The hypotonic infant

MEDICAL PROGRESS

The hypotonic infant A review

Edward F. Rabe, M.D. ~ BOSTON,

MASS,

tirely clear or are due to diseases other than those of the neuromuscular apparatus. Such clinical disorders include malnutrition, rickets, scurvy, arachnodactyly, osteogenesis imperfecta, Ehler-Danlos' syndrome, hypothyroidism, celiac disease, and congenital heart disease. T h e clinical patterns of these diseases are well known and will not be discussed here. Attention will be focused on clinical disord~ers in infants characterized by hypotonia in which the disease apparently lies in the neuromuscular system. An attempt will be made to group the entities according to the sites of basic pathology (Table I). Initially, a plea is made to discard the confusing term "amyotonia congenita." This term was originally applied by Oppenheim 1 to a clinical entity in which from birth infants exhibited a state of generalized hypotonia, muscle weakness, and areflexia. Symptoms improved with time. The fact that these patients had hypotonia without familial incidence, that the symptoms began at the time of birth, and that the disease did not progress seemed to distinguish these

T H E purpose of this article is to review and summarize the present clinical, physiologic, and pathologic concepts concerning the hypotonic infant from birth to 24 months of age. Hypotonia is defined as that state in which the resistance to passive motion of the limbs is obviously less than normally anticipated for the age of the child. When hypotonia exists, a number of sites of pathology can be suspected as the cause of the abnormal state. Consideration of the localization of the site of pathology, although sometimes difficult to assay, will be a part of this review. There are a number of clinical states in which hypotonia is apparent and in which the details of causation either are not en-

From the Department o[ Pediatrics (Neurology), Tufts University School of Medicine, and The Boston Floating Hospital, Boston 11, Mass. This work was supported in part by a Public Health Service research career program award (No. K3-NB-17985) [rom the Institute of Neurological Diseases and Blindness. ~Address, Associate ProJessor o[ Pediatrics (Neurolo,~y), Tu]ts University School ol Medicine.

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cases, it was then thought, from WerdnigHoffman's disease?, a Unfortunately no pathologic material was available to Oppenheim so that the controversy as to exactly what his cases represented will never be resolved. At present, it is generally agreed that "amyotonia congenita" is a symptom complex which is common to some examples of infantile progressive muscular atrophy (Werdnig-Hoffman's disease), congenital myopathy, and infantitle polyneuritis. 4 Each of these entities will be discussed in its appropriate place. THE NATURE

OF

MUSCLE T O N E Normal muscle tone. Normal muscle tone is dependent upon at least three recognized factors: viscoelastic properties of muscle, joint and tendon resistance, and the tonic stretch reflex, s The first two factors probably depend upon the molecular configuration of the components of muscle, tendon, and fibrous tissue. T h e third factor is complex, but its components are reasonably well known and should be recognized. Stretch reflex. This {s basically comprised of a two-neuron reflex arc. The first neuron lies in the dorsal root ganglia of the spinal cord, and its afferent fibers originate in the muscle spindle, a stretch-sensitive organ, whereas its efferent "fibers synapse with the large anterior horn cells, t h e alpha motor neuron. This alpha motor neuron is the second neuron in the arc, and its efferent fibers terminate in the motor end :plates of the muscle fibers. Sudden stretch of muscle fibers by tendon tapping produces a volley of relatively synchronized afferent impulses into the spinal ganglia and anterior horn cells of the spinal cord producing the stimulus for contraction of a large number of muscle fibers, which results in the fast phasic

stretch reflex. Tonic stretch reflex. This reflex is a slower component of the clinical stretch reflex; it is dependent upon the smaller or g a m m a motor neurons in the anterior horn of the spinal cord. The g a m m a motor neuron afferent input is indirectly from the muscle

