Hypotonia and Weakness

Clinical Evaluation

In an infant, historical information must include a complete obstetric history, including the amount and quality of fetal movements, amniotic fluid volume, and intrauterine growth restriction, as well as accurate data about perinatal events, diet, toxic exposures, and family history. The muscle strength, passive tone, joint extensibility, and postural reflexes, including responses to traction, axillary suspension, and ventral suspension of the hypotonic infant, should be compared to those of the normal infant ( Fig. 35.3 ).

Muscle Strength

Muscle strength ( Table 35.5 ) cannot be measured directly in infants, but numerous clinical clues allow the careful observer to identify weakness. The most important of these clues is the spontaneous posture. The weak infant has diminished or no spontaneous movement, often in striking contrast to the usual vigorous and plentiful movements of the infant with normal strength. The lower extremities are abducted and the lateral surfaces of the thighs lie against the examination table in a classic “frog leg” position, whereas the upper extremities lie extended alongside the body or flexed in a flaccid position beside the head ( Figs. 35.4 and 35.5A ). With marked weakness, there are no movements that overcome the pull of gravity. The immobility of the weak infant results in flattening of the occipital bone, which is often associated with occipital hair loss. When placed in a sitting posture, the infant droops forward, the shoulders sink, the head falls forward, and the arms hang limply.

TABLE 35.5

Grading Muscle Strength

0 No contraction 1 Minimal visual or palpable contraction only 2 Moves in horizontal plane but not against gravity 3 Moves against gravity but not against resistance 4 Moves against gravity and minimal resistance 5 Moves against gravity and full resistance

Passive Tone

Passive tone can be assessed by evaluating the resistance to movement of the limbs through their range of motion. Evaluation of the shoulders, elbows, wrists, hips, knees, and ankles is especially helpful. In hypotonic infants, the examiner senses a looseness of the limbs as the limbs are moved. In addition, grasping the midportion of the infant’s limb and passively flapping the extremity allows the examiner to evaluate the degree of limpness of the distal extremity. In the hypotonic infant, the hands and feet wave limply; in the normal infant, the ankle and wrist are maintained fairly rigidly in line with the rest of the extremity.

Even in normal infants, there is a wide variation of muscle tone. Passive muscle tone varies and is particularly diminished after feeding and before sleep. There is profound hypotonia in all infants during sleep. Premature infants, even those without neurologic injury, have diminished tone relative to term infants, due to incomplete myelination of corticospinal and subcorticospinal tracts. Tone can also be affected by the position of the head. The infant whose head is turned to one side may manifest an asymmetric tonic neck response , with increased extensor tone on the side of the body to which the head is turned and increased flexor tone on the contralateral side, resulting in a “fencer’s posture” ( Fig. 35.6 ). This asymmetry of tone may be elicited even in the child who does not exhibit the typical fencer’s posture. Therefore, examination of an infant should always be conducted while the infant’s head is at the midline; the same is true for eliciting muscle stretch reflexes. Hypotonia can also be a secondary finding in a variety of systemic conditions, such as heart failure, sepsis, acidosis, or failure to thrive (see Table 35.1 ).

Clinical Evaluation

Joint Extensibility

The hypotonic child demonstrates hyperextensibility of joints, especially at the elbows, wrists, knees, and ankles. Examination of the small muscles of the fingers across distal joints may also be helpful ( Fig. 35.7 ).

Diagnostic Approach to the Hypotonic Infant

The diagnosis of a particular neurologic disorder depends on the location of the lesion (i.e., which part of the nervous system is impaired or abnormal), the patient’s age, and whether the condition is progressive or static (see Tables 35.1 to 35.3 ).

A careful perinatal history is obtained to identify possible features suggestive of perinatal hypoxic-ischemic brain injury . The infant who has neurologic dysfunction attributable to perinatal asphyxia typically has a history of an acute encephalopathy during the neonatal period (e.g., disturbance of consciousness, poor feeding, seizures, autonomic dysfunction).

A CT study or MRI of the head is helpful to identify evidence of brain malformation, intrauterine infection, hypoxic brain injury, intracranial hemorrhage, or hydrocephalus. If the history suggests seizures, an EEG should be obtained.

