Etiology and Pathogenesis

SMA is caused by an autosomal recessive mutation in the survival of motor neuron 1 (SMN1) gene on chromosome 5q13. The gene product, SMN protein, plays an important role in RNA processing and is expressed in all cells but seems to be of particular importance in motor neurons. In humans, a near-identical homocopy, the SMN2 gene, rescues an otherwise lethal disorder, and the number of copies of SMN2 is inversely related to severity of the phenotype.

Clinical Presentation

SMA is subclassified into four types based on age of onset and the maximal level of motor skills achieved. SMA type 1 (or Werdnig-Hoffmann disease) is the most common and severe of these disorders, accounting for approximately 60% of cases. SMA type 1 presents in the early infancy period (0–6 months) with generalized hypotonia, proximal and symmetric flaccid muscle weakness (initially lower more than upper limbs), and absent deep tendon reflexes. This frequently comes to the attention of the pediatrician with gross motor milestone delay and may present subacutely or more indolently. Most infants also have tongue fasciculations, and some have postural tremor of the fingers or joint contractures. Diaphragmatic sparing with intercostal muscle involvement results in paradoxical breathing and the classic bell-shaped torso (Figure 81-2). Importantly, these infants are alert and interactive with normal cognitive development and no sensory loss or impairment of eye movements. Systemic complications of SMA include pneumonia, scoliosis, poor weight gain, sleep difficulties, and joint contractures. These infants never achieve independent sitting. Most individuals’ expected life span is less than 2 years without invasive ventilatory and nutritional support.

Figure 81-2 Werdnig-Hoffmann disease.

SMA type 2 refers to infants who present usually between 6 and 18 months of age and achieve independent sitting but not ambulation and rely upon power wheelchairs for mobility. SMA type 3 presents after 18 months of age, and these children achieve community ambulation, but about half lose this ability by age 10 years. SMA type 4 presents in the adult years and tends to be slowly progressive.

The differential diagnosis includes other disorders causing acute weakness, including poliomyelitis and infantile botulism. In addition, the general differential diagnosis for hypotonia and more chronic weakness in an infant should be considered (Table 81-1).

Table 81-1 Differential Diagnosis of the Floppy Baby, Infant, and Child

TORCH, toxoplasmosis or Toxoplasma gondii, other infections, rubella, cytomegalovirus, and herpes simplex virus.

Evaluation and Management

SMA type 1 diagnosis is suspected in individuals with an appropriate clinical history and is confirmed with molecular genetic testing for homozygous deletion of the SMN1 gene. Electromyography (EMG) and nerve conduction studies (NCS) confirm a motor neuron process but is not necessary when the clinical presentation is strongly suggestive of SMA. Muscle biopsy is no longer performed as a diagnostic test. Genetic counseling and carrier testing is important after the diagnosis has been established.

There is no cure for SMA. The level of supportive care provided for SMA type 1 includes an ethical dimension, given the progressive nature of the disorder, with many parents electing to pursue a palliative course at home. Nonetheless, with aggressive management of dysphagia, malnutrition, and respiratory insufficiency, the lifespan can be extended considerably, often for several years. This entails early placement of a gastrostomy tube for supplemental feedings and early initiation of bilevel positive airway pressure (BiPAP), cough assist, and using a pump to suction oral secretions. Similar but less intensive nutritional and pulmonary support for patients with type 2 SMA, along with close attention to evolving scoliosis and joint contractures, has enabled these children to live into the third decade and beyond, often attending college, gaining employment, and forming interpersonal relationships. Children with type 3 SMA need mainly orthopedic and physical therapy support.

Future Directions

Much of the research into SMA is now focused on the molecular genetic mechanism of the disease. Several clinical drug trials based on encouraging preclinical data have been conducted on neuroprotection (riluzole), histone diacetylase (HDAC) inhibition (valproic acid), and regulators of SMN2 expression (hydroxyurea and sodium phenylbutyrate). None, however, has demonstrated clinical efficacy as yet. The use of novel oligonucleotides and small molecule drugs that increase SMN2 expression are currently in development, and stem cell and gene correction strategies are being considered.

Etiology and Pathogenesis

Pathologically, the two primary changes seen in GBS are acute inflammatory demyelinating polyradiculoneuropathy and acute axonal degeneration, both of which are thought to be caused by cross-reacting antibodies to the various gangliosides expressed in peripheral and cranial nerves. Campylobacter infections can result in molecular mimicry with the GM1 ganglioside, such that patients with C. jejuni infections are at 100-fold higher risk of developing GBS than the general population (Figure 81-3).

Figure 81-3 Guillain-Barré pathophysiology.

