Chapter 64 Acute Neuromuscular Diseases and Disorders
This chapter is devoted to acute neuromuscular diseases that may be seen in a pediatric intensive care unit (PICU). Although clinicians may encounter a variety of neuromuscular illnesses, this chapter begins with the most common disorders seen in the PICU. Weakness due to spinal cord or other central nervous system abnormalities are discussed in a separate chapter.
Guillain-Barré Syndrome
The most common acute neuromuscular disease seen in the intensive care unit is Guillain-Barré syndrome (GBS). When given the history of an ascending paralysis, a clinician can easily place GBS in the differential diagnosis; however, this history may be difficult to obtain, particularly if the patient is a small child or an infant. GBS is the most common cause of acute flaccid paralysis in children. The incidence is estimated to be 0.38 to 1.1 per 100,000 in a population younger than 15 years.1,2 A prodromal respiratory or gastrointestinal illness is commonly found in the history. The prodromal illnesses may include Campylobacter jejuni and cytomegalovirus. In one study, 70% of patients reported an illness before the onset of symptoms, with 26% having documented cytomegalovirus.3
The neurologic symptoms typically present with progressive paralysis that is relatively symmetrical and may evolve to all extremities. Other symptoms include varying degrees of hyporeflexia or areflexia, or even respiratory embarrassment. Other presentations may include acute ataxia, pain, or cranial neuropathies.4,5 In one study, risk factors for patients requiring ventilation included cranial nerve involvement, elevated cerebrospinal fluid (CSF) protein during the first week of illness, and a short period between antecedent illness and onset of symptoms.6
Autonomic symptoms, which may be overlooked, also are present in some cases. Autonomic instability, particularly cardiac arrhythmias, increase the morbidity of this disease. Cardiac monitoring of the R-R interval with reduction of beat-to-beat variability may possibly identify patients at risk for fatal arrhythmia.7 Cardiac arrhythmias induced by tracheal tube manipulation have been reported.8
Asbury and Cornblath9 have established criteria for the diagnosis of GBS. Per their criteria, the features that are required for the diagnosis include progressive motor weakness of more than one limb and areflexia. Symptoms that are strongly supportive of GBS include the relative symmetry of symptoms, mild sensory symptoms, cranial nerve involvement, autonomic symptoms, and recovery that usually begins 2 to 4 weeks after symptom progression discontinues. Sphincter disturbances rarely occur early in the course of GBS and are usually transient.10
Diagnostic studies include examination of the CSF and nerve conduction studies. The CSF reveals elevated protein amid a relative paucity of white blood cells, usually less than 10 cells/mL, with the protein increasing after the first week of symptoms.9 Electrodiagnostic testing reveals motor conduction velocities in the demyelinating range, conduction block, temporal dispersion, and prolonged F waves. Bradshaw and Jones4 reported that conduction block and temporal dispersion occurred in 74% of patients.
If the symptoms are severe, treatment options for GBS include plasmapheresis and administration of intravenous immunoglobulin (IVIg). In 2003 the American Academy of Neurology published a practice parameter after reviewing the adult literature and made several recommendations.11 First, plasmapheresis and IVIg both hasten recovery, and neither is more efficacious. Using these two treatments sequentially is not superior to using either treatment alone. Finally, steroids do not seem to help. The decision of which therapy to apply to children is controversial because a large randomized study has not been performed. Plasmapheresis may be technically difficult to perform in young or very small children; therefore immunoglobulin may be used with more ease. Results from one adult study in which the two methods were compared showed that 53% of the patients treated with immunoglobulin improved by one or more grades on the functional scale at 4 weeks compared with 34% of the patients treated with plasmapheresis.12 Favorable improvement in pediatric patients treated with immunoglobulin has been reported in several small series.13–16 More recently, a randomized trial in children showed that fewer relapses occurred if 2 g/kg of IVIg were divided over 5 days instead of 2 days.17 If additional courses of IVIg are necessary, a 2-day protocol is often well tolerated.
