Chapter 42 - Neuromuscular Disorders and Other Genetic ...miller8e:... · neuromuscular blocking...

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C h a p t e r 4 2

Neuromuscular Disorders and Other Genetic DisordersALA NOZARI • ARANYA BAGCHI • RICHA SAXENA • BRIAN T. BATEMAN

K e y P o i n t s

• Management of anesthesia in patients with acquired or inherited neuropathies introduces challenges for protecting the involved nerves against pressure, entrapment, or trauma associated with positioning of nerve blocks. Neurologic deficits are assessed and documented before the administration of regional anesthesia (see Chapters 56 and 57).

• Patients with autonomic dysfunction caused by conditions such as diabetes neuropathy or Guillain-Barré syndrome (GBS) are at increased risk for exaggerated hemodynamic response to anesthetics, as well as for aspiration of gastric contents from delayed gastric emptying.

• Prolonged immobility in patients who are critically ill is associated with a relative increase in immature acetylcholine receptors that can lead to insensitivity to nondepolarizing neuromuscular blocking drugs (NMBDs) or sensitivity to depolarizing neuromuscular blockers with the risk for increased potassium efflux (see also Chapter 34).

• Monitoring the neuromuscular transmission is mandatory in patients with myasthenia gravis (MG) if nondepolarizing NMBDs are to be administered. These patients may be extremely sensitive to nondepolarizing NMBDs and yet require a larger dose of succinylcholine than patients who do not have MG (see also Chapter 53).

• Lambert-Eaton myasthenic syndrome (LEMS) is caused by antibodies to the voltage-gated calcium channels on the presynaptic motoneuron terminals, with decreased acetylcholine release in the neuromuscular junction. Sensitivity to depolarizing and nondepolarizing NMBDs is increased, and the response to anticholinesterases is insufficient.

• Spinal anesthesia has been implicated in the postoperative exacerbation of multiple sclerosis (MS), but epidural application of low concentrations of local anesthetics has been successfully used in these patients.

• Because of the risk for rhabdomyolysis and hyperkalemia, succinylcholine should be avoided in patients with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and Becker muscular dystrophy (BMD) (see also Chapters 34 and 43).

• Cardiomyopathy and a progressive decline of pulmonary function are common in patients with DMD and may predispose them to perioperative pulmonary and cardiac complications. Volatile anesthetics are best avoided, and the use of total intravenous (IV) anesthesia should be considered in these patients when possible.

• Pulmonary complications caused by hypotonia, chronic aspiration of gastric contents, and central and peripheral hypoventilation are common in patients with myotonic dystrophy (DM) (see also Chapter 43). The possibility of prolonged postoperative mechanical ventilation should be considered. Cardiac manifestations of this disease include conduction abnormalities, arrhythmias, and cardiomyopathy.

• The extent of organ system involvement should be carefully assessed and documented in patients with mitochondrial disease, with particular emphasis on the degree of myopathy, endocrine and metabolic derangements, and neurologic function.

Acknowledgment: The editors and publisher would like to thank Drs. Jie Zhou, Paul D. Allen, Isaac N. Pessah, and Mohamed Naguid for contributing a chapter on this topic to the prior edition of this work. It has served as the foundation for the current chapter.

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Chapter 42: Neuromuscular Disorders and Other Genetic Disord
• Evidence does not suggest that patients with hyperkalemic periodic paralysis (HyperPP) are susceptible to malignant hyperthermia (MH). Maintaining normothermia, preventing hyperkalemia, and avoiding hypoglycemia are important in these patients (see also Chapter 43).

• The genetics of mitochondrial disorders is a special case of mendelian disorders, and defects may be in mitochondrial DNA (mtDNA)–encoded or nuclear DNA (nDNA)–encoded structural or regulatory components of the mitochondrion. Recent genetic research has begun to unlock the basis for other complex diseases, which will facilitate a better understanding of perioperative implications and provide more effective and safe treatments for individual patients.

K e y P o i n t s — c o n t ’ d

Diseases that affect peripheral nerves, neuromuscular junction, and muscles are rarely encountered in routine anesthetic practice but pose significant challenges to the perioperative management of the affected patient. Car-diovascular and respiratory systems are often involved, posing an increased risk for perioperative dysrhythmias, hypotension, or respiratory failure. Adverse reactions to neuromuscular blocking drugs (NMBDs) should be con-sidered and may include severe hyperkalemia or pro-longed paralysis. Autonomic dysreflexia, when present, increases the risk for cardiovascular instability or aspira-tion upon anesthesia induction. A thorough knowledge of organ system involvement is mandatory, and the choice of anesthetics and NMBDs has to be tailored to the specific needs of each patient.

In this chapter, some of the most common neuro-muscular disorders and their anesthetic implications are reviewed. An overview of the genetics of the mendelian disorders and mitochondrial and complex diseases is also provided, and their implications for clinical translation and perioperative care are discussed. Lastly, because some of these disorders are related to malignant hyperthermia (MH), they are also discussed in Chapter 43. A compari-son of these two conditions will provide additional points of view for the reader.

ACQUIRED AND HEREDITARY NEUROPATHIES

Lesions of peripheral nerves produce motor weakness or sensory disturbance and are accompanied by decreased muscle stretch reflexes. Mononeuropathies involve a single nerve and are commonly due to a compression associated with immobilization, entrapment, ischemia, or trauma with stretch or laceration. Carpal tunnel syndrome is the most common entrapment neuropa-thy caused by compression of the median nerve in the wrist, which results in pain, paresthesias of the hand and fingers, and sensory loss in the distal median nerve territory, including the thenar eminence.1 Weakness of thumb adduction and opposition, resulting in a loss of grip strength, is a typical symptom. Comorbid conditions such as hypothyroidism and diabetes mellitus should be considered, and electromyography and nerve conduc-tion study findings should be obtained for diagnosis and

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prognostication. Ulnar nerve compression and injury at the condylar groove, which lacks soft-tissue protection, is the most common perioperative peripheral neuropa-thy.2 Symptoms include paresthesia of the fourth and fifth digits and weakness of the intrinsic muscles demon-strated as grip weakness and, in severe cases, clawhand. The brachial plexus with its relatively long course from the vertebral foramina to the axilla and its proximity to many mobile bony structures is particularly susceptible to injury from poor perioperative positioning.3 Brachial plexus injuries may occur, nevertheless, despite appro-priate positioning and padding during surgery. The association between hypertension and diabetes mellitus with perioperative peripheral nerve injuries4 suggests a multifactorial etiologic origin. Over 40% of patients with diabetes are reported to develop clinical symptoms or electrophysiologic evidence of neuropathy.5 Diabetic neuropathy includes a number of distinct clinical syn-dromes such as primary sensory polyneuropathy with symmetric and slowly progressive neuropathy of the feet and legs; autonomic neuropathy involving the bladder, bowel, and circulatory reflexes; and plexus neuropathy with severe hip, thigh, and knee pain, as well as weak-ness in the quadriceps muscles, which usually improves within weeks to months. Diabetic amyotrophy or Bruns-Garland syndrome (also known as ischemic mononeuropa-thy multiplex) is another form of plexus neuropathy with abrupt onset of asymmetric pain in the back, hips, thigh, or leg, and progressive muscle weakness.6 Treatment is primarily expectant, although immunotherapy may be considered in severe cases. In patients who are critically ill, phrenic nerve mononeuropathy may develop as a result of prolonged systemic inflammation with immo-bilization during mechanical ventilation. This condition is diagnosed by electroneurography and diaphragmatic electromyographic recordings and may interfere with the ability to wean the patient from ventilator depen-dency and may prolong the stay in the intensive care unit (ICU).

Inherited neuropathies include Charcot-Marie-Tooth (CMT) diseases and hereditary neuropathy with liability to pressure palsies (HNPP). CMT affects approximately 1 in 2500 people and represents the most common inherited neurologic disorder.7,8 It is not a single dis-ease entity; rather, CMT represents a spectrum of disor-ders caused by mutations in myelin or axonal genes.9

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PART IV: Anesthesia Management1268

Although traditionally classified as types 1 through 7, based on electrophysiologic, histologic, and clinical char-acteristics, multiple genetic subtypes7,9 and mutations exist in more than 30 genes involving more than 40 dis-tinct loci that give rise to the disorder.7 The pattern of genetic inheritance is most commonly autosomal domi-nant, but X-linked and autosomal recessive forms also exist, as do sporadic cases as a result of new mutations.7 In approximately two thirds of cases, demyelination as a result of mutations in genes expressed in Schwann cells causes the disorder; axonal dysfunction as a result of mutations expressed in neuronal cells cause the bal-ance of the cases.7,10 Demyelination, slowed motor nerve conduction velocities, and an autosomal dominant pat-tern of inheritance characterize CMT1, the most com-mon type.9 The most prevalent form of CMT1 is subtype CMT1A, which accounts for approximately 75% of CMT1 cases.7 A 1.4 megabase (Mb) duplication in chromosome 17p11.2 causes CMT1A.9,11 Patients with CMT typically experience progressive distal muscle weakness and wast-ing with hyporeflexia or areflexia. Mild sensory loss in a glove and stocking distribution, lower extremity defor-mity (peroneal muscle atrophy is typical), kyphoscoliosis, and neuropathic pain may also develop in some patients. Pes cavus (clawfoot) with hammer toes, footdrop, and fre-quent ankle sprains are not uncommon.9 Onset generally occurs by 20 years of age; although the disorder does not compromise lifespan, it can cause significant disability. Variant forms of CMT exist, including Dejerine-Sottas neuropathy and congenital hypomyelination, which are characterized by onset in infancy and are sometimes fatal.9

Similar to CMT, HNPP is a slowly progressive neu-ropathy, but focal areas of irregular thickening of myelin sheaths (tomaculae) cause HNPP, and it demonstrates recurrent focal neuropathies caused by minor trauma.12 HNPP typically develops during adolescence with attacks of numbness, muscle weakness, peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies. A nerve conduction study showed focal conduction block at the site of injury and generalized mild slowing, con-sistent with diffuse demyelinating disease. Some patients may have long-term neurologic dysfunction, but many show complete recovery after a focal neuropathy.

