History

Fact Explanation
Family history [4] As the disease is genetically determined, family history is important. CMT 1 and CMT 2 are inherited as autosomal dominant neuropathies (HMSN type 2B (Charcot-Marie-Tooth syndrome type 2B) and HSN type 1) and genetic loci are identified as chromosomes 3q13-22 and 9q22.1-22.3, respectively. But there's a genetic heterogeneity. Also autosomal recessive, X-linked inherited conditions are identified. The HMSN classification of Dyck is used for classification. [4]
Gait disturbances [2] [6] Usually these symptoms start as early as 2nd year of life but can be delayed till 5th decade. The cause is due to demyelination and/or axonal loss of the peripheral nerves. As a result there is progressive weakness of the distal musculature particularly peroneal muscular atrophy which is accompanied by progressive weakness of dorsiflexion of the ankle and eventual foot drop. Pes cavus, Pes planus, and/or hammer toes deformities invariably develop as well further destabilizing the gait [2] [6]
Proximal muscle weakness [2] This is a late manifestation and axial muscles are usually spared. [2]
Tingling or burning sensations of the feet [2] This is due to involvement of sensory nerves but some may complain of loss of pain and temperature sensation or loss of all sensory modalities at the onset of the disease. In the early stages of the disease, only toes are affected but later spread to the distal parts of the lower limbs, and can extend up to the knees. [2]
Spontaneous pain [2] This usually occurs in the feet, legs, thighs, hands, or even shoulders. [2]
Easy traumatization, foot ulcers, painless burns [2] Due to reduced muscle mass and sensory disturbance, the nerves are vulnerable to trauma and compression. [2]
Disturbed sweating [2] Hypohidrosis, hyperhidrosis, or anhidrosis occurs as the commonest feature of autonomic nervous system dysfunction. however hypotension, erectile dysfunction, and disturbed lacrimation rarely occur [2]
progressive deafness/ complete deafness [2] [5] This is due to a unique point mutation in PMP22 which causes progressive auditory nerve deafness in addition. [2] [5]
References
  1. AUER-GRUMBACH MICHAELA. Hereditary sensory neuropathy type I. Array [online] 2008 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-3-7
  2. AUER-GRUMBACH MICHAELA, DE JONGHE PETER, VERHOEVEN KRISTIEN, TIMMERMAN VINCENT, WAGNER KLAUS, HARTUNG HANS-PETER, NICHOLSON GARTH A.. Autosomal Dominant Inherited Neuropathies With Prominent Sensory Loss and Mutilations. Arch Neurol [online] 2003 March [viewed 22 September 2014] Available from: doi:10.1001/archneur.60.3.329
  3. TIMMERMAN V, STRICKLAND AV, ZüCHNER S. Genetics of Charcot-Marie-Tooth (CMT) Disease within the Frame of the Human Genome Project Success Genes (Basel) [online] , 5(1):13-32 [viewed 22 September 2014] Available from: doi:10.3390/genes5010013
  4. GABREëLS-FESTEN A. Dejerine-Sottas syndrome grown to maturity: overview of genetic and morphological heterogeneity and follow-up of 25 patients J Anat [online] 2002 Apr, 200(4):341-356 [viewed 22 September 2014] Available from: doi:10.1046/j.1469-7580.2002.00043.x
  5. KOVACH MJ, LIN JP, BOYADJIEV S, CAMPBELL K, MAZZEO L, HERMAN K, RIMER LA, FRANK W, LLEWELLYN B, JABS EW, GELBER D, KIMONIS VE. A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet [online] 1999 Jun, 64(6):1580-93 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/10330345
  6. FERRARIN M, LENCIONI T, RABUFFETTI M, MORONI I, PAGLIANO E, PAREYSON D. Changes of gait pattern in children with Charcot-Marie-Tooth disease type 1A: a 18 months follow-up study J Neuroeng Rehabil [online] :65 [viewed 22 September 2014] Available from: doi:10.1186/1743-0003-10-65

