Pediatric Anesthesia ISSN 1155-5645
REVIEW ARTICLE
Anesthetic considerations in myofibrillar myopathy Gregory J. Latham1 & Grace Lopez2 1 Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, USA 2 Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA, USA
Keywords myofibrillar myopathy; pediatric; anesthesia; cardiomyopathy; cardiac arrhythmia; desmin-related myopathy; neuromuscular disease; malignant hyperthermia; rhabdomyolysis Correspondence Gregory J. Latham, Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA 98105-0371, USA Email: gregory. [email protected] Section Editor: Barbara Brandom Accepted 29 July 2014
Summary Myofibrillar myopathy (MFM) is a relatively newly recognized genetic disease that leads to progressive muscle deterioration. MFM has a varied phenotypic presentation and impacts cardiac, skeletal, and smooth muscles. Affected individuals are at increased risk of respiratory failure, significant cardiac conduction abnormalities, cardiomyopathy, and sudden cardiac death. In addition, significant skeletal muscle involvement is common, which may lead to contractures, respiratory insufficiency, and airway compromise as the disease progresses. This study is the first report of anesthetic management of a patient with MFM. We report multiple anesthetic encounters of a child with genetically confirmed BAG3-myopathy, a subtype of MFM with severe childhood disease onset. A review of the anesthetic implications of the disease is provided, with specific exploration of possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to other anesthetic agents.
doi:10.1111/pan.12516
Introduction Myofibrillar myopathies (MFM) are a relatively newly recognized group of chronic myopathies characterized by destruction of the muscle fiber at the Z-disk and accumulation of protein aggregates. Mutations of at least eight different proteins are currently confirmed genetic causes of MFM (1). Most MFM subsets are late onset myopathies with symptoms beginning between 35 and 50 years of age. Most patients present with progressive muscle weakness over the course of years and subsequently progress to debilitating respiratory failure and cardiac disease. However, some patients present in childhood or even infancy with severely progressive disease, including significant contractures, severe cardiomyopathy or arrhythmogenic disease, and respiratory failure (2). Thus far, there have been no reports in the literature of the anesthetic management or implications in adults or children with MFM. Importantly, there have been no reports exploring whether any of the genetic © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
subsets of MFM share anesthetic implications with other neuromuscular disorders, such as the risk of malignant hyperthermia with central core disease and multicore myopathy, rhabdomyolysis with the muscular dystrophies, anesthetic sensitivity with some mitochondrial disorders, and nondepolarizing muscle relaxant sensitivity in many neuromuscular disorders. In this report, the available MFM literature is reviewed, the experience with multiple anesthetics of a child with BAG3 MFM is discussed, and potential anesthetic implications of patients with MFM are explored. Background Genetics Myofibrillar myopathy (MFM), which was first described in 1996 (3), encompasses a clinically and genetically diverse group of progressive neuromuscular diseases characterized by disintegration of myofibrils at the Z-disk, accumulation of myofibrillar degradation products, and eventual loss of architectural and 231
232
CB, conduction block; CM, cardiomyopathy; LGMD1A, limb girdle muscular dystrophy 1A; LGMD2J, limb girdle muscular dystrophy 2J; HMERF, hereditary myopathy with early respiratory failure; SPS, scapuloperoneal syndrome.
Synonym: HMERF Elevated Mild CM 20–35 years old TTN/titin Titinopathy
Distal, proximal, spine
Infancy to 40 years PLEC/plectin Plectinopathy
Facial, limb, trunk
Rare CM
Rare insufficiency in infants Early insufficiency
Elevated
Synonym: reducing body myopathy Possible severe skin blistering Elevated Childhood to 40 years FHL1/FHL1 FHL1opathy
Distal, proximal, SPS
40–70 years old 40–60 years old Childhood ZASP/ZASP FLNC/filamin C BAG3/BAG3 Zaspopathy Filaminopathy BAG3-myopathy
Distal and proximal Proximal > distal limbs Proximal > distal, neck/spine
CM, CB CM, CB, sudden death Severe CM at disease onset CB
Insufficiency
– – Frequent childhood mortality Elevated Elevated Elevated
Synonym: LGMD1A Elevated
Uncommon insufficiency Unknown Insufficiency Severe Uncommon CM MYOT/myotilin Myotilinopathy
Proximal > distal CRYAB/ab-crystallin ab-crystallinopathy
Distal and proximal
Malabsorption, cataracts Elevated Insufficiency
– Elevated Insufficiency
CM, severe CB, sudden death CM, CB, sudden death
Childhood to young adulthood Middle adulthood, rare infantile form 40–60 years old DES/desmin Desminopathy
Distal > proximal, facial
CK levels Respiratory Cardiac Muscle weakness Onset age Gene/protein Disease
Table 1 Myofibrillar myopathies (1,2,5–7,12,17,33–35)
functional integrity of skeletal, cardiac, and smooth muscle (1). Prior to coining the term MFM in 1996, these disorders were previously lumped together under the terms ‘desmin-related myopathies’ or ‘desmin storage myopathies’ (2). Although a multitude of specific mutations have been found, all mutations thus far have been traced to Z-disk-related proteins. The first six identified mutated proteins (followed by gene name) include desmin (DES), ab-crystallin (CRYAB), myotilin (MYOT), Z band alternatively spliced PDZ-containing protein (ZASP), filamin C (FLNC), and Bcl-2-associated athanogene-3 (BAG3). Recently and with some debate (4), three additional protein mutations have been included under the MFM umbrella: four and a half LIM domain protein 1 (FHL1) (5), plectin (PLEC) (6), and titin (TTN) mutations (7). Table 1 provides an overview of the known causes of MFM. Although the technology of genetic testing for subtype analysis of MFM is rapidly expanding, approximately 50% of biopsy-proven MFM patients do not yet have identifiable genetic mutations (8). There is at least partial overlap in pathology and morphology between MFM and some of the other myopathies, and the nomenclature and categorization of MFM and some closely related myopathies continue to evolve as more is discovered every year (4). For instance, hereditary myopathy with early respiratory failure (HMERF) has been reclassified recently as an