ANESTHETIC CONSIDERATIONS

Management of anesthesia in patients with mononeu-ropathies introduces challenges for protection of the involved nerve against further entrapment or trauma associated with positioning. Autonomic neuropathy may be associated with exaggerated hemodynamic response to the anesthetic as a result of involvement of the cir-culatory reflexes. Patients with diabetic autonomic neu-ropathy are also at greater risk for aspiration pneumonitis from delayed gastric emptying of food particles.13

Patients with CMT frequently require orthopedic sur-gery to correct the musculoskeletal manifestations of the disease, including foot and ankle defects, spinal deformi-ties, and hip dysplasia.14 Evidence regarding the anesthetic management of patients with CMT is limited and consists primarily of case reports and clinical series. Nevertheless,

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important concerns exist when anesthetizing patients with this condition, based on these reports and patho-physiologic considerations. Major considerations for the perioperative care of patients with CMT include the risk of adverse reactions to NMBDs, a susceptibility to MH, and the potential for respiratory weakness requiring pro-longed ventilatory support. An increased sensitivity to hypnotic anesthetics has also been suggested, but intrave-nous and volatile anesthetics have been used in patients with CMT with no reported complications.15 Neverthe-less, multiple reports of worsening CMT symptoms have been recounted in patients exposed to nitrous oxide,16 such that this agent should be avoided when possible. Other medications that are administered in the periop-erative period that have been associated with worsening CMT include metronidazole, amiodarone, linezolid, and nitrofurantoin.16

The literature provides conflicting reports regarding the responses to NMBDs in patients with CMT. Pog-son and associates reported an increased sensitivity to vecuronium,17 whereas cisatracurium and mivacurium have been used with no evident prolongation of the neuromuscular blockade.18-20 Because of the demyelin-ation that occurs in the distal extremities, monitoring the neuromuscular blockade should preferentially occur at the facial rather than the ulnar nerve. Although succi-nylcholine has been successfully used in these patients,21 clinicians are cautioned against its routine use, consider-ing the risk of an exaggerated hyperkalemic response.22 A single case report of MH associated with the admin-istration of sevoflurane to a patient with CMT has been reported.23,24 However, in the largest clinical series pub-lished to date, 77 patients with CMT were exposed to triggering anesthetics without complications.25 No estab-lished association between CMT and MH has been estab-lished, and volatile anesthetics can be reasonably used in these patients.24

Regional anesthesia has been used in patients with CMT without clear evidence of associated complications.25-28 Because of the concern for exacerbating the neurologic symptoms, however, regional anesthesia techniques are often avoided in these patients. Ultrasound-guided peripheral nerve blocks may reduce the risk of neurologic complications but should be reserved for patients with major risks for general anesthesia.29 Neuraxial anesthe-sia has also been used for obstetric procedures in these patients, often with no reported exacerbation of their neurologic symptoms.26,30 It is important that neurologic deficits are assessed and documented before administer-ing anesthesia.24

As with CMT, patients with HNPP pose special con-cerns for their response to NMBDs, as well as the risk to exacerbate neurologic symptoms from patient position-ing. The immobility associated with general anesthesia or regional block can potentially trigger pressure palsies in these patients. However, current literature provides no evidence against the use of neuraxial techniques or local anesthetics.31 Despite the lack of evidence on the effects of surgical positioning in patients with HNPP, it is reasonable to assume that judicious positioning and thorough padding will reduce the risk of neurologic complications.

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Chapter 42: Neuromuscular Disorders and Other Genetic Disorders 1269

GUILLAIN-BARRÉ SYNDROME OR ACUTE INFLAMMATORY DEMYELINATING POLYRADICULOPATHY

Guillain-Barré syndrome (GBS) or acute inflammatory demyelinating polyradiculopathy (AIDP) is an acute onset of progressive peripheral neuropathy that is triggered by humoral and cell-mediated autoimmune response to a sensitizing event, such as a respiratory tract infection.32 Its presentation is typically an ascending paralysis char-acterized by symmetric weakness that can vary from mild difficulty with walking to nearly complete paralysis of all extremities, facial, respiratory, and bulbar muscles. Mild variants can exhibit ataxia, ophthalmoplegia, or hypore-flexia without significant appendicular weakness. Fulmi-nate cases can express severe ascending weakness leading to complete tetraplegia, as well as to paralysis of cranial nerves and phrenic and intercostal nerves leading to facial and respiratory muscle weakness that necessitates ventilatory support.33 Autonomic dysfunction may occur and can cause hemodynamic instability and arrhythmias with the risk for sudden circulatory collapse and death.

Diagnosis is made based on clinical features such as areflexia and progressive motor weakness, cerebrospinal fluid (CSF) analysis with elevated protein but no pleocy-tosis (albuminocytologic dissociation), and electrophysi-ologic studies.34 Electromyography and nerve conduction studies may be normal in the early acute period, but char-acteristic segmental demyelination and reduction of con-duction velocity and dispersion or absence of F waves are usually observed within 1 to 2 weeks.

Management includes respiratory support, measures to prevent aspiration, and nutritional support. Early plasma exchange, typically five exchanges with 5% albumin repletion, may mitigate the course but is contraindicated in a setting of hemodynamic instability, prominent dys-autonomia, and active bleeding.35 Intravenous immuno-globulin (IVIG) is typically administered in the setting of dysautonomia or when a significant risk for catheter-related complications exist with plasmapheresis or when an exchange transfusion is performed.


Cranial nerve paralysis and autonomic dysfunction pre-dispose patients with GBS to an increased risk for aspi-ration. Aspiration precautions, including decompression of the stomach, should therefore be considered before the induction of anesthesia. An absence of compensa-tory cardiovascular responses may be associated with exaggerated hypotension at anesthesia induction or in response to hypovolemia. Conversely, laryngoscopy or noxious stimuli can be associated with an exaggerated increase in blood pressure. The hemodynamic instability is typically short-lived and self-limited, but small doses of short-acting and titratable vasoactive medications may be required.36 Careful hemodynamic monitoring is essential, and continuous monitoring of the blood pressure with an arterial catheter is often considered. These patients may also exhibit abnormal responses to NMBDs, with a hyperkalemic response to succinylcholine even after clinical resolution of symptoms.37 Nondepolarizing NMBDs

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can be used but are typically avoided because of the risk of prolonged muscle weakness. If these drugs are used, then the neuromuscular transmission should be closely monitored with a nerve stimulator since both resistance and sensitivity to these anesthetics have been reported.38 Regional anesthesia is used by some practitioners,39 but its use remains controversial because worsening neuro-logic symptoms have been reported.40

CRITICAL ILLNESS POLYNEUROPATHY AND CRITICAL ILLNESS MYOPATHY

Bolton and associates identified critical illness poly-neuropathy (CIP) in 1987 and described this condition as a characteristically widespread axonal degeneration among motor and sensory fibers with subsequent exten-sive denervation atrophy of limb and respiratory muscle associated with polyneuropathy.41 Although the true incidence of CIP is difficult to determine, critical ill-ness neuropathy and critical illness myopathy (CIM) are believed to affect up to 50% of all patients remaining in the ICU for longer than 2 weeks.42 Bolton also defined the myosin loss syndrome that is often observed in patients with CIM. This condition shows histologic signs of myo-sin loss, as opposed to actin, in skeletal muscle biopsies from affected muscles. The ratio of myosin to actin is typ-ically below 1.0 with some patients showing a complete absence of myosin in skeletal muscle cells. The typical clinical manifestation consists of a profound symmetric limb weakness with reduced or absent tendon reflexes and diaphragmatic and intercostal weakness. CIM affects the lower extremities to a greater extent than the upper extremities and the distal muscle groups more severely than the proximal muscle groups. The autonomic func-tion is not affected, and the extraocular eye movements remain intact. In CIP, no evidence of a neuromuscular junction disorder exists, and the electromyography and nerve conduction study findings are consistent with axo-nal motor and sensory polyneuropathy with amplitude reduction of motor and sensory action potentials and slowed conduction velocities. Serum creatine kinase lev-els are usually normal. Conversely, sensory nerve action potential is often normal in CIM, but compound muscle action potentials are diminished and electromyographic findings are consistent with myopathy. Serum creatine kinase levels may be elevated. No specific treatments are currently available, and management is supportive with aggressive and early rehabilitation. The use of sedation, paralytics, and corticosteroids should be limited,43 and aggressive control of hyperglycemia can reduce the inci-dence of CIP by 44%.44


Anesthetic considerations in these patients are similar to those with other acquired neuropathies (see previous text) and include protection of nerve compression sites, par-ticularly the ulnar and peroneal nerves. Prolonged immo-bility in patients who are critically ill is associated with a relative increase in immature acetylcholine receptors that can lead to an insensitivity to nondepolarizing NMBDs.45

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Conversely, the sensitivity to a depolarizing NMBD (suc-cinylcholine) is increased, with a risk for increased potas-sium efflux after succinylcholine administration.46

MYASTHENIA GRAVIS

Myasthenia gravis (MG) is an autoimmune disorder of synaptic transmission caused by antibodies against nico-tinic acetylcholine receptors (nAChRs). With an annual incidence of 1 in 200,000 to 500,000, MG has a preva-lence of 0.5 to 14.2 per 100,000 in the United States and primarily affects women 20 to 30 years of age and men 60 to 80 years of age. Autoantibodies against the α-subunit of the muscle-type nAChRs destroy these receptors in the neuromuscular junction and cause transmission failure, manifested as muscle weakness and fatigue. The origin of these antibodies is not always known, but they may be associated with thymomas or thymic hyperplasia (80% of generalized MG and 30% to 50% of ocular MG). Auto-antibodies against the muscle-specific tyrosine kinase (MuSK) are associated with the human leukocyte antigen (HLA)–B8 and the DRw3 antigen and are primarily iden-tified in younger patients with MG.47 Skeletal muscles innervated by cranial nerves are especially vulnerable, the involvement of which can lead to extraocular and facial muscle weakness or bulbar and oropharyngeal weakness. Speech and chewing may be affected, as well as the pha-ryngeal function and coordination of swallowing, placing the patient at an increased risk of pulmonary aspiration of gastric or oral contents. Skeletal muscle weakness in MG worsens with repetition or throughout the course of the day and, conversely, improves after rest. The clini-cal course may also be marked by periods of exacerbation and remission. Myocarditis, atrial fibrillation, heart block, takotsubo cardiomyopathy, and sympathetic hyperac-tivity with fluctuations in heart rate and blood pressure have been described in these patients.48,49 The diagnosis of MG is made by neurologic examination and testing of the tendency to exhibit increased muscle weakness dur-ing exercise or repeated contractions. The response to edrophonium, which is administered as a 1- to 2-mg test dose followed by 8 mg intravenously, can confirm the diagnosis (Tensilon test). Improvement in the patient’s preexisting weakness should be evident within 1 to 5 minutes of drug administration. Serologic studies include serum antibodies for acetylcholine receptor (present in 95% of patients), striated muscle, and MuSK (present in 65% of patients who are acetylcholine- receptor nega-tive). Electromyography shows increased jitter, and nerve conduction studies with repetitive simulation produce decremental responses.50 Management includes support-ive care with mechanical ventilation as needed and the administration of cholinesterase inhibitors such as pyr-idostigmine.51,52 Immunomodulatory drugs such as ste-roids and azathioprine are effective but have a delayed onset of action. Although steroids are shown to reduce the number of antibodies to the acetylcholine receptors and can significantly improve the symptoms, they may cause a transient worsening of the weakness at the initia-tion of therapy. IVIG and plasma exchange can be used for more rapid response in patients with severe bulbar

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and oropharyngeal dysfunction or those with MG crisis. Thymoma resection is helpful for paraneoplastic myas-thenia, but its benefit in nonthymomatous autoimmune MG has not been conclusively established.53


A thorough review of the neurologic symptoms and med-ications is of paramount importance. The ability of the patient with MG to protect and maintain a patent airway, to cough, and to clear secretions should be thoroughly assessed. These patients should be advised of the risk for worsening symptoms, which can require prolonged postoperative mechanical ventilation. Increased risk for postoperative myasthenic crisis and ventilatory support is possible if these conditions exist: prolonged duration of disease (longer than 6 years), presence of previous respira-tory problems or coexisting lung disease, pyridostigmine doses of more than 750 mg/day, and preoperative forced vital capacity of less than 2.9 L have been suggested to predict increased risk for postoperative myasthenic crisis and ventilatory support.54 The presence of bulbar symp-toms, history of preoperative myasthenic crisis, preop-erative serum antiacetylcholine receptor antibody level greater than 100 nmol/L, and intraoperative blood loss greater than 1000 mL have also been associated with post-surgical myasthenic crisis.55 Elective surgeries should be performed during a stable phase of the disease and when the patient requires minimal immunomodulatory medi-cation. Most of these medications do not interact with anesthetic agents, but azathioprine can inhibit nondepo-larizing NMBDs and may extend the effect of succinyl-choline. Most clinicians recommend that patients should keep taking their anticholinesterase medication on the day of surgery, but their interaction with the NMBDs should be considered.56 A reduced number of functional acetylcholine receptors results in an increased sensitiv-ity to nondepolarizing NMBDs.57,58 Monitoring the neu-romuscular transmission is mandatory, but clinicians should be cognizant of the possibility to overestimate the degree of neuromuscular blockade in these patients, particularly when the orbicularis oculi muscle responses are monitored. In addition, an uneven spread of muscle weakness exists; therefore, routine neuromuscular mon-itoring at one site (e.g., the hand) does not adequately represent the actual level of block in other muscle groups. The dose of these NMBDs should be cautiously titrated, such as by the administration of small increments corre-sponding to 0.1 to 0.2 times the 95% effective dose (ED95) until the desired effect is achieved. Succinylcholine, on the other hand, often needs to be administered in larger-than-normal doses (ED95 2.6 times the patient without MG) because of the decreased number of functional acetylcholine receptors.59 A rapid desensitization of the myasthenic endplate receptors to succinylcholine has also been reported, indicating a susceptibility to devel-oping phase II neuromuscular block.60 Potent volatile anesthetics have been successfully used in patients with MG, and they commonly cause profound muscular relax-ation, enough to allow most surgical procedures to be performed without the need for an NMBD.61 Intravenous induction anesthetics and opioids have also been used

