Early Neuropathy Assessment Group

Specialising in the early detection of diabetic neuropathy and other neuropathies.

 

 

The Early Neuropathy Assessment (ENA) Group consists of clinician-scientists and PhD students researching the earlier detection of diabetic and other neuropathies.

We have pioneered and validated the use of in vivo corneal confocal microscopy (CCM) as an ophthalmic biomarker for monitoring degeneration and regeneration of corneal sub-basal nerves in peripheral neuropathies and central neurodegenerative disorders.

In 2003, ENA published the first paper that quantified corneal nerve pathology and showed a progressive reduction in corneal nerve fibre density, length and branch density in patients with increasing severity of diabetic peripheral neuropathy (DPN).

We have also developed automated image analysis software available for use for research purposes.

ENA was established by Professor Rayaz A Malik in 2002. Our members are based in the Division of Cardiovascular Sciences at The University of Manchester and at Weill Cornell Medicine in Qatar.

 

Our research

We undertake projects in the early detection of diabetic neuropathy and other neuropathies.

Current projects

Evaluation of CCM as a surrogate endpoint for identifying and predicting diabetic neuropathy

Objective

Evaluate the role of corneal confocal microscopy (CCM) as an ocular biomarker of diabetic neuropathy in patients with type 1 and type 2 diabetes to determine future risk of neuropathy.

Study type

NIH-DP3 multinational study

Enrolment

1040 participants (363 with T1DM without DPN, 151 T1DM and DPN, 241 with T2DM and without DPN and 283 with T2DM and DPN)

Recruiting sites

  • The University of Manchester
  • Toronto General Research Institute
  • Queensland University of Technology

Principal investigators

  • Professor Rayaz Malik (WCM-Q and The University of Manchester PI)
  • Professor Bruce Perkins (Toronto General Research Institute PI, Canada)
  • Professor Nathan Efron (Queensland University of Technology PI, Australia)

 

Abnormal lipids and neuropathy

Principal investigator

Dr Handrean Soran

Bariatric surgery outcomes

Principal investigators

Dr Handrean Soran

Past projects

  • Implementation of Corneal Confocal Microscopy in Primary Care Optometry Practices to screen for Diabetic neuropathy (NIHR/Heidelberg funded study)
  • PROPANE study: Probing the role of sodium channels in painful neuropathies (EUFP7)
  • Longitudinal assessments of novel ophthalmic diabetic markers (LANDMARK) (JDRFI)
  • Corneal Confocal Microscopy: a non-invasive surrogate for diabetic neuropathy (NIDDK)
  • Corneal Confocal Microscopy for the diagnosis of peripheral neuropathies (ISFN, Fabry, Burning Mouth Syndrome)

Publications

View our publications in the Research Explorer.

 

Our techniques

We have pioneered the use of in vivo corneal confocal microscopy (CCM) as a surrogate endpoint of diabetic and other peripheral neuropathies. Besides ophthalmic assessments, we perform skin punch biopsy, foot and autonomic nerve function assessment.

Ophthalmic assessments

CCM

Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging technique. We use the Heidelberg Retina Tomograph 3 with the Rostock Cornea Module (Heidelberg Engineering GmbH).

The CCM utilises a 670 nm diode laser and provides digital images of the cornea. Both eyes are anesthetized using Oxybuprocaine hydrochloride 0.4% (Conjuncain EDO; Fabrik GmbH) followed by a drop of viscose gel (Viscotears, Carbomer 980, 0.2 %; Blumont Healthcare Ltd.).

Study participants are instructed to fixate on a target. Several scans of the subbasal nerve plexus in the central cornea are captured per eye for two minutes. Adjacent images are separated by approximately 1-4 µm. The field of view of each image is 400×400 µm.

CCM image extraction is carried out at a separate time by one investigator unaware of the study group. Three high clarity CCM images per eye are selected using a validated protocol and criteria. Criteria for image selection are depth, focus position and contrast.

CCM measures are quantified by using either CCMetrics, a validated image analysis software for manual nerve tracing or ACCMetrics, a validated image analysis software for automated nerve tracing. Learn more about our software.

There are three central CCM measures:

  • Corneal nerve fiber density (CNFD) (fibers/mm2)
  • Corneal nerve branch density (CNBD) (branches/mm2)
  • Corneal nerve fiber length (CNFL) (mm/mm2)

And in the inferior whorl region:

  • Inferior whorl length (IWL) (mm/mm2)

Watch a video showing the CCM technique (YouTube).