MFM subtype after mutation to TTN and degradation of the Z-disk were discovered (7). Reducing body myopathy has also been reclassified as a MFM subset recently due to discovery of FHL1 mutation in affected children (5). Yet FHL1 mutations also have been identified to be the cause of non-MFM disorders, including X-linked scapuloperoneal myopathy, X-linked myopathy with postural atrophy, Emery–Dreifuss muscular dystrophy, and rigid spine syndrome (9). Furthermore, limb girdle muscular dystrophy 1E and 2R, which are just 2 of the 31 known subsets of limb girdle muscular dystrophy, have now been found to be due to mutation of desmin and cause MFM; all but one of the remaining 29 subsets is likely not MFM (10,11). At least 67 different mutations to the DES gene have been found in patients with desminopathy alone (1), and the clinical heterogeneity is significant between patients with the same subset of MFM and especially between different subsets of MFM. The inheritance pattern among the subsets of MFM is varied, including autosomal dominant, autosomal recessive, X-linked, and de novo mutations (1,8). The variety in phenotypic presentation of MFM and age of onset is believed to relate, at least partially, to not
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Comment
Anesthetic considerations in myofibrillar myopathy
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
G.J. Latham and G. Lopez
only the specific MFM subtype but also the specific mutation to the affected gene (8). Clinical features Myofibrillar myopathy (MFM) is associated with considerable clinical variability (Table 1). The overall phenotype may resemble that of distal myopathy, limb girdle muscular dystrophy, scapuloperoneal syndrome, generalized myopathy, or isolated muscle myopathy (12). In many but not all cases of MFM, skeletal muscle weakness is the presenting symptom and predominates. Weakness frequently begins in distal lower extremity muscles, followed by progression proximally, with eventual involvement of upper extremity, truncal, neck flexor, facial, bulbar, and respiratory muscles, but other patterns of progression occur in several subtypes or individual patients (8). In some cases, nonskeletal muscle involvement can precede or succeed skeletal muscle pathology. Cardiac involvement is characteristic of desmin, ab-crystallin, FHL1, and BAG3 mutations. Myocardial pathology can manifest as conduction abnormalities, dilated or restrictive cardiomyopathy, and heart failure (1,13). Desmin is a major component in Purkinje fibers, such that desmin mutations especially cause significant cardiac conduction abnormalities that may result in sudden death (14). Respiratory pathology is most often from primary failure of respiratory muscles (15), but scoliosis and subsequent restrictive lung disease are especially common in childhood-onset BAG3 and FLH1 subtypes (12). Most patients with MFM present with gradual onset of muscle weakness in middle adulthood, which eventually progresses to severe disability and premature death. However, recessive inheritance of desminopathy, recessive inheritance of ab-crystallinopathy, FLH1opathy, plectinopathy, and BAG3-myopathy typically cause infantile or childhood disease onset (1). BAG3-myopathy, first described in 2009 (16), is a rare subtype of
Anesthetic considerations in myofibrillar myopathy
MFM, having only been described in a few children. It is hallmarked in all cases by onset in the first decade of life with rapidly progressive axial and limb muscle deterioration, rigid spine, significant contractures, early-onset restrictive and hypertrophic cardiomyopathy, and severe respiratory insufficiency or failure by teenage years (16,17). The BAG3 gene encodes the Bag3 protein in cardiac and skeletal muscles, which co-localizes at the Z-disk with myotilin. BAG3 mutation leads to myofibril dissolution and accumulation of degradation products at the Z-disk, which is pathognomonic for MFM (2,16). Because of the marked clinical variability among MFM patients, the disease is difficult to diagnose and is likely underdiagnosed. Muscle biopsy is currently the definitive diagnosis for MFM. To date, no effective therapies to ameliorate the disease progression are known (12). Depending on the subtype of MFM and individual patient, serum creatine kinase (CK) levels vary between normal to 15-fold above the upper limit of normal (16). Case description A Caucasian male, who is currently in his teenage years, first became symptomatic at 2 years old with toe walking and progressive decreased range of motion of the neck and lower extremities. By age 3, he was diagnosed with restrictive cardiomyopathy. At age 4, a muscle biopsy was indicative of MFM and was presumed to be desminopathy; however, recent repeat genetic testing with newly available DNA tests has confirmed that he has BAG3-myopathy. At the age of 5, he received cardiac transplantation at an outside hospital, and per report, he had an uneventful perioperative period with no significant complications. In the subsequent years, he has had profound progression of the noncardiac manifestations of BAG3-myopathy. He has significant scoliosis, rigid spine, and neck extension contracture (Figure 1), which are deemed
Figure 1 Teenager with BAG3-myopathy in natural posture due to severe scoliosis, rigid spine, and neck extension contracture. The possibility of difficult mask ventilation and laryngoscopy is evident. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
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nonamenable to surgical correction. He is currently unable to ambulate more than a few steps due to severe contractures of the lower extremities and loss of gross and fine motor control, but he maintains independence with a prone wheel chair. He has obstructive sleep apnea and severe restrictive lung disease, requiring nighttime noninvasive ventilation and cough assist vest. Over the course of a decade, he has chronic mild elevation of CK levels, ranging from 110 to 510 IUl 1 (normal = 35– 230 IUl 1). He has had 19 anesthetics. Most have been at our hospital, but his cardiac transplantation and occasional annual cardiac catheterizations were performed at another hospital. Table 2 provides a summary of all of the anesthetics. Overall, he has tolerated anesthesia very well with no evidence of malignant hyperthermia or rhabdomyolysis. However, airway management has become problematic over the past 3 years. His