Acute neuromuscular disease and disorders





Pearls





  • Common causes of acute flaccid paralysis in childhood include Guillain-Barré syndrome (GBS), acute flaccid myelitis, botulism, tick paralysis, periodic paralyses, and organophosphate poisoning.



  • Risk factors for respiratory failure in GBS include elevated cerebrospinal fluid protein during the first week of disease, short time interval between prodrome and onset of GBS symptoms, cranial nerve involvement, myasthenia gravis symptoms, ptosis, diplopia, pupillary sparing, and weakness that waxes and wanes.



  • Asbury criteria for GBS include required criteria, that is, progressive motor weakness of more than one limb and areflexia, and supportive criteria, that is, symmetry of symptoms, mild sensory changes, cranial nerve involvement, and autonomic symptoms. Recovery begins 2 to 4 weeks after symptom progression discontinues.



  • Classic botulism symptoms include weak cry, poor suck and swallow, decreased tone, decreased reflexes, weakness in descending pattern, constipation, and autonomic symptoms—especially tachycardia and fluctuating blood pressure, urinary retention, decreased tears and saliva, and flushed skin or pallor.



Neuromuscular diseases that encompass the entire motor unit may have similar presentations initially and must be deciphered in a methodical manner. The motor unit consists of the anterior horn cell, which is located in the spinal cord and terminates in a motor nerve; the myelin associated with the nerve; the neuromuscular junction; and the muscle that the nerve innervates. Any disruption of function along this pathway may produce weakness of some variety. Neuropathies and myopathies have similar clinical findings, including weakness and decreased or absent reflexes. These disease processes may be distinguished, however, by sensory abnormalities and the distribution of the weakness. Neuromuscular junction defects may have reflexes present, as in myasthenia gravis, or absent, as seen in tick paralysis. The clinician can narrow the etiologic possibilities by considering the clinical presentation, family history, recent illness, travel, inciting factors, and the clinical course.


This chapter is devoted to acute neuromuscular diseases that present to a pediatric intensive care unit (PICU). Although clinicians may encounter a variety of neuromuscular illnesses, this chapter begins with the most common disorders presenting to the PICU. Weakness due to spinal cord or other central nervous system abnormalities are discussed in other chapters.


Guillain-Barré syndrome


The most common acute neuromuscular disease to present to the PICU 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 infant. GBS is the most common cause of acute flaccid paralysis in children, with an incidence estimated to be 0.38 to 1.1 per 100,000 in a population younger than 15 years. , A prodromal respiratory or gastrointestinal illness is commonly reported. These illnesses may include Campylobacter jejuni and cytomegalovirus (CMV). In one study, 70% of patients reported an illness before the onset of symptoms, with 26% having documented CMV. Alternatively, patients may develop GBS within 1 week after Zika virus infection; most patients in one cohort had a complete recovery. ,


Neurologic symptoms typically present with progressive paralysis that is relatively symmetric and may evolve to all extremities. Other symptoms include varying degrees of hyporeflexia or areflexia, or even respiratory embarrassment. Presentations may include acute ataxia, pain, or cranial neuropathies. , Of note, pain is often a major complaint in the young child and makes the examination difficult. 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. Autonomic symptoms may be overlooked. Autonomic instability, particularly cardiac arrhythmias, increases morbidity associated with GBS. Cardiac monitoring of the R-R interval with reduction of beat-to-beat variability may identify patients at risk for fatal arrhythmia. Cardiac arrhythmias induced by tracheal tube manipulation have been reported. Additionally, hyponatremia may occur as an occasional complication and is associated with longer PICU stay and increased morbidity, suggesting that some patients may benefit from electrolyte monitoring and correction of hyponatremia.


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 ceases. Sphincter disturbances rarely occur early in the course of GBS and are usually transient. ,


Diagnostic studies include examination of the CSF and nerve conduction studies. The CSF reveals elevated protein (>45 mg/dL) and a relative paucity of white blood cells (WBCs), usually less than 10 cells/mL, with protein increasing after the first week of symptoms. Electrodiagnostic testing reveals motor conduction velocities in the demyelinating range, conduction block, temporal dispersion, and prolonged F waves. Bradshaw and Jones reported that conduction block and temporal dispersion occurred in 74% of the patients.


It is important to recognize that the patients may need intensive care. Criteria for PICU care include rapidly advancing weakness, flaccid quadriparesis, bulbar symptoms, vital capacity less than 20 mL/kg, and cardiovascular instability. If the symptoms are severe, treatment options for GBS primarily include plasmapheresis and intravenous immunoglobulin (IVIG). Based predominantly on adult literature, the American Academy of Neurology has published practice guidelines providing treatment recommendations. , First, plasmapheresis and IVIG both hasten recovery, and neither is more efficacious. Using these two treatments sequentially is not superior to either treatment alone. Finally, corticosteroids do not seem to improve outcome. The decision of which therapy to apply to children is controversial because there has not been a large randomized study performed. Plasmapheresis may be technically difficult in small children; therefore, immunoglobulin is often used as the first intervention. Favorable improvement in pediatric patients treated with immunoglobulin has been reported in several small series and on Cochrane review. 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. 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 (IgG) antibodies against ganglioside GQ1b. In some C. jejuni strains, molecular mimicry exists between the surface epitopes and ganglioside GQ1b. The GQ1b ganglioside is thought to cross-react in the brainstem area of the ophthalmic cranial nerves. The axonal form of GBS has been associated with a more prolonged recovery than the classic form of GBS due to axonal involvement. Early research suggests that CSF levels of neurofilament correspond to levels of axonal damage on EMG testing and may help complement EMG studies to help predict patients with more prolonged recoveries. ,


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 result in complement damage to the AChR. AChR antibodies are found less frequently in juvenile MG compared with adult autoimmune MG and are more easily demonstrated in the postpubertal patient population. Anticholinesterase antibody levels should be drawn in all patients with suspected MG, however. Newer assays are identifying antibodies previously missed in older anticholinesterase antibody assays, including binding, blocking, and modulating antibodies, but these may need to be ordered separately.