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spindle, and its efferent fibers terminate only in the muscle spindle. Since the muscle spindle consists of sensory endings plus contractile fibers (intrafusal fibers) encapsulated between, and separate from, the usual muscle fibers, and since g a m m a neuron discharges cause a contraction of the intrafusal fibers, it is not surprising that this contracture causes a primary sensory discharge from the muscle spindle just as stretch of the extrafusal muscle fibers do in tendon tapping. The subsequent contraction of the extrafusal fibers via the phasic stretch reflex arc unloads the gamma-induced contraction of intrafusal fibers and so counteracts the discharge of g a m m a motor neurons. The muscle spindle with its intact g a m m a motor nerve supply can be thought of as signaling the difference in length between the intrafusal and extrafusal fibers and counteracting the difference by means of the two components of the stretch reflex. The rate of reactivity of the g a m m a motor neuron thus can affect tone. Between the muscle spindle afferent fibers and the alpha and g a m m a motor neuron efferent fibers lie m a n y neuroanatomic structures which by internuncial connections have been shown to exert a variable, modifying influence upon the g a m m a neurons and thus indirectly upon the alpha neuron discharge. These modifiers include the cerebellum, the bulbar anterior reticular formation, the corpus striatum (caudate nucleus and putamen), the thalamus, the parietal cortex, and, in the gray substance of the spinal cord, the internuncial neurons and the feedback neurons, the Renshaw cells. The key to muscle tone is thought to be the g a m m a system, and Rushworth s thinks its functional hypoactivity could lead to decreased tone. Decreased tone can be accompanied by hyporeflexia which in turn can be improved by the Jendrassik maneuver. (This is the familiar maneuver of hooking together the flexed fingers and pulling to amplify the magnitude of the stretch reflex response.) Jendrassik's maneuver is known to activate the g a m m a system. ~ On the basis of this presently accepted theory of the

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origin of motor tone, hypotonia could be anticipated as a result of disease of the brain (especially when the parietal cortex, basal ganglia, a n d / o r the cerebellum are involved), of the spinal cord, of the motor or sensory spinal or peripheral nerves, of the myoneural junction, or of the muscle itself. There are a number of other factors which influence muscle tone. The concentrations of calcium, magnesium, potassium, and hydrogen ions, and the CO2 tension 7 in the fluid bathing the motor end plates and the muscles affect muscle tone, presumably as a result of their effect upon neuromuscular transmission and their effect upon the contractility of the muscle fiber as reflected by the rate of its depolarization and repolarization. HYPOTONIA AS A MANIFESTATION OF CENTRAL NERVOUS

SYSTEM

DISEASE

Mongolism or Down's syndrome. The outstanding example of this entity is mongolism or Down's syndrome. However, there is no universal, consistently noted abnormality of the brain in this disease, although a narrowed superior temporal gyrus is quite commonly foundlS, 9 Hypotonia as an early manifestation of brain disease is seen in three other clinical syndromes: congenital atonic diplegia of Foerster, congenital chorea, and congenital cerebellar ataxia. Congenital atonie diplegia. This is manifested in early infancy by marked hypotonia, intact deep tendon reflexes, and retardation in adaptive behavior and in motor performance out of proportion to the constantly diminishing hypotonia which occurs with increasing chronologic age. An interesting and characteristic phenomenon is present in these hypotonic infants. When the infant is held in the upright position by the trunk, the previously hypotonic limbs acquire tone, and there is spontaneous flexion at the hips and flexion or extension at the knees. Variation in degree of hypotonia and developmental retardation is seen in these patients. There is no obvious ab-

normality of muscle bulk nor of electrical reaction of muscles. The abnormality of the central nervous system is not clearly defined. Foerster reported gross atrophy of the frontal lobes, but no microscopic abnormali. ties.i0, ii The cause of this disease is not known, and very little postmortem material is available. I2 Congenital chorea. Congenital chorea, an entity described by Ford, la is a rare disorder of unknown origin. Clinically the patients are first noted because of the appearance of marked hypotonia within the first 6 months of life. As the infant grows older, involuntary motions complicate purposeful movements of the extremities. These involuntary motions are sudden, jerky, and irregular, somewhat similar to those of Sydenham's chorea. Mental development is retarded. Motor symptoms may be increased by changes in the child's daily routine or by surgical procedures. However, when regression in motor behavior is precipitated iatrogenically, the symptoms improve spontaneously with time. la Neither the pathologic lesion nor the cause of this syndrome is clearly defined. Congenital cerebellar ataxia. Infants and children with congenital cerebellar ataxia may have mild hypotonia and mild retardation of motor development during the first year of life. Adaptive behavior is not necessarily retarded, although children with associated severe motor and mental retardation have been described. I* When these children begin to reach and stand, ataxia of the extremities and trunk appears. Later, staccato speech is noted, but horizontal jerk nystagmus m a y or m a y not be acquired. The neuropathology of the disease includes atrophy of the lateral lobes of the cerebellar hemispheres and vermis, reduced thickness of the g r a n u l a r cell layer of the cerebellum, decreased number of Purkinje cells, and small shrunken inferior olivary nuclei. Associated defects in the cerebral hemispheres are occasionally noted. 1~ The pathologic changes suggest a defect in the development of the cerebellum, but the cause is unknown. As in m a n y forms of con-

