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Neuromuscular Problems of the Critically Ill Neonate and Child


Introduction

Acute neuromuscular disorders occasionally confront the pediatric intensivist and/or the pediatric neurologist. Many of these are primary disorders of the motor unit that present acutely and may require urgent admission to a neurologic critical care unit. We have chosen to discuss these various processes apropos to two respective age groups, infants and children, because some illnesses are unique to infants and toddlers and because similar disorders can have differing presentations in these two age groups. This approach creates somewhat artificial categories, but we feel it provides a practical format for evaluating acute weakness in a child. A third category of acute neuromuscular disorders to be discussed relates to those processes that develop in a child with an acute systemic illness requiring intensive care management and, therefore, concomitantly predisposing the child to another set of acute motor unit disorders.

The differential diagnosis for disorders that present with lesions at each level of the peripheral motor unit is specific to newborns and toddlers. Typical examples seen at or shortly after birth include Werdnig-Hoffman disease (spinal muscular atrophy [SMA], type I), neonatal congenital polyneuropathies, an intrauterine onset of Guillain-Barré syndrome (GBS), and congenital myotonic dystrophy or glycogen/lipid storage myopathies. In contrast, previously healthy infants may develop infantile botulism as well as other unique, genetically determined congenital neuromuscular transmission disorders, and very rarely postvaccine poliomyelitis. Most of these disorders typically present during the first 3–6 months of life, although some may not occur until the infant is almost one year old.

In comparison, the older child and adolescent are predisposed to another set of critical care peripheral motor unit disorders that are usually quite similar to those in the adult patient. These include GBS and myasthenia gravis (MG), which have an increased incidence among older children. However, when GBS and MG affect children, both may vary significantly from their traditional adult presentation. The pseudoencephalopathic form of GBS is a good example. The neuromuscular complications of extended intubation and sepsis affecting either the peripheral nerve, or muscle cell, also occur in children. Careful review of clinical records, by someone as junior as an astute intern, or the nondiagnostic results of an imaging study, often lead clinicians to pursue further diagnostic testing. The differential diagnosis of these various motor unit disorders is also significantly aided by utilizing clinical neurophysiology techniques, particularly nerve conduction studies (NCSs) and electromyography (EMG) or electroencephalography (EEG), as well as cerebrospinal fluid (CSF) analysis. These studies provide the clinician with an objective means to assign a specific patho-anatomic or neurophysiologic site for the child’s illness.

Lastly, there is an interesting but relatively uncommon set of neuromuscular disorders that develop in a child predominantly in association with the following three conditions: (1) treatment with a nondepolarizing neuromuscular blocking agent, (2) high-dose systemic glucocorticoid treatment, or (3) sepsis or other severe illness. These processes may independently affect each primary portion of the peripheral motor unit from the anterior horn cell to the peripheral nerve, neuromuscular junction, or muscle fiber. Thus, in comparison to the other disorders discussed in this chapter wherein a primary individual motor unit disorder presents in an acute fashion requiring intensive care management, this set of illnesses is usually serious but self-limited, and somehow secondary to a toxic process related to the underlying illness.

The acute care motor unit disorders discussed in this chapter illustrate a broad anatomic spectrum from the anterior horn cell to the muscle cell. This review is based on our 35-year experience (1979 to 2014) evaluating children, ages newborn through 18 years, at the Boston Children’s Hospital (BCH) Neuromuscular Program, intensive care units, and EMG laboratory.

Acute Neuromuscular Crises in the Infant

Babies may present during the neonatal period with floppy infant syndrome, or acutely with a flaccid paralysis after being healthy during their first few months of life. Some newborns, presenting primarily with an acute respiratory compromise during the immediate neonatal period, are concomitantly observed to be hypotonic, sometimes to the degree of being identified as a floppy baby. A variety of congenital or developmental lesions at any level of the peripheral motor unit may lead to this picture ( Box 43.1 ).