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. As in adults with MG, pediatric patients have fewer symptoms in the morning or after rest. Increasing fatigability with exercise is an important hallmark of this disorder. The most troublesome symptoms in generalized MG are those involving bulbar muscles (difficulty chewing and swallowing), respiratory muscles, and exercise intolerance.


When a patient is suspected to have MG, the classic diagnostic bedside test is the edrophonium (Tensilon) challenge. Edrophonium is an intravenous short-acting anticholinesterase preparation that has limited availability in many hospitals. The dosing in infants is 0.15 mg/kg and 0.20 mg/kg (maximum, 10 mg) in older children. Only 10% of the entire dose is given initially so that the clinician can observe for muscarinic side effects. Atropine (0.015–0.040 mg/kg) should be available for these possible side effects, which include bradycardia and respiratory distress secondary to bronchial secretions and bronchospasm. After the trial dose is tolerated, the entire dose is then given. In lieu of edrophonium, neostigmine is given at a dose of 0.025 to 0.050 mg/kg intramuscularly. The patient should be observed during the trial for changes in ptosis or fatigability. The onset of action with edrophonium is approximately 30 to 90 seconds after intravenous delivery and remains for approximately 5 minutes. Neostigmine has an onset of action within 15 minutes, and effects may last for 1 hour. Many clinicians also perform a blinded placebo trial of normal saline.


The neurodiagnostic study used in patients with suspected MG is repetitive nerve stimulation. This study is best performed on proximal muscles, although distal muscles are often studied. The confirmatory finding on repetitive nerve stimulation is a 10% decrement in amplitude of the compound muscle action potential.


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%. Newer, more sensitive assays can also identify antibodies with low affinity for AChR. Clinically, MuSK-positive patients tend to have more frequent bulbar involvement and respiratory crises than AChR-positive patients and require larger doses of maintenance corticosteroids, though there is no clear difference in clinical outcomes. Seronegative (AChR-negative and MuSK-negative) patients have a disease severity between the other two groups but appear to have better clinical outcomes.


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 per day divided four to six times daily as needed for symptoms. Immunosuppressant agents—including prednisone, azathioprine, cyclophosphamide, tacrolimus, and rituximab—may be added to the regimen for pyridostigmine nonresponders. Mycophenolate mofetil may also be prescribed though it has not proved more efficacious than placebo in two randomized trials of patients already on prednisone. However, a subsequent study with an extended outcome duration, greater than 25 months compared with 9 months in the previously mentioned studies, demonstrated that mycophenolate mofetil might be effective as either adjunctive therapy with prednisone or monotherapy, but maximum results may not be seen for greater than 1 year. Prednisone is usually initiated at 1 to 2 mg/kg per day. Clinicians must be careful with the use of prednisone because it may exacerbate weakness on initiation.


Many studies have suggested that beneficial effects of thymectomy are best when performed early in the course of MG. , , Because of the spontaneous remission rate reported by Rodriquez et al. as 22.4 per 1000 person-years, 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 adult 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. , Anlar et al. reported that one-third of patients with juvenile MG had at least one episode of crisis. Initial therapy during crisis includes mechanical ventilation, which provides rest for the weakened patient.


Anticholinesterase medications should be discontinued during a crisis 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. A thorough investigation for the cause of crisis should be undertaken.


Plasmapheresis and IVIG (2 g/kg over 2 to 5 days) also play a role in the treatment of myasthenic crisis and acute exacerbation of myasthenic symptoms. In adult crisis, plasmapheresis has been shown to be more efficacious than IVIG. However, plasmapheresis is associated with more complications, including cardiovascular and infectious complications. 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. Evidence supports the use of IVIG for treatment in myasthenic crisis or 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 side effects, including increased secretions, diarrhea, lacrimation, sweating, and bradycardia. These symptoms will improve on withdrawal of the anticholinesterase medications. Some authors argue that cholinergic crisis is rarely the cause for worsening myasthenic symptoms. ,


The clinician must always be cautious when initiating new medications in the patient with MG. Many drugs interfere with the neuromuscular junction; the best known are the aminoglycoside medications. Although not well recognized, corticosteroids can also exacerbate weakness in a patient with MG. For this reason, one must be cautious when beginning prednisone in the patient with refractory MG, observing closely for any initial increased weakness. Other 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 the antiarrhythmics (quinidine, procainamide, and lidocaine) and β-blockers—have also been reported to worsen symptoms. Thyroid replacement medications and phenytoin may also 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. , At www.myasthenia.org , the Myasthenia Gravis Foundation of America maintains a list of medications to avoid and to use with caution.