An ophthalmologic evaluation may detect evidence of ocular malformation (cataracts, microphthalmia, optic hypoplasia), evidence of intrauterine infection (chorioretinitis), or retinal/macular abnormality (retinitis pigmentosa, cherry-red spot) (see Chapter 43 ).

In some cases, requesting a hearing evaluation or brainstem auditory evoked response may be appropriate. A lumbar puncture is necessary if acute or chronic (intrauterine) meningitis is suspected.

Fig. 35.1 summarizes the diagnostic approach to the hypotonic infant. After a thorough history and detailed general and neurologic examinations, the first priority is to determine if there are signs and symptoms of CNS dysfunction because the majority of hypotonia in infants is central in origin (see Table 35.4 ). Extraneural involvement such as the presence of multiorgan dysfunction, bone marrow suppression, organomegaly, or heart failure accompanying hypotonia is highly suggestive of a systemic disease, such as a storage disorder or an inborn error of metabolism. Particular attention should be given to family history, perinatal maternal illnesses and exposures, delivery complications, and the possibility of consanguinity. Signs and symptoms of CNS involvement in an infant include abnormal head circumference (either micro- or macrocephaly), reduced levels of alertness (i.e., encephalopathy), seizures, respiratory and feeding difficulties, hypotonia and later hypertonia, hemibody weakness, hyperreflexia, developmental cognitive regression, and pathologic reflexes such as persistence of the Babinski sign in an older infant or child. The hypotonic infant’s exam findings may change with age, even on the order of weeks to months. Many hypotonic neonates initially thought to have PNS dysfunction eventually develop hypertonia, hyperreflexia, and pathologic Babinski signs over time, indicative of CNS dysfunction; therefore, serial thorough neurologic exams are essential until confirmatory testing yields a firm diagnosis or until a clinical diagnosis is made with reasonable confidence. An MRI of the head is obtained to detect any anatomic abnormalities or other causative lesions. If CNS dysfunction is present, initial recommended testing includes EEG (which may show seizures or cortical slowing) and a complete metabolic screen—serum amino acids (aminoacidopathies, urea cycle disorders, some organic acidurias), urine organic acids (organic acidurias), ammonia (urea cycle disorders, organic acidurias), acylcarnitine profile (organic acidurias, fatty acid oxidation disorders, riboflavin transporter defect), serum and cerebrospinal fluid (CSF) lactate and pyruvate (mitochondrial disease), serum growth differentiation factor-15 (GDF-15) levels (mitochondrial disease), very long-chain fatty acids (peroxisomal disorders), and lysosomal enzyme panel (lysosomal storage disease), since some conditions are treatable and prompt initiation of therapy may halt or slow progression of disease.

An abnormal brain MRI and EEG with a normal metabolic screen suggests a possible static cause such as brain malformation, hypoxic-ischemic encephalopathy (HIE)/stroke, maternal or fetal infection, or a birth complication. Developmental regression is highly suggestive of inborn errors of metabolism, storage disorders, mitochondrial diseases, or neurodegenerative diseases (see Table 35.1 under “systemic” and “cerebral” for specific disorders) (see Chapter 28 ). Regression coupled with an abnormal metabolic screen may suggest urea cycle defects, organic acidurias, aminoacidopathies, fatty acid oxidation defects, lysosomal and peroxisomal disorders, mitochondrial disease, or certain neurodegenerative disorders and should prompt immediate referral to a metabolic specialist for rapid diagnosis and possible treatment. Many of the treatable metabolic disorders are diagnosed early in the United States via newborn screening programs.