Examination

Fact Explanation
Palpably enlarged nerves [3] Due to hypertrophy of affected nerves due to demyelination followed by attempts of remyelination [3]
Wasting of the muscles in the anterior compartment of the lower legs [1] [2] Due to peroneal muscle atrophy [1] [2]
Weakness of dorsiflexion of the ankle and an ultimate foot drop [1] [2] Due to peroneal muscle atrophy [1] [2]
Ankle contractures and painful Pes cavus, planus, hammer toe deformities [2] [4] Due to denervation of intrinsic foot muscles [2] [4]
Contractures of the wrists and ultimately a claw hand [5] Due to wasting of forearm and hand muscles [5]
Lost tendon reflexes [1] Due to demyelination and/or axonal loss of the peripheral nerves. Knee jerk is often preserved or even brisk but disappear with progression of the disease, however Achilles tendon reflexes are diminished or absent [1]
Reduced sensation in the feet [1] Loss pain and temperature is prominenet but complete loss of touch-pressure sensation can occur with proprioception affected in some. Vibration sense maybe preserved for a long time [1]
Spasticity of lower limbs [1] This is not common but can occur in the form of HSN with spastic paraplegia.[1]
References
  1. AUER-GRUMBACH MICHAELA, DE JONGHE PETER, VERHOEVEN KRISTIEN, TIMMERMAN VINCENT, WAGNER KLAUS, HARTUNG HANS-PETER, NICHOLSON GARTH A.. Autosomal Dominant Inherited Neuropathies With Prominent Sensory Loss and Mutilations. Arch Neurol [online] 2003 March [viewed 22 September 2014] Available from: doi:10.1001/archneur.60.3.329
  2. BURNS J, OUVRIER R, ESTILOW T, SHY R, LAURá M, EICHINGER K, MUNTONI F, REILLY MM, PAREYSON D, ACSADI G, SHY ME, FINKEL RS. Symmetry of foot alignment and ankle flexibility in paediatric Charcot-Marie-Tooth disease. Clin Biomech (Bristol, Avon) [online] 2012 Aug, 27(7):744-7 [viewed 22 September 2014] Available from: doi:10.1016/j.clinbiomech.2012.02.006
  3. POGSON D.. Prolonged vecuronium neuromuscular blockade associated with Charcot Marie Tooth neuropathy. [online] 2000 December, 85(6):914-917 [viewed 22 September 2014] Available from: doi:10.1093/bja/85.6.914
  4. BURNS J.. Pes cavus pathogenesis in Charcot-Marie-Tooth disease type 1A. Brain [online] 2006 July, 129(7):E50-E50 [viewed 22 September 2014] Available from: doi:10.1093/brain/awl116
  5. BANCHS ISABEL, CASASNOVAS CARLOS, ALBERTí ANTONIA, DE JORGE LAURA, POVEDANO MóNICA, MONTERO JORDI, MARTíNEZ-MATOS JUAN ANTONIO, VOLPINI VICTOR. Diagnosis of Charcot-Marie-Tooth Disease. Journal of Biomedicine and Biotechnology [online] 2009 December, 2009:1-10 [viewed 22 September 2014] Available from: doi:10.1155/2009/985415