Approximately 16% of patients with juvenile MG exhibit additional autoimmune disease, and may have asthma, rheumatoid arthritis, juvenile diabetes mellitus, hyperthyroidism, chronic inflammatory demyelinating polyneuropathy, and CNS demyelination. , , Seizures have also occurred in 4% to 12% of patients with juvenile MG, although the exact cause is not known.


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. 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. Additionally, the same phenomenon has been reported in infants born to mothers with anti-MuSK. The antibody concentration of the symptom-free neonate rapidly decreases when compared with the antibody concentration of a neonate with symptoms. The symptoms of neonatal transient MG usually include hypotonia, feeding problems (particularly fatigue), weak cry, and respiratory difficulty. Treatment of these symptoms is supportive, with anticholinesterase medications 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. 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. Treatment of congenital MG is different from the treatment of juvenile MG because immunosuppression does not play a role. Symptoms of congenital MG may or may not respond to anticholinesterase medications.


Tick paralysis


The clinician must always entertain tick paralysis in the differential diagnosis of acute flaccid paralysis in children. On presentation, patients with tick paralysis may be mistakenly diagnosed with GBS. The treatment of the two diseases is distinct; therefore, a high index of suspicion for tick paralysis should be maintained.


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 of age and 76% were female. Longer hairstyles have been speculated to be the cause of this female preponderance. A thorough examination 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). However, other types of ticks have also been documented. In Australia, the most common tick variety to cause paralysis is Ixodes holocyclus . 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.


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 then progress rapidly. Symptoms may also include cerebellar signs, such as ataxia. If the tick remains attached, a symmetric 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 (ESR), CSF, and mental status. The removal of the tick results in the rapid reversal of symptoms, usually within 24 hours.


On 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. Needham 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. 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.


Periodic paralyses


Clinicians may encounter various forms of periodic paralysis (PP), including hypokalemic and hyperkalemic. Most forms of the PPs include a family history of the disease. Weakness that eventually results in paralysis is associated with potassium responses, as demonstrated in hyperkalemic or hypokalemic PP. PP may also be accompanied by abnormal cardiac rhythms, including prolonged QT, as in Andersen-Tawil syndrome; checking an electrocardiogram may be prudent regardless of the serum potassium level. Andersen-Tawil consists of a triad of ventricular dysrhythmia, PP, and dysmorphic features. Hypokalemic and hyperkalemic PP are discussed in detail at ExpertConsult.com .


Hypokalemic periodic paralysis


Hypokalemic periodic paralysis (HypoPP) is the most common form of the PPs. The presentation of HypoPP usually occurs within the second decade of life. Number of attacks, which may be frequent, usually decrease as patients get older. Occurrence of HypoPP is 1 in 100,000 people. The inheritance pattern of HypoPP is autosomal dominant, with males more frequently affected, but one-third of cases are sporadic. The most common mutation in familial HypoPP is the dihydropyridine receptor in the voltage-sensitive Ca 2 + channel, located on chromosome 1q. Another common mutation is a voltage-sensitive sodium channel, SCN4A. , , No mutation is found in a minority of cases. ,


Onset of symptoms in 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. Weakness usually begins during sleep, with the patient noticing weakness on awakening. Initially, the weakness is proximal in the legs and then progresses distally before involvement in the upper extremities. It may progress to flaccid paralysis of all limbs, with areflexia and normal sensation. Cranial nerve function remains normal, with swallowing and respiratory function rarely affected. The patient remains alert, with a normal mental status during the attack, and sensation remains intact. Weakness typically lasts a few hours but may last several days. On noticing the initial symptoms of mild muscle cramping, or “heaviness,” some patients are able to abort an attack with light exercise. , Sudden death from cardiac arrhythmias or respiratory failure has been reported. During paralytic attacks, patients have minimal urine output, with decreased potassium excretion and absent defecation. , In HypoPP, myotonia confined to the eyelids has been described. Before this report, myotonia was described as occurring only with hyperkalemic periodic paralysis (HyperPP).


Diagnosis of HypoPP can be confirmed with the identification of hypokalemia during an attack. Laboratory testing during HypoPP reveals a markedly diminished serum potassium concentration. 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 in-excitable muscle cells. During an attack, potassium levels usually fall below 3, but levels below 2 have been reported. Secondary causes of hypokalemia—such as Bartter syndrome, corticosteroids, diuretics, hyperaldosteronism, laxatives, licorice, renal tubular acidosis, amphotericin B, p-aminosalicylic acid, alcoholism, and villous adenoma—must be ruled out.


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 oral potassium (0.2–0.4 mmol/kg every 15–30 minutes) should be considered. Patients with cardiac symptoms or an inability to swallow, however, require parenteral potassium. While the potassium level is corrected, vigilant cardiac monitoring, serial potassium levels, and muscle strength examinations should be undertaken. IV fluids with dextrose or physiologic saline should be avoided because they may prolong an attack or even induce cardiac arrhythmias. , Griggs et al. reported that 5% mannitol solution should be considered as a diluent for IV potassium replacement.