Box 43.1
Conditions Leading to Acute Neuromuscular Crises in the Infant

  • Anterior Horn Cell

    • Spinal muscular atrophy, type 0, type I

    • Vaccine-associated poliomyelitis

  • Peripheral Nerve

    • Congenital hypomyelinating or axonal polyneuropathies

    • Guillain-Barré syndrome *

  • Neuromuscular Junction

    • Transient neonatal myasthenia gravis

    • Congenital myasthenic syndromes

    • Infantile botulism

    • Magnesium treatment in the mother

  • Muscle

    • Congenital myotonic dystrophy

    • Congenital myopathies

    • Metabolic/mitochondrial myopathies

      * Guillain-Barré syndrome rarely occurs during infancy.

Another subset during the first year of life includes those previously healthy infants who unexpectedly develop a precipitous neuromuscular crisis. Specific clinical mechanisms that require consideration in this instance include a previously unrecognized SMA, Guillain-Barré syndrome, infantile botulism, congenital myasthenic syndromes, or very rarely postvaccine poliomyelitis.

Anterior Horn Cell

The Werdnig-Hoffman form of SMA or SMA type I is one of the most common causes of floppy infant syndrome as well as the most common anterior horn cell disorder of infancy. Usually, these infants either present as a floppy baby, or with failure to develop or loss of early motor milestones between 1–3 months of age. Rarely, SMA (classified as type 0 or type IA) may present at birth with profound hypotonia, severe weakness and respiratory failure. Eventually some SMA type I infants will require admission to a neonatal intensive care unit (NICU). Their diagnosis is usually made by a combination of EMG and genetic DNA analysis or just DNA analysis. Occasionally, their SMA is not initially recognized and it is not until they are unable to cope with a respiratory illness that they present to the ICU requiring pulmonary support or cannot be weaned from the ventilator. See Case Example 43.1 .

Case Example 43.1
Werdnig-Hoffman Disease Presenting with Respiratory Distress

This previously “healthy” 4-month-old first child was admitted with an acute bronchiolitis and required intubation. Subsequently, when his pulmonary status had significantly improved, his pediatricians had unexpected difficulty weaning him from the respirator. Neurologic consultation demonstrated generalized hypotonia and absent muscle stretch reflexes.

An EMG was performed because of its ability to provide a rapid means to localize the anatomic site for the baby’s motor unit abnormality. This demonstrated low amplitude compound muscle action potentials (CMAPs), normal motor conduction velocities (MCVs) and distal latencies (DLs), as well as sensory nerve action potentials (SNAPs). Needle EMG demonstrated a marked decrease in the number of motor unit potentials (MUPs) with widespread active denervation characterized by many fibrillation potentials and positive waves. Subsequent to the EMG, DNA analysis was positive (homozygous deletion of exon 7 of the survival of motor neuron 1 [ SMN1 ] gene, which is the most common mutation in SMA patients).

Comment

Infants with SMA are usually easily recognized because of their typical clinical presentation as a floppy baby with an alert facies, absent muscle stretch reflexes, and fasciculations of their tongue. In this instance, DNA analysis of the SMN1 gene is the appropriate means to make the diagnosis today. Occasionally, however, parents and pediatricians have not recognized a relatively subtle clinical presentation until an acute illness leads to hospitalization. In the intensive care setting, as above, one may need to make a more rapid diagnosis, utilizing EMG, to provide appropriate clinical management as well as counseling of the parents. Rarely, infants with non-5q SMAs may have similar clinical and EMG findings.

Another form of acute anterior horn cell disease, vaccine-associated poliomyelitis (see Case Example 43.2 ), deserves mention in the differential diagnosis of any infant or child with an acute weakness.

Case Example 43.2
Acute Post-immunization Poliomyelitis

A previously healthy 11-week-old boy presented with a 2-day history of fever, irritability, lethargy, and head lag. CT examination of the head and brain was normal. CSF analysis demonstrated 580 white blood cells (WBC), 41% polymorphonuclear leukocytes, 59% lymphocytes; glucose 59 mg/dL and protein 143 mg/dL. Although intravenous antibiotics were initiated, the baby soon developed apneic spells requiring intubation. This infant soon developed a weak cry and asymmetric skeletal muscle weakness particularly sparing left plantar flexor and extraocular muscles.