Differential Diagnoses

Fact Explanation
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [1] It produces a symmetrical, progressive, mixed sensory and motor neuropathy and mainly proximal and areflexia. [1]
Guillain-Barre syndrome [2] This is an acute inflammatory polyneuropathy with an autoimmune etiology. This produces a progressive flaccid paralysis with areflexia and variety of motor, sensory and autonomic symptoms [2]
Friedreich Ataxia [3] This has an autosomal recessive inheritance with progressive gait and limb ataxia, absent lower limb reflexes, extensor plantar responses, dysarthria, and reduction in or loss of vibration sense and proprioception (sensory modalities mediated by posterior column neurones) [3]
Spinal Muscular Atrophy [4] This has an autosomal recessive inheritance with degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. [4]
Diabetes Mellitus neuropathy [5] Diabetes mellitus is the most common cause of neuropathy and in DM, a distal symmetrical sensory polyneuropathy is seen and is usually axonal, but can also show demyelinating features on electrophysiology. But in contrast to CMT, diabetic neuropathy has predominantly sensory and autonomic manifestations. [5]
Leprosy [6] In early stages peripheral nerves are affected. M. leprae can invade human peripheral nerves and cause disfigurement and deformity in leprosy [6]
Drug induced polyneuropathy [7] [8] Plant alkaloids, interferons, antimitotics, taxanes, and platinum based compounds, alcohol can cause peripheral neuropathy [7] [8]
Toxic, metabolic. vitamin deficiency induced polyneuropathy [9] [10] [11] Lead, organophosphate, arsenic, thallium can cause a polyneuropathy. As well as uremia, thyroid disease, porphyria, amyloidosis can cause polyneuropathy. Vitamin B1, B6, B12, nicotinic acid deficiency can result this as well [9] [10] [11]
Polyneuropathy due to vasculitis [12] SLE, Polyarteritis nodisa, Churg Strauss syndrome can also cause a polyneuropathy [12]
Myopathy [13] Sometimes muscle disease can also cause features similar to polyneuropathy [13]
Refsum Disease [14] This is a rare disease with a clinical onset of 4 and 7 yr of age, with intermittent motor and sensory neuropathy, Ataxia, progressive neurosensory hearing loss, retinitis pigmentosa and loss of night vision, ichthyosis, and liver dysfunction also develop in various degrees [14]
HIV induced polyneuropathy [15] HIV can cause several demyelinating polyneuropathies and antiretroviral drugs themselves can also cause polyneuropathies [15]
References
  1. OVERELL J. R, WILLISON H. J. Chronic inflammatory demyelinating polyradiculoneuropathy: classification and treatment options. Practical Neurology [online] 2006 April, 6(2):102-110 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.2006.089433
  2. GONZáLEZ-SUáREZ INéS, SANZ-GALLEGO IRENE, RODRíGUEZ DE RIVERA FRANCISCO, ARPA JAVIER. Guillain-Barré Syndrome: Natural history and prognostic factors: a retrospective review of 106 cases. Array [online] 2013 December [viewed 22 September 2014] Available from: doi:10.1186/1471-2377-13-95
  3. DELATYCKI M. B. Friedreich ataxia: an overview. [online] 2000 January, 37(1):1-8 [viewed 22 September 2014] Available from: doi:10.1136/jmg.37.1.1
  4. D'AMICO ADELE, MERCURI EUGENIO, TIZIANO FRANCESCO D, BERTINI ENRICO. Spinal muscular atrophy. Array [online] 2011 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-6-71
  5. BANSAL V, KALITA J, MISRA UK. Diabetic neuropathy Postgrad Med J [online] 2006 Feb, 82(964):95-100 [viewed 22 September 2014] Available from: doi:10.1136/pgmj.2005.036137
  6. SHARMA R., LAHIRI R., SCOLLARD D. M., PENA M., WILLIAMS D. L., ADAMS L. B., FIGAROLA J., TRUMAN R. W.. The armadillo: a model for the neuropathy of leprosy and potentially other neurodegenerative diseases. Disease Models & Mechanisms [online] December, 6(1):19-24 [viewed 22 September 2014] Available from: doi:10.1242/dmm.010215
  7. GROSSET K A. Prescribed drugs and neurological complications. Journal of Neurology, Neurosurgery & Psychiatry [online] 2004 September, 75(suppl_3):iii2-iii8 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.2004.045757
  8. GRISOLD W., CAVALETTI G., WINDEBANK A. J.. Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. Neuro-Oncology [online] December, 14(suppl 4):iv45-iv54 [viewed 22 September 2014] Available from: doi:10.1093/neuonc/nos203
  9. RUBENS O. Peripheral neuropathy in chronic occupational inorganic lead exposure: a clinical and electrophysiological study. [online] 2001 August, 71(2):200-204 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.71.2.200
  10. WILLISON H, WINER J. CLINICAL EVALUATION AND INVESTIGATION OF NEUROPATHY J Neurol Neurosurg Psychiatry [online] 2003 Jun, 74(Suppl 2):ii3-ii8 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.74.suppl_2.ii3
  11. BECKER DANIELLE A., BALCER LAURA J., GALETTA STEVEN L.. The Neurological Complications of Nutritional Deficiency following Bariatric Surgery. Journal of Obesity [online] 2012 December, 2012:1-8 [viewed 22 September 2014] Available from: doi:10.1155/2012/608534
  12. LEVY Y. Intravenous immunoglobulins in peripheral neuropathy associated with vasculitis. Annals of the Rheumatic Diseases [online] 2003 December, 62(12):1221-1223 [viewed 22 September 2014] Available from: doi:10.1136/ard.2002.003996
  13. OSKARSSON B.. Myopathy: Five New Things. Neurology [online] December, 76(Issue 7, Supplement 2):S14-S19 [viewed 22 September 2014] Available from: doi:10.1212/WNL.0b013e31820c3648
  14. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-9-38
  15. ROSENBERG N R. Diagnostic investigation of patients with chronic polyneuropathy: evaluation of a clinical guideline. [online] 2001 August, 71(2):205-209 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.71.2.205