Volume 64 Number 3

genital encephalopathy, the symptoms of these children improve with time, and p a tients with uncomplicated congenital cerebellar ataxia m a y acquire almost completely normal motor function with increasing age. 16 Kernicterus. Hypotonia developing in the coarse of kernicterus has,been described? ~ Following the initial symptoms of hypertonicity and opisthotonus which begin during the second to the fifth d a y of life, the child with kernicterus may improve, and by the third month of life diffuse hypotonia may gradually appear. H y p o t o n i a is greatest in the neck and upper extremities. Within a few months, restless movements appear in these children, and these take the form of chorea or athetosis or both. A s the abnormal involuntary movements develop, hypotonia recedes. In this particular complication of kernicterus, mental retardation is frequently present. The pathology of acute kernicterus is that of gross yellow pigmentation accompanied by some neuronal degeneration in the globus pallidus, Caudate nucleus, m a m millary bodies, nucleus subthalamicus, substantia nigra, hippocampus, vestibular nuclei, and superior olivary nuclei. I n patients who survived the acute phase of kernicterus and developed chronic posticteric encephaiopathy, and then succumbed to other causes, gliosis of the brain has been noted in the areas involved in the acute stage of the disease and also in the thalamus and roof nuclei of the cerebellum, as It is likely that unconjugated bilirubin is responsible for the pathology in conjunction with some other insult such as anoxia? 9, 2o Prevention of kernicterus by exchange transfusions is at present the only effective form of therapy. Ganglioside storage disease of Tay-Sachs. Progressive central nervous system degeneration with dissolution Of function and the appearance of hyp0t0nia usually between the ages of 4 and 8 months followed by progressively developing spasticity is noted in the ganglioside storage disease of TaySachs. 21 Macular degeneration of the retina producing the so-called "cherry red spot" surrounded by a white halo of ganglioside-

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425

containing retinal neurons can be seen between 3 and 6 months of age and is an aid in the early recognition of this familial disease. HYPOTONIA AS A MANIFESTATION OF SPINAL CORD DISEASE

Infantile spinal muscular atrophy or Werdnig-Hoffman's disease.2, s This is a familial disease with a pattern of inheritance suggesting an autosomal recessive trait. 22 Since the disease is frequently fatal before the attainment of puberty, it is self limiting. Clinical manifestations may be present at birth or m a y appear in early infancy from 2 to 6 months of age or not until later infancy between 12 and 18 months of age. Weakness may be generalized at first but usually it is first evident in the lower extremities and gradually progresses upward to involve the intercostal muscles, but rarely, if ever, the diaphragm. The final stage leads to involvement of the tongue and the muscles of deglutition, and of facial movements. Deep tendon reflexes are gradually lost but there are no pyramidal tract, sensory, or sphincteric abnormalities. Retardation of development in other than the motor sphere does not occur. The earlier the onset of symptoms, the more rapidly progressive is the disease. 2s Death is frequently the result of intercurrent infection or aspiration pneumonitis. Fasciculations are occasionally visible in the tongue in young patients, but only infrequently can they be seen in the muscles of the extremities. This fact is due to the relative thickness of subcutaneous fat in infants. Muscle fasciculations can be seen in older children with wasting. Electromyography may reveal fibrillations, fasciculations, and decreased number of action potentials; in some instances electromyography may be normal. 24 Biopsy of muscles from the involved extremities reveals atrophy of fibers in a "motor unit" or grouped distribution with preservation of the normal fascicular pattern of muscle. Large "B" fibers of Wohlfart can be

