Among the many diseases with known genetic origin, some are degenerative and affect two important things to providing what many humans cherish most: Life and Independence. These are the neurons and nerves that control the muscles, and the muscles. The diseases that affect them are known as Neuromuscular diseases (NMDs).1

Currently close to 40 NMDs are known, catalogued into two groups (Neuropathies and Myopathies) designated by the type of tissue that is affected. In the case of Myopathies, there are Muscular Dystrophies, Inflammatory Myopathies, Metabolic Myopathies caused by endocrine abnormalities. In case of Neuropathies, there are Motor Neuron Diseases,            Neuromuscular Junction Disorders and Peripheral Nerve Disorders.1

Among these, Muscular Dystrophies in their diverse forms constitute the most common group of NMDs which are well known and widespread around the world. As such, Muscular Dystrophy is used traditionally (though sometimes inappropriately) to refer to more than 40 Neuromuscular Diseases. The Muscular Dystrophies are currently classified into 9 types (Duchenne, Becker, Limb-Girdle, Fascioscapulohumeral, Congenital, Oculopharyngeal, Distal, Emery-Dreifuss and Myotonic), and some of these are categorised into further subtypes.1 Each of these types and subtypes has a different genetic origin and a defect in some gene that causes the absence, flaw, or deficiency of one of the proteins necessary for muscular function, bringing with it deterioration and progressive destruction of the muscle tissue. These entities vary greatly in severity of presentation; however, many of their indications for anesthesiologists are similar.2,3

Muscular Dystrophy
Duchenne Muscular Dystrophy (DMD)
It is the most common childhood muscular dystrophy with an incidence of 1:3500 live births. An X-linked recessive disorder, it appears in childhood with progressive wasting and weakness usually of the proximal muscles. It becomes fatal by late adolescence from respiratory or cardiac failure. Sufferers may present with a waddling gait and pseudohypertrophy of calf muscles between the ages of 3 and 5. It also accounts for cardiac manifestations and slight mental retardation. DMD is progressive. Although a neonate with DMD may appear normal, serum creatine kinase (CK) will be elevated. A positive family history (90%) and delayed motor milestones are evident: late walkers, difficulty in climbing stairs by age 5. Affected males are often wheelchair bound before their teens and suffer from contractures, marked scoliosis, restrictive lung function and cardiomyopathies with up to 50% of sufferers having a dilated cardiomyopathy by the age of 15. Death occurs from cardiac or respiratory failure in the second or third decade.4,5,6

Those with the disorder lack dystrophin—a protein that helps to anchor muscle cells to the extra-cellular matrix. In 1985, Kunkel and colleagues discovered the gene coding for dystrophin, which in Duchenne muscular dystrophy is defective. This leads to the absence of dystrophin expressed within the sarcolemma, rendering the sarcolemma weak. Muscle fibres are then inadequately tethered and these fibres then become replaced with fibrous connective
tissue leading to the pseuodhypertrophy seen. The sarcolemma also becomes increasingly permeable, with increased intracellular calcium levels.6

Pre-operative evaluation: 7

• ECG: Right ventricular strain, tall R waves, deep Q waves and inverted T waves.
• Echocardiogram: Ventricular systolic dysfunction progressing to dilated cardiomyopathy.

  (Limiting physical activity)

• PFT: If the vital capacity (VC) < 30%, there would be a very high Pulmonary risk
• Blood gases: Hypoxaemia and CO2 retention suggest necessity of postoperative ventilation.
• Elevated CK levels: Would most likely be 50 - 300 times the normal levels.

Anaesthetic concerns: 7
The clinical manifestations of DMD are bimodal: During early childhood when skeletal muscle is being destroyed, rhabdomyolysis and hyperkalaemia can occur in response to triggers.