extreme cervical extension and associated distorted airway have led to extreme difficulties with mask ventilation, inability to seat an laryngeal mask airway, and no visualization of the glottis with direct laryngoscopy. Fiber-optic intubation was required the last time he was intubated. Lastly, supine positioning is difficult, as can be seen in Figure 1. Discussion Myofibrillar myopathy (MFM) is a rare type of hereditary myopathy, and subsets that present during the infant or childhood years (desminopathy, BAG3-myopathy, FHL1opathy, plectinopathy, and rarely ab-crystallinopathy) are even less common. However, given the profound impact on skeletal, respiratory, and cardiac systems, multiple anesthetic considerations exist. Perhaps, most confusing with any neuromuscular disorder are the questions of whether the patient is at risk for malignant hyperthermia (MH), rhabdomyolysis, sensitivity to volatile or other anesthetic agents, and sensitivity to neuromuscular blockade. Compounding this uncertainty is the child presenting for a diagnostic muscle biopsy under anesthesia who does not yet have a diagnosis or sufficient progression of the disease to narrow down a differential diagnosis of the myriad myotonias, muscular dystrophies, core myopathies, and enzymopathies that may have associated anesthetic considerations. To our knowledge, this is the first report in the literature of the anesthetic experience with a patient with MFM. He showed no signs of MH, rhabdomyolysis, or sensitivity to anesthetic agents during any of his anesthetics. His only anesthetic issues were related to his cardiac status, restrictive lung disease, and difficult airway. What follows then is a brief review of possible 234
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associations of patients with MFM to MH, rhabdomyolysis, and sensitivity to anesthetic agents. Malignant hyperthermia Malignant hyperthermia (MH) is a rare phenomenon, and the MH literature is far from definitive regarding risk stratification of MH susceptibility in various hereditary disorders (18). The primary but not exclusive gene for MH susceptibility is mutation of the RYR1 gene. A second gene, CACNA1S, has recently been implicated in approximately 1% of MH cases (19,20). To date, the disorders frequently occurring with RYR1 mutations and associated with MH susceptibility include King– Denborough syndrome, central core disease, and multiminicore disease. Disorders with unclear but possible association of MH susceptibility include carnitine palmitoyltransferase Type II deficiency, McArdle’s disease, and myoadenylate deaminase deficiency (19). Myofibrillar myopathy (MFM) is not associated with RYR1 or CACNA1S mutations, and MH rarely presents with a myopathic phenotype (21). Some ultrastructural findings do overlap between MFM and myopathies with MH risk: central core disease and a newly described recessive RYR1 mutation have ultrastructural features such as Z-disk extensions and myofibrillar disorganization, but other ultrastructural findings are exclusive between these diseases and MFM (22,23). Furthermore, phenotypic presentations are unique between MFM and central core disease, and there have been no reported cases of MH in patients with desminopathy or other MFM subtypes. Thus, while the risk of MH in children with MFM cannot be stated to be zero, there is not yet any evidence of a putative mechanism for MH susceptibility. Although no MFM subtypes have been associated with RYR1 mutation, it is theoretically possible that an MFM subtype may be associated with alteration of RyR1 channel function that modifies calcium homeostasis in the skeletal muscle and is thus at risk for MH. Rhabdomyolysis Anesthesia-induced rhabdomyolysis (AIR), which is often confused with MH, results from muscle breakdown and release of intracellular contents, potentially leading to acute renal failure, hyperkalemia, and potential cardiac arrest. AIR is hallmarked by an increase in serum creatine kinase (CK). Succinylcholine, which causes some degree of muscle damage in healthy muscle tissue, can cause significant rhabdomyolysis in myopathic muscles and is the most commonly implicated drug in AIR (19). Overall, the use of succinylcholine is contraindicated in patients with MFM or any © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
Procedure
Cardiac cath
Muscle biopsy
Cardiac cath
Cardiac transplant Cardiac cath Cardiac cath Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Age (years)
4
4
5
5
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
5 5 5
5
5
6
7
8
9
10
11
12
Y
Y
Y
Y
N
N
N
N
N
N
N
Y
Y – induction only
N
Y
Y
(No record) (No record) Y
(No record)
Y
Y
Y
(No record) (No record) Y – induction only
(No record)
Y
N
Y
Y – induction only
Y
Propofol infusion
Volatile anesthetic
Table 2 Summary of anesthetics for child with BAG3-myopathy
1
N
2.7 mgkg 1 at induction 0.8 mgkg 1 at induction 3 mgkg 1 at induction 4.25 mgkg 1 at induction
N
N
N
N
N
Y
Y
N
N
N
N
N
N
N
N
N
(No record) (No record) N
(No record)
N
N
N
NDMR
N
(No record) (No record) N
(No record)
N
N
N
Sux
None
(No record) (No record) 200 lgkg 1min 1 = 9 mgkg 1 total dose 150 lgkg 1min 1 = 4.5 mgkg 1 total dose 50 lgkg 1min 1 = 3 mgkg 1 total dose 175 lgkg 1min 1 = 13 mgkg 1 total dose None
150 lgkg min = 11.25 mgkg 1 total dose 1.2 mgkg 1 at induction 200 lgkg 1min 1 = 13.5 mgkg 1 total dose (No record) 1
Propofol infusion rate or total dose
310
N
273
200
(No record)
(No record)
N
N
N
(No record) (No record) N
(No record)
N
N
N
Postop CK (normal = 35–230)
At outside hospital At outside hospital –
N – per parents N – per parents N
Difficult airway, none other
N
N
N
N
N
N
N
Difficult mask, unsuccessful laryngeal mask airway, difficult fiberoptic intubation
Difficult mask
–
At outside hospital, midazolam/fentanyl sedation only At outside hospital, midazolam/fentanyl sedation only –
–
–
–
At outside hospital
N – per parents
N
–
–
–
Comment
N
N
N
Complications
G.J. Latham and G. Lopez Anesthetic considerations in myofibrillar myopathy
235
236
N N N None N
N
None N
N
N
114
N
Midazolam, fentanyl sedation only Midazolam, fentanyl sedation only Midazolam, fentanyl sedation only N (No record) N None N
N
Propofol infusion rate or total dose
G.J. Latham and G. Lopez