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Neuromuscular Disorders and Other Genetic Disorders 1271
Chapter 42:
without significant adverse effects. If regional anesthe-sia is used, then careful monitoring of muscle function and ventilation is equally important. As ester-type local anesthetics are metabolized by the pseudocholinesterase, anticholinesterase treatment in patients with MG may potentiate their effects and lead to prolonged blockade. Although amide local anesthetics have been successfully used in patients with MG, judicious dosing is essential, as is the preparedness to manage worsening muscle weak-ness safely.62,63

LAMBERT-EATON-MYASTHENIC SYNDROME

Lambert-Eaton myasthenic syndrome (LEMS) is caused by antibodies to the voltage-gated calcium channels on the presynaptic motoneuron terminals, which lead to a decreased release of acetylcholine. This syndrome is fre-quently part of the paraneoplastic phenomenon (typi-cally, a small-cell lung cancer is present in 50% to 60% of patients) but can also occur without associated cancer.64 In more than 80% of patients with associated cancer, symptomatic onset of myasthenia precedes the diagnosis of their cancer. Symptoms are usually subacute at onset and are typically characterized by weakness in the proxi-mal lower extremities, although upper extremity weak-ness, bulbar symptoms, and respiratory muscle weakness may also be present. Unlike MG, patients with LEMS are usually worse in the morning and gradually improve throughout the day. Their weakness also improves after brief exercise but can worsen with sustained physical activity. Improvement of muscle function with exercise is due to the accumulation of presynaptic calcium and subsequent improved release of acetylcholine. Auto-nomic dysfunction and cholinergic symptoms, includ-ing dryness of the mouth and impaired lacrimation, may be present. The diagnosis of LEMS is made by physical examination, showing proximal lower limb weakness, depressed tendon reflexes with posttetanic potentiation, and evidence of autonomic disturbances. Electromyog-raphy typically shows small compound muscle action potential (CMAP) amplitudes and a transient incremen-tal CMAP response to rapid nerve stimulation (20 to 50 Hz) but a decremental response to slow nerve stimulation (1 to 5 Hz).65 Autoantibodies against P/Q-type voltage-gated calcium channels are highly specific and have been detected in 85% to 90% of patients with LEMS.66

Cholinesterase inhibitors do not consistently pro-duce improvement in these patients but may improve the muscle weakness or dry mouth in some. Aminopyri-dines (e.g., 3,4-diaminopyridine) are the first-line treat-ment for patients with symptomatic LEMS and improve the strength and autonomic function with minimal side effects in most patients.67 Aggressive immunotherapy, plasma exchange, and immunoglobulin therapy result in rapid but transient improvement of symptoms.


Similar to patients with MG, those with LEMS should be carefully assessed for the risk of postoperative respiratory

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failure and the need for prolonged mechanical ventila-tion. Sensitivity to depolarizing and nondepolarizing NMBDs is increased, and the response to anticholines-terases is insufficient. Autonomic dysfunction may be associated with an exaggerated response to vasodilators and anesthesia induction drugs. Close monitoring of the neuromuscular transmission is important, and in patients whose train-of-four responses are insufficient, monitoring of the tetanic stimulation and posttetanic facilitation should be considered.68 Reversal of the neuro-muscular blockade with anticholinesterase drugs may be ineffective in patients who receive aminopyridines, and a combination of oral aminopyridine and an anticholin-esterase may be more effective.69 Epidural anesthesia has been successfully used in these patients,70 but, as with patients with MG, neuraxial anesthesia should be used with extreme caution in patients with LEMS, considering the possibility of increasing muscle weakness and respira-tory failure.

MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a demyelinating disease of the optic nerves, cerebrum, and spinal cord where it primar-ily affects the corticospinal tract and posterior columns. It is considered an autoimmune disorder and is char-acterized by sensitization of the peripheral leukocytes to the myelin antigen and a subsequent inflammatory response, monocytic and lymphocytic perivascular cuff-ing and glial scars, with plaque formation within the central nervous system, especially in the periventricular white matter. Genetic predisposition and environmental factors have also been implicated in its pathophysiologic mechanisms. The disease affects mainly women between 10 to 60 years of age, with the greatest peak between ages 20 to 40 years. Exacerbations and remissions character-ize its clinical course in most patients, but continuous neurologic deterioration is also reported in up to 10% of cases (primary progressive MS). Acute symptoms, which are related to the site and extent of sclerosing central nervous system plaque, commonly include visual distur-bances (e.g., diplopia, blurring, field cuts), sensory abnor-malities with numbness and paresthesias, and an electric shock sensation that radiates down the spine and into the limbs upon flexion of the neck (Lhermitte sign). Cranial nerve dysfunction, ataxia, and bladder and bowel distur-bances are also common. A localized or, late in the course of the disease, generalized muscle weakness with the legs affected more than the arms is typical. Chronic symp-toms can also include spastic paraparesis, appendicular tremor, and psychiatric disturbances such as depression or euphoria (la belle indifférence) and dementia. In severe cases, respiration may be involved with the development of hypoxemia. MS can be associated with autonomic dys-function and, hence, an increased risk for exaggerated hemodynamic response to anesthetic induction, vasodi-lator, and sympathomimetic drugs.71 A diagnosis of MS is currently based on a combination of clinical symptoms and laboratory tests, including CSF antibody analysis and radiology (detection of central nervous system plaque by magnetic resonance imaging). Diagnosing MS after

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a single, acute remitting, clinically isolated syndrome is discouraged, whereas repeated attacks with increased CSF immunoglobulin G (IgG) and multifocal magnetic resonance imaging abnormalities are strongly supportive of the diagnosis.72 Acute attacks are treated with various combinations of immunosuppression modalities includ-ing glucocorticoids, which have been shown to increase the rate of recovery but not an overall level of recovered function. Preventive therapy with interferon β1a or glat-iramer acetate (a mixture of polypeptides synthesized to mimic myelin basic protein) may be used in individu-als with the relapsing-remitting subtype of MS. Specific treatments aimed at chronic symptoms include baclofen and benzodiazepines for spasticity, anticonvulsants or propranolol for tremor, oxybutynin and propantheline for bladder spasticity, and selective serotonin reuptake inhibitors (SSRIs) or other antidepressive agents for mood disorders.


MS symptoms may be intensified after physical and emotional stress or in the perioperative period. These patients should therefore be informed of the impact of surgical stress on the natural progression of the disease and the potential for aggravated symptoms in the post-operative period, regardless of the anesthetic approach. Increased body temperature is often cited as an offend-ing mechanism, possibly by causing a complete block of conduction in demyelinated nerves. Body temperature should therefore be closely monitored and controlled during the perioperative period. Great care must also be exercised to minimize changes in fluid homeostasis and central hemodynamics (i.e., preload, afterload). In general, preoperative chronic immunosuppressive medi-cations should be continued during the perioperative period. Although the literature provides no evidence to support the use of any specific inhaled or intravenous anesthetic, many clinicians believe that general anesthe-sia causes fewer exacerbations and is superior to neurax-ial techniques in these patients. Avoiding administering depolarizing NMBDs such as succinylcholine to patients with MS is reasonable; denervation or misuse myopathy may lead to a risk for exaggerated release of muscle potas-sium, causing hyperkalemia and cardiac arrhythmias. Nondepolarizing NMBDs are safe to use but should be cautiously administered since both prolonged responses (increased sensitivity in patients with preexisting mus-cle weakness) and resistance to these NMBDs have been reported. Speculation suggests that the demyelination associated with MS renders the spinal cord susceptible to the neurotoxic effects of local anesthetics. Nevertheless, epidural application of low concentrations of local anes-thetics has been successfully used in patients with MS.73 Spinal anesthesia, on the other hand, has been impli-cated in postoperative exacerbations of MS symptoms. Because demyelination may also damage the blood-brain barrier, spinal anesthesia is usually not recommended for these patients. Clearly, the need for postoperative care is dependent on the preoperative symptoms, the type of surgery, and the expected complications. The need for extended postoperative care and respiratory support


should be considered for those with severe preopera-tive weakness, respiratory compromise, and pharyngeal dysfunction.

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a mixed upper and lower motor neuron disease with degeneration of anterior horn α-motoneurons in the spinal cord and brainstem motor nuclei and corticospinal tracts. Patients demon-strate gradually spreading focal weakness and muscle atrophy (typically of the hands), spasticity, and hyper-reflexia of lower extremities. Dysarthria and dyspha-gia, tongue atrophy, and fasciculations may also occur. Progressive weakness can lead to respiratory failure and death. Sensory functions, including intellectual capacity and cognition, as well as bowel and bladder function, are not usually affected in ALS.

ALS has an incidence of approximately 2 in 100,000 and prevalence of 4 to 6 per 100,000. The onset of the disease usually occurs between 50 and 75 years of age, and men are more often affected than women. Most cases are sporadic, and although the pathophysiologic process remains unclear, an association with superox-ide dismutase (SOD) mutations has been suggested. SOD is an important antioxidant, and its mutation can lead to decreased clearance of free radicals, increased oxida-tive stress, and mitochondrial dysfunction. Most familial forms are associated with the mutation of C9ORF72 on 9p21, TDP43, FUS, and VCP genes. Electromyographic and electroneurographic studies and neurologic exami-nation, which demonstrates early spastic weakness of the upper and lower extremities, typical subcutaneous muscle fasciculations, and bulbar involvement affect-ing pharyngeal function, speech, and the facial muscles, confirm the diagnosis. No curative treatment is currently available, and patients are therefore treated symptomati-cally. Riluzole, a glutamate-release inhibitor, may provide neuroprotection and extend survival in these patients.74 Tracheostomy and gastrostomy surgeries and other sup-portive treatments including mechanical ventilation are often required.


Patients with ALS may have an increased sensitivity to the respiratory depressant effects of sedatives and hyp-notics. Bulbar involvement, in combination with respira-tory muscle weakness, leads to a risk for aspiration and pulmonary complications. Sympathetic hyperreactivity and the implications of autonomic dysfunction, often displayed as orthostatic hypotension and resting tachy-cardia, should be considered during the perioperative management of these patients.75 Succinylcholine should be avoided because of the risk for hyperkalemia as a result of denervation and immobilization. Nondepolar-izing NMBDs may cause prolonged and pronounced neu-romuscular block and hence should be used with great caution.76 General anesthesia may be associated with exaggerated ventilatory depression. Regional anesthe-sia is also often avoided for fear of exacerbating disease



symptoms. However, both general and epidural anesthe-sia have been successfully administered to these patients without reported complications.