Investigations - for Diagnosis

Fact Explanation
Full blood count and blood picture [1] [5] This is done to exclude anemia due to vitamin B12 deficiency and blood picture may show oval macrocytes in vitamin B12 deficiency and lead poisoning may show microcytic hypochromic anemia [1] [5]
Erythrocyte sedimentation rate [1] This is often elevated in connective tissue diseases [1]
Fasting blood sugar [1] [3] This is done to exclude polyneuropathy due to diabetes mellitus [1] [3]
Thyroid function tests [1] This is done to exclude polyneuropathy due to hypo or hyperthyrodism [1]
Renal function tests- Serum creatinine, Blood urea nitrogen [4] This is done to exclude polyneuropathy due to uremia [4]
Serum Vitamin B12 level [1] This is done to exclude vitamin B12 deficiency causing polyneuroapthy [1]
Serum Anti nuclear antobodies, Anti-DNA antibodies, Anti-Sm antibodies and Anti-phospholipid antibodies [1] These tests are done mainly to exclude connective tissue disorders such as SLE, Polyarteritis nodosa [1]
HIV screening [4] To exclude HIV causing polyneuropathy [4]
Nerve conduction studies [2] Motor and sensory nerve conduction velocities are very much reduced and nerve Conduction Velocity (NCV) in the motor median nerve is used to divide autosomal dominant CMT into CMT1 (<38 m/s), CMT2 (>38 m/s) and dominant intermediate CMT (25–45 m/s). Autosomal recessive CMT is called CMT4 and X-linked CMT CMTX independent of the NCV [2]
Electromyography (EMG) [6] This can help to detect active axonal damage, with spontaneous muscle fiber activity at rest (denervation). In neuropathic conditions, reinnervation changes are also seen [6]
Cerebrospinal fluid (CSF) for protein [1] May be elevated, but no cells appear in the CSF. It also useful to distinguish immune mediated neuropathies such as CIDP or chronic immune mediated axonal neuropathies where the CSF protein is raised. [1]
Sural nerve biopsy [1] [4] Characteristic onion bulb formations of proliferated Schwann cell cytoplasm surround axons is seen and this pathologic finding is called interstitial hypertrophic neuropathy. In addition large- and medium-sized myelinated fibers are reduced in number, collagen is increased, and extensive segmental demyelination and remyelination also occur [1]
Genetic analysis [2] CMT1A is predominantly caused by a 1.5 Mb duplication on chromosome 17p11.2 that includes the PMP22 gene. But due to the clinical and genetic heterogeneity, the low sensitivity of genetic testing for CMT2 and scarcity of clinical data, CMT can be difficult to be diagnosed by genetic testing always. [2]
References
  1. WILLISON H, WINER J. CLINICAL EVALUATION AND INVESTIGATION OF NEUROPATHY J Neurol Neurosurg Psychiatry [online] 2003 Jun, 74(Suppl 2):ii3-ii8 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.74.suppl_2.ii3
  2. ØSTERN R, FAGERHEIM T, HJELLNES H, NYGåRD B, MELLGREN SI, NILSSEN Ø. Diagnostic laboratory testing for Charcot Marie Tooth disease (CMT): the spectrum of gene defects in Norwegian patients with CMT and its implications for future genetic test strategies BMC Med Genet [online] :94 [viewed 22 September 2014] Available from: doi:10.1186/1471-2350-14-94
  3. SINGLETON J. R., SMITH A. G., BROMBERG M. B.. Increased Prevalence of Impaired Glucose Tolerance in Patients With Painful Sensory Neuropathy. Diabetes Care [online] 2001 August, 24(8):1448-1453 [viewed 22 September 2014] Available from: doi:10.2337/diacare.24.8.1448
  4. ROSENBERG N R. Diagnostic investigation of patients with chronic polyneuropathy: evaluation of a clinical guideline. [online] 2001 August, 71(2):205-209 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.71.2.205
  5. MANI J., CHAUDHARY N., KANJALKAR M., SHAH P. U. Cerebellar ataxia due to lead encephalopathy in an adult. Journal of Neurology, Neurosurgery & Psychiatry [online] 1998 November, 65(5):797-798 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.65.5.797
  6. MILLS K R. The basics of electromyography. Journal of Neurology, Neurosurgery & Psychiatry [online] 2005 June, 76(suppl_2):ii32-ii35 [viewed 22 September 2014] Available from: doi:10.1136/jnnp.2005.069211