Several GBS variants exist. The best known are the Miller-Fisher variant and acute inflammatory axonal polyneuropathy, the axonal form of GBS. The neurologic triad found in the Miller-Fisher syndrome includes ataxia, areflexia, and ophthalmoparesis. Miller-Fisher syndrome has been linked to immunoglobulin G antibodies against ganglioside GQ1b.18 In some C. jejuni strains, molecular mimicry exists between the surface epitopes and ganglioside GQ1b.19 The GQ1b ganglioside is thought to cross-react in the brainstem area of the ophthalmic cranial nerves.20 The axonal form of GBS has been associated with a more prolonged recovery than the classic form of GBS, which is attributed to axonal involvement. Early research suggests that CSF levels of neurofilament correspond to levels of axonal damage on electromyographic (EMG) testing and may help complement EMG studies to help predict patients who will have more prolonged recoveries.21,22
Myasthenia Gravis
Myasthenia gravis (MG) has many forms that may present in the pediatric population. The juvenile form of MG is the most common and is clinically identical to the autoimmune adult form of MG. Overall, however, juvenile MG is rare and comprises 10% of all cases of MG in Western populations. Antibodies directed toward the acetylcholine receptor (AchR) at the postsynaptic neuromuscular junction cause this form of the disease. These antibodies result in blockade of the AchR, increase the degradation of the AchR, and also result in complement damage to the AchR.23 Fenichel24 reported that 75% of cases occur after age 10 years; however, this age of onset has been debated in recent years.25,26 AchR antibodies are found less frequently in juvenile MG compared with adult autoimmune MG and are more easily shown in the postpubertal patient population.27 Anticholinesterase antibody levels should be determined, however, in all patients with suspected MG. Newer assays are finding antibodies previously missed in older anticholinesterase antibody assays, including binding, blocking, and modulating, but these assays may need to be ordered separately.28–30
The most common heralding symptoms of weakness in MG include ptosis (with pupillary sparing) and diplopia (from restricted eye movements). These symptoms wax and wane, and the weakness may generalize to the extremities. The two clinical forms of juvenile MG are ocular and generalized. In ocular MG, symptoms include ptosis and diplopia, but the weakness does not progress to other areas of the body. Generalized MG may begin with ocular symptoms and progress to generalized weakness, usually within 1 year of onset; however, generalized weakness may be the initial presentation. The exact prevalence of generalized compared with ocular forms of juvenile MG is disputed. As in adults with MG, pediatric patients have the fewest symptoms in the morning or after rest, with increasing fatigability with exercise being a hallmark of this disease. The most troublesome symptoms seen in generalized MG are those involving bulbar and respiratory muscles, which may result in difficulty chewing or swallowing and exercise intolerance.
Antibodies have been found that can block, bind, or modulate AChR. Approximately 80% of patients will have antibodies to AChR found in standard assays. Antibodies directed against muscle specific kinase (MuSK) appear to account for some of the remaining 20%.28 Newer, more sensitive assays can also find antibodies with low affinity for AChR.30 Clinically, MuSK-positive patients tend to have more frequent bulbar involvement and respiratory crises than do AChR-positive patients and require larger doses of maintenance corticosteroids, although there is no clear difference in clinical outcomes.31 Seronegative (AChR-negative and MuSK-negative) patients have a disease severity between the other two groups but appear to have better clinical outcomes.31
Treatment of MG begins with anticholinesterase medications. The symptoms of MG usually respond to pyridostigmine bromide (Mestinon), the most common oral form of anticholinesterase medication. The dosage of pyridostigmine bromide is 7 mg/kg/day divided four to six times daily as needed for symptoms. Immunosuppressant agents, including prednisone, azathioprine, cyclophosphamide, and tacrolimus, may be added to the regimen for pyridostigmine nonresponders.32 Mycophenolate also may be prescribed, although it has not proved more efficacious than placebo in two randomized trials of patients already taking prednisone.33,34 Prednisone is usually initiated at 1 to 2 mg/kg/day. Clinicians must be careful when using prednisone because it may exacerbate weakness on initiation.