On the seventh day of his illness an EMG was performed demonstrating an anterior horn cell disease pattern. Subsequently repetitive motor nerve stimulation (RMNS) failed to identify a neuromuscular transmission defect (NMTD).

Review of this baby’s immunization records documented that he had received type 3 Sabin live poliomyelitis vaccine 3 weeks prior to onset of his illness. His recovery was poor; he was ventilator dependent more than 2 years later.

Comment

Three cases of acute flaccid paralysis occurring in infants, secondary to immunization-related poliomyelitis, became known to one of the authors (HRJ) within just a few years during the mid-1990s. (Goldstein J, personal communication, 1995). All three babies were 3–4 months old, each having received type 3 live polio immunization less than one month earlier. An acute febrile illness preceded a progressive asymmetric extremity weakness, head lag, irritability, and lethargy. A CSF pleocytosis with 100–580 WBC was associated with protein values between 82–143 mg/dL in all and glucose of 49 mg/dL in one. EMG demonstrated classic electrophysiologic evidence of an acute asymmetric anterior horn cell disorder.

Most instances of paralytic poliomyelitis from the attenuated live Sabin oral vaccine occurred among infants less than age 1 year usually subsequent to their first polio vaccine, and within 2 weeks of immunization. Revised CDC guidelines require that the initial immunization protocol utilize the Salk killed vaccine as the primary immunization method for all children. This revised infantile immunization protocol has made postvaccination related poliomyelitis of historical interest in North America. However, the live vaccine is still being utilized in certain countries.

Peripheral Nerve

Some congenital hypomyelinating or axonal polyneuropathies present in the newborn period with a clinical phenotypic appearance similar to that of SMA I, Werdnig-Hoffman disease. These infants may be so ill that they require intensivist support. See Case Example 43.3 .

Case Example 43.3
Severe Newborn Infantile Demyelinating Polyneuropathy

A 2-week-old old infant was delivered after what the mother perceived as a normal pregnancy with normal fetal movements in utero . Since birth, he had a “paucity of spontaneous movements,” and a weak cry. His mom stated that he was still able to breastfeed although he did not hold the pacifier tightly. His gag was weak. Fasciculations of the tongue were present. This alert baby was markedly hypotonic with frog leg posture, no spontaneous movements of the legs, wrist drops, weak palmar grasp, and arthrogryposis multiplex. He assumed the inverted U posture when held prone. He was areflexic and the plantar responses were mute. He responded to noxious stimuli applied to all extremities.

The cerebrospinal fluid (CSF) protein was elevated at 190 mg/dL. Sensory NCS failed to demonstrate any median SNAP. Median and peroneal CMAPs were widely dispersed, of very low amplitude (0.05 and 0.02 mV), and had prolonged latencies (3.6 and 8.2 msec), and there were very slow MCVs of 6 and 8 m/sec. EMG demonstrated mild diminution in the number of MUPs which were of slightly longer duration, polyphasic, and normal amplitude and firing at increased frequency. The only areas with occasional fibrillations and positive waves were present in the most distal muscles. These findings were compatible with an acquired, diffuse, predominantly demyelinating, peripheral neuropathy.

Sural nerve biopsy demonstrated hypomyelination with abortive onion bulb formation. These findings did not provide a base to distinguish between an inborn error of myelination or an unusual acquired autoimmune demyelinating peripheral neuropath, such as intrauterine GBS. A trial of prednisone was unsuccessful. Subsequently, progressive respiratory failure ensued. The baby died at age 2 months; an autopsy was declined.

Comment

Any floppy infant presenting with a frog leg posture and tongue fasciculations most likely has SMA type 0 or type I. In contradistinction, this baby’s EMG findings of very slow MCVs, with dispersed low amplitude CMAPs, and absent SNAPs, were diagnostic of an acquired demyelinating polyneuropathy and not an abnormality primarily at the motor neuron level. The incidence of peripheral neuropathies was 6 percent in our BCH review of over 100 floppy babies seen in our EMG lab. These were more common among the infants who also had arthrogryposis. The absence of sensory responses is the most important pediatric EMG clue to the appropriate diagnostic conclusion that the baby has one of these rare neonatal neuropathies. The nerve pathologies included primary axonal, demyelinating, and widespread neuronal degeneration.