Links et al. studied a large kindred with HypoPP and reported that all family members older than 50 years had permanent muscle weakness. The authors concluded that while all patients eventually exhibit permanent muscle weakness, 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 daily doses of 250 to 750 mg are administered. Some patients, however, have been reported to have an exacerbation of attacks when taking acetazolamide. Another report revealed that acetazolamide prophylaxis improved strength between attacks in 80% of patients who displayed persistent weakness between paralytic attacks. Daily oral potassium chloride does shorten the duration of the attacks but does not appear to prevent attacks. Other medications used for prophylaxis of attacks include triamterene and spironolactone in patients not responsive to acetazolamide. , Considerations for the prevention of attacks include avoidance of high-sodium, high-carbohydrate meals, prolonged rest, and arduous exercise.


Thyrotoxic PP is another entity of weakness with concomitant hypokalemia. As the name implies, a thyrotoxic state underlies this disease. It is mostly found in adult Asian males, although it has been reported in Asian-American children. Treatment of this disease focuses on alleviation of the hyperthyroid state (see also Chapter 84 ).


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. The name HyperPP actually correlates to the response that these patients have to potassium. HyperPP is also referred to as potassium-sensitive PP , which may be more appropriate and less confusing. HyperPP is autosomal dominant, with a common gene located on chromosome 17q affecting the α-subunit of the sodium channel, but other sodium channels may also be affected. , , Sporadic cases have been reported as well. , HyperPP usually presents in the first decade of life.


Rest after exercise is the most common provoking feature. Other provoking factors include cold temperatures and meal skipping. The pattern of weakness is similar to HypoPP: the legs are usually affected before the arms, with symmetric weakness. Weakness during the attacks varies from mild to flaccid quadriplegia with areflexia, but respiratory weakness rarely occurs. The sensory examination is normal. The length of attacks is typically shorter than that of HypoPP attacks, usually resolving in a few hours, but may persist for days. Myotonia and the Chvostek sign are often found in these patients.


Attacks may be provoked by potassium intake and relieved by glucose intake. Light exercise can prevent an attack. Most attacks do not require treatment. In the rare severe attack, IV glucose, thiazides, acetazolamide, and β-adrenergic agents can be used. Cardiac monitoring is important if medical intervention is needed because cardiac arrhythmias may occur. Prophylactic therapy should be considered in these patients because permanent muscle weakness does develop over time. Acetazolamide and thiazides have also been used for prophylaxis of this disease.


Botulism


Infantile botulism is a syndrome predominately found in infants 6 days to 12 months of age. In infantile botulism, Clostridium botulinum enters the body as a spore through ingestion. Germination occurs, and the organism begins to produce the neurotoxin that is the cause of the symptoms. It differs from food-borne botulism, in which the preformed toxin is actually ingested. In mouse models, the relationship of the gut and spores is important, with the pH of the gut and transient lack of competitive intestinal flora being essential in allowing the spores to germinate. Infants appear to be susceptible, as are adults who have abnormal intestinal flora from abdominal surgery, gut abnormalities, or antibiotic use.


Most cases of infantile botulism occur in California, Pennsylvania, and Utah. In one report, more than 75% of the patients with botulism had C. botulinum in their home environment. Other sources include soil disruption from cultivation or construction and parental occupations that involve soil exposure. The consumption of honey and corn syrup is a risk factor. Children younger than 12 months should not be fed these products. The disease-modifying role of breast-feeding remains controversial. ,


The botulinum toxin irreversibly binds at the presynaptic segment of the neuromuscular junction, inhibiting acetylcholine release and causing neuromuscular weakness. The autonomic system is also affected because the toxin binds the acetylcholine-mediated preganglionic parasympathetic and sympathetic synapses as well as the postganglionic parasympathetic synapse.


The most common symptoms include weak cry, poor suck and feeding, decreased tone with decreased reflexes, weakness in a descending pattern, and constipation. Autonomic symptoms, often the first to appear, include constipation, tachycardia, fluctuating blood pressure, urinary retention, decreased tears and saliva, and flushed skin or pallor. , L’Hommedieu and Polin proposed an algorithm of symptoms beginning with tachycardia and constipation and progressing to loss of head control, difficulty feeding, and weak cry. A depressed gag reflex is followed by peripheral muscle weakness and, finally, diaphragmatic weakness. Because of the combination of autonomic and neuromuscular symptoms, the infant with botulism may be mistaken to be septic or dehydrated. Enlarged, sluggishly reactive pupils may also be present but are less common than the other autonomic symptoms. The most concerning consequence of botulism is respiratory embarrassment. Schreiner et al. reported that only 24% of the patients reviewed did not require ventilation or an artificial airway. Patients with botulism have also become apneic during procedures, including lumbar puncture and IV catheter placement. Hypoxic ischemic encephalopathy resulting from respiratory arrest has been described as well as syndrome of inappropriate secretion of antidiuretic hormone, urinary tract infections, pneumonia, and autonomic instability. , Aminoglycosides exacerbate the neuromuscular blockade and should be avoided in botulism.


The diagnosis of botulism is clinical but confirmed by isolation of the organism or toxin in stool. Electromyography (EMG) in patients with botulism reveals decreased compound motor action potential (CMAP) amplitude and facilitation of the CMAP amplitude with high-frequency repetitive motor nerve stimulation.