DUCHENNE MUSCULAR DYSTROPHY

Genetic defects in components of muscle cells, which result in progressive skeletal and smooth muscle dysfunc-tion, are the cause of a group of disorders collectively referred to as muscular dystrophies. The most common and severe form of muscular dystrophy is Duchenne muscu-lar dystrophy (DMD), which affects approximately 1 in 5000 male births.77,78 DMD is an X-linked recessive dis-order caused by mutations in the gene that encodes the protein dystrophin.79,80 A deletion within the gene most commonly causes DMD, but duplication and point muta-tion have also been described.80 Although most cases are due to inherited mutations, approximately 10% are due to spontaneous mutations, which can be explained by the large size of the dystrophin gene.79

The dystrophin gene is expressed in skeletal, smooth, and cardiac muscle. Although it only accounts for 0.002% of protein in striated muscle,81 dystrophin plays an important role in sarcolemmal stability and muscle mem-brane integrity. A cytoskeletal protein links intracellular actin to a group of cell membrane proteins called the dys-trophin-associated protein complex.82 This complex, in turn, links via laminin to the extracellular matrix (Fig. 42-1).82 In DMD, not only is dystrophin absent, but an abnormal expression of the dystrophin-associated protein complex is evident.82 A hallmark of the disease at its early stages is increased membrane permeability and leakage of intra-cellular components, including creatine phosphokinase out of the cell and extracellular ions (including calcium into the cell). Traditionally, the absence of dystrophin has been thought to render the sarcolemma fragile and


susceptible to rupture with contraction and that this accounts for the increased membrane permeability.83 Recently, however, this mechanism has been called into question, and evidence has suggested that the disease alterations in channel function in the early stages lead to an increase in intracellular calcium, which activates pro-teases and reactive oxygen species.79,82

Infants with DMD are often normal. Symptoms gener-ally emerge between 2 and 5 years of age84; in one pop-ulation-based sample, the first signs or symptoms were noted at a mean age of 2.5 years and definitive diagnosis was made at a mean age of 4.9 years85 (see also Chapter 93). The common signs and symptoms at presentation include proximal muscle weakness79 that results in gait disturbance (including waddling and toe walking), dif-ficulty climbing stairs, calf hypertrophy, and the classic Gowers sign (in which the child uses his hands to climb up their thighs to stand).84 Creatine kinase level provides a good screening test; in children with DMD, the level is elevated (usually between 5000 and 150,000 IU/L).84 Motor development plateaus between ages 3 and 6 years, and by 9 to 12 years of age, most patients are wheelchair bound.84

After children become wheelchair bound, spinal defor-mity generally ensues secondary to truncal weakness.86,87 This deformity, combined with progressive respiratory muscle weakness, can compromise the pulmonary func-tion. These patients become highly susceptible, par-ticularly in the setting of infection, to acute respiratory failure.84 Additionally, they are vulnerable to upper air-way dysfunction and sleep apnea.79 Cardiomyopathy occurs in nearly all patients with DMD.88,89 Dystrophin is present in cardiac muscle cells, and the degeneration of cardiomyocytes results in fibrosis.89 This fibrosis ini-tially affects the posterobasal segment of the left ven-tricle,89 which leads to increased myocardial wall stress and a progressive decrease in left ventricular systolic

Figure 42-1. Diagram of the cell-surface and cytoskeleton protein complex. (From Zhou J, Allen PD, Pesah IN, et al: Neuromuscular dis-orders and malignant hyperthermia. In Miller RD, editor: Miller’s anes-thesia, ed 7. Philadelphia, 2010, Elsevier (Churchill Livingstone), pp 1171-1196.)

Laminin-2

Sarcoglycancomplex

Basal lamina

Extracellular

Intracellular

Dystrobrevin

COOH

Dystrophin NH2

Actin

Sarcolemma

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function that eventually results in ventricular dilatation and dysfunction. These changes are evident as character-istic electrocardiographic abnormalities including tall R waves over V1; deep and narrow Q waves over I, V5, and V6; sinus tachycardia; and right axis deviation.90 Initially, the echocardiogram will show areas of regional wall motion abnormalities at the sites of fibrosis, and, even-tually, ventricular dysfunction will be apparent. Fibrosis of the posterior papillary muscle can result in significant mitral regurgitation.91 As a consequence of the structural changes, patients with DMD are highly susceptible to a range of arrhythmias.92

The primary treatment for DMD is glucocorticoids. Meta-analysis of the available data suggests that treat-ment with glucocorticoids improves short-term muscle strength and function.93 The most effective regimen appears to be prednisolone at 0.75 mg/kg/day.93 Recent data suggest that the addition of bisphosphonates to steroids may be beneficial.94 Management of the cardio-myopathy consists of angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and diuretics.89 Pul-monary support, including continuous positive air-way pressure, bilevel positive airway pressure, and full ventilatory support after a tracheostomy, is frequently required.84 Novel molecular therapies, including gene replacement therapy, mutation suppression, and exon skipping, are being developed and hold promise for the treatment of this disease.95 The clinical course is one of progressive decline with death, usually from respira-tory or cardiac failure that generally occurs in the third decade of life.96


Patients with DMD have a frequent need for anesthesia for procedures including muscle biopsy, spine surgery for scoliosis, release of contractures, and fractures requiring operative intervention. The principal anesthetic concerns depend on the stage of the disease. In young patients when skeletal muscle is deteriorating, anesthetic triggers can cause profound rhabdomyolysis and hyperkalemia.79 In older patients, including adolescents and adults, respi-ratory and cardiac concerns predominate.79 Irrespective of age, a careful anesthesia consultation, along with consultations from other relevant medical specialists, is required for patients with DMD who undergo nonemer-gent surgery.97-99

Because progressive pulmonary function decline is a hallmark of the disease and the majority of deaths in patients with DMD are due to pulmonary causes, preop-erative pulmonary assessment is required. Experts rec-ommend the performance of preoperative pulmonary function tests including measurement of forced vital capacity (FVC), maximum inspiratory pressure, maxi-mum expiratory pressure (MEP), peak cough flow (PCF), and oxyhemoglobin saturation measured by pulse oxime-try in room air.98 For patients with an FVC less than 50%, consideration should be given to preoperative training in noninvasive positive pressure ventilation.98,100 Such training may result in higher rates of successful use in the postoperative period. Patients with DMD, defined in adults by a PCF less than 270 L/min or an MEP less than

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60 cm of water, are considered at high risk for respiratory complications as a result of impaired cough. For these patients, experts recommend training in manual and mechanically assisted cough.98

As discussed, DMD results in a progressive dilated cardiomyopathy, which predisposes the patient to both acute heart failure and arrhythmias during the periop-erative period.99,101 Preoperative assessment with an electrocardiogram and echocardiogram and consultation with a cardiologist are generally recommended to ensure that patients are optimized for surgery.98 However, nor-mal preoperative cardiac workup does not preclude the possibility of perioperative cardiac decompensation.101 Optimization of preoperative nutrition is also essential. Malnutrition can occur as a consequence of increased work of breathing or an inability to eat as a result of dyspnea.98 The introduction of appropriate ventilatory support may help with this problem. Preoperative mea-surement of prealbumin and albumin may be indicated to identify patients with suboptimal nutrition status who are at risk for impaired wound healing.98

Because DMD is a terminal illness, experts recom-mend clarifying with patients and guardians resuscitation parameters and, when appropriate, instituting advanced directives before major surgery.98

Several intraoperative considerations are important for patients with DMD. First, succinylcholine is considered contraindicated in patients with DMD. Succinylcholine can precipitate hyperkalemia via two mechanisms in these patients: (1) excess potassium release as a result of the activation of extrajunctional fetal (although its pres-ence in patients with DMD is controversial) and adult acetylcholine receptors102; and (2) massive rhabdomy-olysis with muscle contraction secondary to an unstable sarcolemma.79,103 Indeed, hyperkalemic cardiac arrest after the administration of succinylcholine to young male patients with undiagnosed DMD has led to a black box warning cautioning its use in children and adoles-cents.79 Second, volatile anesthetics are probably best avoided in these patients,24,79,104 and most experts sug-gest the use of total intravenous anesthesia when pos-sible. Although rare, exposure to volatile anesthetics can precipitate a life-threatening MH-like reaction character-ized by profound rhabdomyolysis.103,104 This reaction can occur at low concentrations and may even develop postoperatively, which presents an argument for the use of a clean anesthesia machine.79,104 Although some earlier reports suggest an association between DMD and MH, a shared genetic risk for DMD and MH is thought to be unlikely—the causal mutation for DMD is on the X chromosome, and the mutations associated with MH are generally on chromosome 19.103 Rather, the mechanism of this adverse reaction to volatile anesthetics is thought to be isolated rhabdomyolysis and hyperkalemia without the signs of hypermetabolism.104 As such, dantrolene is unlikely to be clinically useful in these circumstances,104 and treatment should be focused on the standard man-agement of hyperkalemia. Some authors argue that evi-dence for considering volatile anesthetics as absolutely contraindicated remains insufficient79 and have argued that brief exposure in circumstances such as a difficult airway is reasonable.104

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Chapter 42:
DMD presents several challenges with respect to air-way management. First, the incidence of difficult intuba-tion is likely higher in these patients. In a recent series involving 232 cases of patients with DMD undergoing orthopedic surgery, the incidence of difficult direct laryn-goscopy was 4%,105 likely owing to higher rates of mac-roglossia, obesity, limited mouth opening, and decreased cervical spine range of motion.105 Decreased laryngeal reflexes and slowed gastric emptying, which increase the risk for aspiration, may further complicate airway man-agement. Sleep disordered breathing including obstruc-tive sleep apnea and hypoventilation are common in patients with DMD.106 It is widely recognized that sleep disordered breathing increases sensitivity to opiates in children.107,108 Therefore, opiates should be judiciously used and titrated to effect in patients with DMD.79

Patients with DMD exhibit increased sensitivity to the effects of nondepolarizing NMBDs with a given dose, resulting in greater train-of-four ratio depression and a longer period of neuromuscular block.109,110 This may be due to the decrease in muscle mass observed with DMD.79 A delay in the onset of block has also been observed for rocuronium, which may have implications for its use in rapid sequence induction.110

Data are mixed regarding whether a bleeding diathe-sis is present in DMD. Some studies have found evidence of platelet function deficiency,111,112 whereas other stud-ies have not.113,114 A relatively recent study found that patients with DMD have increased bleeding times in the setting of normal platelet function. Based on the pres-ence of dystrophin in normal vascular smooth muscle, the authors argued that the impaired hemostasis was due to a defect in vascular smooth muscle reactivity.114 Some experts recommend the use of aminocaproic acid in patients with DMD who are undergoing major surgery.79

Regional anesthesia can be safely used in patients with DMD115 and may be preferable in some clinical circum-stances, considering the problems with volatile anesthet-ics and NMBDs previously described. Regional anesthesia may also have particular benefits for postoperative anal-gesia, considering the risks for postoperative respiratory complications in these patients.