The Guillain-Barré syndrome (GBS) rarely affects newborn infants. It needs consideration in the differential diagnosis of neonatal flaccid paralysis. In one instance GBS onset was soon after birth. The baby’s mother had an autoimmune disease, chronic ulcerative colitis. During the 30 th week of her pregnancy she had observed significantly decreased fetal movements. Her baby was quadriparetic when delivered at 37 weeks with an Apgar score of 6 at 10 minutes. At age 3 days neurologic exam demonstrated severe leg and moderate proximal arm weakness, with generalized absence of muscle stretch reflexes. The CSF protein was normal, 38 mg/dL. In contrast motor NCS demonstrated profound motor NCV slowing between 3 and 15 m/sec, with conduction block and temporal dispersion in many nerves. Needle EMG revealed active denervation in many muscles. He had gradual and complete recovery by age 1 year without any specific treatment.

Another pregnant mother, aged 33, developed severe GBS during the 29th week of her pregnancy. She became tetraplegic and was still respirator dependent when her baby was born at the 38th week. He developed hypotonia, marked respiratory distress, and feeding problems 12 days postpartum although he was well at birth. His CSF protein was 243 mg/dL. An EMG was typical for GBS. Both the mother and child had IgG antibodies positive for recent CMV infection. Intravenous immunoglobulin therapy was associated with a complete symptomatic resolution in 2 weeks. One presumes his GBS developed in utero .

GBS affected another pregnant woman. Her baby had poor spontaneous ventilation at delivery requiring brief intubation. During the next five days of observation, there were no other signs of GBS. Despite such, both this infant and his mother had high antibody titers to human peripheral nerve myelin glycolipids.

Even without any known intrauterine events, the Guillain-Barré syndrome may occur shortly after birth, as early as age 3 weeks. These previously healthy babies present with an acute, rapidly progressive and often severe hypotonia, with possible respiratory distress, and feeding difficulties. Chronic inflammatory demyelinating polyneuropathy (CIDP) subsequently developed in one 7-week-old infant with acute GBS. An EMG is particularly helpful for the differentiation of GBS from other acute floppy infant syndromes. Absent SNAPs, profound motor conduction slowing, and dispersed CMAPs are the quintessential EMG clues for the diagnosis of neonatal GBS. In our BCH EMG review of more than 100 floppy babies, there was a 6 percent incidence of peripheral neuropathies. Only one of these six infants had EMG findings commensurate with GBS.

Although tick paralysis mimics acute GBS in children, we are unaware of an infantile case. Nonetheless, any baby with an acute onset of generalized muscle weakness needs to be searched for a tick, particularly in the scalp.

Neuromuscular Junction (NMJ)

Various NMJ disorders are occasionally encountered during infancy. Autoimmune maternal associated myasthenia gravis is the most easily recognized and probably most common NMJ pathologic entity occurring in this age group. This relatively short-lived disorder typically occurs at birth in 15–20% of infants whose mothers have myasthenia gravis. Rarely, infants born to mothers who had eclampsia and received magnesium treatment also have the potential to develop an acute infantile presynaptic NMJ disorder. These two NMTDs only occasionally come to the attention of the pediatric neurologist as pediatricians are well versed in the management of these infants.

There are also a number of relatively rare congenital myasthenic syndromes (CMSs) with a primary pathophysiologic site of difficulty varying between the presynaptic NMJ, the synapse, or the postsynaptic NMJ. An endplate deficiency of choline acetyltransferase is a CMS that predisposes the baby to an acute onset NMJ disorder. Typically, these babies have recurrent episodic apnea. In contrast, it is unusual for other CMS forms to have such an acute presentation.

Infantile botulism is the one other presynaptic NMTD that will also acutely affect previously healthy babies and toddlers ( Case Example 43.4 ). Clinical suspicion, with subsequent EMG, is crucial to making this diagnosis. Because of its somewhat varied presentation we are concerned that possibly infantile botulism is more common than recognized.