Many studies have suggested that the beneficial effects of thymectomy are best when it is performed early in the course of MG.27,35,36 Because of the spontaneous remission rate of 22.4 per 1000 person-years reported by Rodriguez et al.,37 as however, many clinicians are reluctant to proceed with early thymectomy, particularly with young children.
Myasthenic crisis is an exacerbation of myasthenic symptoms requiring ventilatory assistance. In adults with MG, myasthenic crisis has been reported to occur in 15% to 20% of patients, with 74% having their first crisis within 2 years of disease presentation.38,39 Anlar et al.40 reported that one third of patients with juvenile MG had at least one episode of crisis. Crisis duration in adults has been reported as having a median duration of 13 days by Thomas et al.39 Initial therapy during crisis includes mechanical ventilation, which provides rest for the weakened patient. Two retrospective studies suggest that the use of biphasic positive airway pressure) may prevent intubation and shorten hospital stay.41,42 In each study, hypercapnia was a predictor of biphasic positive airway pressure failure.41,42
Anticholinesterase medications should be discontinued because they increase secretions that could lead to mucous plugging. Myasthenic crisis is most commonly heralded by infection in 38% of patients; however, 30% of patients have no obvious trigger for their crisis other than respiratory or bulbar weakness.39 A thorough investigation for the cause of the crisis should be undertaken. The mortality rate has fallen with improvements in health care; however, Thomas et al.39 recently reported a 10% mortality rate in patients with myasthenic crisis.
Plasmapheresis and IVIg (2 g/kg over 2 to 5 days) also play a role in the treatment of myasthenic crisis and acute exacerbations of myasthenic symptoms. In cases of adult crisis, plasmapheresis has been shown to be more efficacious than IVIg; however, plasmapheresis has more deleterious adverse effects, including cardiovascular and infectious complications.43 In the first randomized adult trial between plasmapheresis and IVIg, no significant difference was found between the two treatments; however, this study also included myasthenic exacerbations, as well as crisis.44 Only small numbers of juvenile MG exacerbations or crisis treated with IVIg have been reported.45,46 These reports have been favorable for IVIg in acute exacerbations of MG.45,46 IVIg has been shown to be superior to placebo in a randomized controlled trial, with significant improvements seen as early as 14 days after infusion and lasting through 28 days.47 Several dosing regimens have been used. The previous study used 2 g/kg divided over 2 days; another study failed to find a difference between a 1 g/kg dosage of IVIg given over 1 day and a 2 g/kg dosage given over 2 days.48 Evidence supports the use of IVIg to treat patients experiencing myasthenic crisis or to treat an exacerbation in patients in whom plasmapheresis is not feasible.
Cholinergic crisis must also be a consideration in a patient with an MG exacerbation. Cholinergic crisis occurs with an overdose of anticholinesterase drugs in patients with MG. The overdose causes depolarization of skeletal muscles and muscarinic adverse effects, including increased secretions, diarrhea, lacrimation, sweating, and bradycardia. These symptoms will improve upon withdrawal of the anticholinesterase medications. Some authors argue that cholinergic crisis is rarely the cause for worsening myasthenic symptoms.38,49
The clinician must always be cautious when initiating new medications in patients with MG. Many drugs interfere with the neuromuscular junction; the drugs best known for doing so are the aminoglycoside medications. Steroids can exacerbate weakness in a patient with MG, although this potential is not well recognized. For this reason one must be cautious when initiating the use of prednisone in a patient with refractory MG; it is necessary to observe the patient closely for any initial increased weakness. Antibiotics that have been implicated in the worsening of myasthenic symptoms include ampicillin, ciprofloxacin, clindamycin, erythromycin, sulfonamide, tetracycline, and the peptide antibiotics (polymyxin A and B and colistin). Cardiovascular medications including antiarrhythmic agents (e.g., quinidine, procainamide, and lidocaine) and β-blockers (e.g., propranolol, timolol, and others) also have been reported to worsen symptoms. Thyroid replacement medications and phenytoin also may cause problems. The neuromuscular junction blockers, including vecuronium, rocuronium, and pancuronium, as well as succinylcholine, should be used with caution because the effects of these medications are prolonged in patients with MG.49,50 The Myasthenia Gravis Foundation of America maintains a list of medications to avoid and to use with caution on their Web site at www.myasthenia.org.