The principal concerns in the postoperative care of patients with DMD include the potential for respiratory or cardiac compromise (or both). Careful consideration should be given to the postoperative care setting, and many patients are likely to benefit from admission to an ICU. For patients with an FVC less than 50%, extuba-tion directly to noninvasive positive pressure ventilation should be considered.98 In some circumstances, if ade-quate pain control is likely to result in hypoventilation or excessive sedation, then extubation may be delayed for 1 to 2 days.98 Additional recommendations for post-operative care of these patients include manually or mechanically assisted coughing and the use of cardiology consultants to aid in the management of postoperative fluid shifts and other cardiac issues. Given the gastroin-testinal motility issues that can accompany DMD, experts recommend the use of bowel preparation and prokinetic drug regimens and gastric decompression in appropriate patients.98 Early enteral or parenteral nutritional support is also recommended when oral intake is not possible.98


BECKER MUSCULAR DYSTROPHY

Becker muscular dystrophy (BMD) is a milder form of DMD with an incidence that is approximately 20% that of DMD.116 It affects approximately 14 per 100,000 males.117 The onset of clinical symptoms in BMD generally occurs later than in DMD, with ambulation being maintained by most affected patients into the third decade of life.118 Life expectancy is substantially longer than what is observed in DMD, often extending into the fifth decade of life.79

An important feature of BMD is the frequent presence of cardiac involvement, even in the presence of benign or subclinical myopathy. In one series, 72% of patients with subclinical myopathy exhibited cardiac involvement.119 Early right ventricular involvement and later left ventricu-lar dilatation and a reduced ejection fraction characterize the cardiac manifestations.119 Since skeletal muscle is less involved in BMD, patients are hypothetically able to per-form strenuous exercise, which creates cardiac stress that damages the dystrophin-deficient myocardial cells.119


Anesthetic considerations are dependent on the sever-ity of the disease but, in general, are similar to those for DMD. These patients appear to be susceptible to the anesthetic-induced rhabdomyolysis observed in DMD. In fact, case studies report patients with previously undi-agnosed BMD who experienced massive rhabdomyoly-sis (without hypermetabolism) and cardiac arrest upon exposure to volatile anesthetics.120 Accordingly, as with DMD, volatile anesthetics should be generally avoided. Succinylcholine is also contraindicated for these patients. Considering the high prevalence of cardiomyopathy in patients with BMD,119 performing a preoperative electro-cardiogram and echocardiogram in patients undergoing moderate- or high-risk surgery is prudent. The manifesta-tions of the patient’s disease, particularly cardiac status, and the type of surgical procedure will dictate the type of postoperative monitoring and care.

LIMB-GIRDLE MUSCULAR DYSTROPHY

Limb-girdle muscular dystrophies are a clinical and genet-ically heterogeneous group of myopathies characterized by progressive weakness that begins in the proximal mus-cles, typically the shoulder or pelvic girdle muscles, spar-ing other muscle groups at early disease stages.121,122 The age of onset can be from childhood to late adulthood, depending on the subtype. Inheritance pattern can be autosomal dominant or recessive. To date, 24 genetically distinct limb-girdle muscular dystrophies have been iden-tified, and that number is likely to increase substantially with advances in next-generation sequencing.122 Treat-ment, at present, is supportive.


The literature on the anesthetic management of patients with limb-girdle muscular dystrophy is primarily lim-ited to case reports.123-125 The clinical manifestations of



the disease and the planned procedure should dictate the anesthetic plan. Preoperative discussion with a neu-romuscular disease specialist to understand the clinical features of the patient’s disease subtype is warranted. Some types of limb-girdle muscular dystrophy will have a prominent cardiac component and therefore require preoperative cardiac testing. The patients may be suscep-tible to the same volatile anesthetic-induced rhabdomy-olysis observed in DMD and BMD123; therefore, avoiding these agents may be prudent. Succinylcholine should be avoided.

MYOTONIC DYSTROPHIES

Myotonic dystrophies (DMs) are autosomal dominant multisystem diseases characterized by myotonia, muscu-lar dystrophy, cardiac conduction defects, cataracts, and endocrine disorders.126 DMs have two major subtypes: myotonic dystrophy type 1 (DM1), classically known as Steinert disease or Batten-Gibb disease; and myotonic dystrophy type 2 (DM2). An expanded cytosine-thy-mine-guanine (CTG) repeat in the 3’ untranslated region on chromosome 19 encoding the dystrophia myotonica-protein kinase gene causes DM1.126 Normal individuals generally have fewer than five of these repeats, whereas those who are affected can have repeats into the thou-sands.127 In DM1 disease, onset and severity gener-ally correlates with the number of repeats,128 and DM1 is often divided into congenital, childhood onset, and adult onset. An expanded CTG repeat in intron 1 of the zinc finger protein 9 gene causes DM2.126 Although both disorders share the same core clinical manifestations, in general, DM2 develops later and has a milder clinical course.126

Facial muscle weakness and wasting is a prominent component of DM1, resulting in a characteristic “hatchet face” appearance.129 In addition, weakness of the neck flexors and external rotators of the arm are characteris-tic130; other muscle groups, including hands, ankles, and pharyngeal muscles, can also be involved. Proximal mus-cle weakness, particularly of the lower extremity is a com-mon component of DM2 and was previously referred to as proximal myotonic myopathy.131 DM has, in general, impor-tant cardiac manifestations, and these patients have a rel-atively high incidence of sudden cardiac death.129 DM1 is associated with conduction abnormalities, tachyarrhyth-mias (particularly atrial tachyarrhythmias), cardiomyopa-thy, and valvular disorders.132 Cardiomyopathy may not always be clinically apparent because of the limited capac-ity for exertion secondary to the myopathy.132 In general, the cardiac manifestations are less severe in patients with DM2, compared with those with DM1.129

Patients with DM1 are also susceptible to respiratory complications including aspiration (as a result of pharyn-geal muscle weakness) and hypoventilation (as a result of diaphragm weakness and decreased central respiratory drive).129 Respiratory complications are less common in patients with DM2. Similarly, patients with DM1 are at risk for a number of gastrointestinal problems, including impaired esophageal peristalsis, delayed gastric emptying, and dysphagia.129

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Because of the high risk for perioperative respiratory complications, the possibility of prolonged postopera-tive mechanical ventilation should be considered in all patients with DM1, in particular those with severe mus-cular disability (as assessed by proximal muscle weakness) or those who are scheduled for upper abdominal sur-gery.133 In a series of pediatric patients with DM1, the risk of postoperative respiratory complications was related to the degree of muscular impairment, the number of CTG repeats, and the duration of surgery. The use of muscle relaxants without reversal was a potentially modifiable risk factor.134 In general, perioperative complications in patients with DM2 are less common than in DM1.135,136

Because of the cardiac manifestations of this disease, including conduction abnormalities, arrhythmias, and cardiomyopathy, consulting with a cardiologist may be appropriate to ensure that all of these conditions are identified and optimized before surgery. In some circum-stances, an echocardiogram and even electrophysiologic studies may be necessary before surgery.129 The potential for impaired gastrointestinal motility should also be eval-uated before surgery and taken into consideration in plan-ning the approach to airway management. Finally, these patients may show enhanced sensitivity to the respiratory depressant effects of anesthetic medications137 and seda-tives. Anesthetic and analgesic medications should there-fore be carefully titrated to effect.

MYOTUBULAR OR CENTRONUCLEAR MYOPATHY

Similar to other congenital myopathies, specific struc-tural changes in muscle fibers, early onset with hypoto-nia and weakness, and a genetic basis and nonprogressive course characterize myotubular myopathy (MTM) or centronuclear myopathy (CNM).138 MTM was originally described in 1966, and early childhood weakness affect-ing the extraocular, facial, neck, and limb muscles char-acterized this disorder. MTM is now divided into three groups based on clinical and genetic features139: the severe X-linked recessive (myotubular) form, the auto-somal (centronuclear) recessive form, and the relatively mild autosomal dominant form with late onset. The esti-mated frequency of the X-linked form is 1 in 50,000 male newborns.140 The X-linked recessive MTM is the most severe form of the disease. The gene responsible for MTM has been localized to Xq28, which encodes myotubularin, a tyrosine phosphatase protein.141,142 Onset is commonly in utero and may be associated with polyhydramnios and reduced fetal movement.138 Affected male newborns typi-cally exhibit severe floppiness at birth, feeding difficulties, and respiratory distress that requires assisted ventilation. Cardiac muscle is spared, and, in the absence of cerebral hypoxia, cognitive development is normal. Other charac-teristic features include birth length more than the 90th percentile, macrocephaly (+/− hydrocephalus), a narrow elongated face, and slender, long digits.143 Serum creatine kinase levels, electromyography, and motor nerve con-duction velocities are typically normal. The characteristic

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histologic feature is the presence of centrally placed nuclei in muscle fibers resembling fetal myotubules.138 The long-term prognosis is poor, although studies have reported survival of affected patients for as long as 27 years, with most patients being partially or completely ventilator dependent.144 Liver function tests may be altered in some patients.144

The autosomally inherited forms of MTM or CNM are rare, both familial and sporadic forms.138 The majority of patients with autosomal recessive CNM demonstrate the disorder in infancy or early childhood. Clinical features include hypotonia, respiratory distress, bulbar weakness, and ophthalmoplegia. The course may be slowly progres-sive, with development of scoliosis and a loss of ambu-lation by adolescence. Laboratory findings are similar to other patients with MTM. A late onset, autosomally dominant form has also been described that has a milder course than the other two forms. Autosomal recessive CNM is associated with mutations in the BIB1 gene that encodes for amphyphysin-2,145 whereas autosomal domi-nant CNM has been linked to the gene that encodes for dynamin-2.146 Treatment is entirely supportive.


A primary concern when providing anesthesia for a patient with a congenital myopathy is the risk of pre-cipitating MH with triggering anesthetics (e.g., volatile anesthetics, succinylcholine).147 Some of the congeni-tal myopathies (e.g., central core disease, multiminicore myopathy, nemaline rod myopathy) are clearly linked with the risk of MH because they may all be associated with mutations in the ryanodine (RYR1) gene.148 The risk of MH in MTM or CNM is likely to be low, but all reported cases have used nontriggering anesthetics, such as propo-fol and remifentanil.149 However, one case study reports MH-like symptoms developing during cardiopulmonary bypass in a patient with late-onset CNM, even in the absence of administering triggering anesthetics.150 Thus the most prudent course in patients with MTM or CNM is probably avoiding volatile anesthetics and succinylcho-line. A risk of prolonged paralysis with nondepolarizing muscle relaxants exists.151 However, avoiding the use of muscle relaxants altogether should be easy, considering the hypotonia in these patients.

DISORDERS OF MUSCLE ENERGY METABOLISM

The source of energy used by muscle for metabolism depends on several factors, most importantly the type, intensity, and duration of exercise. At rest, muscles pre-dominantly use fatty acids. At submaximal exercise (70% to 80% of maximum oxygen consumption [VO2max]) aer-obic metabolism of glycogen is the most crucial source of energy. At intensities close to VO2max, anaerobic glycoly-sis is the major source of energy.152 Glycogen serves as a dynamic but limited reservoir of glucose, mainly stored in skeletal muscle and liver. Glycogen storage disorders (GSDs) are a group of metabolism disorders caused by enzyme deficiency or dysfunction. They reduce effective

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glucose storage by interfering with normal glycogen syn-thesis and degradation. Synthetic errors cause decreased normal glycogen, whereas degradation errors tend to block the breakdown of glycogen. Subsequently, hypo-glycemia and the accumulation of glycogen in tissues could occur as a result of defective substrate use. More than 12 types of GSDs are assigned Roman numerals based on the enzyme deficiencies. Type II, acid maltase deficiency (AMD), is discussed in this text.