• Suxamethonium is contraindicated. It has been implicated in intra-operative cardiac arrests
secondary to Rhabdomyolysis and hyperkalemia.
• Can inhalational agents cause hyperkalaemic arrest? There are continued reports of arrest,
even during the recovery period. The most ‘at risk’ group is the patients under eight years of
age, with still some muscle generation. This Anaesthetic-Induced Rhabdomyolisis (AIR) is
unrelated to Malignant Hyperthermia.
• Ensure a trigger-free anaesthetic and “clean” anaesthesia machine. Most literature reviews
suggest a total Intravenous technique
• Minimise cardiac and respiratory depression. Prone positioning and large blood losses may
unmask cardiac Dysfunction dramatically.
• Drugs should be short-acting and rapidly metabolised. There is an increased sensitivity to
non-depolarising muscle relaxants. Use opioids sparingly.
• Close post-operative monitoring is needed and ventilation is often indicated.
19
Becker’s Muscular Dystrophy (BMD)
This is the second most common form of dystrophy, occurring in 1:30000 live male births. Dystrophin is abnormal, but still partly functional.The dystrophy is much milder with a slower onset. However, these patients can develop severe cardiac manifestations. Symptoms start at around 11 years of age, often with a history of delayed motor milestones for walking, running and jumping. Later, they struggle with climbing stairs or getting up, fall frequently or walk on their toes.7

The disorders of dystrophin including DMD and BMD result in progressive end-organ dysfunction thereby possessing several perioperative challenges. Specific perioperative concerns include the potential for difficult airway management in patients with DMD because of macroglossia, 8 co-morbid cardiac disease with alterations in conduction and contractility, reduced pulmonary capacity, rhabdomyolysis, and an increased sensitivity to various anesthetic agents. The primary cause of mortality remains cardiac thereby emphasizing the need for a thorough preoperative evaluation of myocardial contractility and conduction. Perioperative respiratory insufficiency may result from pre-existing skeletal muscle weakness, upper airway issues or sensitivity to anesthetic agents. Patients with a significant diminution in preoperative respiratory function may benefit from a transition to non-invasive ventilation following tracheal extubation. Additional concerns include the potential for morbidity related to choice of anesthetic agents. Increased sensitivity to non-depolarizing neuromuscular blocking agents should be expected while succinylcholine is absolutely contraindicated. Given the increased life expectancy of these patients, their need for perioperative care continues to increase.9

Theoretical concerns have also been raised with the use of propofol and its effects on mitochondrial oxidative function as there is a known defect in mitochondrial oxidative capacity in the dystrophinopathies.10 Rhabdomyolysis that has been postulated to be due to
disruption of mitochondrial fatty acid oxidation has been reported with prolonged propofol infusion in the Pediatric ICU setting and there is a known defect in mitochondrial oxidative capacity in the muscular dystrophies.11,12 Despite such concerns, TIVA with propofol and a synthetic opioid remains the most commonly chosen anesthetic regimen. Especially when used in combination, the hemodynamic effects of these agents which can result in a decrease in SVR and depressed myocardial function must be considered especially in patients with co-morbid cardiac disease.

Pre-operative evaluation:7
• ECG/echocardiogram: Dilated cardiomyopathy often presents before skeletal muscle    
symptoms and arrhythmias can also occur.
• Respiratory: Optimise chest infections and assess function (deterioration may occur as a
result of scoliosis, Muscle weakness and aspiration pneumonia)
• Post-operative ventilatory assistance may be necessary.
• CK level elevation will be less marked than DMD: 50 - 100 times.

Anaesthetic concerns
The main anesthetic implications of DMD and BMD are related to the profound myopathies. As would be expected in patients with muscle weakness, significant postoperative respiratory insufficiency can result from either disease. Cardiac muscle and conduction are also involved and drugs that further depress cardiac function, or which increase the likelihood of arrhythmias, should be avoided. All patients with DMD or BMD should receive a full cardiology evaluation and PFTs prior to any surgery. Lastly, dysphagia is common and gastric motility may be decreased requiring expedient control of the airway. The association of malignant hyperthermia with DMD and BMD appears to be coincidental only. Both DMD and BMD patients can have rhabdomyolysis and hyperkalemia in response to succinylcholine; thus succinylcholine is contraindicated in these patients. It is unclear whether volatile anesthetics alone can cause rhabdomyolysis in these patients.13

Other forms of congenital muscular dystrophy exist that also involve other proteins necessary for attaching the contractile machinery to the extracellular matrix. While this is a heterogeneous group of mutations, it is probably best to treat these patients as if they had DMD. These are discussed below.