Clinical Presentation

AIDP presents 2 to 4 weeks after a respiratory or GI illness with paresthesias of the extremities and a symmetric, length-dependent weakness (beginning distally in the lower limbs) with areflexia that may ascend over hours to days. About 50% of children have autonomic dysfunction as well, including cardiac dysrhythmias, blood pressure fluctuations, or bladder dysfunction.

The differential diagnosis of GBS should include other causes of peripheral neuropathy (including toxic neuropathy, critical care neuropathy, or tic paralysis), diseases of the neuromuscular junction, or spinal cord pathology.

Evaluation and Management

A child with suspected GBS should be evaluated with lumbar puncture, which classically shows albuminocytologic dissociation (high protein without pleocytosis) in the cerebrospinal fluid (CSF). The CSF may be normal within the first week of symptom onset, though, and in a child with clinical GBS and a normal CSF profile, treatment should still be initiated. EMG and NCS demonstrate multifocal demyelination or axonal degeneration. Magnetic resonance imaging of the spine should be considered in children with atypical presentation to rule out external compressive myelopathy and often demonstrates enhancing nerve roots after gadolinium administration.

In the appropriate clinical context, treatment for GBS should be initiated based on history and examination with supportive studies when able. First, children should have forced vital capacity (FVC) and negative inspiratory force (NIF) followed regularly and cardiorespiratory instability closely monitored with cardiac monitor and pulse oximeter. Hypertension may need medication to control. About 15% to 20% of children with GBS require assisted ventilation for respiratory failure sometime during their course. If the child is immobile in bed, sequential compression devices should be used, as well as consideration of prophylactic subcutaneous heparin. In children with stable or improving weakness without respiratory distress, supportive care may be enough.

In children with rapidly worsening weakness, worsening respiratory status, significant bulbar weakness, or inability to walk, more aggressive therapy should be initiated with intravenous immunoglobulin (IVIG) or plasmapheresis. Corticosteroids are not effective in AIDP.

Children with GBS typically have a shorter course with more complete recovery (in ≈85%) compared with adults. The best indicator of prognosis is based on EMG or NCS and the degree of axonal damage involved in a given case. Children who have had GBS should not receive live vaccinations for 1 year after their clinical symptoms. Recurrence is uncommon.

Etiology and Pathogenesis

MG is caused by an antibody-mediated response attacking the nicotinic acetylcholine receptor on the postsynaptic motor endplate of the neuromuscular junction (Figure 81-4). Two specific antibodies are thought to be responsible for most MG. The first is an antibody directed against the acetylcholine receptor (anti-Ach-R Ab), which is positive in 56% of prepubertal children with JMG and 82% of children with peripubertal onset. Of the adult patients that test negative for anti-Ach-R Ab, 40% to 70% have antibodies that bind to the extracellular domain of muscle specific kinase (anti-MuSK Ab). The prevalence of anti-MuSK Ab is unclear in children.

Figure 81-4 Myasthenia gravis pathophysiology.

Because of this dysfunction at the neuromuscular junction, patients with MG are particularly sensitive to nondepolarizing neuromuscular blocking drugs (e.g., vecuronium), aminoglycoside antibiotics, phenytoin, magnesium and β-blockers. If a patient presents with a sudden flare of uncertain etiology, his or her medication list should be checked for possible offending drugs.

Clinical Presentation

JMG typically presents after 10 years of age (although cases have been reported in children younger than 1 year old) and is characterized by fatigable weakness of ocular, facial, bulbar, respiratory, and extremity striated muscles. Most patients present with ocular symptoms, but others can present with generalized fatigue, swallowing dysfunction, slurred speech, acute respiratory failure, or difficulty chewing. Differential diagnosis of MG includes is broad and includes a similar list as that of GBS.

Evaluation and Management

A clinical diagnosis of myasthenia is suspected based on the presentation above. Physical examination findings specific to MG include the hallmark of fatigable weakness (test for eyelid droop with sustained upward gaze, the curtain sign, Cogan’s eyelid twitch), and frequently a preferential involvement of proximal limb muscles. Neck flexion and extension strength may correlate with respiratory muscle strength.

The edrophonium (Tensilon) test is useful in establishing the diagnosis when there is definite weakness that can be objectively assessed for change. This test should be done in a child in a controlled setting with a cardiac monitor and with atropine available if a bradycardic response evolves. Diagnosis is made serologically, looking for anti-Ach-R antibodies and or anti-MuSK antibodies in the serum. Conventional NCS with slow repetitive stimulation of nerves in affected limbs shows a classic decremental response of the compound muscle action potential. Single-fiber EMG shows increased jitter and blocking of motor unit generation.

