Corneal confocal microscopy: A novel noninvasive means to diagnose neuropathy in patients with fabry disease

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. Muscle Nerve, 2009

[1]  G. Sunder-Plassmann,et al.  Measurement of renal function in patients with Fabry disease , 2005, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[2]  D. F. Moore,et al.  Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease , 2003, Muscle & nerve.

[3]  R. Schiffmann,et al.  Cutaneous silent periods in patients with Fabry disease , 2000, Muscle & nerve.

[4]  A. Mehta,et al.  Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey , 2006, British Journal of Ophthalmology.

[5]  R. Schiffmann,et al.  Enzyme replacement therapy and intraepidermal innervation density in Fabry disease , 2006, Muscle & nerve.

[6]  P. Hossain,et al.  Early detection of diabetic peripheral neuropathy with corneal confocal microscopy , 2005, The Lancet.

[7]  P. Dyck,et al.  Loss of small peripheral sensory neurons in Fabry disease. Histologic and morphometric evaluation of cutaneous nerves, spinal ganglia, and posterior columns. , 1974, Archives of neurology.

[8]  P. Elliott,et al.  Effects of enzyme replacement therapy on the cardiomyopathy of Anderson–Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa , 2007, Heart.

[9]  R. Schiffmann.  Neuropathy and Fabry disease: pathogenesis and enzyme replacement therapy. , 2006, Acta neurologica Belgica.

[10]  J. Charrow,et al.  Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. , 2007, Journal of the American Society of Nephrology : JASN.

[11]  B. Stemper,et al.  Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients , 2000, PAIN®.

[12]  P. Carpineto,et al.  Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. , 2006, American journal of ophthalmology.

[13]  C. O'donnell,et al.  An evaluation of corneal nerve morphology and function in moderate keratoconus. , 2005, Contact lens & anterior eye : the journal of the British Contact Lens Association.

[14]  P. Thomas,et al.  Peripheral nerve involvement in Fabry's disease. , 1970, Archives of neurology.

[15]  J. Kint.  Fabry's Disease: Alpha-Galactosidase Deficiency , 1970, Science.

[16]  M. Brys,et al.  Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy. , 2004, Neurology.

[17]  K. Toyooka,et al.  Nerve biopsy findings in hemizygous and heterozygous patients with Fabry’s disease , 1997, Journal of Neurology.

[18]  M. Beck.  The Mainz Severity Score Index (MSSI): development and validation of a system for scoring the signs and symptoms of Fabry disease. , 2006, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[19]  A. Rolfs,et al.  The microstructure of cornea verticillata in Fabry disease and amiodarone-induced keratopathy: a confocal laser-scanning microscopy study , 2009, Graefe's Archive for Clinical and Experimental Ophthalmology.

[20]  R. A. Malik,et al.  Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients , 2003, Diabetologia.

[21]  K. Macdermot,et al.  Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males , 2001, Journal of medical genetics.

[22]  R. Brady,et al.  Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. , 1967, The New England journal of medicine.

[23]  H. Terasaki,et al.  Histopathologic Findings of Cornea Verticillata in a Woman Heterozygous for Fabry's Disease , 2001, Cornea.

[24]  Atul Mehta,et al.  Nature and Prevalence of Pain in Fabry Disease and Its Response to Enzyme Replacement Therapy—A Retrospective Analysis From the Fabry Outcome Survey , 2007, The Clinical journal of pain.

[25]  C. Sommer,et al.  Small‐fibre neuropathy in female Fabry patients: reduced allodynia and skin blood flow after topical capsaicin , 2006, Journal of the peripheral nervous system : JPNS.

[26]  J. Dambrosia,et al.  Physiological characterization of neuropathy in Fabry's disease , 2002, Muscle & nerve.

[27]  I. Immonen,et al.  Corneal structure and sensitivity in type 1 diabetes mellitus. , 2000, Investigative ophthalmology & visual science.

[28]  Nathan Efron,et al.  Corneal nerve tortuosity in diabetic patients with neuropathy. , 2004, Investigative ophthalmology & visual science.

[29]  M. Brys,et al.  Enzyme replacement therapy improves function of C-, Aδ-, and Aβ-nerve fibers in Fabry neuropathy , 2004, Neurology.

[30]  U. Ramaswami,et al.  The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents , 2003, European Journal of Pediatrics.

[31]  P. Dyck,et al.  Neuropathy Symptom Profile in health, motor neuron disease, diabetic neuropathy, and amyloidosis , 1986, Neurology.

[32]  T. Sherwin,et al.  Involvement of corneal nerves in the progression of keratoconus. , 2003, Experimental eye research.

[33]  A. Boulton,et al.  Foot ulcer risk is lower in South-Asian and african-Caribbean compared with European diabetic patients in the U.K.: the North-West diabetes foot care study. , 2005, Diabetes care.

[34]  Nathan Efron,et al.  Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy , 2007, Diabetes.

[35]  R. Schiffmann,et al.  Pathophysiology and assessment of neuropathic pain in Fabry disease , 2002, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[36]  Dipika V Patel,et al.  Mapping the corneal sub-basal nerve plexus in keratoconus by in vivo laser scanning confocal microscopy. , 2006, Investigative ophthalmology & visual science.

[37]  M. C. Acosta,et al.  Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. , 2007, Investigative ophthalmology & visual science.

[38]  M. Ghosh,et al.  Corneal changes in Fabry's disease: a clinico-pathologic case report of a heterozygote. , 1985, Ophthalmic paediatrics and genetics.

[39]  M. Brys,et al.  Small Fiber Dysfunction Predominates in Fabry Neuropathy , 2002, Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society.

[40]  P. Ashton-Prolla,et al.  Nerve conduction studies, electromyography and sympathetic skin response in Fabry's disease , 2003, Journal of the Neurological Sciences.

[41]  A. Boulton,et al.  Corneal Sensitivity Is Reduced and Relates to the Severity of Neuropathy in Patients With Diabetes , 2007, Diabetes Care.