Management of patients with botulism has advanced over the last few decades. Previously, clinicians could offer only supportive care until axonal sprouting could reestablish the neuromuscular junction. The median length of hospital stay was 27 to 37 days, and patients typically required mechanical ventilation for a median of 13 to 16 days. , , In respiratory compromise, mechanical ventilation should be instituted until the patient regains protective reflexes and respiratory strength. If patients are unable to tolerate oral feeds, nasogastric or nasojejunal feeding should be initiated. Human Botulism Immune Globulin (BIG) has provided the first direct pharmacologic treatment. A randomized controlled trial has shown that BIG decreased mean hospital stay (from 5.7 to 2.6 weeks), mean duration of mechanical ventilation, mean duration of NG/ND or IV feeding, and mean hospital charges with no adverse effects related to BIG. A retrospective article spanning 30 years complemented the randomized trial. Resolution of symptoms occurs in the reverse pattern of presentation, with return of head control appearing to be a reliable measure of improving muscle function.


Diphtheria


Although diphtheria was the leading killer of children in the early 20th century, the United States currently reports fewer than 10 cases of diphtheria annually. Epidemics still occur in developed and developing countries. ,


The most common form of diphtheria in children is an upper respiratory tract infection. Initial mild infection of the pharynx is followed by tonsillar pseudomembrane formation. The pseudomembrane consists of necrotic epithelium, fibrin, and numerous bacterial colonies covering the airways and pharynx to the main bronchi down into the smaller bronchi. It can lead to aspiration and complete obstruction of the airway. Extensive soft-tissue edema and lymph node enlargement occur.


Toxic cardiomyopathy is estimated to occur in 10% to 25% of patients and is responsible for 50% to 60% of deaths. It often arises in the second to third week of illness when the affected individual appears to be clinically improving. Abnormalities of the myocardium, conductive system, and pericardium occur. The conductive disturbances are in response to the toxin. Cardiac ectopy is 100% sensitive and specific in predicting fatal outcome in children with severe diphtheria.


When there is severe disease, neuropathy is seen in approximately three-fourths of the patients. , In a classic case of diphtheria, local paralysis of the soft palate occurs 2 to 3 weeks after the beginning of the oropharyngeal infection. Weaknesses of the pharyngeal, facial, and ocular nerves follow. The symmetric polyneuropathy occurs in a stocking-glove distribution, which begins between 10 days to 3 months following the oropharyngeal infection. , ,


The distal ascending weakness and spinal fluid findings may be indistinguishable from GBS. Additionally, rare cases can have autonomic dysfunction with associated hypertension and cardiac failure. Typically, there is complete neurologic recovery among survivors.


Diagnostically, cultures should be obtained from the nose, throat, and infected mucocutaneous area. Giving the antitoxin is critical even if the diagnosis is only presumptive. If the antitoxin is administered on the first day, the mortality is 1% compared with a mortality of 20% if administration is delayed until the fourth day. Immunoglobulin preparations have also been hypothesized as helpful. The only antimicrobials that have had prospective studies proving efficacy are penicillin and erythromycin.


One should anticipate airway complications, congestive heart failure, and malnutrition. Studies have revealed no reduction in the occurrence of carditis, neuritis, or death in those receiving corticosteroids. Digitalis is associated with increased occurrence of arrhythmias. Overall prognosis depends on multiple variables, including the delay in the administration of the antitoxin, immunization status, and age. The mortality rate of 10% for respiratory tract diphtheria has not changed in 50 years.


Acute intermittent porphyria


The most common of the four types of porphyria is acute intermittent porphyria (AIP). Clinical symptoms in acute attacks span multiple medical subspecialties and may be precipitated by numerous medications, hormonal variations, caloric restriction, and alcohol. AIP most commonly occurs in females, with the age of onset between 15 and 40 years, and rarely occurs before puberty. ,


An acute neuropathy is found in approximately 40% of AIP attacks. The neuropathy typically follows the onset of the attack by 1 to 4 weeks but may do so as late as 11 weeks. Although paresthesias and distal sensory changes may be a prodromal finding, the motor signs are much more prominent. Classically, the patient has symmetric upper extremity proximal weakness, but it may advance to involve the lower extremities. Generalized weakness is documented in approximately 42% of patients. In AIP’s most dramatic setting, the patient can have a rapid progression of weakness that leads to a flaccid involvement of all four extremities and respiratory compromise. When cranial nerves (CNs) are involved, CN VII and CN X are the most frequently affected. Ocular vascular compromise has been documented in individuals with vision loss, which may be monocular or total. Although this vision loss is usually transient, it can be permanent.


AIP is often difficult to diagnose. The chief complaints are typically nonspecific abdominal and back pain. This colicky abdominal pain often leads to the consideration of surgical intervention. Notably, AIP is not associated with temperature elevation, leukocytosis, or rebound tenderness. , Neurologic and psychiatric symptoms often accompany the onset of attack. Of note, many antiepileptic medications can worsen or induce an attack. Worsening has been reported with phenytoin, carbamazepine, phenobarbital, valproate, lamotrigine, and potentially tiagabine, and topiramate. Gabapentin and levetiracetam have been successfully used. Oxcarbazepine is a consideration but there are concerns regarding hyponatremia. ,


Another important management issue in AIP is the significant hyponatremia and associated seizures that may be further precipitated by the use of IV fluids containing dextrose and water. Cardiovascular complications include hypertension and tachycardia. In its most extreme case, there may be significant hypertension with associated hypertensive encephalopathy and ischemic changes. An intravenous infusion of magnesium sulfate may be helpful. Nutritional support is important in order to avoid a catabolic state, which will further complicate the clinical picture. In the event that IV nutrition is required, high-dextrose solutions are recommended. Enteral feeding is preferred, with carbohydrates providing 50% to 60% of energy needs. In a recent phase 1 trial, givosiran, an investigational RNA interference agent, was found to partially block the activity of δ-aminolevulinic acid synthetase. The treated patients were found to have a reduced number of attacks and the levels of δ-aminolevulinic acid and porphobilinogen nearly normalized.