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seen quite intact in the center of an atrophic fasciculus? 3 This is probably the result of these fibers having sensory and not motor innervation. Vital staining by Co~r's method reveals abnormalities of the motor nerve endings and in some instances branching of terminal nerve fibers. 2~ The basic pathology in Werdnig-Hoffman's disease is the gradual change in the cytoplasm of the neurons of the ventral horns in the spinal cord, their disappearance with neuronophagia, and the final replacement of these neurons by astrocytes. These changes occur with varying intensity at all levels of the spinal cord and also involve in varying degrees the motor nuclei of all the cranial nerves from 12 to 5. The greatest changes are seen in the lower cranial nerve nuclei when the medulla is involved. Consequent to the fall-out in the neurons of the anterior horn of the spinal cord, there is a maJ:ked decrease in the size of the ventral spinal roots and the motor cranial nerves of the involved nuclei. The muscle atrophy which is noted is obviously secondary to the neuronal disease. The changes that are reported from time to time in the cerebral and cerebellar cortices are typically anoxic changes which are secondary to the terminal episode? ~ The course of Werdnig-Hoffman's disease is usually progressively downhill. However, patients with characteristic findings in muscle biopsy and with clinical attributes typical of the disease have survived to adulthood. These survivors are markedly impaired in function owing to muscular atrophy and to contractures but their mental ability is clearly intact. ~6 The etiology of Werdnig-Hoffman's disease is not known, and no form of therapy has been obviously successful. Arthrogryposis multiplex congenita. This is a clinical syndrome characterized by congenital fixation of two or more joints. This syndrome is due to a number of causes which include myelopathic and myopathic disease. ~ In myelopathic arthrogryposis, passive motion may not be resisted until the limitation of the tight joint structures is

March 1964

encountered. Muscular weakness and hypotonia are prominent features of most of these infants. 28 I n 3 cases of this syndrome in which adequate neuropathology was observed,27, 2s there was neural atrophy of the muscles of the involved extremities. In the spinal cord there was an obvious reduction or complete disappearance of the anterior horn cells at levels appropriate to the clinical symptomatotogy. The etiology of what, by inference, appears to be an intrauterine affectation of the spinal cord is not clear. The joint stiffness appears to be due to abnormal development of the capsular ligaments of the joints, which is t h o u g h t to be secondary to any factor preventing active motion of the limbs during the third or fourth fetal months. TM a0 Poliomyelitis. As a cause of diffuse hypotonia in infants poliomyelitis has not been common in the past and will be less likely to occur in the future if immunization of children and young adults is continued. Certain facts should be known since sporadic cases will undoubtedly appear. Poliomyelitis is rare in babies under 2 weeks of age. 31 Transplacental transmission is quite uncommon but can occur. 3~' ~a When poliomyelitis occurs in infants under 6 months of age, about half of them usually develop total or diffuse flaccidityY 1 The occurrence of fever, abnormal spinal fluid findings, and the development of weakness within a few days in a previously well infant with a normal developmenta! history should suggest poliomyelitis as a diagnostic possibility.

HYPOTONIA SECONDARY TO DISEASE OF SPINAL NERVES Acute infectious polyneuritis (GuillainBarr6 disease). It is commonly thought of as a disease affecting older children or young adults which comes on 10 to 21 days after an apparent upper respiratory infection and produces a symmetrical and predominantly motor deficit and a less marked sensory deficit. It does not result in persistent disturbances of bowel or bladder sphincters; the cranial nerves are often not involved, and complete recovery occurs within 3 to 6