Case Example 43.4
Infantile Botulism

A previously healthy, 4-month-old baby was admitted to another hospital with a 1-week history of constipation, and subsequently poor feeding, lethargy, a weak cry and dehydration. She had lost her ability to roll over, lift her head, or sit up. A full septic evaluation was unremarkable including CSF examination. After she developed cyanosis with an acute apneic spell, and subsequent increasing lethargy, she was transported to BCH.

Attempt to wean her from the ventilator was unsuccessful. Neurologic examination here demonstrated no extraocular muscle movements, absent corneal responses, and no gag reflex. At this time she still had movement in all extremities, and intact muscle stretch reflexes (MSRs). The initial clinical impression was an “indeterminate encephalopathy.” This conclusion was based on nonspecific EEG findings in the right occipital lobe, as her brain MRI, CSF, bacterial and viral cultures, and metabolic evaluation were all normal. During this evaluation, she became increasingly hypotonic and areflexic. Seven days after onset of symptoms and subsequent to further clinical review by a diligent intern, at change of service, an EMG was requested for possible infantile botulism.

The EMG evaluation, in the MICU, demonstrated low amplitude median and peroneal CMAPs (0.56 mV and 0.2 mV, respectively; normal >3.5 mV and 1.6 mV) with normal motor NCV, and distal latencies. Repetitive motor nerve stimulation (RMNS) of the median nerve at 2 Hz demonstrated an 11% decrement, and with 20 Hz stimulation a 160% facilitation. Motor unit potentials were very “myopathic.” These EMG findings were consistent with a diagnosis of infantile botulism. Subsequently, a stool sample, as well as an assay of a honey specimen from home, were both positive for type A botulinum toxin. She gradually improved, with supportive treatment, during the next few months.

Comment

Infantile botulism usually has a stereotyped clinical presentation. Typically, a previously healthy infant, between ages 10 days and 12 months, has the acute onset of hypotonia, generalized descending weakness, poor feeding, oculomotor and pupillary abnormalities, dysphagia, and constipation. However, one also needs to consider this diagnosis in the setting of unexplained respiratory distress in any baby under 12 months of age. Infantile botulism has been linked to honey ingestion. In its most severe state the presentation may be acute and require ventilatory support. Treatment with human botulinum antitoxin can expedite the infant’s recovery.

Bacteriologic confirmation usually requires a few weeks, but a mouse bioassay and real-time PCR assays can provide a rapid confirmation of the diagnosis. EMG is the most useful early diagnostic tool. Most babies with infantile botulism have clear-cut evidence of a NMTD. Low rate RMNS, at 2–5 Hz, often but not always demonstrates a decremental response. More rapid RMNS rates of 20–50 Hz provide the primary electrophysiologic technique for diagnosing infantile botulism. A post-tetanic facilitation (PTF) varying between 23% and 313%, with a mean of 73%, was documented in 23 of 25 babies. A longer period of post-tetanic facilitation is also observed. One may not always be able to confirm a diagnosis of infantile botulism with EMG as not all cases have a documented facilitation with RMNS. However, in most instances of infantile botulism, babies will have a typical EMG diagnostic triad. This includes: (1) low amplitude CMAPs (beware normal maturation standards for age), (2) post-tetanic facilitation, and (3) absence of post-tetanic exhaustion.

Muscle

Congenital myopathies typically present as a floppy infant syndrome but most babies are not ill enough to require NICU monitoring. In addition, only a small subset of myopathies cause acute infantile flaccid paralysis and/or respiratory distress. However, occasionally we are asked to see a NICU baby who is found to have a primary myopathy. See Case Examples 43.5 and 43.6 .

Case Example 43.5
Neonatal Myotonic Dystrophy

Respiratory distress developed soon after birth in this baby girl, with clubfeet. She required intubation for her first month of life. An EMG was requested for evaluation of her generalized hypotonia when she was 2 months old. Motor NCS demonstrated low amplitude CMAPs but other parameters were normal including SNAPs. Profound and prolonged decrescendo myotonic discharges occurred during her EMG. These were associated with rare fibrillation potentials. Her MUPs were normal. The mother had no myotonia detectable by physical examination or on EMG but she recalled that her father had difficulty releasing his grip when driving a car.

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