Diagnostically, urine and stool can be tested for α-aminolevulinic acid (ALA). Also, there is a marked elevation of urinary porphobilinogen (PBG). In the blood, PBG deaminase is helpful in that its level is abnormal even between the acute attacks. AIP should be a consideration in the differential diagnosis of progressive weakness. It is most often confused with GBS. The ascending weakness that is classic in GBS is rare in acute porphyria. Additionally, acute porphyria does not have elevation of CSF protein or leukocytosis. The associated abdominal discomfort and tachycardia that are seen in porphyria would not be anticipated in GBS. Differential considerations should also include lead intoxication and hereditary tyrosinemia. Elder and Hift provide a review of AIP therapy. The two recommended approaches are carbohydrate loading and administration of heme to replenish the depleted heme that is the principal product of porphyrin metabolism. If the patient has severe symptoms—such as seizures, hyponatremia, and initial signs of neuropathy—aggressive therapy should begin as early in the crisis as possible. In mild attacks, it may be possible to wait 24 hours to determine whether the attack will resolve spontaneously. Carbohydrate loading is delivered as a 20% glucose solution provided via a central venous catheter. Studies that support the use of heme are primarily noncontrolled and have difficulty reaching statistical significance, but the overall consensus is that it does provide benefit. Daily measurements of urinary ALA or PBG may be a helpful clinical monitor.


Spinal muscular atrophy


Spinal muscular atrophy (SMA), a disease of the anterior horn cell, is most commonly inherited in an autosomal recessive manner. The responsible gene is the survivor motor neuron gene on chromosome 5q13. , SMA has three subtypes that present in childhood; both autosomal-dominant and X-linked inheritance have been reported. The combined incidence of all forms of SMA has been estimated as 1 case in 6000 to 25,700 live births. , After cystic fibrosis, SMA is the next most common fatal disease with an autosomal recessive pattern of inheritance. The most severe form was previously known as Werdnig-Hoffmann disease but is now more commonly referred to as SMA type I . It classically presents shortly after birth. The findings should be apparent before age 6 months; type I SMA is often clinically defined by the inability for the patient to achieve independent sitting. SMA type II usually presents between ages 6 and 18 months and is characterized by the patient sitting but never standing or walking. In SMA type III, patients do stand independently and walk.


In patients with SMA type I, the examination reveals a floppy baby with proximal weakness greater than distal. The lower extremities are more affected than the upper extremities, and the only spontaneous movement in these infants may be in the hands and feet. When supine, the infant will assume a frog-legged position. Polyminimyoclonus, a fine tremor most easily visualized in the hands, may also be present in these patients. Areflexia, tongue fasciculations, facial weakness, and normal sensation are also found. , Retrospectively, some mothers will report decreased fetal movement during the pregnancy with the affected infant. Death often occurs before 2 years of age as a result of respiratory failure. Patients with clinical symptoms within the first day of life have a life expectancy between 2 and 6 months, with a mean age at death slightly before 4 months.


Patients with SMA type II usually have delayed motor milestones after having normal motor development in infancy. Polyminimyoclonus is also present in these patients. Life expectancy is variable, with many patients not surviving past adolescence. Life expectancy can be enhanced, however, with fastidious respiratory care. Not surprising was the correlation that patients with an earlier onset of the disease had an earlier death.


In SMA type III, weakness is again more proximal than distal, with the lower extremities being more severely affected. The gait exhibited in these patients has a waddling quality, and lumbar lordosis is also prominent. If symptoms begin after age 2 years, ambulation may continue to a median age of 44 years. If symptoms begin before age 2 years, ambulation continues to a median age of 12 years. Life expectancy for patients with SMA type III may be the same as in the normal population because muscle weakness appears to stabilize in these patients.


Electrodiagnostic studies on these patients reveal normal motor conduction velocities. Over time, the amplitude of the compound muscle action potential may be decreased. Results from sensory nerve conduction studies are normal. EMG reveals evidence of acute denervation with spontaneous activity and chronic denervative changes with polyphasic motor units. Muscle biopsy specimens reveal angulated fibers suggestive of denervation. The creatine phosphokinase (CPK) level may or may not be increased. Genetic testing is used to confirm the diagnosis.


Respiratory complications are the most concerning aspect of this disease, which include aspiration, pneumonia, and respiratory failure. Respiratory failure may even be the presenting symptom in SMA type I. Respiratory muscle weakness results in restrictive lung disease with a weak cough and hypoventilation. Hypercapnia is also a consequence of restrictive lung disease—as a result, isolated supplemental oxygen may have devastating consequences, including apnea and death. If supplemental oxygen is needed, conventional ventilation or noninvasive ventilation should be instituted.