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months. The characteristic laboratnry finding is a marked elevation of the cerebrospinal fluid protein without pleocytosis. All of these criteria are not present in each patient. In some instances, symptoms may persist longer than is usually appreciated: in a group of 26 infants and children, 7 had weakness and muscular atrophy during a fotlow-up interval of 3 to 5 years from the onset of their disease, a4 Idiopathic polyneuropathy. A chronic form of idiopathic polyneuropathy also occurs in infants. Reports have been published concerning infants and children who have been hypotonic from birth or in whom hypotonia appeared between the second and twelfth months of life, in whom there were absent or weak deep tendon reflexes without abnormal plantar reflexes, without sensory deficits, and with abnormalities of the cerebrospinal fluid total protein. Electromyograms revealed fibrillation potentials. These children have normal mentality and their clinical course is characterized by slow worsening or by lack of improvement. Those who have walked have d o n e so later than their peers. During the course of their illness, visibly thin musculature has in some instances been associated with Contractures and limitation of motion of joints, as' ~6 Muscle biopsy in these children has been helpful; there is bot.h random and grouped atrophy without an increase in endomysial connective tissue. The nerves visible between muscle fasciculi have been thought to show a decrease in the number of myeIinated 3~ fibers (a point somewhat difficuit to justify) or a gross thickening of the nerve with microscopic evidence of increase in the endoneurium and perineurium, a6 The etiology of what appears pathologically to be two forms of infantile chronic polyneuritis is unknown. The course in the few reported cases is one of persistence of symptoms in each type. One child who had proliferative polyneuritis as demonstrated Pathologically showed slight gradual improvement while receiving cortisone therapy. 36 In summary, peripheral polyneuropathy

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427

does occur in infants and is a cat,s(' of dilluse hypotonia. It can appear as tim classical Guillain-Barr~ syndrome with an acute onset and a subacute course. Peripheral polyneuropathy can also be a cause of chronic hypotonia and weakness in infants. In this latter instance, histologic examination may reveal one of two possible patterns: neural muscular atrophy with a questionable decrease in myelinated peripheral nerve fibers or neural muscular atrophy with hypertrophic interstitial polyneuropathy. HYPOTONIA DUE TO DISEASE OF T H E M Y O N E U R A L J U N C T I O N

Myasthenia gravis. This is a disease of the myoneural junction; there is no obvious disease of the central or peripheral nervous system or of muscle. The basic abnormality appears to be a block in neuromuscular transmission mediated by acetylcholine in patients with myasthenia gravis. This block seems to be due either to an abnormal response of the motor end plates to substances normally released from the motor end plates when they are stimulated or to the formation of an abnormal product of acetylcholine hydrolysis which blocks depolarization of the muscle membrane, a7 Transient myasthenla gravis. Transient myasthenia gravis occurs in newborn infants whose mothers have had myasthenia gravis. The clinical disease begins a few hours to several days after birth and lasts for a week or two up to several months. Symptoms and signs include generalized muscular weakness with little spontaneous motion, a weak Moro reflex, poor facial motion, ptosis of the eyelids, poor sucking capacity, dysphagia, and weakness of respiratory efforts. If not treated, the disease can be fatal. 3s When treated with anticholinesterase drugs, the symptoms improve or even subside and relapses are not known to occur. ~9 Congenital myasthenia gravis. This occurs in infants whose mothers do not have myasthenia gravis, and the symptoms persist throughout childhood. Symptoms are present at birth and include a weak cry, hypotonia,

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T a b l e I. C l i n i c a l s y n d r o m e s c h a r a c t e r i z e d by h y p o t o n i a

Clinical syndrome

Site o[ patholoey

Associated [Hereditary mental reor tardation [amilial

Diagnostic aids

Therapy affect. " ing muscle function

Congenital atonic diplegia

Brain

Yes

No

Estimation of devel- None opmental level motor and mental, repeatedly

Congenital cerebellar ataxia

Cerebellum: and occasionally medulla, pons, and cerebrum

Often normal

No

Estimation of devel- None opmental level motor and mental, repeatedly

Congenital chorea

Brain

Yes

Ne

Estimation of devel- None opmental level motor and mental, repeatedly

Kernicterus

Multiple areas of basal ganglia, pons, medulla, hippocampus

Yes

No

Estimation of devel- None opmental level motor and mental, repeatedly

Tay-Sachs disease

Central nervous system

Yes

Yes

Funduscopic examination

None

Infantile spinal mus- Anterior gray horns cular atrophy of spinal cord (Werdnig-Hoffman's disease)

No

Yes

Muscle biopsy

None

Myelopathic arthrogryposis multiplex congenita

Anterior gray horns of spinal cord

No

No

Muscle biopsy

Physiotherapy

Poliomyelitis

Anterior gray horns of spinal cord

No

No

C.S.F. examination Isolation of agent from stool

Physiotherapy

Acute infective polyneuritis ( Guitlain-Barr~ disease)

Spinal roots and peripheral nerves

No

No

Nerve conduction time C.S.F. examination

Physiotherapy Steroids (?)