Investigations - Fitness for Management

Fact Explanation
Full blood count [1] [2] To detect and correct any anemia prior to surgery [1] [2]
Coagulation studies [1] [2] To detect and correct any coagulopathy before surgical management [1] [2]
Renal function tests- Serum creatinine, Blood urea nitrogen [1] [2] To determine any renal dysfunction prior to anesthesia [1] [2]
References
  1. KUMAR A, SRIVASTAVA U. Role of routine laboratory investigations in preoperative evaluation J Anaesthesiol Clin Pharmacol [online] 2011, 27(2):174-179 [viewed 22 September 2014] Available from: doi:10.4103/0970-9185.81824
  2. SHULMAN M. A., THOMPSON B. R.. I. Not fit for a haircut ... how should we assess fitness and stratify risk for surgery?. British Journal of Anaesthesia [online] December, 112(6):955-957 [viewed 22 September 2014] Available from: doi:10.1093/bja/aeu003

Investigations - Followup

Fact Explanation
Foot care [1] Foot ulcers in HSMN are similar to diabetic neuropathic ulcers therefore called "pseudodiabetic foot syndrome". Careful follow up similar to a diabetic foot is needed with treatment of foot ulcers and infections [1]
References
  1. AUER-GRUMBACH MICHAELA. Hereditary sensory neuropathy type I. Array [online] 2008 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-3-7