In the setting of persistent hypotonia with normal MRI, EEG, and metabolic screening, syndromic genetic causes should be considered. Common congenital considerations such as Prader-Willi syndrome, spinal muscular atrophy, and myotonic dystrophy type 1 may lack other overt phenotypic features beyond reduced tone and require specific genetic testing to detect the underlying pathogenic genetic abnormalities, which may not be detected on exome or genome sequencing. In the case of Prader-Willi syndrome, DNA methylation testing detects >99% of affected individuals, whereas sequence analysis detects <1%. For patients not identified prenatally or on newborn screening, deletion/duplication analysis of the SMN1 gene detects >95% of patients with spinal muscular atrophy, whereas sequence analysis typically detects <5%. Targeted analysis of DMPK is required to identify pathologic expansion of a CTG trinucleotide repeat leading to myotonic dystrophy type 1. If these targeted analyses are negative in patients with a high suspicion of a genetic disorder, exome sequencing with copy number variant analysis should be pursued to detect other genetic etiologies of hypotonia. Detailed phenotyping is essential in interpreting the results of genetic sequencing. Some syndromes, such as trisomy 21 or 22q11.2 deletion syndrome, have characteristic features that may allow for presumptive clinical diagnosis while awaiting confirmatory genetic testing. For other disorders, dysmorphic facial features to note in infancy include low-set ears, large/small ears, hyper- or hypotelorism, epicanthal folds, asymmetric crying facies, short or webbed neck, cleft lip/palate, and maxillary or mandibular hypoplasia (see Chapter 29 ). Body dysmorphisms in infancy include abnormal limb length, palmar crease, club feet, polydactyly/syndactyly, genitourinary abnormalities, spinal abnormalities, and ophthalmologic abnormalities. These phenotypic findings may provide additional context for the interpretation of sequence or copy number variants of uncertain significance.

If a careful neurologic exam demonstrates a sensory or motor level, such as strong arms and flaccid legs with a pathologic Babinski sign and lower extremity hyperreflexia, then spinal cord pathology is suspected. MRI of the entire spine (with and without gadolinium) typically captures anatomic abnormalities as well as intra- and extramedullary spinal abnormalities.

If hypotonia persists and MRI of the brain and spine, EEG, metabolic screening, and preliminary genetic syndrome screens are negative, then motor neuron, nerve, muscle, or NMJ diseases should be considered (see Tables 35.1 and 35.3 ).

Profound and persistent hypotonia in the setting of normal intellectual function is the typical pattern for the majority of PNS diseases, and the physical examination does not tend to evolve as much during infancy as it does in CNS disease. In addition, hyporeflexia and absence of a pathologic Babinski sign are the norm with a few exceptions, such as in congenital muscular dystrophy. The most useful initial tests for these patients are a creatine kinase (CK), thyroid-stimulating hormone (TSH), and electromyography with nerve conduction study (EMG/NCS, or simply EMG). In motor neuron disease, CK is typically normal but occasionally might be slightly elevated, while the EMG shows a pure motor neuropathy (see Table 35.2 ). When obtaining EMG, at least one sensory and motor nerve conduction assessment should be done in an upper and lower extremity and needle EMG should be performed on at least one proximal and one distal muscle. If ptosis, ophthalmoparesis, episodic weakness, or feeding/breathing difficulties are present clinically, then doing a 3-Hz repetitive nerve stimulation (RNS) on an affected muscle may be informative to assess for fatigability suggestive of NMJ disorders. Needle EMG in newborns can be difficult to interpret; waiting for the child to be at least 2 months old might yield more meaningful results. In the meantime, other avenues of testing, such as muscle biopsy and genetic testing, should be pursued as appropriate.

Nerve disorders demonstrate involvement of both sensory and motor nerves either in an axonal or demyelinating pattern on EMG; CK is normal. Muscle diseases have a myopathic EMG, typically with normal sensory nerve conductions. An elevated CK is a hallmark of muscular dystrophies due to the continual degeneration and regeneration of muscle fibers, whereas myopathies typically have a normal CK. Duchenne muscular dystrophy is the prototypical muscular dystrophy with a markedly elevated CK >10,000 U/L in an infant. A parental history of distal weakness with grip myotonia suggests congenital myotonic dystrophy . The congenital muscular dystrophies have variable brain MRI findings ranging from normal to lissencephaly, with clinical findings of intellectual delay and seizures. Pompe disease is characterized by concomitant cardiomegaly, feeding difficulties, and failure to thrive. When EMG suggests a myopathy and the CK is normal, then a muscle biopsy can help distinguish between congenital myopathy, mitochondrial disorders, and metabolic myopathies.