GLYCOGEN STORAGE DISEASE TYPE II (ACID MALTASE DEFICIENCY)

Acid maltase is a lysosomal α-glucosidase that releases glu-cose from maltose, oligosaccharides, and glycogen. Three clinical forms of AMD have been described. The infantile form (Pompe disease) is the most common, and symptoms are typically expressed during the first 3 months of life. The affected patients develop severe muscle weakness, car-diomegaly, hepatomegaly, and respiratory insufficiency. Cardiorespiratory failure usually causes death before 2 years of age.153 Presentation of the childhood form of AMD is primarily a myopathy. Motor milestones are delayed, and weakness is greater in the proximal than in the distal muscles. Calf enlargement can occur, resulting in a clinical picture that simulates muscular dystrophy. The disease progresses relatively slowly; however, most patients die of respiratory failure by the second decade of life.153 The adult form usually begins in the third or fourth decade of life but can begin as late as the seventh decade. Respiratory failure and diaphragmatic weakness are often initial manifestations, heralding progressive proximal muscle weakness. The heart and liver are not involved.154

The plasma creatine kinase is elevated by as much as 10-fold in the infantile and childhood forms but may be normal in adult-onset disease. Electromyography dem-onstrates a myopathic pattern with distinctive myotonic discharges, trains of fibrillation and positive waves, and complex repetitive discharges. The muscle biopsy in infants typically reveals vacuoles containing glycogen and the lysosomal enzyme, acid phosphatase. However, muscle biopsies in late-onset AMD may demonstrate only nonspecific anomalies.154

Pompe disease is inherited as an autosomal recessive mutation of the α-glucosidase gene. Enzyme replacement therapy (ERT) with intravenous recombinant human glucosidase has been shown to be beneficial in infantile-onset Pompe disease.155 Clinical benefits in the infan-tile disease include reduced heart size, improved muscle function, reduced need for ventilatory support, and lon-ger life. In late-onset cases of Pompe disease, ERT has not been associated with the dramatic response that can be seen in classic infantile Pompe disease, yet it appears to stabilize the disease process, somewhat improving motor and respiratory function.156


Anesthesia reports in patients with AMD are rare, but pay-ing close attention to the cardiac function in infantile Pompe disease is reasonable, considering the associated cardiomyopathy. In a series of five infants with Pompe

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disease, Ing and colleagues observed that the left ventricu-lar mass, assessed by echocardiography, was between four and five times greater than normal.157 Isolated intraopera-tive cardiac arrest during halothane anesthesia in infantile AMD has been documented.158 Despite the problem noted with halothane, enflurane and sevoflurane have been used without complications.157 Although halothane may make the myocardium more prone to arrhythmias, meticulous attention to the hemodynamic parameters and preven-tion of a vicious cycle of hypotension and compromised myocardial perfusion are likely more important than the choice of a volatile anesthetic agent. Some have suggested that ketamine might be preferable to propofol or sevoflu-rane induction, primarily because ketamine is an indirect sympathomimetic.159 Although ketamine is certainly a reasonable choice in these patients, its side effects, such as tachycardia and the consequent increase in myocardial oxygen consumption, need to be kept in mind.

In patients with late onset AMD, the degree of preop-erative weakness and respiratory compromise should be considered to plan for the anesthetic accordingly. Epi-dural analgesia, used as an adjunct to general anesthe-sia, has been administered with success in a patient with adult-onset Pompe disease.160 Femoral nerve blocks and caudal blocks have also been successfully used in chil-dren with Pompe disease.161 A combined epidural-spinal technique has also been reported in the management of a pregnant woman with adult-onset Pompe disease for a cesarean section.162

Succinylcholine should be avoided because of the risk of hyperkalemia in a patient with myopathy. Nondepo-larizing NMBDs are safe to use, provided close attention is paid to neuromuscular monitoring.163 It should be noted that prolonged postoperative weakness has been reported even without NMBDs.164

MITOCHONDRIAL MYOPATHIES

The concept of disease as a result of mitochondrial dys-function was first introduced in 1962 when Swedish investigators described a patient with severe hypermetab-olism without thyroid dysfunction.165 These investigators defined mitochondrial disease on the basis of (1) morpho-logic evidence of abnormal mitochondria in muscle, (2) biochemical documentation of “loose coupling” between oxidation and phosphorylation in isolated mitochondria, and (3) correlation between biochemical abnormalities and clinical features (hypermetabolism).166 Mitochon-drial diseases may be classified in terms of defects in the five main steps of mitochondrial metabolism: substrate transport, substrate utilization, the Krebs cycle, the elec-tron transport chain, and oxidation and phosphorylation coupling.167 The terms mitochondrial encephalomyopathies and mitochondrial myopathies are reserved for those dis-orders that are the result of defects in the respiratory or electron transport chain.166 The respiratory chain is com-posed of five multimeric complexes (I to V) embedded in the inner mitochondrial membrane, plus two small mobile electron carriers, coenzyme Q10 (CoQ10) and cyto-chrome c, for a total of more than 80 proteins. mtDNA encodes 13 of these proteins, and nDNA encodes all

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others. mtDNA is different from nDNA in several aspects: (1) mtDNA is circular and contains no intron, (2) it has a greater number of copies than nDNA and a significantly higher spontaneous mutation rate, and (3) its inheritance is maternal. Considering the dual genetic control of the respiratory chain, that is, of both mtDNA and nDNA, multiple mutations in either can give rise to mitochon-drial disease.166

Primary mtDNA mutations may include point muta-tions in polypeptide, transfer RNA (tRNA), or ribosomal RNA (rRNA) encoding regions and large-scale rearrange-ments, duplications, or deletions. Some of the common conditions caused by point mutations include myoclonic epilepsy with ragged-red fibers (MERRF); mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS); neuropathy, ataxia, and retinitis pigmentosa (NARP); Leigh disease; and Leber hereditary optic neurop-athy (LHON). Sporadic large-scale mutations may lead to Kearns-Sayre syndrome (KSS), progressive external oph-thalmoplegia, and Pearson syndrome. nDNA mutations can cause deficiencies in complexes I to IV and in CoQ10 of the electron transport chain.166

Mitochondrial diseases present a diagnostic challenge as a result of their clinical heterogeneity. Since mitochon-dria are ubiquitous, mtDNA mutations can affect every tis-sue in the body. Disorders as a result of nDNA mutations follow a mendelian pattern and thus are phenotypically “all or none,” whereas inheritance of mtDNA is stochas-tic, leading to greater variability. The overall incidence of mitochondrial myopathy is estimated to be 1 in 4000.168 Clinically, certain symptoms or signs are “red flags” for mtDNA-related conditions because of their frequency. These include syndromic or isolated sensorineural hearing loss, short stature, progressive external ophthalmoplegia, axonal neuropathy, diabetes mellitus, and hypertrophic cardiomyopathy.169 Pure myopathies vary considerably in the age of onset, distribution of weakness, and course, ranging from early onset severe disease with respiratory failure to adult onset with mild or even reversible weak-ness. In addition to fixed weakness, patients with mito-chondrial myopathies complain of exercise intolerance and premature fatigue; some experience recurrent myo-globinuria.166 The histologic hallmark of these diseases is the “ragged-red fiber” when muscle tissue is stained with the Gomori trichrome stain.170 Common laboratory find-ings include a high lactate-to-pyruvate ratio (50 to 250), instead of a normal ratio (less than 25:1), increased blood levels of free carnitine, and occasionally low levels of folate (as in KSS). Computed tomography and magnetic resonance imaging of the brain may be helpful. For exam-ple, patients with MELAS demonstrate basal ganglia calci-fications and strokelike patterns not confined to vascular territories.170 Clinical features of two relatively common encephalomyopathies, MELAS and MERRF, are briefly discussed in the following text.

MITOCHONDRIAL MYOPATHY, ENCEPHALOPATHY, LACTIC ACIDOSIS, AND STROKELIKE EPISODES

MELAS is the most common mitochondrial encephalo-myopathy. Onset is most commonly before age 20 years.

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Chapter 42:
Seizures are common and strokelike episodes (strokelike because they do not conform to vascular distributions) may produce hemiparesis, hemianopia, and cortical blindness. Any patient younger than 40 years of age with a history of stroke should be assessed for MELAS. Associ-ated findings include diabetes mellitus, hearing loss, pitu-itary and thyroid hypofunction, and lack of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden state, and death. No specific treatment is currently available.154

MYOCLONIC EPILEPSY WITH RAGGED-RED FIBERS

MERRF is a multisystem disorder characterized by myoc-lonus, generalized epilepsy, ataxia, and ragged-red fibers on muscle biopsy. Other clinical features may include hearing loss, peripheral neuropathy, optic atrophy, dementia, short stature, and exercise intolerance.166 Car-diomyopathy is occasionally present. Laboratory features include an increased lactate level at rest and with exer-cise, and a myopathic picture on an electromyogram and electroencephalogram shows generalized spike and wave discharges with background slowing. Only supportive treatment is available.


The anesthesiologist may be involved in the care of patients with mitochondrial disease in multiple situations and often in the setting of obtaining a muscle biopsy in a child with an undiagnosed myopathy.171 These patients may also have surgical procedures related to the disease (such as implantation of a permanent pacemaker in a patient with KSS),172 for incidental medical problems, as well as in the labor and delivery suite for labor anal-gesia.173 The diversity of clinical presentations encoun-tered in the mitochondrial myopathies dictates that each patient be thoroughly evaluated and that the anesthetic plan be tailored to the patient’s specific needs.

Preoperatively, the extent of organ system involve-ment should be carefully assessed and documented with particular emphasis on the degree of myopathy and neurologic function. Looking for evidence of cardiomy-opathy or rhythm disturbances is imperative. In addi-tion, close attention should be paid to endocrine issues because myotonic dystrophies may frequently be present together with other metabolic derangements such as elec-trolyte imbalances.174 Varying degrees of respiratory com-promise may be exhibited, and these patients may be at a higher risk of postoperative respiratory complications.168 Baseline blood gases and lactate levels are helpful as well, although a normal lactate level certainly does not rule out a mitochondrial process.

Every class of anesthetics is associated with a theoretic risk of complications in patients with mitochondrial dis-ease. Volatile anesthetics and succinylcholine raise the specter of MH. Propofol and midazolam are known to inhibit the mitochondrial respiratory chain in a dose-dependent manner.175 Indeed, mitochondrial dysfunction has been postulated as a mechanism for the propofol-related infusion syndrome (PRIS).176 NMBDs are associated


with the risk of prolonged paralysis, and narcotics may worsen preexisting respiratory depression.177 Even local anesthetics have been reported to cause mitochondrial toxicity.178 Fortunately, notwithstanding the potential pit-falls previously mentioned, almost every anesthetic tech-nique has been safely used in patients with mitochondrial disease.174,179 The caveat, of course, is that given the rarity of the mitochondrial diseases, all anesthetic experiences reported to date take the form of individual case reports or small series that do not permit definitive conclusions.

The association of MH to patients with mitochondrial disease probably dates back to a single case described in 1985 by Ohtani and associates.180 Another patient with a mitochondrial myopathy had a positive halothane contracture test but did not have clinical evidence of MH.181 On the other hand, volatile anesthetics have been used on numerous occasions in this patient population without any adverse effects.173,182 At present, evidence does not support an association between MH and mito-chondrial disease. However, avoiding succinylcholine in patients with extensive myopathy to minimize the risk of hyperkalemia may be prudent, although the safe use of succinylcholine has been documented in at least one patient with KSS.183 Similarly, propofol has been safely used in patients with MELAS, and PRIS has never been described in this group of patients. Nevertheless, propofol should not be used as an ICU sedation in patients with mitochondrial dysfunction. Although using propofol as an anesthetic-induction drug is safe, using a propofol infusion for long periods should probably be avoided.

Several studies report sensitivity to nondepolarizing muscle relaxants, including mivacurium, atracurium, vecuronium, and rocuronium, although resistance to cisatracurium in a patient with MELAS is also reported.174 Being cautious when using muscle relaxants in patients with myopathies is important. Finally, several studies report the successful use of spinal and epidural anes-thetics in patients with mitochondrial diseases.173,184,185 Before choosing a neuraxial technique, close attention should be paid to any preexisting neurologic dysfunction.

Perhaps more important than the specific choice of anesthetics are the implications of the patient’s comor-bidities and metabolic status. Normothermia should be maintained during surgeries, and intravenous fluids should be warmed to body temperature. Lactated Ringer solution should probably be avoided, considering the risk of preexisting lactic acidosis, although evidence does not indicate that lactated Ringer solution has worsened acidosis when used.174 Multiple studies have reported hyponatremia (and occasionally hyperkalemia) in these patients.174,186,187 In such situations, adrenal insufficiency should be considered, particularly when accompanied by hypotension.174 Finally, these patients are at increased risk of cardiac conduction abnormalities and cardiomy-opathy that should be taken into consideration when for-mulating an anesthetic plan.