Most children with JMG who require maintenance therapy are treated with anticholinesterase agents (e.g., pyridostigmine) with or without a variety of immunosuppressive agents. Oral corticosteroids may control symptoms and reduce the incidence of disease generalization at 2 years in patients with pure ocular MG. Other steroid-sparing immunosuppressive agents used in JMG treatment include azathioprine, cyclosporine, mycophenolate, and cyclophosphamide. Plasmapheresis or IVIG may be used as a chronic, intermittent therapy in patients with refractory disease. IVIG is sometimes preferred as first-line chronic therapy over corticosteroid mediation in growing children. As with adults, thymectomy has been demonstrated to be beneficial for generalized disease but is not typically used for purely ocular myasthenia.

For myasthenic crisis, FVC, NIF, and clinical examination should be followed closely. Overuse of anticholinergic medication in a patient on pyridostigmine therapy needs to be considered as a cause. Plasmapheresis and IVIG are also used in crisis.

Future Directions

Most research in MG is currently trying to better understand the disease, what exactly causes the autoimmune response, and attempts to better define the relationship between the thymus gland and MG.

Etiology and Pathogenesis

Botulinum spores reside primarily in soil and are disrupted by local construction or agricultural cultivation. Less commonly, they may be found in contaminated wild honey or home-canned foods. Infection occurs when spores are ingested and germinate in the intestines, which leads to bacterial colonization and toxin release. Infants may be more susceptible to infection than adults because of immaturity and age-related changes in the competitive bowel flora, which allows extensive colonization.

Clinical Presentation

Affected infants incubate their botulinum spores for 3 to 30 days and then present with a progressive clinical picture of neuromuscular blockade, nadiring at 1 to 2 weeks. Infants initially demonstrate poor feeding and constipation followed by a subacute progression of descending bulbar and extremity hypotonia and weakness (Figure 81-5). Cranial nerve dysfunction manifests early as pupillary paralysis, ptosis, diminished extraocular movements, facial diplegia, and a weak suck and gag. Autonomic dysfunction presents with decreased salivation and tearing, widely fluctuant heart rate and blood pressure, and flushed skin. Decreased extremity movement and areflexia are later signs followed by flaccid paralysis and respiratory failure in 50% to 70%. Without treatment, the total duration of illness is approximately 1 to 2 months.

Figure 81-5 The floppy baby.

The differential diagnosis is that of the hypotonic infant (see Table 81-1). In clinical practice, SMA type 1 and metabolic disorders are the most frequent mimics of infantile botulism.

Evaluation and Management

Infantile botulism should be suspected in any infant with weak suck, ptosis, inactivity, and constipation, particularly in an endemic area. The gold standard of diagnosis is isolation of C. botulinum spores from stool and is confirmed by the identification of botulinum toxin in stool samples. However, collection of stool may be difficult because of the accompanying constipation, and anaerobic stool cultures may take up to 6 days to grow, resulting in a significant delay in treatment if all cases were confirmed before initiation. Electrophysiologic testing may be helpful in the diagnosis of infantile botulism, but findings of abnormal incremental response with repetitive nerve stimulation and short-duration, low-amplitude motor unit potentials on EMG are not pathognomonic and are not always present in very early disease.

For any case of suspected infantile botulism, the California Department of Health Services, Infant Botulism Treatment and Prevention Program should be contacted (http://www.infantbotulism.org/ or 24-hour telephone number, 510-231-7600), and the infant should be immediately treated empirically with intravenous botulism immune globulin (or “babyBIG”) while the prolonged confirmatory testing described above is pending. Prompt babyBIG therapy has been shown to decrease the mean duration of hospital stay from 5.7 to 2.6 weeks, decrease the duration of mechanical ventilation from 4.4 to 1.8 weeks, and decrease hospital costs by $89,000 (in 2004 United States dollars). Management of patients with infantile botulism is otherwise supportive. Aminoglycoside antibiotics should be avoided because they can potentiate the effects of the toxin. With appropriate treatment, the case fatality rate is under 2%, and full recovery is expected.

Future Directions

Research directed at development of a variety botulism vaccines is currently underway, and in clinical trials, some vaccines are already available to adults at risk, particularly those in the military to counteract the risk of bioterrorism with botulinum toxin.

Etiology and Pathogenesis

The dystrophin gene is the largest human gene isolated to date, spanning 2.5 million base pairs, and including 79 exons, which make up 0.6% of the gene. In approximately 60% of DMD patients, a deletion of one or more exons is found. Other causes are exon duplication, small insertions, or deletions or single-base pair changes, which may result in a premature stop codon. These mutations all result in stunted and abnormal RNA, which rapidly decays and leads to the production of a small amount of truncated and nonfunctional proteins. Identifying the type of mutation is now important for both genetic counseling and because newer treatments focus on the type of mutation (see below).