Corneal sensitivity with non-contact corneal aesthesiometer (NCCA)

The NCCA (Glasgow, Caledonian University, UK, 1996) is used to measure corneal sensitivity using a controlled pulse of air stimuli to determine the sensitivity threshold.

Skin punch biopsy

Intra-epidermal nerve fibre density (IENFD) is quantified as the number of nerve fibres per millimetre in agreement with EFNS guidelines.

A camera (Sony 2CCD, CCD-IRIS) and a computer program (Leica QWin Standard V2.4, Leica Microsystem Imaging Ltd, Clifton Road, Cambridge, CB1 3QH, England) are used to quantify the epidermal length and by directly counting the IENF passing through the basement membrane.

At least three sections per case are assessed and the average IENFD is calculated.

Neuropathy assessment

Nerve conduction studies (NCS)

NCS are performed by a consultant neurophysiologist using the Dantec keypoint system (Dantec Dynamics, Bristol, UK). Nerve conduction velocity, amplitude and latency are recorded of peroneal and tibial motor and sural sensory nerves.

Vibration perception threshold (VPT)

VPT is evaluated using the neurothesiometer (Horwell, Scientific Laboratory Supplies, Wilford, Nottingham, UK) on the tip of the big toe.

Thermal perception threshold

Cold and warm sensation thresholds are measured using TSA-II NeuroSensory Analyser (Medoc, Ramat-Yishai, Israel) on the dorsolateral aspect of the non-dominant foot.

Neuropathy disability score (NDS)

The modified NDS is used to assess vibration, temperature, pin-prick perception and the presence or absence of ankle reflexes.

Autonomic nerve function assessment

Heart rate variability

Heart rate variability (HRV) assessments are performed using the ANX 3.0 autonomic nervous system monitoring device (ANSAR, Medical Technologies, Philadelphia, PA, USA). Deep breathing HRV, 30:15 ratio, Valsalva ratio and sympathetic (LFA) and parasympathetic (RFA) dysfunction.

Neuropad test

The Neuropad test is used to assess sudomotor dysfunction. A plaster is adhered to the plantar surface of the foot for 10 minutes to measure sweat production based on the colour change of a cobalt II compound from blue to pink.

Our software

Our CCMetrics and ACCMetrics software offer manual and automated tracing of the nerve fibres, enabling the rapid and objective quantification of corneal nerve fibre morphology.

We have shared the software under a license agreement for research purposes with more than 100 centres around the world. We have hosted CCM training workshops for undertaking CCM image acquisition and analysis in both the UK and Qatar.

We also offer Sudometrics, an image analysis program that quantifies the percentage colour change in pink over the whole area of Neuropad. Neuropad is a visual screening test that provides a visual means of identifying diabetic patients at risk of foot ulceration.

Learn more about our software on our dedicated website:

 

Who we are

Our members are based in the Division of Cardiovascular Sciences at The University of Manchester and at Weill Cornell Medicine in Qatar.

Rayaz Malik MBChB, PhD

Rayaz MalikProfessor of Medicine, Weill Cornell Medicine – Qatar
Honorary Professor of Medicine, The University of Manchester
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Andrew J M Boulton MD, DSc

Andrew BoultonProfessor of Medicine, The University of Manchester
Email: andrew.j.boulton@manchester.ac.uk
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Handrean Soran MSc, MD, FRCP

Handrean SoranConsultant Physician and Endocrinologist, Manchester
Email: handrean.soran@manchester.ac.uk
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Maryam Ferdousi BSc, MSc, PhD

Maryam FerdousiResearch Associate in Medicine, The University of Manchester (assessment of peripheral neuropathies utilising corneal confocal microscopy)
Email: maryam.ferdousi@manchester.ac.uk
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Alise Kalteniece BSc, MSc, PhD

Alise KaltenieceResearch Associate in Medicine, The University of Manchester (assessment of peripheral neuropathies utilising corneal confocal microscopy)
Email: alise.kalteniece@manchester.ac.uk
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Shazli Azmi MBChb, PhD, MRCP

Shazli AzmiConsultant Diabetologist, Manchester (assessment of peripheral neuropathies utilising corneal confocal microscopy)
Email: shazli.azmi@manchester.ac.uk
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Andy Marshall MD

Consultant neurophysiologist, Manchester (electrophysiology and nerve conduction studies)
Email: andy.marshall@manchester.ac.uk
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Maria Jeziorska MD, PhD

Honorary Senior Lecturer, The University of Manchester
Email: maria.jeziorska@manchester.ac.uk
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Contact us

If you have any questions about ENA or our software, please get in touch.

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