Facioscapulohumeral (FSH), Emery-Dreifuss (ED) & Limb girdle muscular dystrophy (LG) - The most common remaining dystrophies are much milder in their presentations14

FSH is one of the most common muscular dystrophies, but the molecular basis of FSH is unknown. FSH is the most benign muscular dystrophy usually with little respiratory involvement.15  However, the neck, face and scapular stabilizing muscles are often weak, and the ability to raise the head may be of little use in determining respiratory muscle strength. Importantly, these patients may lose the ability to swallow well and therefore be unable to protect their airway during emergence from anesthesia.

Emery-Dreifuss dystrophy may result from multiple causes. The most common form of ED usually has its onset in the teenage years and results from mutations in emerin, an inner nuclear membrane protein which interacts with laminin (part of the nuclear matrix) and transcription regulators. These patients have cardiac conduction defects, cardiomyopathy, contractures (positioning problems) and often a fusion of C3-C5 resulting in a less mobile neck (difficulty during intubation).16

Limb-girdle dystrophy results from mutations in several proteins (at least 11 known), such as α-sarcoglycan, which associate with dystrophin. LG is associated with some respiratory muscle weakness and significant cardiac conduction abnormalities. At least some cases of LG result from a defect in a protein which interacts with muscle cell membrane and is implicated in membrane repair.17

Anesthetic Concerns:
There is little experience in the literature on the interaction of anesthetics with LG dystrophy.18  In all three forms of muscular dystrophy, succinylcholine should be avoided as hyperkalemia can result. MH is not reported in these three milder forms of muscular dystrophy. Thus, though not universal, the recurring themes with muscular dystrophy are to avoid succinylcholine, to watch for respiratory depression, and to avoid cardiac depressants and arrhythmogenic drugs.

It is important to note that anesthetic complications have been reported in most of these forms of muscular dystrophy.19 These episodes most commonly result from a hyperkalemic episode and sudden cardiac arrest may occur. Such events can occur in patients who are still in a subclinical stage of their disease and in whom the crisis may be the first manifestation. For this reason, many clinicians reserve their use of succinylcholine in all patients to only those cases in which there exists a specific indication for their use.

Other Dystrophies
More than 30 different forms of congenital muscular dystrophy are now known, and are caused by defects in a wide array of components of the basement cell membrane and extracellular matrix.20 These are not discussed in detail as their clinical implications are similar to each other. Examples are the absence of laminin, or a related protein merosin, which give rise to similar forms of congenital dystrophies. These often have profound effects both on skeletal muscle and the nervous system.

Postoperative Care In Muscular Dystrophies
Extubation should not occur until the patient is able to maintain adequate tidal volumes and airway reflexes have returned, as respiratory failure and aspiration are common. Post operatively careful monitoring must be continued and there is a low threshold to manage these patients in a high dependency or intensive care environment. Hypoxia, hyperkalaemia, rhabdomyolysis, electrolyte disturbance, hypothermia can all have catastrophic consequences in the post-operative period and should be monitored closely. A urine dip for myoglobin or serum CK may be sent to assess level of muscle injury.21

 

Conclusion
Anaesthetic procedures in Muscular Dystrophies have become safer. The reduced administration of suxamethonium as muscle relaxant has led to a decreased incidence of hyperkalaemic induced cardiac arrest in patients with pre-symptomatic muscular dystrophies. TIVA using newer short-acting anaesthetic agents, opioids and non-depolarising muscle relaxants, as well as the more recently introduced volatile anaesthetics sevoflurane and desflurane, accelerate recovery and thus reduce post-operative complications.22