If the 3-Hz RNS shows significant decrement and CK is normal, then an NMJ disorder is likely. Clinically, NMJ disorders appear similar to each other with fluctuating ptosis, ophthalmoparesis, feeding and respiratory difficulties, limb and trunk weakness, and poor head control, but key differences help narrow the differential diagnosis. If the mother is known to have autoimmune myasthenia, then a hypotonic infant may have transplacental-derived transient neonatal myasthenia. If the hypotonic infant has autonomic dysfunction such as dilated pupils or constipation, then botulism must be considered. If the infant was previously healthy and then rapidly developed symptoms that localize to the NMJ, autoimmune myasthenia is possible, and antibodies should be tested. A child with a history of persistent feeding and respiratory difficulties since birth, worsened by illness or suddenly without an identified cause, should prompt evaluation for congenital myasthenic syndromes, which are a heterogeneous group of genetic disorders.

Arthrogryposis multiplex congenita , the finding of multiple joint contractures affecting two or more body areas and present at birth, can be caused by lesions anywhere in the neural axis including the CNS and PNS, connective tissue and joint disorders, and maternal and fetal factors ( Table 35.6 ). In an infant with arthrogryposis, determining if the cause is central or peripheral or neither is often crucial to making a diagnosis.

Diagnostic Approach to the Child with Weakness

The diagnostic approach to the weak child is very similar to the hypotonic infant, with emphasis placed on identifying systemic disorders first and then determining if signs and symptoms localize to the CNS or PNS. Fig. 35.8 outlines an algorithm for determining the cause of weakness in a child.

Disorders of the cerebral cortex commonly cause axial hypotonia but appendicular hypertonia in children. Some progressive neurologic disorders affect both the brain and peripheral nerves (metachromatic dystrophy, Krabbe disease, adrenoleukodystrophies, and some mitochondrial disorders). Other progressive disorders may affect both brain and muscle (Duchenne muscular dystrophy, myotonic dystrophy, dystroglycanopathies, and some mitochondrial disorders).

Sometimes disturbance of function at one site conveys a predilection for injury to another site in the nervous system, making neuraxial localization more challenging. For instance, children with congenital muscle weakness (e.g., congenital myopathy) are likely to have had severe respiratory impairment at birth that results in secondary anoxic injury to the brain. Because hypotonia itself is nonspecific with regard to localizing the site of nervous system dysfunction, the evaluation of the child with hypotonia must begin with a search for clues that might identify the location of the abnormality.

Is the Problem a Systemic Disorder?

Systemic disorders are a common cause of generalized hypotonia in toddlers and children (see Table 35.1 ). Hypotonia is commonly seen in association with sepsis and other infections, heart failure, failure to thrive, hypercalcemia, renal failure, hypothyroidism, acidosis, hypoxia, hyperammonemia, hypoglycemia, rickets, scurvy, amino and organic acid disorders, severe malnutrition, and other chronic disorders. This observation warrants a careful search for a systemic or metabolic abnormality in children with hypotonia, particularly (but not exclusively) when the onset of hypotonia is acute ( Fig. 35.9 ).

Frequently overlooked causes of hypotonia are those that are not traditionally considered neurologic disorders, though may mimic neurologic disorders. Connective tissue disorders often produce a phenotype similar to those of neurologic causes of hypotonia in infancy and early childhood, with associated delay of developmental milestones. Connective tissue disorders are distinguished by joint hyperextensibility disproportionate to the extent of weakness and by the absence of other neurologic abnormalities or microcephaly (velocardiofacial syndrome, achondroplasia, Marfan syndrome, Ehlers-Danlos syndrome). In several congenital disorders, hypotonia is a regular feature as a result of a combination of abnormalities of neurologic, muscle, and connective tissue function, including Sotos syndrome, Prader-Willi syndrome, Angelman syndrome, Noonan syndrome, Rett syndrome, and Smith-Lemli-Opitz syndrome.