Management - General Measures

Fact Explanation
Patient education [2] Education regarding the course of the disease, prognosis and the extent of exercise capacity should be explained. [2]
Psychological support [2] Group and family counseling may be beneficial and patients should be referred to support groups for psychological support and problem solving. If necessary, a patient should be referred to a mental health professional [2]
Genetic counseling [1] [3] As there's often a family history genetic counseling may help to prevent new cases [1]
Prenatal diagnosis [1] [3] When the disease causing mutation is known, this maybe helpful. When a patient is male, artificial insemination with donor sperm can be discussed with the couple. [1]
Physiotherapy [3] Patients with CMT appeared to benefit significantly from a strengthening programme and help to reduce muscle wasting, and deformities and contractures [3]
Occupational therapy [3] This may help to carry out day to day activities [3]
Avoidance of certain neurotoxic agents [3] Especially vincristine, can have a devastating effect, even in low dose therefore should be avoided [3]
Optimal control of blood sugar level [3] Because co-existence of diabetes mellitus in a CMT1A patient can exacerbate symptoms of the peripheral neuropathy [3]
Medical treatment with Phenytoin or Carbamezapine [3] For burning paresthesias of the feet [3]
Protection of the leg from compression neuropathies [4] Placement of soft pillows beneath or between the lower legs [4]
Supportive care for the legs with stabilization of the ankles [3] This includes exercise training, shoe inlays, orthopaedic shoes and orthoses for stabilization of ankles. Wearing a thumb opposition splint may improve manual dexterity in CMT [3]
Foot care [1] Proper foot care should be taken and patients should be educated on foot care, and early treatment of infections, ulcers should be done. Properly fitted foot wear should be worn [1]
References
  1. AUER-GRUMBACH MICHAELA. Hereditary sensory neuropathy type I. Array [online] 2008 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-3-7
  2. AXELROD FELICIA B, GOLD-VON SIMSON GABRIELLE. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Array [online] 2007 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-2-39
  3. VAN PAASSEN BARBARA W, VAN DER KOOI ANNEKE J, VAN SPAENDONCK-ZWARTS KARIN Y, VERHAMME CAMIEL, BAAS FRANK, DE VISSER MARIANNE. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies. Array [online] 2014 December [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-9-38
  4. FLOR-DE-LIMA FILIPA, MACEDO LILIANA, TAIPA RICARDO, MELO-PIRES MANUEL, RODRIGUES MARIA LURDES. Hereditary Neuropathy with Liability to Pressure Palsy: A Recurrent and Bilateral Foot Drop Case Report. Case Reports in Pediatrics [online] 2013 December, 2013:1-5 [viewed 22 September 2014] Available from: doi:10.1155/2013/230541

Management - Specific Treatments

Fact Explanation
Surgical interventions [2] [3] Flexor Digitorum Superficialis Opposition tendon transfer has showed improved hand function, reduce disability, and improve quality of life. Surgical fusion of the ankle can also be done [2] [3]
Neurotrophin-3 (NT-3) [1] Treatment with this led to slight improvement of sensory and reflex scores in CMT1A patients. NT-3 therapy resulted in measurable NT-3 secretion levels in blood and improvement in motor function, histopathology, and electrophysiology of the peripheral nerves [1]
Ultrasound guided nerve block for post operative pain [3] These may help in hypertrophic peripheral neuropathy [Charcot–Marie–Tooth disease type 1 (CMTD1)] to alleviate the severe post operative pain [3]
References
  1. VAN PAASSEN BW, VAN DER KOOI AJ, VAN SPAENDONCK-ZWARTS KY, VERHAMME C, BAAS F, DE VISSER M. PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies Orphanet J Rare Dis [online] :38 [viewed 22 September 2014] Available from: doi:10.1186/1750-1172-9-38
  2. ESTILOW T, KOZIN SH, GLANZMAN AM, BURNS J, FINKEL RS. Flexor digitorum superficialis opposition tendon transfer improves hand function in children with Charcot-Marie-Tooth disease: Case series Neuromuscul Disord [online] 2012 Dec, 22(12):10.1016/j.nmd.2012.07.011 [viewed 22 September 2014] Available from: doi:10.1016/j.nmd.2012.07.011
  3. BARBARY J. B., REMERAND F., BRILHAULT J., LAFFON M., FUSCIARDI J.. Ultrasound-guided nerve blocks in the Charcot-Marie-Tooth disease and Friedreich's ataxia. British Journal of Anaesthesia [online] December, 108(6):1042-1043 [viewed 22 September 2014] Available from: doi:10.1093/bja/aes160