Other complications may also occur over time including scoliosis and contractures. Scoliosis also complicates pulmonary function over time because of chest wall alterations. In addition, feeding difficulties play a prominent role, particularly in the developing infant with SMA type I. If concerns arise, feeding evaluation should be performed to rule out aspiration. Supplemental feeding through nasogastric tube or gastrostomy may be necessary.


Aggressive symptomatic treatment, including more frequent use of ventilation and gastrostomy, has been associated with longer lifespans. Multiple pharmacologic treatments have not been successful. However, more recent developments have occurred in the treatment of patients with SMA. Nusinersen is the first drug approved by the US Food and Drug Administration (December 2016) to treat children and adults with SMA. Nusinersen, an antisense oligonucleotide that increases production of survival motor neuron (SMN) protein by modification of the SMN2 gene, is administered intrathecally, initially as loading doses given in frequent intervals followed by maintenance dosing every 4 months. Nusinersen versus sham control studies in both infantile-onset and later-onset SMA have demonstrated improvements in motor function when compared with control groups. , Another treatment that is on the horizon is an IV administered adeno-associated virus carrying the missing SMN 1 copy that promotes SMN production. AVXS-10 is given IV as a single dose and has been shown to result in longer survival and greater motor function than in historical cohorts in patients with SMA type I.


Poliomyelitis


The paralytic form of polio represents only 1% to 2% of the actual infections. Aseptic meningitis represents less than 10% and is often thought to be a nonspecific illness; the remainder of those affected have no apparent infection. Patients with the paralytic disorder present with very high fevers, significant muscle pain, and lack of reflexes. Paralysis rapidly progresses over a few hours to a complete asymmetric loss of motor use in one or more extremities. Classically, the weakness peaks at 5 days. The distribution of weakness is predominantly proximal and in the lower extremities, with cranial nerve abnormalities reported in 5% to 35% of the patients. Bowel and bladder problems may occur over the initial 3 days. Sensory abnormalities are rare. Classically, the “head drop” may occur on examination: as the examiner lifts the patient’s shoulders and raises the trunk from supine, the head falls backward in a limp fashion. It is thought that this is not due to paralysis of the neck muscles because it can occur in the nonparalytic form. The clinical course may include significant respiratory muscle weakness. Involvement of the bulbar muscles, brainstem, and respiratory center result in respiratory compromise. Cranial nerve involvement leads to paralysis of the pharynx and vocal cords, further posing difficulties in breathing. Respiratory compromise leads to most deaths in the paralytic form. Typically, 50% of patients with any paralysis exhibit some degree of residual deficits, although most do improve. A 10% mortality is now reported in the patients with the paralytic form. Before mechanical ventilation, 60% of the individuals died.


Early in the course of pharyngeal infection, throat cultures may reveal poliovirus. Later in the course, a stool culture becomes increasingly helpful. Spinal fluid culture has lower sensitivity. Usually, the results of routine laboratory tests are unremarkable. CSF findings are characteristic of aseptic meningitis. In the first few hours after the onset of symptoms, polymorphonuclear leukocytes may predominate. However, within 12 hours, the predominance of lymphocytes is seen.


Numerous other clinical manifestations may occur. With myocarditis, the heart is extremely sensitive to development of arrhythmias. Hypertension is well recognized and can be severe enough to cause encephalopathy. Analgesics, including opiates, may be required for pain relief. Hot packs have been noted to be effective when applied every 2 to 4 hours. Constipation and bladder paralysis are major issues early in the course and should be monitored closely. The risk of aspiration and airway compromise necessitates a high level of vigilance. If the patient demonstrates respiratory compromise, a tracheostomy is indicated with accompanying mechanical ventilation. Use of antiviral agents is debated. Additionally, some authors argue that corticosteroids are not indicated in enteroviral infections.


Children with mild weakness generally have full recovery. If paralysis is present, the recovery remains ongoing for 2 years, with 80% realized by 6 months. Adults may have new symptoms long after the infection resolves, including weakness and muscle atrophy that is related to continued normal attrition of anterior horn cells.


Polio-like syndromes


Polio-like syndromes have been reported, with West Nile virus and multiple subtypes of enterovirus (most notably D68 and A71) being prominent agents. These cases are often associated with a prior illness (either gastrointestinal or respiratory) and may present with respiratory failure and an acute flaccid paralysis of one or more limbs consistent with anterior horn cell disease. Interestingly, these clusters of cases with acute flaccid myelitis have predominantly occurred on alternate years. Between 2014 and 2018, there were 480 cases reported in 40 states ( www.cdc.gov/acute-flaccid-myelitis/hcp/clinical-management.html ).


Consistent clinical characteristics include rapid progression from hours to days of flaccid weakness. These findings are typically asymmetric, predominantly involving the upper extremities (C5, C6) and proximal greater than distal. CSF pleocytosis as well as elevated protein is the rule. Culture of the virus in the CSF is very rare and should not be expected. Magnetic resonance imaging (MRI) of the brain and spine are very important. Injury of the spinal motor neurons is best visualized on T2 and fluid attenuation inverse recovery, with multiple levels involved, at times involving the entire spine and later in the course involving nerve root enhancement. Brainstem lesions may be seen as well. Supratentorial lesions are observed in approximately 10% of MRI studies. Cranial nerve abnormalities may accompany limb weakness and mostly involve CN VI, CN VII, CN IX, and CN X. There are variable reports of seizures, altered mental status, and bowel/bladder dysfunction. Sensation is classically spared, as in polio, but there are reports of some involvement. Multiple treatment modalities have been tried, but there are no definitive treatments that have been shown to be effective. The Centers for Disease Control and Prevention has provided the Summary of Interim Considerations, a consensus statement emphasizing the lack of current treatment efficacy ( www.cdc.gov/acute-flaccid-myelitis/hcp/clinical-management.html#summary-interim-considerations ). New studies are on the horizon that will hopefully offer efficacious treatment options.