Additional immune diseases have been associated in approximately 16% of patients with juvenile MG.37 The autoimmune diseases may include asthma, rheumatoid arthritis, juvenile diabetes mellitus, hyperthyroidism, chronic inflammatory demyelinating polyneuropathy, and central nervous system demyelination.25,37,51,52 Seizures have occurred in 4% to 12% of patients with juvenile MG, although the exact cause is not known.25,37
Congenital and Transient Neonatal Myasthenia Gravis
The other forms of MG are congenital MG and neonatal transient MG. Neonatal transient MG is unique in neonates who are born to mothers with autoimmune MG. Neonates can manifest symptoms of neonatal transient MG even if the mothers were symptom free during pregnancy and delivery. Neonatal transient MG occurs in approximately 12% of infants born to mothers with MG.53 If a mother with MG gives birth to an infant with neonatal MG, her subsequent neonates are also at increased risk of having this transient disorder. Neonatal MG usually resolves in the first few weeks after birth, when the maternally derived antibody level diminishes in the neonate. Results from several studies have shown that even symptom-free infants born to mothers with MG have elevated titers of AchR antibodies.54 Additionally, the same phenomenon has been reported in infants born to mothers with anti-MuSK.40 It is not known why some infants appear to be more susceptible than others for having transient neonatal MG. The antibody concentration of the symptom-free neonate rapidly decreases when compared with the antibody concentration of a neonate with symptoms.55 The symptoms of neonatal transient MG usually include hypotonia, feeding problems (particularly fatigue), weak cry, and respiratory difficulty. These symptoms are treated with supportive care, and anticholinesterase medications are used for severe symptoms.
Congenital MG usually presents in childhood, with symptoms similar to those of juvenile MG. Many defects are responsible for causing symptoms in congenital MG, including congenital abnormalities resulting in presynaptic, synaptic, or postsynaptic defects of the neuromuscular junction.56 Congenital MG is always negative for Ach antibody, and a family history of congenital MG may or may not be present. The inheritance of congenital MG may be autosomal recessive or dominant, or sporadic.56 Treatment of congenital MG is different from the treatment of juvenile MG because immunosuppression obviously does not play a role. Symptoms of congenital MG may or may not respond to anticholinesterase medications.
Tick Paralysis
Affected patients are usually between the ages of 1 and 5 years. A review of 33 patients with tick paralysis reported that 82% were younger than 10 years, and 76% were female patients.57 Longer hairstyles have been speculated to be the cause of this female preponderance. A thorough search of the patient should ensue because more than one tick may be attached. The ticks most commonly implicated in North America are Dermacentor andersoni (wood tick) and Dermacentor variabilis (dog tick)58; however, other types of ticks have been documented. In Australia, the most common tick variety to cause paralysis is Ixodes holocyclus.58 The cause of the weakness is a neurotoxin that is secreted in the saliva of the gravid female tick. The neurotoxin is produced during the engorgement phase of feeding after mating. The neurotoxin inhibits the release of acetylcholine at the presynaptic terminal.58
The symptoms in North American hosts begin with vague complaints of fatigue, irritability, and pain. Vague symptoms may not begin until approximately 5 days after tick attachment, but they progress rapidly.59 Symptoms may include cerebellar signs, such as ataxia.59 If the tick remains attached, a symmetrical ascending flaccid paralysis with areflexia develops. Subsequently, bulbar and facial weakness as well as respiratory involvement occur. No systemic features are seen in tick paralysis. Patients are afebrile with normal vital signs, erythrocyte sedimentation rate, CSF, and mental status. The removal of the tick results in the rapid reversal of symptoms, usually within 24 hours.