myopathic disease to avoid the risk of AIR, especially in a condition associated with elevated CK (20,24). Although the mechanism is unknown, volatile anesthetics have been implicated in a minority of cases of AIR, predominately in patients with muscular dystrophy (19,21). Thus, practitioners have classically avoided volatile anesthetics for patients with dystrophinopathies or in the setting of undiagnosed muscle weakness. Our patient did not experience any clinical signs of AIR and, when measured, did not have a postoperative increased CK level above his already elevated baseline, despite receiving multiple anesthetics with volatile agents. He also received volatile anesthetics during most years of his childhood. Unlike the experience in the dystrophinopathies, where the risk of AIR predominates at a young age when the muscles are most frail and not yet fibrotic, our patient had no evidence of rhabdomyolysis during his anesthetics at a young age, arguing against a similar risk (25). None of the MFM subtypes directly involve dystrophin, the abnormal protein in muscular dystrophy, but some of the affected proteins in MFM are associated to the dystrophin–glycoprotein complex as part of the multiproteic complex of the costamere (26). Thus, it is unclear if MFM subtypes are at risk for the type of muscular fragility and risk of volatile anesthetic-induced rhabdomyolysis seen in some patients with muscular dystrophy. However, in a retrospective study of children with muscular disorders receiving volatile anesthetic for a muscle biopsy, none had AIR or MH, including nine children with a muscular dystrophy (27). This study demonstrates that a lack of AIR in a patient cohort does not necessarily imply that all patients with that disease are without risk for AIR, as the muscular dystrophies clearly are. Thus, while there is no direct evidence that patients with MFM are at increased risk for AIR from volatile anesthetics, the simple absence of AIR in our patient cannot argue against the risk in all patients with MFM. Until more is known, perhaps, it is safest to use volatile anesthetics cautiously or even sparingly in patients with MFM and to maintain vigilance for signs of AIR.
15
N Cardiac cath
14
N
Cardiac cath at outside hospital Cardiac cath
N
Other anesthetic agents
13
Procedure Age (years)
Table 2 Continued
Volatile anesthetic
Propofol infusion
Sux
NDMR
Postop CK (normal = 35–230)
Complications
Comment
Anesthetic considerations in myofibrillar myopathy
Total intravenous anesthesia (TIVA) with propofol in patients with mitochondrial cytopathies can cause propofol infusion syndrome (PRIS) and severe acidosis (21). There is no evidence that patients with MFM have alteration of mitochondrial metabolism and ATP production, and thus, there is no clear reason to avoid the use of propofol TIVA in patients with MFM. Our patient tolerated several anesthetics with propofol infusion, and intraoperative laboratory evaluation during cardiac catheterization did not reveal any unexpected acidosis. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
G.J. Latham and G. Lopez
Anesthetic considerations in myofibrillar myopathy
Some clinicians administer glucose-containing fluids during propofol infusion to avoid PRIS (28). Propofol impairs the mitochondrial electron transport chain in a dose-dependent fashion, and it has been suggested that ensuring adequate serum glucose will balance the aerobic needs of the mitochondria and avoid PRIS (29). Again, the risk of PRIS and therefore benefit of concomitant glucose infusion during a relatively short anesthetic is unlikely in children with MFM, but the innocuous nature of providing glucose-containing maintenance fluids could argue for its prophylactic use in children receiving propofol TIVA if concern for PRIS is present. Ketamine appears to be a safe anesthetic agent for children with neuromuscular disease, and patients with MFM are likely no exception. Although ketamine abuse as a street drug has been reported to cause rhabdomyolysis, presumably due to excessive dosage, prolonged agitation, and dehydration (30,31), adverse effects have not been reported in the anesthetic literature for adults or children with neuromuscular disorders (32). The use of nondepolarizing muscle relaxants (NDMR) should be titrated according to patient response in all patients with neuromuscular diseases, including MFM, as intrinsic muscle disease can alter the expected response to a dose of neuromuscular blockade (24). NDMR administration was documented twice for this patient (11- and 12-year-old cardiac catheterization), and there was no documentation that it relieved muscle rigidity or improved airway visualization. It is unlikely that administration of NDMR would improve the muscle rigidity in this patient. Regarding sensitivity to any other anesthetic medications, it must be understood that MFM, as with other myopathies, is a multiorgan disease that often will have multiple ramifications on the anesthetic plan.
anesthetic considerations exist, including cardiomyopathy, cardiac arrhythmias, restrictive lung disease, airway obstruction, difficult airway, and positioning difficulties in the presence of muscle contractures. Children with MFM should be considered at risk for at least subclinical cardiac and respiratory compromise. As with any anesthetic, the decision to perform preoperative testing of cardiopulmonary status is dependent on the history, physical, and surgical procedure. Whether a ‘nontriggering’ anesthetic should be employed is unknown. As discussed above, there is no known or theoretical risk of MH susceptibility in patients with MFM, but the possibility cannot yet be completely excluded. It is unknown whether the use of volatile anesthetics poses a risk of AIR in patients with MFM. Until more is known, perhaps, it is safest to use volatile anesthetics cautiously or even sparingly in patients with MFM. As with other muscle diseases with elevated CK levels, succinylcholine is contraindicated to avoid the risk of AIR and hyperkalemia. Use of propofol infusion appears to be safe as there is no evidence that patients with MFM suffer disorders of mitochondrial metabolism. Ketamine also seems devoid of specific risks for patients with MFM. As in any patient with neuromuscular disease, paralysis with NDMRs should be carefully titrated to clinical effect. Lastly, sensitivity to any other anesthetic agent would likely be according to any dysfunction of the patient’s cardiac or pulmonary system. Disclosure/Acknowledgments Informed consent was obtained. This research was carried out without funding. Conflict of interest
Conclusion
No conflict of interest declared.