Organophosphate and carbamate poisoning


The clinician must always maintain a high index of suspicion and consider poisoning in the differential diagnosis in patients with altered mental status, respiratory symptoms, or weakness (see also Chapters 125 and 126 ). Zwiener and Ginsburg reported in their study of 37 children with organophosphate or carbamate poisonings that 43% of these patients were evaluated by their primary care doctor, and pesticide toxicity was not suspected. Patients commonly do not provide a known history of exposure. Exposure to these substances may occur as inhalation, ingestion, or dermal contact. In one study of 37 infants and children with organophosphate and carbamate poisonings, 76% of these patients ingested these substances (which were improperly stored), 16% had transcutaneous exposure (through contact with treated carpets, linens, and lawns), and 8% were poisoned by an unknown etiology. Cholinesterase, which is present in the neuromuscular junction, is irreversibly inhibited by organophosphates and reversibly inhibited by carbamate compounds. Therefore, a constellation of muscarinic, nicotinic, and central nervous system symptoms may occur.


Symptoms may originate from various systems. Muscarinic symptoms include miosis, excessive salivation, sweating, lacrimation, diarrhea, urination, and bradycardia. In severe poisonings, flaccid paralysis with areflexia is common. In moderate poisonings, muscle fasciculations may be present. CNS symptoms include coma and seizures; however, seizures are less common in carbamate toxicity. Pulmonary symptoms—including bronchoconstriction, increased pulmonary secretions, and wheezing—have been reported. In one study of 52 children with organophosphate or carbamate poisoning, 100% of these patients exhibited hypotonia, stupor, or coma. With further analysis of the 16 patients with organophosphate poisoning, the other common symptoms included miosis (56%), salivation (37%), pulmonary edema (37%), diarrhea (30%), and bradycardia (25%). Various cardiac rhythms may occur with pathologic signs of cardiotoxicity. Overall, carbamate poisonings are usually less severe and shorter in duration, although the symptoms are essentially the same as those found in organophosphate poisonings.


If organophosphate and carbamate compounds are ingested, gastric lavage and activated charcoal should be initiated. If contaminated, the patient’s skin and hair should be rinsed and cleansed thoroughly with soap, and clothes should be changed to reduce further exposure.


In both forms of poisonings, atropine is used as an antidote for the muscarinic symptoms. Treatment with atropine, however, does not reverse the nicotinic symptoms, which include muscle weakness and respiratory failure. Atropine should be administered as quickly as possible and in adequate doses. In children older than 12 years, the dosing is 1 to 2 mg IV every 10 to 30 minutes. In children younger than 12 years, the initial dose is 0.05 mg/kg with maintenance doses of 0.02 to 0.05 mg/kg over 10 to 30 minutes. In organophosphate and carbamate poisonings, the atropine dose is 5 to 10 times greater than conventional atropine dosing. Atropine should be continued until the muscarinic symptoms begin to abate. The signs of atropinization include mydriasis, tachycardia, and xerostomia; they help provide parameters for adequate dosing. Atropine should be continued for at least 24 hours after severe exposures and then tapered if symptoms are improving.


Pralidoxime chloride, the only cholinesterase reactivator in the United States, is an antidote for only the nicotinic symptoms of organophosphate poisonings. Therefore, atropine must be used concomitantly. Pralidoxime chloride does not help in carbamate exposures. Various doses have been reported for pralidoxime in patients older than 12 years. A conservative dose is 0.5 to 1.0 g IV over 15 to 30 minutes, repeated every 10 to 12 hours, beginning 1 to 2 hours after the initial dose. More recently, another study suggests a 2-g loading dose with a continuous infusion of 1 g/h for 48 hours. These doses have not been directly compared to each other. In patients younger than 12 years, the dose is 25 to 50 mg/kg IV over 15 to 30 minutes, repeated every 10 to 12 hours, beginning 1 to 2 hours after the initial dose (maximum, 2 g/dose). , ,


After the antidotes are given, the mainstay of treatment is supportive. If necessary, ventilation should be provided until the patient regains respiratory strength. Suctioning of secretions in both the oropharynx and proximal conducting airway is essential. Seizures should be treated with diazepam or lorazepam. Cardiac monitoring should be implemented because complex ventricular arrhythmias may occur. , Early feeding may prolong hospital stay. Death usually occurs as a result of respiratory arrest and pulmonary complications, including excessive secretions, edema, and bronchoconstriction.


Diagnosis is based on clinical findings and response to antidote medications. Serum and red blood cell cholinesterase levels should be obtained to assist in the diagnosis of organophosphate poisoning. Treatment should be initiated immediately and not delayed while waiting for cholinesterase level results. Cholinesterase levels do not assist in the diagnosis of carbamate exposure because the reversal of the enzyme occurs too rapidly to be quantified.



Key references

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May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Acute neuromuscular disease and disorders
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