients compared to controls suggests central sensitisation to peripheral inputs, which may have been enhanced by dopamine therapy.

Focal loss volume of ganglion cell complex in diabetic neuropathy.

The aim was to investigate the relationship between diabetic peripheral neuropathy (DPN) and abnormalities in ganglion cell complex (GCC); specifically, focal loss volume (FLV) and global loss volume (GLV).

Response to Comment on Almurdhi et al. Reduced Lower-Limb Muscle Strength and Volume in Patients With Type 2 Diabetes in Relation to Neuropathy, Intramuscular Fat, and Vitamin D Levels. Diabetes Care 2016;39:441-447.

Secondary Stroke Prevention: Improving Diagnosis and Management with Newer Technologies.

Treatment of hypertension, diabetes, high cholesterol, smoking cessation, and healthy lifestyle have all contributed to the decline in the incidence of vascular disease over the last several decades. Patients who suffer an acute stroke are at a high risk for recurrence. Introduction of newer technologies and their wider use allows for better identification of patients in whom the risk of recurrence following an acute stroke may be very high. Traditionally, the major focus for diagnosis and management has focused on patient history, examination, imaging for carotid stenosis/occlusion, and detection of AF and paroxysmal AF (PAF) with 24-48 h cardiac monitoring. This review focuses on the usefulness of three newer investigative tools that are becoming widely available and lead to better prevention. Continuous ambulatory blood pressure measurements for 24 h or longer and 3D Doppler measures of the carotid arteries provide key useful information on the state of vascular health and enhance our ability to monitor the response to preventive therapies. Furthermore, the detection of PAF can be significantly improved with prolonged cardiac monitoring for 3 weeks or longer, enabling the initiation of appropriate prevention therapy. This review will focus on the potential impact and importance of these emerging technologies on the prevention of recurrent stroke in high-risk patients.

A fully automatic nerve segmentation and morphometric parameter quantification system for early diagnosis of diabetic neuropathy in corneal images.

Diabetic Peripheral Neuropathy (DPN) is one of the most common types of diabetes that can affect the cornea. An accurate analysis of the nerve structures can assist the early diagnosis of this disease. This paper proposes a robust, fast and fully automatic nerve segmentation and morphometric parameter quantification system for corneal confocal microscope images. The segmentation part consists of three main steps. First, a preprocessing step is applied to enhance the visibility of the nerves and remove noise using anisotropic diffusion filtering, specifically a Coherence filter followed by Gaussian filtering. Second, morphological operations are applied to remove unwanted objects in the input image such as epithelial cells and small nerve segments. Finally, an edge detection step is applied to detect all the nerves in the input image. In this step, an efficient algorithm for connecting discontinuous nerves is proposed. In the morphometric parameters quantification part, a number of features are extracted, including thickness, tortuosity and length of nerve, which may be used for the early diagnosis of diabetic polyneuropathy and when planning Laser-Assisted in situ Keratomileusis (LASIK) or Photorefractive keratectomy (PRK). The performance of the proposed segmentation system is evaluated against manually traced ground-truth images based on a database consisting of 498 corneal sub-basal nerve images (238 are normal and 260 are abnormal). In addition, the robustness and efficiency of the proposed system in extracting morphometric features with clinical utility was evaluated in 919 images taken from healthy subjects and diabetic patients with and without neuropathy. We demonstrate rapid (13 seconds/image), robust and effective automated corneal nerve quantification. The proposed system will be deployed as a useful clinical tool to support the expertise of ophthalmologists and save the clinician time in a busy clinical setting.

Abnormal Anterior Corneal Morphology in Diabetes Observed Using In Vivo Laser-scanning Confocal Microscopy.

To assess if diabetes alters corneal epithelial, anterior stromal and subbasal nerve plexus morphology and to determine the associations between these and other clinical variables.

Subjects With Extreme-Duration Type 1 Diabetes Exhibit No Structural or Functional Abnormality on Cardiac MRI.