Friedrich’s Ataxia

Friedrich’s ataxia is an autosomal recessive neurogenerative disorder and is the most common hereditary ataxia with a prevalence of 1 in 50,000 in European populations (Dürr et al., 1996). The disorder is due to a genetic abnormality in the frataxin gene located on chromosome 9. In addition to the neurologic manifestation, cardiac and endocrinological organ involvement is widely reported (Weidemann et al., 2015). Clinically, features include spinocerebellar ataxia involving all four limbs, cerebellar dysarthria, diminished-to-absent reflexes in the lower limbs, sensory loss and pyramidal signs, including bulbar symptoms. The onset of symptoms is usually before 20 years of age, and the progression of the disease is relentless. Skeletal deformities and cardiomyopathy are found in a majority of patients, and there is an increased risk of impaired glucose tolerance and diabetes (Dürr et al., 1996). Importantly, Friedreich’s ataxia is associated with a progressive hypertrophic cardiomyopathy characterised by electrical abnormalities, myocardial fibrosis and ultimately heart failure (Weidemann et al., 2015). Therefore, key anaesthetic considerations include the degree of cardiac involvement, the degree of diaphragmatic involvement and the risk of respiratory failure and the degree of bulbar dysfunction and risk of aspiration. Denervation may also be a feature and depolarising muscle relaxants should be avoided.

Charcot-Marie-Tooth

Once considered a specific disease entity, Charcot-Marie-Tooth disease (CMT) is now known to be a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterised by chronic peripheral neuromuscular denervation. Currently classified into nine genetic subtypes with autosomal recessive, dominant and X-linked inheritance (Jani-Acsadi et al., 2015), the disease is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people in North America (Ekins et al., 2015). CMT disease is caused by mutations in a number of genes crucially expressed in myelinating (Schwann) cells and neuronal axons. Typically, patients present with progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve followed by weakness and atrophy of hands, sensory loss and characteristic foot abnormalities (pes cavus) which often require orthopaedic correction. Based upon electrophysiological studies, two main subtypes of CMT can diagnosed, one with slow nerve conduction velocities and pathological evidence of a primary hypertrophic demyelinating neuropathy (CMT type 1), and another with relatively preserved nerve conduction velocities with pathological evidence of primary axonal loss (CMT type 2) (Jani-Acsadi et al., 2015). Skeletal abnormalities, including scoliosis, may be associated and increase the risk of respiratory compromise in patients undergoing general anaesthesia. Controversy exists regarding the potential for local anaesthetics to worsen axonal pathology; however, case reports have been published demonstrating the safe use of neuroaxial and regional anaesthesia in patients with CMT (McSwain, Doty and Wilson, 2014).

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a diverse group of inherited neuromuscular diseases with an incidence of 1:11,000 births (Prior et al., 2010), and is the most common genetic cause of death in infants (Arnold, Kassar and Kissel, 2014). The most common form of the disease is due to a homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene (Prior et al., 2010), causing anterior horn spinal motor neurone dysfunction and loss. The characteristic clinical features usually include symmetrical, proximal muscle weakness and atrophy. The earlier the age of onset, the more severe the symptoms, and death ensues due to bulbar dysfunction and respiratory muscle weakness, whereas adult forms may present with only mild proximal muscle weakness and have normal life expectancy (Arnold et al., 2014). The major anaesthetic concern relates to hyperkalaemia associated with depolarising muscle relaxants and sensitivity to non-depolarising muscle relaxants in the presence of significant skeletal muscle denervation.

Motor Neurone Disease

Motor neurone disease (MND) is a pre-junctional neurodegenerative disorder that is thankfully a relatively uncommon disease with a prevalence of 5–7 per 100,000 in various epidemiological studies (Worms, 2001). Onset is in adulthood and leads to progressive weakness of limb, bulbar and respiratory muscles. Death typically occurs within 5 years, usually due to respiratory failure (Wood-Allum and Shaw, 2010). Three forms of MND are generally recognised; amyotrophic lateral sclerosis (ALS) affecting both upper (UMN) and lower motor neurons (LMN), progressive muscular atrophy (PMA) predominantly affecting the LMNs and primary lateral sclerosis (PLS) that predominantly involves the UMNs (Wood-Allum and Shaw, 2010). ALS is by far the most common, and involvement of UMN and LMNs produces the characteristic mixed-picture disease due to involvement of the brainstem and multiple spinal cord regions. Patients can present with limb-onset disease, bulbar-onset disease or, more rarely, with initial trunk or respiratory involvement. ALS importantly is associated with fronto-temporal dementia in 10 per cent of cases (Wood-Allum and Shaw, 2010). Muscle denervation ultimately leads to muscle atrophy, weakness, fasciculations and the development of extra-junctional acetylcholine receptors. There is no sensory loss, which distinguishes motor neurone disease from multiple sclerosis and other polyneuropathies. Interestingly in all forms of MND, the ocular cranial nerves and pelvic floor muscles are not affected (Wood-Allum and Shaw, 2010). Hyperkalaemia may be associated with depolarising neuromuscular blocking agents, while prolonged block may occur with non-depolarising neuromuscular blocking agents. Respiratory muscle weakness, bulbar dysfunction and skeletal abnormalities make the risk of respiratory compromise significant after anaesthesia.

