UMEÅ UNIVERSITY MEDICAL DISSERTATIONS Chronic Exertional Compartment Syndrome of the lower leg A novel diagnosis in diabetes mellitus A clinical and morphological study of diabetic and non-diabetic patients David Edmundsson Umeå 2010 From the Department of Surgery and Perioperative Science, Division of Orthopaedics, Umeå University Hospital and Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, SWEDEN UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New series no: 1334 ISSN 0346-6612 ISBN 978-91-7264-957-6 Department of Surgery and Perioperative Science, Division of Orthopaedics, Umeå University Hospital and Department of Integrative Medical Biology, Section For Anatomy, Umeå University, Umeå, SWEDEN 2 To my wife Thorey and my son Jonathan 3 TABLE OF CONTENTS ABBREVATIONS..................................................................................................................... 6 POPULÄRVETENSKAPLIG SAMMANFATTNING............................................................. 7 ABSTRACT............................................................................................................................... 8 ORIGINAL PAPERS.................................................................................................................9 INTRODUCTION.................................................................................................................... 10 COMPARTMENT SYNDROMES.......................................................................................... 10 CHRONIC EXERTIONAL COMPARTMENT SYNDROME .............................................. 10 History................................................................................................................................... 10 Symptoms and signs.............................................................................................................. 11 Muscle morphology............................................................................................................... 11 Pathophysiology.................................................................................................................... 12 Diagnosis............................................................................................................................... 12 Intramuscular pressure measurements .................................................................................. 13 Pressure levels indicating CECS........................................................................................... 14 Treatment, prognosis and complications............................................................................... 14 Differential diagnosis ............................................................................................................ 17 DIABETES MELLITUS.......................................................................................................... 17 Diabetic complications......................................................................................................... 18 Leg disorders in DM ............................................................................................................ 19 THE ANATOMY OF THE LOWER LEG.............................................................................. 19 MUSCLE STRUCTURE ......................................................................................................... 20 Muscle fibers........................................................................................................................ 20 Muscle fiber composition..................................................................................................... 21 Muscle capillarization .......................................................................................................... 22 Muscle plasticity .................................................................................................................. 22 AIMS OF THE STUDY........................................................................................................... 23 PATIENTS AND METHODS................................................................................................. 24 Patients ................................................................................................................................. 24 CLINICAL EVALUATION .................................................................................................... 26 Criteria for diagnosis of CECS............................................................................................. 26 Reproduction of symptoms .................................................................................................. 27 Measurements of IMP .......................................................................................................... 27 4 Treatment with fasciotomy.................................................................................................... 27 MUSCLE BIOPSIES ............................................................................................................... 28 METHODS FOR ANALYSIS FOR MUSCLES..................................................................... 28 Immunohistochemistry.......................................................................................................... 28 Enzyme-histochemistry......................................................................................................... 29 Fiber classification ................................................................................................................ 29 Morphometric analysis.......................................................................................................... 30 Capillary variables................................................................................................................. 30 Statistical analysis ................................................................................................................. 30 RESULTS................................................................................................................................. 31 CECS IN UNSELECTED PATIENTS WITH EXERTIONAL LOWER LEG PAIN............ 31 CECS IN PATIENTS WITH DIABETES MELLITUS .......................................................... 32 BASELINE MUSCLE MORPHOLOGY ................................................................................ 34 Muscle pathology .................................................................................................................. 34 Fibertypes and their mitochondrial oxidative capacity ......................................................... 34 Relative frequency of fiber phenotypes, fiber area and variability in fiber size ................... 34 Muscle capillarization ........................................................................................................... 35 MORPHOLOGY AT FOLLOW-UP 1 YEAR AFTER FASCIOTOMY................................ 37 Muscle pathology .................................................................................................................. 37 Fibertypes and their mitochondrial oxidative capacity ......................................................... 38 Relative frequency of fiber phenotypes, fiber area and variability in fiber size ................... 39 Muscle capillarization ........................................................................................................... 39 DISCUSSION .......................................................................................................................... 39 Main findings ........................................................................................................................ 39 CECS in diabetes mellitus..................................................................................................... 40 Clinical implications ............................................................................................................. 41 Why does CECS occur in diabetes patients? ........................................................................ 42 Muscle alterations in diabetes patients with CECS............................................................... 43 CECS in non-diabetic patients .............................................................................................. 44 Pathophysiological theories in non-diabetic patients............................................................ 45 SUMMARY ............................................................................................................................. 48 ACKNOWLEDGEMENTS ..................................................................................................... 49 REFERENCES......................................................................................................................... 50 5 ABBREVATIONS AGE Advanced glycosylated end products ATP Adenosine triphosphatase CAFA Capillaries around fibers related to its cross sectional area CAF Capillaries around fibers CECS Chronic exertional compartment syndrome CD Capillary density CT Computed tomography CV Coefficient of variation DM Diabetes mellitus IMP Intramuscular pressure mAb Monoclonal antibody MRI Magnetic resonance imaging MyHC Myosin heavy chain NADH-TR Nicotineamide adenine dinucleotide-tetrazolinium reductase NIRS Near-infrared spectroscopy SD Standard deviation 6 SAMMANFATTNING Kroniskt kompartmentsyndrom (KKS) i underbenen, ett tillstånd med ansträngningsutlöst smärta orsakad