Chronic idiopathic polyneuropathy

Peripheral nerve

No

No

Myasthenia gravis-neonatal, transient

Myoneural junction

No

Yes

Nerve conduction Steroids (?) time Physiotherapy EMG Muscle biopsy Response to neostig- Neostlgmine mine or edriphonium chloride

Myasthenia gravis-congenital

Myoneural junction

No

No

Response to neostig- Pyridostigmlne mine or edriphonium bromide chloride Neostigmine

Benign congenitaI hypotonia

Muscle--?

No

No

Muscle biopsy EMG

None

Universal hypoplasia of muscle

Muscle--?

No

Yes

Muscle biopsy

None

No

Yes

.Muscle biopsy Serum enzyme concentrations Creatine and creatinine coefficients EMG

Not proved

Infantile congenital Muscle myopathy (muscular dystrophy of infancy)

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T h e hypotonic infant

4 29

Table I. Cont'd

Clinical syndrome Site oi pathology Central core disease Muscle

Associated IHereditary I mental r e or I familial I Diagno~t:c a:d~ tardation No Yes Muscle biopsy

Specific therat)v None

Rod body myopathy

Muscle

No

?

Muscle biopsy

None

Dystrophica Myotonica

Muscle, gonads

Yes

Yes

Muscle biopsy EMG

None

Polymyositis

Muscle

No

No

Muscle biopsy

Steroids (?)

Glycogen storage disease

Muscle and central nervous system

?

Probably

Muscle biopsy

None

and ptosis of the eyelids. Facial weakness, strabismus, and dysphagia are also present in some instances. Although prostigmine (neostigmine) produces symptomatic improvement in these patients, it is not complete, and mild-to-moderate ptosis, dysphagia, and external ophthalmoplegia persist throughout childhood. External ophthalmoplegia is not altered much by anticholinergic drugs, so that its persistence after therapy does not mitigate against the diagnosis of myasthenia gravis. The diagnosis of myasthenia gravis can be established in infants by observing the response to 0.125 mg. of neostigmine methylsulfate intramuscularly or subcutaneously. Improvement in signs and symptoms is noted within 10 to 30 minutes after the injection. If response is-noted, neostigmine can be given orally at 3 to 6 hour intervals as needed; the total dose varies from 6 to 24 mg. per 24 hours? ~ The muscarinic effects of this drug can be COl~trolled, if needed, by intramuscular or subcutaneous injections of atropine in doses of 0.1 to 0.2 mg. This may be needed especially after the diagnostic test dose of neostigmine? ~ Prostigmine (neostigmine) therapy can be gradually reduced in patients with the neonatal transient disease and in a short time stopped altogether. Infants with the congenital disease will in all likelihood require continued therapy. The aim of obtaining a maximum cholinergic effect which is not fatal 42 and is without overwhelming muscarinic effects is not always realized .with prostigmine. Pyridostigmine bromide (Mestinon),