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, leading to demyelination and scarring occurring around the brain and spinal cord. MS is characterised by a variable clinical course with episodes of demyelination and remyelination; however, over time, the pathological changes become dominated by disease progression and accumulation of disability (Compston and Coles, 2008). The prevalence of MS ranges between 2 and 150 per 100,000, depending on the country or specific population, and is highest in the temperate regions of the world (Alshekhlee et al., 2009). The cause for MS is complex, but thought to be triggered by environmental factors in individuals with genetic susceptibility. Symptoms predominately start in early adulthood with a mean age of 30, and women are disproportionately affected. Initial clinical manifestations may include any component of the sensory, motor or autonomic nervous system with visual disturbances, sensory deficits, limb weakness/gait ataxia and bowel and bladder dysfunction. Three main types are defined according to the natural history of the disease: relapsing remitting MS, which is the most common, including almost 90 per cent of the patients affected, primary progressive MS and secondary progressive MS (Compston and Coles, 2008).

The clinical diagnosis of MS can be difficult as few of the clinical features are disease-specific; however, published criteria exist to aid diagnosis. Clinical findings combined with central nervous system MRI showing characteristic white matter plaques and electrophoresis of CSF displaying oligoclonal bands are the mainstay of diagnosis (Schmitt and Muenster, 2009). Serial MRIs can guide disease management, and demonstration of white matter plaques that vary in place and time and that occur in more than 95 per cent of patients confirms the diagnosis (Compston and Coles, 2008).

While general anaesthesia with intravenous or volatile agents is safe in patients with MS, there is contradictory evidence regarding the use of regional anaesthesia. Initial case reports suggested local anaesthetics may cause toxicity to demyelinated axons and exacerbate symptoms; however, larger case series have suggested that both spinal and epidural anaesthesia may be safely administered in patients with MS (Lirk, Birmingham and Hogan, 2011).

Guillain-Barré Syndrome

Guillain-Barré syndrome (GBS) is a rare immune-mediated polyneuropathy with an incidence of up to 2 per 100 000 in Western populations (Chiò et al., 2003). It is characterised by acute ascending flaccid paralysis causing symmetrical weakness of the limbs and associated hyporeflexia or areflexia reaching maximal severity at about 4 weeks. Sensory symptoms, including paraesthesia or numbness, similarly start distally and have a symmetrical pattern (Van den Berg et al., 2014). GBS is considered a post-infectious disease in which the immune response generates antibodies that cross-react with gangliosides present on nerve membranes, resulting in inflammation and degenerative changes. A significant number of patients will report a history of a respiratory or gastrointestinal tract infection before the onset of GBS. Commonly associated organisms include C. jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumonia, Haemophilus influenzae and influenza A virus (Van den Berg et al., 2014).

Clinically distinct subtypes of GBS exist, including acute inflammatory demyelinating polyneuropathy (AIDP), which is the most common, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN) and, less commonly, Miller-Fisher syndrome (MFS), which is characterised by ophthalmoplegia, ataxia and areflexia. Treatment is predominantly supportive, though intravenous immunoglobulin (IVIg) and plasma exchange are proven effective treatments for GBS (Van den Berg et al., 2014). Despite treatment, up to two thirds of patients are unable to walk independently at the time of maximum weakness, and respiratory insufficiency occurs in 25 per cent of patients requiring respiratory support. Among severely affected patients, 20 per cent remain unable to walk 6 months after the onset of symptoms. Overall, the clinical course, severity and outcomes of GBS can be highly variable, ranging from full recovery to residual deficits, including persistent weakness and chronic pain (Van den Berg et al., 2014).

