Hypotonia or floppiness is a common symptom in infancy. Conditions causing decreased strength may present as hypotonia, but hypotonia is a more general symptom associated with a wide variety of conditions, not all of which are associated with weakness. We focus on tone because this can be assessed in the young, uncooperative infant, whereas strength can only be inferred in the absence of some degree of cooperation.
Muscle tone is the tension found in muscles at rest. Observation of the infant's resting posture gives clues to muscle tone. The premature infant lying supine with all extremities extended, thighs abducted and in contact with the mattress throughout their length, and head rolled to one side is surely hypotonie. Rigid extension of the extremities, adduction of the thighs, fisting of the hands, and hyperextension of the neck suggest hypertonia.
Tone varies with the gestational and postnatal age of the infant, being decreased in otherwise healthy prematures and increasing with postnatal age. The normal generalized hypotonia seen in a 30- week gestation premature would be pathologic in a newborn. The assessment of tone, therefore, requires experience with normals of varying ages.
We would suggest the following:
1. Note head and leg position in prone horizontal suspension.
2. With the infant lying supine, pull him by the hands to a sitting position, noting resistance of arms, grasping with fingers, and the relationship of the head to the trunk.
3. With the infant supine, pick up each extremity individually, feel the resistance, and note how it falls to the mattress when released.
4. Note resistance to movement of individual joints, paying particular attention to resistance to rapid abduction of the flexed thighs, a common site for the first evidence of developing spasticity.
Since muscle tone is a reflection of neurologic function at many levels, we can pursue our diagnosis by systematically considering each level of the nervous system, as follows (Table 1):
1. Cerebrum and diffusively acting lesions
2. Cerebellum and brain stem
3. Spinal cord - transecting lesions
4. Spinal cord - diffuse lesions
5. Peripheral nerves
6. Motor end-plate region
CEREBRAL AND DIFFUSE LESIONS
Diffuse cerebral dysfunction is the most common cause of infantile hypotonia. Asphyxia, craniocerebral trauma, subarachnoid hemorrhage, and congenital abnormalities of the brain are common causes, but almost any severe infantile encephalopathy can result in hypotonia. The severity and duration of persistence of hypotonia following perinatal insult provide a crude measure of the magnitude of cerebral injury. Hypotonia is common in infants destined to develop spastic or athetotic cerebral palsy syndromes in the latter part of the first year. Spasticity and athetosis are seldom, if ever, seen in children who are under six months of age.
A number of generalized conditions, mostly involving the brain, are associated with hypotonia, although the precise cause of the hypotonia is frequently unclear. These include chromosome abnormalities, especially trisomy 21, hypothyroidism, inborn errors of metabolism, and certain generalized mental retardation syndromes, such as Prader-Willi syndrome and Laurence-Moon-Biedl syndrome. Certain generalized disorders of connective tissue that do not involve the nervous system, such as the Ehlers-Danlos syndrome, can cause hypotonia, but the vast majority of hypotonie children have definable abnormalities of the nervous system or muscle.
The conclusion that hypotonia is cerebral in origin requires the demonstration of other evidence of cerebral abnormality or dysfunction. Typically, one would look for other abnormalities on the examination, such as microcephaly or macrocephaly, craniocerebral anomalies, abnormal levels of consciousness, altered vision, or absence of age-appropriate social responses. A history of seizures or an abnormal EEG suggests a cerebral abnormality, as does a history of asphyxia or hypoglycemia. Hypotonia may also be due to excess depressant medication, such as phenobarbital, used to control seizures. In general, hypotonia of cerebral origin is not profound. Stretch reflexes (deep tendon reflexes) are usually preserved and may be increased.
USEFUL LABORATORY STUDIES IN INFANTILE HYPOTONIA
CEREBELLUM AND BRAIN STEM
Cerebellar lesions are important causes of hypotonia after infancy but are not important causes of infantile hypotonia. Indeed, it seems unlikely that any conclusions about cerebellar function can be drawn from the neurologic examination in the first six months of life. Brain-stem lesions are rarely causes of hypotonia but would be diagnosed by the demonstration of other evidence of brain-stem dysfunction, such as cranial nerve abnormalities.
Transecting lesions. Local lesions, interfering with spinal cord function, ordinarily do not present a diagnostic problem. The most common of these is myelomeningocele, but vascular malformations of the spinal cord and extramedullary compressive lesions should be considered. A midline ectodermal defect, such as a hemangioma or hairy patch, suggests the possibility of a developmental defect involving the spinal cord or its coverings. The diagnosis is suspected when tone is markedly less in the lower than in the upper extremities. Sensory level can sometimes be determined in an infant by finding the lowest level of eliritation of the trunk incurvation reflex (Galant reflex).*
Diffuse lesions. Anterior horn cell loss diffusely throughout the spinal cord is the most common cause of profound hypotonia in infancy. This occurs in infantile spinal muscular atrophy (Werdnig-Hoffmann disease), which is characterized by early onset of hypotonia and usually by progressive weakness leading to early death. In general, early onset is associated with a bleak prognosis, whereas onset after a year may be associated with slow, or even apparent arrest of, symptom progression.
Poliomyelitis and, rarely, other enterovirus infections may attack anterior horn cells but rarely present a disseminated, symmetrical picture. Most patients with hypotonia due to polio have a history dating the onset of symptoms to a febrile illness during an epidemic period. Pompe's disease (glycogenosis type ?) may involve anterior horn cells but also involves skeletal muscle, heart, and liver.