References

• Muscular Dystrophy and Neuromuscular Diseases Day on the Internet Manifesto: www.distrofia-mexico.org/diadm/ingles.htm
• Kerr TP, Duward A, Hodgson SV, Hughes E, Robb SA. Hyperkalaemic cardiac arrest in a manifesting carrier of Duchenne muscular dystrophyfollowing general anaesthesia. Eur J Pediatr. 2001;160:579 –580.
• Schmidt GN, Burmeister MA, Lilje C et al. Acute heart failure during spinal surgery in a boy with Duchenne muscular dystrophy. Br J Anaesth. 2003;90:800-804.
• Klingler W, Lehmann-Horn F, Jurkat-Rott K. Complications of anaesthesia in neuromuscular disorders. Neuromuscul    

Disord 2005; 15: 195–206.

• Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: an old anaesthesia problem revisited. Pediatr Anaesth 2008; 18: 100–6.
• Stevens R. Neuromuscular disorders and anaesthesia. Curr Opin Anaesthesiol 2001; 14: 693–8.
• Dekker E. Anaesthesia and the paediatric patient with neuromuscular disease. S Afr J Anaesthesiol Analg 2010;16(1)
• Gray RM. Anaesthesia and the paediatric muscle disorders. South Afr J Anaesth Analg  2013;19(1)
• H. E. Chen, L. Cripe, J. D. Tobias. Perioperative management of a patient with Becker’s muscular dystrophy. Pediatric Anesthesia and Critical Care Journal 2013; 1(2):50-60
• Hopkins PM. Anaesthesia and the sex-linked dystrophies: between a rock and a hard place   

       Br J Anaesth 2010;104:397-400.

• Vasile B, Rasulo F, Candiani A, Latronico N. Thepathophysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003;29:1417-25.
• Kuznetsov AV, Winkler K, Wiedemann FR, von Bossanyi P, Dietzmann K, Kunz WS. Impaired

              mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mouse.                              
Mol Cell Biochem 1998;183:87-96.

• Phil G. Morgan. Smith’s Anesthesiology for Infants and Children (8th edition); Eds. Davis PJ, Cladis FP, Motoyama EK. (2011), Pub. Elsevier. Chapter 36 Systemic Disorders.
• Emery AE. The muscular dystrophies. Lancet. 2002 Feb 23;359(9307):687-95.
• Fitzsimons RB. Facioscapulohumeral muscular dystrophy. Curr Opin Neurol. 1999;12(5):501-11.
• Aldwinckle RJ, Carr AS. The anesthetic management of a patient with Emery-Dreifuss muscular dystrophy for orthopedic surgery. Can J Anaesth. 2002 May;49(5):467-70.
• Capanni C, Sabatelli P, Mattioli E et al. Dysferlin in a hyperCKaemic patient with caveolin 3 mutation and in C2C12 cells after p38 MAP kinase inhibition. Exp Mol Med. 2003 Dec 31;35(6):538-44.
• Pash MP, Balaton J, Eagle C. Anaesthetic management of a parturient with severe muscular dystrophy, lumbar lordosis and a difficult airway. Can J Anaesth. 1996 Sep;43(9):959-63.
• Farrell PT. Anaesthesia-induced rhabdomyolysis causing cardiac arrest: case report and     

       review of anaesthesia and the dystrophinopathies. Anaesth Intensive Care. 1994 Oct;22(5):597-601.

• Engvall E, Wewer UM. The new frontier in muscular dystrophy research: booster genes. FASEB J. 2003 Sep;17(12):1579-84.
• Nicola Ross, Sarah Marsh. Neuromuscular Disorders & Anaesthesia. Anaesthesia Tutorial of The    

Week 126;23RD March 2009

• Werner Klingler, Frank Lehmann-Horn, Karin Jurkat-Rott. Complications of   

       anaesthesia in neuromuscular disorders. Neuromuscular Disorders 15 (2005) 195–20.