Patients with GBS with respiratory muscle weakness are at significant risk of post-operative respiratory failure and longer-term ventilation. If denervation is a feature, depolarising neuromuscular blockers should be avoided. It is important to consider that GBS can worsen during the perioperative period in the absence of surgery or anaesthesia. Patients with GBS may display increased sensitivity to opioids and non-depolarising neuromuscular blockers. Avoidance of general anaesthesia and tracheal intubation may offer advantages and, thankfully, neuroaxial and regional anaesthetic techniques are considered safe in this population, though increased local anaesthetic sensitivity may also occur (McSwain et al., 2014).

Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction which results in the clinical hallmark of a fluctuating, pronounced weakness that is limited to the voluntary muscles. Characteristically, muscular exertion increases the myasthenic weakness. It is a generalised disorder that often manifests initially as focal weakness, particularly of the eye muscles, resulting in diplopia and ptosis. Myasthenic crisis is the life-threatening exacerbation of MG due to bulbar weakness and respiratory muscle weakness in addition to limb girdle weakness (Sieb, 2014).

Myasthenia gravis is the most common disorder of the neuromuscular junction (NMJ), with a prevalence of around 15 per 100,000 (Alshekhlee et al., 2009). The incidence is bimodal in nature with a preponderance of women in the younger age group and a reversed sex ratio in older patients (Spillane, Beeson and Kullmann, 2010). Myasthenia gravis is considered a T-cell-mediated disease with auto-antibodies directed to the post-synaptic neuromuscular junction. Classically, the auto-antibody is directed against the nicotinic ACh receptor, although MG can also be caused by auto-antibodies directed against other components of the NMJ (Ha and Richman, 2015). The thymus appears to play an important role in the pathogenesis of early-onset MG associated with anti-ACh receptor antibodies and is frequently enlarged due to immune activity. In 10 per cent of cases of MG, a thymoma is detected (Spillane et al., 2010).

Treatment of MG depends upon the disease severity, age of onset, antibody specificity and thymic pathology (Sieb, 2014). The aims of treatment are to relieve symptoms by the improvement of neuromuscular transmission by acetylcholine esterase inhibitors, such as pyridostigmine, and to prevent disease progression by immunosuppression and/or thymectomy. Treatment of acute exacerbations is achieved with plasmapheresis, immunoadsorption or intravenous immunoglobulin (IVIG) to remove causative auto-antibodies (Spillane et al., 2014). However, there is little evidence that these strategies can be used in the perioperative period to reduce anaesthetic complications (Racca et al., 2013).

Myasthenic Syndrome (Lambert-Eaton Syndrome)

Lambert-Eaton Myasthenic Syndrome (LEMS) is an autoimmune disorder affecting presynaptic P/Q-type voltage-gated calcium channels of the neuromuscular junction causing impaired release of acetylcholine into the synaptic cleft, leading to muscle weakness (Ha and Richman, 2015). LEMS is much less common than MG. It usually begins in mid-to-late life and affects males and females equally. It is associated with a malignancy, most often small-cell carcinoma of the lung (SCLC), in approximately 50 per cent of cases (Spillane et al., 2010). The clinical picture of LEMS is often one of proximal limb weakness and reduced tendon reflexes. While ocular and bulbar muscles are usually not affected, respiratory muscle weakness can result in respiratory failure, and autonomic dysfunction is common and often results in a dry mouth, erectile dysfunction, gastrointestinal slowing and postural hypotension (Hirsch, 2007).

Treatment of the underlying malignancy with surgery, radiotherapy or chemotherapy remains the priority and can lead to clinical improvement or remission (Hirsch, 2007). Established treatment of muscle weakness in LEMS is with aminopyridines or immunosuppression. Aminopyridines, including 3,4-diaminopyridine, block potassium channels and prolong the duration of the presynaptic action potential, increasing neurotransmitter release at the synapse. Acetylcholine esterase inhibitors are less effective than in MG and are generally not used as monotherapy. Immunosuppression with prednisolone alone or in combination with azathioprine may have benefit, and IVIG has been shown to be useful in treatment-resistant patients (Spillane et al., 2010).