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REVIEW ARTICLE
Anesthetic considerations in myofibrillar myopathy Gregory J. Latham1 & Grace Lopez2 1 Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA, USA 2 Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA, USA
Keywords myofibrillar myopathy; pediatric; anesthesia; cardiomyopathy; cardiac arrhythmia; desmin-related myopathy; neuromuscular disease; malignant hyperthermia; rhabdomyolysis Correspondence Gregory J. Latham, Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, WA 98105-0371, USA Email: gregory. [email protected] Section Editor: Barbara Brandom Accepted 29 July 2014
Summary Myofibrillar myopathy (MFM) is a relatively newly recognized genetic disease that leads to progressive muscle deterioration. MFM has a varied phenotypic presentation and impacts cardiac, skeletal, and smooth muscles. Affected individuals are at increased risk of respiratory failure, significant cardiac conduction abnormalities, cardiomyopathy, and sudden cardiac death. In addition, significant skeletal muscle involvement is common, which may lead to contractures, respiratory insufficiency, and airway compromise as the disease progresses. This study is the first report of anesthetic management of a patient with MFM. We report multiple anesthetic encounters of a child with genetically confirmed BAG3-myopathy, a subtype of MFM with severe childhood disease onset. A review of the anesthetic implications of the disease is provided, with specific exploration of possible susceptibility to malignant hyperthermia, rhabdomyolysis, and sensitivity to other anesthetic agents.
doi:10.1111/pan.12516
Introduction Myofibrillar myopathies (MFM) are a relatively newly recognized group of chronic myopathies characterized by destruction of the muscle fiber at the Z-disk and accumulation of protein aggregates. Mutations of at least eight different proteins are currently confirmed genetic causes of MFM (1). Most MFM subsets are late onset myopathies with symptoms beginning between 35 and 50 years of age. Most patients present with progressive muscle weakness over the course of years and subsequently progress to debilitating respiratory failure and cardiac disease. However, some patients present in childhood or even infancy with severely progressive disease, including significant contractures, severe cardiomyopathy or arrhythmogenic disease, and respiratory failure (2). Thus far, there have been no reports in the literature of the anesthetic management or implications in adults or children with MFM. Importantly, there have been no reports exploring whether any of the genetic © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
subsets of MFM share anesthetic implications with other neuromuscular disorders, such as the risk of malignant hyperthermia with central core disease and multicore myopathy, rhabdomyolysis with the muscular dystrophies, anesthetic sensitivity with some mitochondrial disorders, and nondepolarizing muscle relaxant sensitivity in many neuromuscular disorders. In this report, the available MFM literature is reviewed, the experience with multiple anesthetics of a child with BAG3 MFM is discussed, and potential anesthetic implications of patients with MFM are explored. Background Genetics Myofibrillar myopathy (MFM), which was first described in 1996 (3), encompasses a clinically and genetically diverse group of progressive neuromuscular diseases characterized by disintegration of myofibrils at the Z-disk, accumulation of myofibrillar degradation products, and eventual loss of architectural and 231
232
CB, conduction block; CM, cardiomyopathy; LGMD1A, limb girdle muscular dystrophy 1A; LGMD2J, limb girdle muscular dystrophy 2J; HMERF, hereditary myopathy with early respiratory failure; SPS, scapuloperoneal syndrome.
Synonym: HMERF Elevated Mild CM 20–35 years old TTN/titin Titinopathy
Distal, proximal, spine
Infancy to 40 years PLEC/plectin Plectinopathy
Facial, limb, trunk
Rare CM
Rare insufficiency in infants Early insufficiency
Elevated
Synonym: reducing body myopathy Possible severe skin blistering Elevated Childhood to 40 years FHL1/FHL1 FHL1opathy
Distal, proximal, SPS
40–70 years old 40–60 years old Childhood ZASP/ZASP FLNC/filamin C BAG3/BAG3 Zaspopathy Filaminopathy BAG3-myopathy
Distal and proximal Proximal > distal limbs Proximal > distal, neck/spine
CM, CB CM, CB, sudden death Severe CM at disease onset CB
Insufficiency
– – Frequent childhood mortality Elevated Elevated Elevated
Synonym: LGMD1A Elevated
Uncommon insufficiency Unknown Insufficiency Severe Uncommon CM MYOT/myotilin Myotilinopathy
Proximal > distal CRYAB/ab-crystallin ab-crystallinopathy
Distal and proximal
Malabsorption, cataracts Elevated Insufficiency
– Elevated Insufficiency
CM, severe CB, sudden death CM, CB, sudden death
Childhood to young adulthood Middle adulthood, rare infantile form 40–60 years old DES/desmin Desminopathy
Distal > proximal, facial
CK levels Respiratory Cardiac Muscle weakness Onset age Gene/protein Disease
Table 1 Myofibrillar myopathies (1,2,5–7,12,17,33–35)
functional integrity of skeletal, cardiac, and smooth muscle (1). Prior to coining the term MFM in 1996, these disorders were previously lumped together under the terms ‘desmin-related myopathies’ or ‘desmin storage myopathies’ (2). Although a multitude of specific mutations have been found, all mutations thus far have been traced to Z-disk-related proteins. The first six identified mutated proteins (followed by gene name) include desmin (DES), ab-crystallin (CRYAB), myotilin (MYOT), Z band alternatively spliced PDZ-containing protein (ZASP), filamin C (FLNC), and Bcl-2-associated athanogene-3 (BAG3). Recently and with some debate (4), three additional protein mutations have been included under the MFM umbrella: four and a half LIM domain protein 1 (FHL1) (5), plectin (PLEC) (6), and titin (TTN) mutations (7). Table 1 provides an overview of the known causes of MFM. Although the technology of genetic testing for subtype analysis of MFM is rapidly expanding, approximately 50% of biopsy-proven MFM patients do not yet have identifiable genetic mutations (8). There is at least partial overlap in pathology and morphology between MFM and some of the other myopathies, and the nomenclature and categorization of MFM and some closely related myopathies continue to evolve as more is discovered every year (4). For instance, hereditary myopathy with early respiratory failure (HMERF) has been reclassified recently as an MFM subtype