Upon discovery, the tick needs to be promptly removed. Removal of the tick is performed with blunt curved forceps or tweezers. The tick should be grasped at the point of attachment, as close to the skin as possible. The tick should be pulled upward with steady pressure. Twisting or jerking motions may cause parts of the tick to break off, particularly the mouth parts. The tick should not be handled with bare hands. Needham60 evaluated various methods of tick removal including fingernail polish, petroleum jelly, 70% isopropyl alcohol, and a hot kitchen match. None of these passive techniques induced tick detachment.
Tick paralysis is more severe in Australia than in North America. The presenting symptoms are similar to those in the North American cases; however, ocular involvement with nonreactive pupils has been described.61 Flaccid paralysis may take days to evolve, unlike in North American hosts. The major difference in Australian tick paralysis occurs after the tick is removed. Australian patients must be carefully observed because maximal weakness may not occur until 48 hours after tick removal.61 Another distinguishing feature of Australian tick paralysis is the possible use of an antitoxin for treatment. The antitoxin, a canine hyperimmune serum, is used cautiously in humans because of potential reactions, including serum sickness.61 Efficacy of the antitoxin remains uncertain because no controlled studies have been performed.61
Periodic Paralyses
Clinicians may encounter several forms of periodic paralysis (PP), including hypokalemic, hyperkalemic, and normokalemic. Persons with most forms of the periodic paralyses have a family history of the disease. The weakness, which eventually results in paralysis, is associated with potassium response as demonstrated in hyperkalemic PP (HyperPP) or potassium serum levels in hypokalemic PP (HypoPP). PP also may be accompanied by cardiac abnormalities, as in Andersen-Tawil syndrome, and thus checking an electrocardiogram may be prudent, regardless of the serum potassium level.62
Hypokalemic Periodic Paralysis
HypoPP is the most common form of the periodic paralyses. The presentation of HypoPP usually occurs within the second decade of life. The number of attacks, which may be frequent, usually decrease as patients get older. The rate of occurrence of HypoPP is 1 in 100,000 people. The inheritance pattern of HypoPP is autosomal dominant, with boys/men more frequently affected, but one third of cases are sporadic.63,64 The most common mutation in familial HypoPP is the dihydropyridine receptor in the voltage sensitive Ca channel, located on chromosome 1q.65 Another common mutation is a voltage-sensitive sodium channel, SCN4A.64,66 In a minority of cases no mutation is found.67
The onset of symptoms in persons with HypoPP usually occurs after the consumption of a high-carbohydrate meal or after vigorous exercise followed by rest. Other provoking factors include cold temperature, emotional stress, menses, and pregnancy.64,66,68 In one study of a large affected family, Chinese food was specifically cited as a specific provocative factor.68 Weakness usually begins during sleep with the patient noticing weakness upon awakening. The weakness usually begins proximally in the legs and then progresses distally before the upper extremities become involved; it may progress to flaccid paralysis of all limbs with areflexia and normal sensation. Cranial nerve function remains normal, and swallowing and respiratory function are rarely affected. The patient remains alert with a normal mental status during the attack, and sensation remains intact. Weakness usually lasts a few hours but may last several days. Upon noticing the initial symptoms of mild muscle cramping or “heaviness,” however, some patients are able to abort an attack with light exercise.69 Sudden death from cardiac arrhythmias or respiratory failure has been reported.70,71 During paralytic attacks, patients have minimal urine output, with decreased potassium excretion and absent defecation.68,72 In persons with HypoPP, myotonia confined to the eyelids has been described.73 Before this report, myotonia was described as occurring only with hyperkalemic periodic paralysis.