Patients with anterior horn cell loss usually have absent stretch reflexes (deep tendon reflexes) and may have visible fasciculations in the tongue as it lies at rest in the mouth. The electromyogram (EMG) is valuable in confirming the presence of muscle denervation, but nerve conduction velocity studies may show either normal or reduced values. Patients whose anterior horn cell loss has begun in utero may be born with arthrogryposis multiplex congenita.
Muscle biopsy is of critical importance in confirming the diagnosis of spinal muscular atrophy. The finding of grouped atrophy of nearly all fibers in a muscle fascicle, with preservation of fibers in adjacent fascicles, strongly suggests partial denervation of that muscle. The muscle biopsy picture does not permit differentiation of anterior horn cell from peripheral nerve disease.
All types of generalized peripheral neuropathy are uncommon in infancy and early childhood. The clinical signs suggesting peripheral neuropathy are distal hypotonia (hypotonia predominantly involving distal muscles of the extremities), hyporeflexia, the presence of palpably enlarged nerves, and distal sensory impairment. Postinfectious polyneuritis (Guillain-Barré syndrome) is the most common neuropathy in childhood and can occur at any age. Unlike most childhood neuropathies, it has a rapid onset that usually follows an illness. Motor weakness is predominant, and spinal fluid protein concentration becomes elevated shortly after onset. Mild pleocytosis is common early but usually disappears within a few days.
Most other childhood neuropathies are subacute or chronic in their evolution. Many are genetically transmitted, and most are associated with elevation of cerebrospinal fluid protein concentration. EMG typically shows fibrillations at rest and highvoltage polyphasic potential on voluntary contraction. Nerve conduction velocities are reduced. Muscle biopsy is only occasionally helpful in differentiating the specific neuropathies. On occasion, the demonstration of neuropathy in a patient with cerebral degeneration is of great value in differential diagnosis (e.g., metachromatic leukodystrophy, globoid leukodystrophy).
Disorders at the neuromuscular junction are rarely causes of infantile hypotonia, and most are treatable. The most important is myasthenia gravis, which may be a transient, transplacentally acquired disorder or may appear at any time from birth on. Transient myasthenia gravis is seen in 15 per cent of infants born to myasthénie mothers, and even children of mothers whose myasthenia is in remission are at risk. Typically, symptoms are seen within the first three days and may persist for as long as a month. The diagnosis of myasthenia gravis in an infant is best made by demonstrating improved tone and strength 10 to 15 minutes following intramuscular injection of 0.1 mg. of neostigmine methylsulfate. Because of its extremely short duration of action, edrophonium is not as useful a test agent in young children.
Cholinesterase inhibitors, which are used to treat myasthenia gravis and are components of some insecticides, can also cause hypotonia and weakness. Typically, one would find other evidence of parasympathetic overactiviry, such as gastrointestinal overactivity, bronchospasm, increased salivation, and tearing. Treatment of poisoning with cholinesterase inhibitor is with pralidoxime, 20-40 mg./kg. administered intravenously, plus intravenously administered atropine.
A myasthenialike syndrome may also be seen in association with administration of certain antibiotics, including neomycin, streptomycin, kanamycin, polymixin, bacitracin, lincomycin, and colistin. Response may be seen to neostigmine or calcium.
Muscle biopsy is the cornerstone in diagnosis of the various myopathie causes of hypotonia. Most importantly, it distinguishes between primary myopathy and denervated muscle (atrophy). Muscle biopsy permits differentiation of noninflammatory myopathy from the frequently treatable myositis due to primary muscle inflammation or generalized vasculitis. Myotonie muscular dystrophy may present in infancy with poor sucking, poor swallowing, and facial weakness . The term "congenital muscular dystrophy" is used when infantile hypotonia is accompanied by histopathologic muscle changes like those seen in classic forms of muscular dystrophy. Congenital muscular dystrophy is extremely variable in its course, and the term probably encompasses a number of disorders.
In recent years, special techniques of handling biopsy tissue - including histochemistry, electron microscopy, and specific chemical tests - have permitted the identification of a variety of previously unrecognized myopathies. They are generally uncommon and variable in their clinical course, but in many cases genetics have been worked out. Glycogenosis type ? (Pompe's disease) has been known for years and is due to acid maltase deficiency. Muscle, liver, heart, and occasionally the CNS are affected. When glycogenosis type II occurs in infancy, it is usually fatal; later on, it is associated with a much more benign course. Central core disease is associated with altered staining, especially with histochemical methods, of central portions of muscle fibers. It has not usually been associated with severe weakness, but symptoms are commonly present from early life. Nemaline myopathy (rod body myopathy) is characterized by masses of threadlike bodies, apparently composed of material from the Z bands of muscle. Symptoms may begin in infancy and be severe, or they may develop later in life and be associated with variable degrees of weakness. The diagnosis is made by muscle biopsy but requires special staining (PTAH, modified trichrome) to demonstrate the characteristic abnormalities. A large number of other specific myopathie causes of hypotonia have been described in recent years. * The diagnosis of most of these depends on the use of special techniques, such as enzyme histochemistry, electron microscopy, and chemical analysis.
Benign congenital hypotonia is a clinical diagnosis that can be made only after specific nosologie entities have been excluded. The diagnosis of benign congenital hypotonia implies a generally favorable prognosis.
USEFUL LABORATORY STUDIES IN INFANTILE HYPOTONIA