There are a number of anaesthetic considerations regarding junctional disorders such as myasthenia gravis and myasthenic syndrome. The use of muscle relaxants in a myasthenic patient presents a significant concern. Patients with MG exhibit a relative resistance to suxamethonium but an increased sensitivity to non-depolarising neuromuscular blockers. On the contrary, patients with LEMS have been reported to have increased sensitivity to both depolarising and non-depolarising neuromuscular blockers (Hirsch, 2007); if non-depolarising neuromuscular blockers are to be used, neuromuscular monitoring should be employed and titrated to effect. Furthermore, anti-cholinesterases should be avoided because of unpredictable effects, including the prolongation of depolarising neuromuscular blockade, but may also precipitate a cholinergic crisis. General anaesthesia is considered safe; however, volatile anaesthetics impair neuromuscular conduction in a dose-dependent manner and the risk of post-operative respiratory depression remains high. Neuroaxial and regional anaesthesia is also considered safe in myasthenic patients and offers the avoidance of general anaesthesia and muscle relaxants (Schmitt and Muenster, 2009). It is important to remember that there are a number of medications that may worsen the muscular weakness by inhibiting neuromuscular transmission (Table 11.2).

Muscular Dystrophies

The muscular dystrophies are a group of hereditary diseases characterised by progressive muscle weakness due to degenerating/regenerating muscle fibres, fibrosis and typical fatty replacement. They are caused by a number of related mutations in genes encoding key glycoproteins that anchor and stabilise myocytes to the extracellular matrix. The dystrophinopathies, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), are caused by mutations in the dystrophin gene and are the most common causes of muscular dystrophy (Bushby et al., 2010). Continuing advances in genetic diagnosis means that there are now more than 40 hereditary muscular dystrophies (Flanigan, 2014), and it is beyond the scope of this chapter to review these diseases in significant detail (Table 11.3). Suffice to say, the muscular dystrophies are a heterogeneous group of post-junctional disorders with varying natural history, clinical features and perioperative considerations.

DMD is the archetypal and most common childhood neuromuscular disease and is characterised by early onset in childhood of progressive skeletal muscle weakness with patients usually wheelchair bound by the age of 10. There is progressive respiratory insufficiency with reduction in forced vital capacity and scoliosis is frequent. A dilated cardiomyopathy is associated with DMD and occurs with increasing frequency with age (Flanigan, 2014). Importantly, many patients will require orthopaedic intervention for scoliosis and lower limb abnormalities. Glucocorticoids are the only medication currently available that slows the decline in muscle strength and function in DMD (Bushby et al., 2010).

Controversy remains regarding the anaesthetic management of patients with DMD. Historically, the use of depolarising muscle relaxants and volatile anaesthetics has been associated with episodes of malignant hyperthermia (MH)–like syndromes in patients with DMD and BMD. More recently, increasing scientific understanding of the dystrophinopathies has led to the recognition that these case studies more likely represent an entity called anaesthesia-induced rhabdomyolysis (AIR) rather than true malignant hyperthermia (Hayes, Veyckemans and Bissonnette, 2008). The administration of either of these agents has been linked to a hypermetabolic syndrome characterised by hyperkalaemia, hyperthermia, tachycardia and rhabdomyolysis with raised CK levels; however, as opposed to MH, dantrolene has no effect (Hayes et al., 2008). Suxamethonium and volatile anaesthetics should therefore be avoided in the dystrophinopathies due to the risk of hyperkalaemic cardiac arrest or severe rhabdomyolysis (Schmitt and Muenster, 2009). Racca and colleagues, in their recent review of anaesthesia and neuromuscular disorders, further suggest that although only a few specific myopathies are truly MH-susceptible (see earlier in this chapter), the abnormal nature of muscle in these post-junctional disorders carries a risk for either MH or AIR and depolarising muscle relaxants and volatile anaesthetics should be avoided (Racca et al., 2013).

Myotonias

Myotonia describes an abnormal delay in muscle relaxation following voluntary forceful contraction. Affected individuals describe muscular stiffness upon initiating movement. The myotonias can be divided into dystrophic and non-dystrophic myotonias. In patients with dystrophic myotonias, which includes myotonic dystrophy, muscle wasting and weakness are seen. In contrast are the non-dystrophic myotonias, which are a group of hereditary skeletal muscle channelopathies, including myotonia congenita and familial periodic paralysis (Lossin and George, 2008). Opposed to weakness, the main symptom in these myotonias are prolonged muscle contraction following stimulation.