PERIODIC PARALYSES

The periodic paralyses are a group of disorders that are characterized by alterations of function in voltage-gated



ion channels; these diseases are sometimes termed skeletal muscle channelopathies.188 The symptoms of the particu-lar channelopathy depend on the specific ion channel involved and can be divided into three broad categories: (1) chloride channelopathies—myotonia without paraly-sis, such as myotonia congenita; (2) sodium channelo-pathies—myotonia with paralysis, such as hyperkalemic periodic paralysis; and (3) other cation channelopa-thies—paralysis without myotonia, such as hypokalemic periodic paralysis (HypoPP).189

HYPERKALEMIC PERIODIC PARALYSIS

Hyperkalemic periodic paralysis (HyperPP) is an auto-somal dominant disease with a high penetrance that equally affects males and females. It has a prevalence of approximately 1 in 200,000.189 The term hyperkalemic can be misleading because patients may have normal potas-sium levels during attacks. This characteristic led to the erroneous categorization of such patients as having nor-mokalemic periodic paralysis. However, normokalemic peri-odic paralysis has now been unequivocally established as a variant of HyperPP.190 The defining characteristic of the disease is paralysis precipitated by potassium administra-tion.191 Mutations at various sites on the voltage-gated sodium channel SCN4A gene cause HyperPP. The mutant channels, once activated by a depolarizing agent such as potassium, cannot inactivate; they flicker between open and inactivated states. This action produces persistent depolarization (causing muscle weakness) and a shift of sodium into the muscle cells and potassium to be released from the muscle cells (causing hyperkalemia). When potassium diuresis relieves the hyperkalemia, the cycle is probably terminated.189

Attacks of weakness begin in the first decade of life, are generally short-lived and infrequent, although they may later increase in frequency and severity. Precipitating factors include potassium-rich foods and rest after exer-cise. In addition, a cold environment, emotional stress, fasting, glucocorticoids, and pregnancy can provoke or worsen the attacks. In between attacks, a mild myoto-nia is common but does not impede activity. Laboratory studies may show elevated or normal potassium levels during attacks. Creatine kinase levels are often elevated. It is rare for serum potassium to reach cardiotoxic levels, and the electrocardiogram is usually normal. Electromyo-graphic recordings will often show myotonic discharges during and between attacks. Muscle biopsies may show small peripheral vacuoles in the sarcoplasm. Treatment includes medication with acetazolamide (a carbonic anhydrase inhibitor) and mexiletine (an antiarrhythmic with a mechanism of action similar to lidocaine). Behav-ioral modification, such as avoiding potassium-contain-ing foods, strenuous exercise, fasting, and exposure to cold, are also important.189

HYPOKALEMIC PERIODIC PARALYSIS

Familial hypokalemic periodic paralysis (HypoPP) is the most common form of the periodic paralyses, although its prevalence is only 1 in 100,000.192 It is autosomal

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dominant with a reduced penetrance in women and affects men more commonly. Genetically, two types of HypoPP are clinically identical. Patients with type 1 HypoPP (the more common) have a mutation in the L-type calcium channel gene CACN1AS.193 Type 2 HypoPP is the result of mutations in the same sodium channel gene (SCNA4) that causes HyperPP.194 Although it remains unclear how defects in the same gene (SCNA4) give rise to patho-logic characteristics with diametrically opposing clinical manifestations, it has been speculated that HyperPP is a “gain-of-function” sodium channelopathy, whereas type 2 HypoPP is a “change-of-function” channel disease.194

The presentation of HypoPP occurs between child-hood and the third decade of life. Proximal muscles are disproportionally affected, with rare ocular and bul-bar muscle involvement. Respiratory muscle weakness, although unusual, may be life threatening. Continuous physical activity and carbohydrate-rich meals may pro-voke the attacks. Other triggers include bacterial or viral infections, alcohol ingestion, fasting, lack of sleep, dehy-dration, prolonged bed rest, stress, menstruation, and pregnancy.189 Remaining aware of the differences in the clinical features between HyperPP and HypoPP is impor-tant. HypoPP is not associated with myotonia; a sponta-neous attack is associated with hypokalemia (a diagnostic criterion), potassium is a remedy, and glucose triggers an attack.189 Treatment is centered on the identification and avoidance of triggers. Potassium administration can be useful in the treatment of an acute attack. The prophy-lactic medication of choice in type 1 HypoPP is acetazol-amide195; however, acetazolamide can worsen symptoms in type 2 HypoPP.196 Such patients may respond to potas-sium-sparing diuretics such as spironolactone.197

THYROTOXIC PERIODIC PARALYSIS

Thyrotoxic periodic paralysis (TPP) clinically resem-bles HypoPP. TPP occurs later in life than HypoPP, has a strong male predominance, and is significantly more common in patients of oriental descent. Loss-of-function mutations in the inward rectifying potassium channel gene (Kir2.6) may be involved in some cases of TPP.198 The condition responds to antithyroid medications such as methimazole.189


Knowledge of the pathophysiologic processes and pre-cipitating conditions for the different types of periodic paralyses guide the anesthetic approach to patients with these disorders. Salient features are discussed in the fol-lowing text.

HyperPPIf possible, all patients with HyperPP should be preopera-tively admitted to allow preoperative fasting to be accom-panied by the administration of a dextrose-containing, potassium-free intravenous fluid.199 Depolarizing agents such as potassium, succinylcholine, and anticholines-terases aggravate the myotonia in HyperPP and are con-traindicated.189 Nondepolarizing NMBDs may be safely used.199,200 Although succinylcholine can cause masseter

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spasm and rigidity in HyperPP,201,202 these are related to severe myotonic reactions and are not due to MH. No evi-dence suggests that patients with HyperPP are susceptible to MH.148 The safe use of both volatile anesthetics and propofol has been documented.199,200,203 Myotonic con-tractions during anesthesia may be improved with the administration of lidocaine, as chronic myotonic symp-toms are improved by mexiletine.189

Intraoperatively, maintaining normothermia, prevent-ing hyperkalemia, and avoiding hypoglycemia are impor-tant.200 Both spinal and epidural techniques have been successfully used in these patients,204,205 including the use of epidural labor analgesia.206 Nonneuraxial regional techniques have not been extensively investigated; how-ever, a recent report documents the use of a femoral nerve block in a single patient with HyperPP.207

HypoPPPatients with HypoPP undergoing general anesthesia have been reported to exhibit weakness and respiratory distress in the postoperative period.208,209 Important trig-gers to avoid include perioperative stress, glucose loading, hypothermia, and depolarizing NMBDs.189 Although the safe use of intermediate- and short-acting nondepolariz-ing NMBDs such as atracurium and mivacurium has been documented,210-212 avoiding long-acting muscle relax-ants is probably prudent.213 The use of epidural (includ-ing for labor analgesia) and spinal techniques appears to be safe,212-214 although hypokalemia has been docu-mented with the use of epidural techniques, both with and without epinephrine.215 Unlike HyperPP, an associa-tion between HypoPP and MH cannot be categorically ruled out,148 although the use of isoflurane in HypoPP has been reported.212 A number of MH-like metabolic crises in patients with HypoPP have been reported.216-218 Contracture-like responses to succinylcholine have also been described.219 In one of the prior descriptions, two unrelated mutations conferring both HypoPP and sensi-tivity to MH in the same patient seemed likely.218 Con-sequently, although the probability of MH in a given patient with HypoPP is likely to be remote, it cannot be ruled out, and the safest course might be the use of a non-triggering anesthetic. If volatile agents are used, then they should be used with extra vigilance.148

GENETICS OF MENDELIAN, MITOCHONDRIAL, AND COMPLEX DISEASES

With the emergence of technologies that perform genetic sequencing quickly, accurately, and inexpensively, an understanding of the genetic basis of heritable diseases has recently accelerated. The conditions discussed in this chapter generally focus on diseases that have mendelian or mitochondrial inheritance. Recent research has also begun to unlock the genetic basis for complex diseases, including coronary artery disease, diabetes, and hyperten-sion, with which anesthesiologists interact in the course of their clinical practice. The pace of genetic discovery is expected to accelerate in the upcoming decades and become a more integral component of clinical practice.

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It is important for anesthesiologists to be familiar with modern approaches to genetic study; therefore, an over-view of the genetics of mendelian, mitochondrial, and complex diseases is presented.

MENDELIAN DISEASES

Over the last two decades, gene discovery has led to an understanding of the causal mechanisms underlying rare, familial genetic disorders.220 This understanding has transformed diagnosis, management, treatment, and anesthetic practice for patients with these disorders. Men-delian, or single-gene disorders, exhibit simple autosomal or sex-linked inheritance patterns with variable expres-sivity and penetrance. Traditionally, genes for these dis-orders have been identified by positional cloning, which includes linkage analysis (a measure of cosegregation of chromosomal markers with disease phenotype in families) to localize a disease gene to a subchromosomal region, and subsequent sequencing of genes and transcripts under the linkage peak in affected and unaffected fam-ily members to identify causal mutations. In the last few years, direct mutation screening using next-generation sequencing of the entire exome (protein coding region of all known genes in the genome) or entire genome in a small number of affected and unaffected family mem-bers has revolutionized gene identification for mendelian diseases.221,222 To date, causal genes for more than 3600 common diseases have been identified, demonstrating a large extent of locus heterogeneity (in which mutations in different genes lead to the same phenotype) and allelic heterogeneity (in which different mutations in the same gene are present in patients from different families. (Visit Online Mendelian Inheritance in Man [http://www.ncbi.nlm.nih.gov/omim].)220

MITOCHONDRIAL DISEASES

The genetics of mitochondrial disorders is a special case of mendelian disorders because defects may be in mtDNA- or nDNA-encoded structural or regulatory com-ponents of the mitochondrion.223 Maternal inheritance is observed in mtDNA disorders, which often exhibit a range of systemic phenotypes with varying severity, as discussed in the previous section on mitochondrial dis-orders. Typically, affected members from these pedigrees carry germline mutations in mtDNA, but their tissues and organs may contain both normal and mutant copies of mtDNA (heteroplasmy). Because each cell consists of hundreds to thousands of mitochondrial DNA genomes that may segregate unevenly during mitosis, the relative ratio of normal-to-mutant mitochondrial genomes in the body can influence the variability in disease pheno-types.224 Sequencing of the 16.6 kb mtDNA molecule in affected family members, with a comparison against the background mitochondrial haplogroup as defined by lin-eage-specific polymorphisms, and determining the func-tional consequences on respiratory chain activity in vitro typically identify mutations that cause disease.225-227 Mitochondrial disorders caused by nDNA-encoded com-ponents of the mitochondrial machinery are similar to

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http://www.ncbi.nlm.nih.gov/omim

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other mendelian disorders with variable phenotypes, and genes encoding these are increasingly being identified because of better catalogs of the mitochondrial proteome and next-generation sequencing methods.228

COMPLEX DISEASES

The discovery of genes for complex diseases is a powerful approach to identify important biologic pathways con-tributing to disease pathogenesis. Mechanistic insights gained from an understanding of these pathways can lead to new strategies for disease prevention, diagnosis, and treatment. Common diseases are complex traits influ-enced by multiple genes and environment, in contrast to rare diseases caused by single gene defects (mendelian traits). The heritability of a complex trait is the sum of the genetic contribution to the trait,229,230 and the dem-onstration of significant heritability in twin or family studies is usually the first step in justifying gene discov-ery efforts. Causal genetic variation contributing to the genetic component of a trait can arise as a single nucleo-tide substitution (termed a single nucleotide polymorphism when its frequency is present in more than 1% of the population), or an insertion, duplication, or deletion ranging from one base to hundreds of kilobases in length (termed a copy number polymorphism when its frequency is present in more than 1% of the population). This varia-tion can either directly alter the coding sequence of the protein encoded by the gene disrupting protein function or influence the regulatory regions of genes altering gene expression, splicing, or transcript stability. Genetic varia-tion between humans is limited, and most variations in the genome are common.231 Deleterious mutations in single genes causing mendelian diseases do not reach appreciable frequencies in the population because these mutations decrease reproductive fitness and are thus sub-jected to purifying selection. Common diseases are not subject to negative selection because they typically do not influence reproductive fitness and often have a late onset.232 Similarly, for complex pharmacogenetic traits, drug exposures have not occurred until recently in evo-lutionary history; consequently, drug targets or metabo-lizing enzymes may not have been subjected to selective pressure.