after mutation to TTN and degradation of the Z-disk were discovered (7). Reducing body myopathy has also been reclassified as a MFM subset recently due to discovery of FHL1 mutation in affected children (5). Yet FHL1 mutations also have been identified to be the cause of non-MFM disorders, including X-linked scapuloperoneal myopathy, X-linked myopathy with postural atrophy, Emery–Dreifuss muscular dystrophy, and rigid spine syndrome (9). Furthermore, limb girdle muscular dystrophy 1E and 2R, which are just 2 of the 31 known subsets of limb girdle muscular dystrophy, have now been found to be due to mutation of desmin and cause MFM; all but one of the remaining 29 subsets is likely not MFM (10,11). At least 67 different mutations to the DES gene have been found in patients with desminopathy alone (1), and the clinical heterogeneity is significant between patients with the same subset of MFM and especially between different subsets of MFM. The inheritance pattern among the subsets of MFM is varied, including autosomal dominant, autosomal recessive, X-linked, and de novo mutations (1,8). The variety in phenotypic presentation of MFM and age of onset is believed to relate, at least partially, to not
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Comment
Anesthetic considerations in myofibrillar myopathy
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
G.J. Latham and G. Lopez
only the specific MFM subtype but also the specific mutation to the affected gene (8). Clinical features Myofibrillar myopathy (MFM) is associated with considerable clinical variability (Table 1). The overall phenotype may resemble that of distal myopathy, limb girdle muscular dystrophy, scapuloperoneal syndrome, generalized myopathy, or isolated muscle myopathy (12). In many but not all cases of MFM, skeletal muscle weakness is the presenting symptom and predominates. Weakness frequently begins in distal lower extremity muscles, followed by progression proximally, with eventual involvement of upper extremity, truncal, neck flexor, facial, bulbar, and respiratory muscles, but other patterns of progression occur in several subtypes or individual patients (8). In some cases, nonskeletal muscle involvement can precede or succeed skeletal muscle pathology. Cardiac involvement is characteristic of desmin, ab-crystallin, FHL1, and BAG3 mutations. Myocardial pathology can manifest as conduction abnormalities, dilated or restrictive cardiomyopathy, and heart failure (1,13). Desmin is a major component in Purkinje fibers, such that desmin mutations especially cause significant cardiac conduction abnormalities that may result in sudden death (14). Respiratory pathology is most often from primary failure of respiratory muscles (15), but scoliosis and subsequent restrictive lung disease are especially common in childhood-onset BAG3 and FLH1 subtypes (12). Most patients with MFM present with gradual onset of muscle weakness in middle adulthood, which eventually progresses to severe disability and premature death. However, recessive inheritance of desminopathy, recessive inheritance of ab-crystallinopathy, FLH1opathy, plectinopathy, and BAG3-myopathy typically cause infantile or childhood disease onset (1). BAG3-myopathy, first described in 2009 (16), is a rare subtype of
Anesthetic considerations in myofibrillar myopathy
MFM, having only been described in a few children. It is hallmarked in all cases by onset in the first decade of life with rapidly progressive axial and limb muscle deterioration, rigid spine, significant contractures, early-onset restrictive and hypertrophic cardiomyopathy, and severe respiratory insufficiency or failure by teenage years (16,17). The BAG3 gene encodes the Bag3 protein in cardiac and skeletal muscles, which co-localizes at the Z-disk with myotilin. BAG3 mutation leads to myofibril dissolution and accumulation of degradation products at the Z-disk, which is pathognomonic for MFM (2,16). Because of the marked clinical variability among MFM patients, the disease is difficult to diagnose and is likely underdiagnosed. Muscle biopsy is currently the definitive diagnosis for MFM. To date, no effective therapies to ameliorate the disease progression are known (12). Depending on the subtype of MFM and individual patient, serum creatine kinase (CK) levels vary between normal to 15-fold above the upper limit of normal (16). Case description A Caucasian male, who is currently in his teenage years, first became symptomatic at 2 years old with toe walking and progressive decreased range of motion of the neck and lower extremities. By age 3, he was diagnosed with restrictive cardiomyopathy. At age 4, a muscle biopsy was indicative of MFM and was presumed to be desminopathy; however, recent repeat genetic testing with newly available DNA tests has confirmed that he has BAG3-myopathy. At the age of 5, he received cardiac transplantation at an outside hospital, and per report, he had an uneventful perioperative period with no significant complications. In the subsequent years, he has had profound progression of the noncardiac manifestations of BAG3-myopathy. He has significant scoliosis, rigid spine, and neck extension contracture (Figure 1), which are deemed
Figure 1 Teenager with BAG3-myopathy in natural posture due to severe scoliosis, rigid spine, and neck extension contracture. The possibility of difficult mask ventilation and laryngoscopy is evident. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
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nonamenable to surgical correction. He is currently unable to ambulate more than a few steps due to severe contractures of the lower extremities and loss of gross and fine motor control, but he maintains independence with a prone wheel chair. He has obstructive sleep apnea and severe restrictive lung disease, requiring nighttime noninvasive ventilation and cough assist vest. Over the course of a decade, he has chronic mild elevation of CK levels, ranging from 110 to 510 IUl 1 (normal = 35– 230 IUl 1). He has had 19 anesthetics. Most have been at our hospital, but his cardiac transplantation and occasional annual cardiac catheterizations were performed at another hospital. Table 2 provides a summary of all of the anesthetics. Overall, he has tolerated anesthesia very well with no evidence of malignant hyperthermia or rhabdomyolysis. However, airway management has become problematic over the past 3 years. His extreme cervical extension and associated distorted airway have led to