Familial Periodic Paralysis

Malignant Hyperthermia Susceptibility and Congenital Myopathies

Malignant hyperthermia (MH), first recognised in the 1960s, is a potentially fatal adverse drug reaction that can be triggered by volatile anaesthetics and suxamethonium (Hopkins, 2011). It has been shown that most patients susceptible to MH have an autosomal dominant inheritance in abnormalities of skeletal muscle calcium regulation. The prevalence of genetic variants predisposing to MH has been estimated to be as high as 1:2,000 (Brady et al., 2009).

At the physiological and biochemical levels, MH-susceptible individuals have abnormal resting skeletal calcium homeostasis and once triggered, there is an acute and uncontrolled increase in cytosolic calcium leading to a hypermetabolic state. The classical fulminant MH reaction is characterised by hypercapnoea, skeletal muscle rigidity, tachycardia, hyperthermia, acidosis and rhabdomyolysis. Death ensues if the condition is not rapidly recognised and treated (Hopkins, 2011).

The majority of patients (50–70%) display mutations in the ryanodine receptor gene (RYR1) and since the first MH susceptibility locus was mapped, the number of single nucleotide variants in RYR1 has grown to almost 400 (Fiszer et al., 2015). In addition, five other loci have been identified, including the CACNA1S gene encoding the main subunit of the voltage-gated dihydropyridine receptor, in MH-susceptible patients (Fiszer et al., 2015; Stowell, 2014). However, there appears to be significant variation between the genotype and the clinical phenotype (Snoeck et al., 2015). That is, the clinical MH presentation may indeed be different in patients with similar point mutations in susceptibility loci.

The gold standard for diagnosis of MH is the in vitro contracture test (IVCT), using skeletal muscle biopsy and exposure to incremental concentrations of caffeine or halothane and the responses recorded (The European Malignant Hyperpyrexia Group, 1984). The IVCT is highly sensitive but lacks specificity, and while DNA-based diagnostic tests can be used in addition to the IVCT, they must be interpreted with caution. There is significant heterogeneity of MH in both the number of RYR1 variants and the potential involvement of other genes. Furthermore, DNA-based diagnosis for MH susceptibility can be performed only in families with mutations that have been functionally characterised (Stowell, 2014).

Mutations in the skeletal muscle RYR1 gene have emerged as a common cause of inherited neuromuscular disease, of which malignant hyperthermia susceptibility is an example. A number of congenital myopathies are associated with RYR1 gene mutations. Autosomal dominant disorders include central core disease, King-Denborough syndrome, exertional rhabdomyolysis and late-onset axial myopathy. Autosomal recessive RYR1-related myopathies include forms of multi-minicore disease, centronuclear myopathy and congenital fibre type disproportion (Snoeck et al., 2015). Patients with these conditions should be considered MH-susceptible and anaesthetic triggers avoided.

Detailed discussion of the management of MH-susceptible patient is beyond the scope of this chapter; however, it is important to note that the only proven anaesthetic triggers of MH are volatile anaesthetics and the depolarising muscle relaxant suxamethonium (Wappler, 2010). Furthermore, dantrolene, a drug with skeletal relaxant properties, is the only clinically available agent for the specific treatment of MH, fundamentally changing this anaesthetic complication from one of high mortality (70–80%) to less than 10 per cent (Wappler, 2010). Specific steps should be taken in the perioperative care of these patients to ensure safe post-operative outcomes. Preoperative consultation is imperative for patients with known or suspected MH susceptibility. Effort should be made to gather all available information regarding previous anaesthetic exposures in the patient and family members. Previously performed IVCTs should be reviewed to confirm the diagnosis and time should be allowed to explain aspects of the anaesthetic procedure, including avoidance of triggering agents, adequate monitoring and the availability of dantrolene to alleviate patient anxiety. The anaesthetic workstation should be decontaminated from triggering agents by removing the vaporisers and flushing the machine and circuit for a minimum of 10 minutes with 10L/min of fresh gas flow (Wappler, 2010). In reality, these published guidelines relate to older-style anaesthetic machines and may not apply to modern-day machines. Consultation with the manufacturers to confirm the procedure for adequate decontamination is advised. Ideally, patients should be offered regional or neuroaxial anaesthesia or even have the procedure performed under local anaesthetic if the clinical situation allows. Patients with MH susceptibility requiring general anaesthesia should be given trigger-free anaesthetics. Modern anaesthetic practice provides sufficient pharmalogical choice to allow for trigger-free anaesthetics. Dantrolene should be available in sufficient quantities to allow for successful treatment of an MH crisis. All perioperative staff should be made aware of the patient’s MH susceptibility and appropriate post-operative ward or hospital discharge planned.