Diagnosis of HypoPP can be confirmed with the identification of hypokalemia during an attack. Laboratory testing during HypoPP reveals a markedly diminished potassium level. Although serum potassium levels are decreased, the total body amount of potassium remains normal. The decreased potassium level is due to a shift of the potassium into the muscle cells, resulting in inexcitable muscle cells.74 During an attack, potassium levels usually fall below 3, but levels below 2 have been reported.75 Secondary causes of hypokalemia such as Bartter’s syndrome, use of corticosteroids and diuretics, hyperaldosteronism, ingestion of laxatives and licorice, renal tubular acidosis, amphotericin B, p-aminosalicylic acid, alcoholism, and villous adenoma must be ruled out.76
The paralytic attack may be reversed with normalization of the potassium level. The clinician must be careful when correcting the potassium level, remembering that the total body amount of potassium remains normal. Correction with orally administered potassium (0.2 to 0.4 mmol/kg every 15 to 30 minutes) should be considered. Patients with cardiac symptoms or an inability to swallow, however, require parentally administered potassium.63 While the potassium level is corrected, vigilant cardiac monitoring, monitoring of serial potassium levels, and muscle strength examinations should be used. Administration of intravenous fluids with dextrose or physiological saline solution should be avoided because they may prolong an attack or even induce cardiac arrhythmias.76,77 Griggs, Resnick, and Engel76 reported that a 5% mannitol solution should be considered as a diluent for intravenous potassium replacement.
Links et al.68 studied a large kindred with HypoPP and showed that all family members older than 50 years had permanent muscle weakness. Muscle biopsy specimens from patients with HypoPP reveal vacuoles in the muscle fibers.71 Vacuolar changes in the muscle also have been shown in family members of persons with HypoPP who have not had any paralytic attacks.68 Links et al.68 concluded from their study that all patients eventually exhibit permanent muscle weakness but that only 60% may have paralytic attacks.
Once a patient is known to have HypoPP, prophylactic medications should be initiated. Acetazolamide has been shown to prevent future attacks in patients with and without a family history of the disease when they take daily doses of 250 to 750 mg.78 Some patients, however, have been reported to have an exacerbation of attacks when taking acetazolamide.79 Another report revealed that acetazolamide prophylaxis improved strength between attacks in 80% of patients who displayed persistent weakness between paralytic attacks.78 Daily oral ingestion of potassium chloride shortens the duration of the attacks but does not appear to prevent attacks.78 Other medications used for prophylaxis of attacks include triamterene and spironolactone in patients who are not responsive to acetazolamide.78,79 Other considerations for the prevention of attacks include avoidance of high-sodium, high-carbohydrate meals as well as arduous exercise followed by prolonged rest.
Thyrotoxic periodic paralysis is another entity of weakness with concomitant hypokalemia. As the name implies, a thyrotoxic state is the impetus of this disease. It is mostly found in adult Asian boys/men, although it has been reported in the Asian-American pediatric population.80 The purpose of treatment of this disease is to alleviate the hyperthyroid state (also see Chapter 77).
Hyperkalemic Periodic Paralysis
The term hyperkalemic periodic paralysis (HyperPP) may be misleading because high, normal, and low levels of potassium have been reported in these attacks.81 The name “HyperPP” actually correlates to the response these patients have to potassium. HyperPP is also referred to as potassium-sensitive PP, a term that may be more appropriate and less confusing. HyperPP is autosomal dominant with a common gene located on chromosome 17q, affecting the alpha subunit of the sodium channel, but other sodium channels also may be affected.64,82,83 Sporadic cases have been reported.64,84 HyperPP usually presents in the first decade of life.