an anticholinergic drug with less tendency to induce muscarinic effects than prostigmine, in a dose 4 times that of prostigmine, can also be used. Intravenous edrophonium chloride (Tensilon) a rapidly acting anticholinergic drug with a short period of effectiveness, may be helpful in determining the need for more or less of the anticholinergic drug in problem cases. Such a combination of agents can be lifesaving in difficult situations. 43 H Y P O T O N I A D U E TO P R I M A R Y DISEASE OF MUSCLE Benign congenital hypotonia. Walton 4~ described a clinical syndrome, which he termed "benign congenital hypotonia." As infants these patients evidenced muscular weakness and generalized hypotonia from birth. Tendon reflexes were found to be highly variable, being present in some and absent in others. With time, symptoms improved spontaneously and no intellectual impairment was noted. These patients usually sat spontaneously later than the average infant (average 13 months, range 6 to 36 months) and walked later than the average child (average 24.5 months, range 10 to 60 months). It eventually became apparent that there were two Clinical patterns among the 17 children observed by Walton. In 8 of the children the clinical abnormalities disappeared completely in 1 to 10 years. By contrast although all of the remaining 9 patients improved gradually and eventually walked, none could be regarded as completely normal. Each one had small muscles, mild persistent hypotonia, and a shambling

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gait. T w o of these nine children developed kyphoscoliosis, and one, a contracture of the Achilles tendon. A familial incidence of the disease was not apparent. Electromyography was performed on 5 of the children and excessive polyphasic potentials were found in 2, and an excess of short duration potentials was found in 3 others. Muscle biopsy was performed in 6 patients, in 2 who recovered without sequelae, and in 4 who had persistent weakness in the small muscles. In no instance was any abnormality noted in the sections of muscle s t a i n e d by hematoxylin and eosin. The nature of this disease is not known. There is reason to question the validity of grouping the 2 categories of patients together. However, the two groups have 4 things in common: hypotonia at birth, gradual decrease in hypotonia as the years passed, lack of familial incidence of the disease, and no clear evidence of disease of the central nervous system or of the peripheral nerves. The propriety of classifying the cases under the heading of primary muscle disease is perhaps also to be questioned. However, the electromyographic changes in the few cases tested were compatible with, but not diagnostic of, myopathie disease. Also, the presence of small weak muscles in some of the children in this series as well as another patient reported upon ~5 favors regarding so-called "benign congenital hypotonia" as a primary muscle disease with a reasonably favorable prognosis. Universal hypoplasia of muscle. The term universal hypoplasia of muscle is applied to a syndrome which is clinically similar to the "second group" of the one described before as benign congenital hypotonia. The infant is hypotonic at birth, and the muscular weakness, although it improves slightly with time, persists throughout life. Apparently the only difference between these two syndromes is the probability of genetic transmission in universal hypoplasia of muscle. To date 7 cases have been reported. 46-'~~ Deep tendon reflexes were usually present in these patients and there were no sensory

March 1964

abnormalities: As the subcutaneous fat layer became thinner with increasing age, it was obvious that the muscle mass in these patients was smaller than in that of their peers. All of these patients eventually were able to walk and there was no apparent mental impairment. Muscle biopsy obtained in several cases TM 00 revealed no definite abnormality, and electrical reactions of the muscles were found to be normal. The basic nature of this familial syndrome with universally small musculature is not known. However, it appears to differ f r o m benign congenital hypotonia in its manner of transmission and f r o m other congenital myopathies in the absence of clearly defined microscopic changes in the muscle. Effective therapy is unknown. Muscular dystrophy. This occurs in infancy. At times it is associated with multiple fixations of joints or arthrogryposis multiplex congenita. The coexistence of these two conditions suggests that the muscle weakness developed in early intrauterine life. As previously mentioned , it has been proposed that muscular weakness beginning in the third to the fourth month of fetal life and persisting throughout gestation can result in limited intrauterine movements and this in turn to tight ligaments and connective tissue about joints producing at birth the clinical picture of arthrogryposis. 29, 30 Infants with congenital muscular dystrophy exhibit hypotonia and weakness from birth; there is weakness of all the voluntary muscles including the diaphragm. As a result, these children have a weak cough and m a y die in infancy from pneumonia. In those who survive, there is a gradual improvement in muscle strength and tone; the children are able to walk, eventually to lead a useful life, and interestingly, do not develop contractures. These patients are distinguishable from other infants with hypotonia by the findings on muscle biopsy. Grossly, the muscle is pale in color, thin, and somewhat firm in consistency. Microscopically, there is a great variation in the size of muscle fibers within fascicles. There is an obvious increase in