extreme difficulties with mask ventilation, inability to seat an laryngeal mask airway, and no visualization of the glottis with direct laryngoscopy. Fiber-optic intubation was required the last time he was intubated. Lastly, supine positioning is difficult, as can be seen in Figure 1. Discussion Myofibrillar myopathy (MFM) is a rare type of hereditary myopathy, and subsets that present during the infant or childhood years (desminopathy, BAG3-myopathy, FHL1opathy, plectinopathy, and rarely ab-crystallinopathy) are even less common. However, given the profound impact on skeletal, respiratory, and cardiac systems, multiple anesthetic considerations exist. Perhaps, most confusing with any neuromuscular disorder are the questions of whether the patient is at risk for malignant hyperthermia (MH), rhabdomyolysis, sensitivity to volatile or other anesthetic agents, and sensitivity to neuromuscular blockade. Compounding this uncertainty is the child presenting for a diagnostic muscle biopsy under anesthesia who does not yet have a diagnosis or sufficient progression of the disease to narrow down a differential diagnosis of the myriad myotonias, muscular dystrophies, core myopathies, and enzymopathies that may have associated anesthetic considerations. To our knowledge, this is the first report in the literature of the anesthetic experience with a patient with MFM. He showed no signs of MH, rhabdomyolysis, or sensitivity to anesthetic agents during any of his anesthetics. His only anesthetic issues were related to his cardiac status, restrictive lung disease, and difficult airway. What follows then is a brief review of possible 234
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associations of patients with MFM to MH, rhabdomyolysis, and sensitivity to anesthetic agents. Malignant hyperthermia Malignant hyperthermia (MH) is a rare phenomenon, and the MH literature is far from definitive regarding risk stratification of MH susceptibility in various hereditary disorders (18). The primary but not exclusive gene for MH susceptibility is mutation of the RYR1 gene. A second gene, CACNA1S, has recently been implicated in approximately 1% of MH cases (19,20). To date, the disorders frequently occurring with RYR1 mutations and associated with MH susceptibility include King– Denborough syndrome, central core disease, and multiminicore disease. Disorders with unclear but possible association of MH susceptibility include carnitine palmitoyltransferase Type II deficiency, McArdle’s disease, and myoadenylate deaminase deficiency (19). Myofibrillar myopathy (MFM) is not associated with RYR1 or CACNA1S mutations, and MH rarely presents with a myopathic phenotype (21). Some ultrastructural findings do overlap between MFM and myopathies with MH risk: central core disease and a newly described recessive RYR1 mutation have ultrastructural features such as Z-disk extensions and myofibrillar disorganization, but other ultrastructural findings are exclusive between these diseases and MFM (22,23). Furthermore, phenotypic presentations are unique between MFM and central core disease, and there have been no reported cases of MH in patients with desminopathy or other MFM subtypes. Thus, while the risk of MH in children with MFM cannot be stated to be zero, there is not yet any evidence of a putative mechanism for MH susceptibility. Although no MFM subtypes have been associated with RYR1 mutation, it is theoretically possible that an MFM subtype may be associated with alteration of RyR1 channel function that modifies calcium homeostasis in the skeletal muscle and is thus at risk for MH. Rhabdomyolysis Anesthesia-induced rhabdomyolysis (AIR), which is often confused with MH, results from muscle breakdown and release of intracellular contents, potentially leading to acute renal failure, hyperkalemia, and potential cardiac arrest. AIR is hallmarked by an increase in serum creatine kinase (CK). Succinylcholine, which causes some degree of muscle damage in healthy muscle tissue, can cause significant rhabdomyolysis in myopathic muscles and is the most commonly implicated drug in AIR (19). Overall, the use of succinylcholine is contraindicated in patients with MFM or any © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
Procedure
Cardiac cath
Muscle biopsy
Cardiac cath
Cardiac transplant Cardiac cath Cardiac cath Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Cardiac cath
Age (years)
4
4
5
5
© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
5 5 5
5
5
6
7
8
9
10
11
12
Y
Y
Y
Y
N
N
N
N
N
N
N
Y
Y – induction only
N
Y
Y
(No record) (No record) Y
(No record)
Y
Y
Y
(No record) (No record) Y – induction only
(No record)
Y
N
Y
Y – induction only
Y
Propofol infusion
Volatile anesthetic
Table 2 Summary of anesthetics for child with BAG3-myopathy
1
N
2.7 mgkg 1 at induction 0.8 mgkg 1 at induction 3 mgkg 1 at induction 4.25 mgkg 1 at induction
N
N
N
N
N
Y
Y
N
N
N
N
N
N
N
N
N
(No record) (No record) N
(No record)
N
N
N
NDMR
N
(No record) (No record) N
(No record)
N
N
N
Sux
None
(No record) (No record) 200 lgkg 1min 1 = 9 mgkg 1 total dose 150 lgkg 1min 1 = 4.5 mgkg 1 total dose 50 lgkg 1min 1 = 3 mgkg 1 total dose 175 lgkg 1min 1 = 13 mgkg 1 total dose None
150 lgkg min = 11.25 mgkg 1 total dose 1.2 mgkg 1 at induction 200 lgkg 1min 1 = 13.5 mgkg 1 total dose (No record) 1
Propofol infusion rate or total dose
310
N
273
200
(No record)
(No record)
N
N
N
(No record) (No record) N
(No record)
N
N
N
Postop CK (normal = 35–230)
At outside hospital At outside hospital –
N – per parents N – per parents N
Difficult airway, none other
N
N
N
N
N
N
N
Difficult mask, unsuccessful laryngeal mask airway, difficult fiberoptic intubation
Difficult mask
–
At outside hospital, midazolam/fentanyl sedation only At outside hospital, midazolam/fentanyl sedation only –
–
–
–
At outside hospital
N – per parents
N
–
–
–
Comment
N
N
N
Complications
G.J. Latham and G. Lopez Anesthetic considerations in myofibrillar myopathy
235
236
N N N None N
N
None N
N
N
114
N
Midazolam, fentanyl sedation only Midazolam, fentanyl sedation only Midazolam, fentanyl sedation only N (No record) N None N
N
Propofol infusion rate or total dose
G.J. Latham and G. Lopez