GENETIC ARCHITECTURE OF COMPLEX TRAITS

Emerging evidence suggests that the genetic architecture of common diseases typically spans the continuum from mendelian subtypes of a common trait featuring very rare, highly deleterious mutations in a single gene, through a low-frequency range of single nucleotide or copy number variants with medium individual effect, to more common single nucleotide polymorphisms (SNPs) or copy number polymorphisms (CNPs) of modest effect segregating in the larger population.

Linkage analysis, which measures cosegregation of chromosomal markers with disease phenotypes in fami-lies, has been successful in positional cloning of genes for mendelian disease, but genetic association analysis is a study design better powered to detect the role of common


genetic variation underlying complex traits.233 Genetic association studies search for statistically significant allele frequency differences in covariate- and ethnicity-matched cases and controls to identify genetic variants altering the risk of disease. Candidate gene–association studies with the aim to validate the role of known biologic pathways identified through model organism or in vitro studies of disease physiologic processes have met with some success but have been plagued with inconsistency and irrepro-ducibility primarily because of a lack of power in small, individual studies, insufficient accounting for population structure, technical problems with genotyping, or lack of stringent statistical thresholds for multiple testing correc-tion.234 Genome-wide association studies (GWASs) have been the breakthrough method that has validated candi-date disease genes and revealed many more new, unsus-pected genes contributing causally to common disease. GWASs typically interrogate more than 1 million com-mon SNPs and copy number variants across the genome for statistically significant differences in allele frequency between large sets of carefully matched cases or controls. GWASs can also be used to identify genetic variants con-tributing to the variation in disease-related quantitative traits, highlighting roles of genes in specific disease pro-cesses. Several key advances over the last decade have made GWASs possible. These include the availability of the human genome reference sequence; catalogs of common variation, mapping of the correlation structure between variants in continental populations through the Interna-tional HapMap Consortium235; advances in oligo array technology leading to high-throughput, cost-effective, and high-quality genotyping236; and analytic approaches that account for systematic biases such as population structure.237 Although over 10 million common vari-ants have been identified in human populations, GWASs enable testing of approximately 85% of all common vari-ations over 5% frequency because of the phenomenon of linkage disequilibrium, in which neighboring genetic variation is inherited together in “blocks” disrupted only by ancestral recombination events that occur at hotspots (linkage disequilibrium).231,238 Thus, SNPs in close prox-imity are highly correlated to each other, and one marker can serve as a surrogate for multiple variants. Common genetic variation in humans can be categorized into one of a small range of haplotypes or specific patterns of varia-tion with populations of recent African ancestry showing the most diversity, whereas populations that arose out of Africa have fewer haplotypes and longer regions of link-age disequilibrium.239

Successful designs for GWASs require careful phe-notype and covariate definition, sample selection and matching, high-throughput genotyping and quality con-trol, including the removal of low-quality, cryptically related or population outlier samples and the removal of SNPs with a low-genotyping call rate or departure from Hardy-Weinberg equilibrium.240 Population stratifica-tion, or differences in allele frequency between ethnic populations unequally apportioned between cases and controls, can be a major source of type 1 error and can be overcome by selecting a homogeneous study popula-tion or by analytic methods that adjust for genome-wide variation patterns.237 Rigorous statistical significance



thresholds are typically set at 5 × 10−8, correcting for the approximately 1 million common independent tests in the genome identified by simulation studies.241 Finally, replication of significant association signals from GWASs in independent samples in a multistage design is impor-tant to distinguish true, reproducible signals from poten-tial sources of error or bias in the original GWAS.240

The National Human Genome Research Institute cata-logs the growing and significant GWASs reported in the literature. To date, more than 8000 associations to dis-ease, biomarker, or behavioral traits have been identified (http://www.genome.gov/gwastudies/).242 GWASs have led to new insights on the genetic architecture of com-plex traits, namely:

1. Many human traits are highly polygenic, sometimes with more than 100 loci contributing modest effects to disease risk.

2. Most individual common variant effects are modest, with an odds ratio in the range of 1.1 to 1.5; therefore, large sample sizes (1000s to 100,000s) are needed to have sufficient power to detect these effects robustly.

3. Causal SNPs and genes are challenging to pinpoint under an association peak and require intensive bioin-formatic and experimental follow-up, especially since many signals are far from known genes and may repre-sent distant regulatory elements.

4. A single gene may harbor rare alleles of strong effect and one or more common independent alleles of weak effect, contributing to disease etiologic origin.

5. Most discovered loci were not previously suspected as biologic candidates, emphasizing the fruitfulness of an unbiased genome-wide screen.

6. Most effects are observed across multiple ethnic groups, but the relative role of a genetic variant may be different across populations based on differing allele frequencies across populations.

7. Both the overlap of associations between traits (e.g., the same SNP influencing type 2 diabetes and a related trait, insulin secretion) and the unexpected pleiotropy across traits are expected.232

The contribution of rare variants to complex disease is being investigated, largely based on rapid advances in next-generation sequencing.243,244 Large-scale sequenc-ing projects (e.g., the 1000 genomes project245 and the National Heart, Lung and Blood Institute [NHLBI]–funded Exome Sequencing Project246) have now sequenced tens of thousands of individuals, leading to deeper catalogs of rare variation than that queried by GWASs. These projects provide a window into querying the role of low-frequency variation (0.1% to 5% frequency) in disease, especially in protein-coding regions of all known genes in the genome (the exome) in which the impact of a protein-altering variant can be predicted in silico and is amenable to easier interpretation than regulatory variation. Recently, the exome chip, made up of approximately 240,000 vali-dated protein-altering variants (>1:1000 frequency) has been developed.247 This genotyping array includes novel missense, splice-site and nonsense variants, and is pre-dicted to capture 95% of exome variation in an average individual. Even more rare variants contributing to com-mon disease are being sought by exome or whole genome


sequencing of thousands of cases and controls for many complex disease traits.248 Since these variants are individ-ually rare, methods to test the aggregate mutation bur-den or perform association analysis across gene regions have been developed.248 Exome sequencing has proven immensely successful at identifying novel causal muta-tions in families with mendelian segregation of traits, including in mendelian subtypes of common disease, and is an unbiased approach that allows for combined posi-tional cloning (using linkage) and direct-coding mutation detection.221

Efforts are now directed toward identifying the entire allelic spectrum of mutations for many common diseases. Even when all causal genetic variations contributing to a complex trait are defined, understanding gene-gene and gene-environment interactions will be important to explain the full genetic variance of a trait.249 More sophisticated systems’ biologic approaches, such as net-work medicine that integrates genetics with multiple genomic technologies, may also help understand the underlying perturbations of biologic networks that result in disease.250

IMPLICATIONS FOR CLINICAL TRANSLATION

Advances in complex disease gene identification should lead to clinical advances of benefit for all patients and in some scenarios to personalized medicine, depending on a patient’s genetic risk. Identification of novel causal path-ways provides new opportunities for the identification of therapeutic targets for drug development for disease treatment or prevention in all patients. Identification of causal pathways should also lead to new biomarkers to improve diagnoses, monitor disease progression, and response to therapy. Validated genetic markers are also proving to be valuable tool to determine whether rela-tionships between existing biomarkers and disease are causal through mendelian randomization studies.251 In certain clinical scenarios, personal disease risk prediction based on the genetic risk variant profile may lead to per-sonalized therapy, as is now common in cancer therapeu-tics. However, for most diseases, such clinical use is still in the future because in the aggregate, known genetic varia-tion explains such a small fraction of disease risk.

IMPLICATION FOR ANESTHESIOLOGISTS

The greatest clinical promise of complex trait genetics in anesthesiology is to predict and understand the response to anesthetics or the pharmacologic drugs used for pain medicine to tailor the most effective and safe treat-ment.252,253 Mendelian and mitochondrial genetics have led to the identification of genes of rare diseases as pre-sented in this chapter, and the biologic understanding of the disease has led to anesthetic considerations that max-imize safety and efficacy. Pharmacogenomics is the study of genetic variation that contributes to the interindivid-ual variability in treatment response, which is a complex trait. Although many biologic and lifestyle factors such


http://www.genome.gov/gwastudies/


as age, sex, liver and kidney function, diet and exercise, smoking and alcohol use, and severity of illness may con-tribute to the variability in the treatment response, if vari-ability persists after accounting for these covariates, then genetic factors may be considered.254 Two categories of genes are recognized to harbor variants influencing drug response: pharmacokinetic (PK) and pharmacodynamic (PD) genes.

PK genes influence interindividual differences in drug metabolism including absorption, distribution, metabo-lism, and excretion (ADME). PK gene variability may lead to either slower or more rapid drug uptake and conver-sion and excretion, leading to either the elimination of the drug before the therapeutic effect is achieved or the drug remaining too long or in too high a dose in the body, thereby increasing the risk of adverse effects. Many metabolizing enzymes in the liver, including the cyto-chrome P450 gene family, are important PK genes with poor or ultrarapid metabolizing alleles, such as the gene CYP2D6, which contributes to metabolism of up to 25% of drugs in clinical use today.255

PD genes are either drug-target receptors or molecu-lar components in the signal transduction pathway tar-geted by the drug. Variation in PD genes is likely to be involved when the variation in drug response is dose independent and may involve synergistic, independent, or antagonistic interactions among multiple components of the signaling pathway. Thus PD effects are likely more complex than PK effects, and early pharmacogenetic studies suggest that they contribute more to the varia-tion in treatment response than PK effects. For example, PK and PD effects are seen in warfarin anticoagulation therapy, which displays tenfold variation in treatment response among individuals. Although carriers of poor metabolizer alleles of the metabolizing enzyme CYP2C9 (PK gene) require lower doses and have a higher risk of bleeding, genetic variation in a subunit of the warfarin target VKOR (VKORC1, a PD gene) is the major deter-minant of the amount of warfarin required to achieve a therapeutic effect.

Progress in the field of pharmacogenomics has been slow. Most pharmacogenetic discoveries have come from candidate gene studies of PK and PD genes; how-ever, GWASs and sequencing approaches are beginning to be applied.256,257 Importantly, several challenges remain. First, thorough phenotyping is critical to mea-sure the variation in response precisely and to identify nongenetic factors influencing the variability that should be accounted for. Second, genetic study designs should include well-powered, large samples from a homogenous population of preferably one ancestry and analytic meth-ods with adequate quality control for technical or popula-tion artifacts and correction for multiple testing. Studies must be relatively large because predicting how large an individual gene effect may be is not possible before-hand; a priori power calculations to calculate sample size are not possible. Replication in an independent sample is necessary, but finding a replication sample with the same phenotype may be difficult for some pharmacoge-nomic studies. Encouragingly, small early pharmacoge-nomic GWASs have detected genome-wide significant findings with n = 100 cases suggesting that effect sizes

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of pharmacogenomic alleles seem to be larger than those of disease susceptibility alleles and may involve fewer genes.256 In the next few years, unbiased, whole genome genetic approaches should lead to a greater understand-ing of the genetic basis of PKs and PDs of anesthetics and pain drugs.

Complete references available online at expertconsult.com

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