DMD occurs in about one per 3500 live male births and is transmitted in an X-linked recessive mechanism; however, about 30% of cases are spontaneous new mutations. Most patients are therefore boys; however, girls may also rarely manifest some DMD symptoms because of uneven lyonization or Turner’s syndrome. The severity of disease is frequently related to the effect of the deletion on the disruption of the protein transcription reading frame.

Clinical Presentation

Patients with DMD classically present around the age of 3 years old with gross motor delay, excessive falling, and gait abnormalities. Calf hypertrophy and neck flexion weakness are evident by 3 to 4 years of age. Hip girdle muscles are typically affected sooner than shoulder girdle muscles, causing the classic Trendelenburg (or waddling) gait and the Gowers’ sign (Figure 81-6). As the disease progresses, weakness spreads distally. Joint contractures can develop and further worsen gait. Untreated, DMD follows a fairly predictable progressive course. Untreated, children lose the ability to walk (typically by 10 years of age and always by 13 years of age), then develop kyphoscoliosis, and finally develop cardiac and respiratory involvement and failure in the later second decade of life. The differential diagnosis includes other myopathies (see Table 81-1), dystrophies, and SMA type 3.

Figure 81-6 Duchenne’s muscular dystrophy.

Evaluation and Management

Creatine kinase (CK) is elevated in affected children, from 10,000 to 30,000 IU (reference range, <250 IU). EMG may be helpful in distinguishing a myopathic process from a neurogenic disorder if this is in question. Definitive confirmation of a dystrophinopathy is made with molecular genetic testing; the diagnosis of DMD versus BMD remains a clinical one. Muscle biopsy is infrequently needed for diagnosis, but dystrophin protein expression can be identified by specific monoclonal antibody tagged immunostains or quantified with Western Blot analysis.

Glucocorticosteroids (prednisone or deflazacort) are the only medications with demonstrated benefit for DMD. They improve strength and motor function in the short term and prolong the time to reach nonambulatory status. They also postpone significant scoliosis, deterioration in pulmonary function, and possibly the evolution of cardiomyopathy. Thus, morbidity has been reduced and mortality extended since steroid use has been widely adopted and better pulmonary, cardiac, and orthopedic management implemented.

The remainder of the management is multidisciplinary. Pulmonary manifestations of DMD largely result from weakness of intercostal and diaphragmatic muscles, although it is also complicated by scoliosis. Monitoring of pulmonary function is important to pursue regularly by the early teen years, with annual spirometry and cough force, and if the patient is symptomatic for nocturnal hypoventilation, with a sleep study. Treatment includes implementing a cough-assist device and BiPAP, regular immunizations, and prompt attention to respiratory infections. Cardiac manifestations include dilated cardiomyopathy and regional wall motion abnormalities in areas of fibrosis (on echocardiography), arrhythmias, and chronic heart failure. Echocardiographic abnormalities are uncommon in the first decade but are seen in all boys with DMD by the late teens. Monitoring with regular electrocardiography and echocardiography is recommended every 2 years up to age 10 years and then annually. Treatment of heart failure is usually with an angiotensin-converting enzyme inhibitor, such as lisinopril, and a β-blocker is sometimes added.

With improved supportive care, the mean age of mortality has extended from 17 years to the mid-twenties, and some patients now survive into the fourth decade. Recent clinical care guidelines for DMD have been published (see Suggested Readings). Death is still usually from cardiomyopathy.

Boys with DMD overall have an intelligence quotient (IQ) curve shifted to the left, with one study identifying the mean as 83. DMD patients are also more prone to dysthymic disorder and major depressive disorder than their nonaffected peers.

There are several specific drug considerations in caring for DMD patients. In particular, they should not receive anticholinergic drugs or ganglionic blocking agents given the risk of decreased muscle tone. They may also be more susceptible to malignant hyperthermia, which care providers should be aware of before administration of general anesthesia. Cardiotoxic drugs should not be used.

Future Directions

Novel research into DMD is focusing on strategies to bypass the dystrophin mutation. Clinical trials are currently exploring two approaches: ribosomal read-through of premature stop codons, in the approximately 13% of DMD patients with this type mutation, by a small molecule drug named PTC124 (ataluren) and exon skipping, using oligonucleotides, now being tested for a subset of patients with deletions. In addition, pharmacologic therapies to ameliorate disease are targeting fibrosis, inflammation, and other downstream secondary pathways.