myopathic disease to avoid the risk of AIR, especially in a condition associated with elevated CK (20,24). Although the mechanism is unknown, volatile anesthetics have been implicated in a minority of cases of AIR, predominately in patients with muscular dystrophy (19,21). Thus, practitioners have classically avoided volatile anesthetics for patients with dystrophinopathies or in the setting of undiagnosed muscle weakness. Our patient did not experience any clinical signs of AIR and, when measured, did not have a postoperative increased CK level above his already elevated baseline, despite receiving multiple anesthetics with volatile agents. He also received volatile anesthetics during most years of his childhood. Unlike the experience in the dystrophinopathies, where the risk of AIR predominates at a young age when the muscles are most frail and not yet fibrotic, our patient had no evidence of rhabdomyolysis during his anesthetics at a young age, arguing against a similar risk (25). None of the MFM subtypes directly involve dystrophin, the abnormal protein in muscular dystrophy, but some of the affected proteins in MFM are associated to the dystrophin–glycoprotein complex as part of the multiproteic complex of the costamere (26). Thus, it is unclear if MFM subtypes are at risk for the type of muscular fragility and risk of volatile anesthetic-induced rhabdomyolysis seen in some patients with muscular dystrophy. However, in a retrospective study of children with muscular disorders receiving volatile anesthetic for a muscle biopsy, none had AIR or MH, including nine children with a muscular dystrophy (27). This study demonstrates that a lack of AIR in a patient cohort does not necessarily imply that all patients with that disease are without risk for AIR, as the muscular dystrophies clearly are. Thus, while there is no direct evidence that patients with MFM are at increased risk for AIR from volatile anesthetics, the simple absence of AIR in our patient cannot argue against the risk in all patients with MFM. Until more is known, perhaps, it is safest to use volatile anesthetics cautiously or even sparingly in patients with MFM and to maintain vigilance for signs of AIR.
15
N Cardiac cath
14
N
Cardiac cath at outside hospital Cardiac cath
N
Other anesthetic agents
13
Procedure Age (years)
Table 2 Continued
Volatile anesthetic
Propofol infusion
Sux
NDMR
Postop CK (normal = 35–230)
Complications
Comment
Anesthetic considerations in myofibrillar myopathy
Total intravenous anesthesia (TIVA) with propofol in patients with mitochondrial cytopathies can cause propofol infusion syndrome (PRIS) and severe acidosis (21). There is no evidence that patients with MFM have alteration of mitochondrial metabolism and ATP production, and thus, there is no clear reason to avoid the use of propofol TIVA in patients with MFM. Our patient tolerated several anesthetics with propofol infusion, and intraoperative laboratory evaluation during cardiac catheterization did not reveal any unexpected acidosis. © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
G.J. Latham and G. Lopez
Anesthetic considerations in myofibrillar myopathy
Some clinicians administer glucose-containing fluids during propofol infusion to avoid PRIS (28). Propofol impairs the mitochondrial electron transport chain in a dose-dependent fashion, and it has been suggested that ensuring adequate serum glucose will balance the aerobic needs of the mitochondria and avoid PRIS (29). Again, the risk of PRIS and therefore benefit of concomitant glucose infusion during a relatively short anesthetic is unlikely in children with MFM, but the innocuous nature of providing glucose-containing maintenance fluids could argue for its prophylactic use in children receiving propofol TIVA if concern for PRIS is present. Ketamine appears to be a safe anesthetic agent for children with neuromuscular disease, and patients with MFM are likely no exception. Although ketamine abuse as a street drug has been reported to cause rhabdomyolysis, presumably due to excessive dosage, prolonged agitation, and dehydration (30,31), adverse effects have not been reported in the anesthetic literature for adults or children with neuromuscular disorders (32). The use of nondepolarizing muscle relaxants (NDMR) should be titrated according to patient response in all patients with neuromuscular diseases, including MFM, as intrinsic muscle disease can alter the expected response to a dose of neuromuscular blockade (24). NDMR administration was documented twice for this patient (11- and 12-year-old cardiac catheterization), and there was no documentation that it relieved muscle rigidity or improved airway visualization. It is unlikely that administration of NDMR would improve the muscle rigidity in this patient. Regarding sensitivity to any other anesthetic medications, it must be understood that MFM, as with other myopathies, is a multiorgan disease that often will have multiple ramifications on the anesthetic plan.
anesthetic considerations exist, including cardiomyopathy, cardiac arrhythmias, restrictive lung disease, airway obstruction, difficult airway, and positioning difficulties in the presence of muscle contractures. Children with MFM should be considered at risk for at least subclinical cardiac and respiratory compromise. As with any anesthetic, the decision to perform preoperative testing of cardiopulmonary status is dependent on the history, physical, and surgical procedure. Whether a ‘nontriggering’ anesthetic should be employed is unknown. As discussed above, there is no known or theoretical risk of MH susceptibility in patients with MFM, but the possibility cannot yet be completely excluded. It is unknown whether the use of volatile anesthetics poses a risk of AIR in patients with MFM. Until more is known, perhaps, it is safest to use volatile anesthetics cautiously or even sparingly in patients with MFM. As with other muscle diseases with elevated CK levels, succinylcholine is contraindicated to avoid the risk of AIR and hyperkalemia. Use of propofol infusion appears to be safe as there is no evidence that patients with MFM suffer disorders of mitochondrial metabolism. Ketamine also seems devoid of specific risks for patients with MFM. As in any patient with neuromuscular disease, paralysis with NDMRs should be carefully titrated to clinical effect. Lastly, sensitivity to any other anesthetic agent would likely be according to any dysfunction of the patient’s cardiac or pulmonary system. Disclosure/Acknowledgments Informed consent was obtained. This research was carried out without funding. Conflict of interest
Conclusion
No conflict of interest declared.
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© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 25 (2015) 231–238
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