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endomysial and perimysial connective tissue. Some muscle fibers show degenerative changes with loss o f striation and hyalinization. There are splitting of muscle fibers and an increase in the number of sarcolemreal nuclei. Some of these nuclei may appear in long rows or chains, and some m a y be atrophic or vesicular. In cross sections the sarcoIemmaI nuclei are frequently in the center of the muscle fiber and the peripheral nuclei may be increased in number. Some areas of muscle m a y be replaced by fat and fibrous tissue. Intramuscular nerve endings are normal. These findings are similar to those of pseudohypertrophic muscular dystrophy. There have been 15 cases of congenital myopathy or muscular dystrophy reportedSlS8; 7 patients died before the age of 6 months, while 8 survived into adolescence or adulthood. Among the infants who died, 2 had arthrogryposis multiplex congenita, 6 had siblings similarly afflicted with hypotonia, and all of the patients died after repeated bouts of bronchopneumonia. Five patients were examined post mortem; all showed histologic evidence of a primary myopathy and a normal central and peripheral nervous system. The eight surviving children were derived from two families. 5~-5s All of these hypotonic babies survived . infancy without difficulty and became stronger as time passed. Two children showed mild arthrogryposis multiplex when examined in mid-childhood, but the time of onset of this symptom was not clear. Muscle biopsy in one m e m b e r of each family showed microscopic evidence of a myopathy. Mental development was normal in all of these children. Thus a form of neonatal myopathy which is familial clearly exists. ,How and if this myopathy differs fundamentally from muscular dystrophy of later clinical onset is not now obvious. No form of therapy has been proved to be curative in patients with muscular dystrophy. Recently, a combination of an anabolic steroid and digitoxin has seemed to offer promise of clinical improvement in

The hypotonic infant

43 1

some patients. 6~ However, all of the patients observed were older children and adults, and the results were far from conclusive. Central core disease. A familial disorder characterized by muscular weakness with delayed motor development is central core disease; it was described by and named after Shy and Magee. ~ T h e disorder has been reported in only one kinship in which 5 children, 4 males and t female, in 3 generations were involved. Muscle wasting was not a promient feature of the disease and no disturbance in sensation or mentality was noted. The microscopic picture of muscle obtained by biopsy was characteristic. There were huge fibers whose diameters were 3 times those of average fibers as well as fibers of normal size. In both normal and large fibers, there was a centrally placed dark staining area which was period acidSchiff positive; the name of the disease is based on this histochemically abnormal central core. In addition, internal sarcolemmal nuclei often appeared in chains. The nerves to the muscle were normal. Detailed investigation Of one patient revealed an absence of mitochondria in the central core with deficiency of oxidative e n z y m e activity and phosphory!ase activity. This disease differs from MeArdle's familial muscle phosphorylase deficiency not only microscopically but also physiologically a n d chemically: in central core disease there is no pain with exercise; there is a normal rise of blood pyruvate and lactate with exercise, and homogenates of muscle produce activation of phosphorylase on addition of adenosine5-phosphate. 8t Rod body myopathy. Another form of nonprogressive m y o p a t h y designated as rod body myopathy has been reported in a 4year-old girl who had marked weakness since birthY ~ Clinical details are lacking, and it is only presumptive that hypotonia was present in addition to the muscular weakness. The microscopic lesion was characterized by the presence of small rod-shaped bodies in some but not all muscle fibers. Only this one case of rod body myopathy has been reported.

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Myotonic dystrophy. This familial disease is transmitted as an autosomal dominant trait a n d is not usually manifest in childhood2 3 It is characterized by progressive atrophy and weakness of the distal muscles of the extremities, the muscles of the face, jaw and neck, progressive baldness, and testicular atrophy. In addition, symptoms suggestive of hypothyroidism often occur and the incidence of cataracts both in symptomatic patients as well as in their asymptomatic relatives is high. Symptoms of muscular, weakness and atrophy do not usually begin before the third decade in the first generation of an affected family; feeblemindedness and onset of dystrophy in childh o o d tend to occur in the second generation2 4 Myotonia is demonstrable clinically and electromyographically and is characterized by slow contraction and relaxation of a muscle before a warm-up period; progressive improvement in function follows repetition of the movements. In myotonic dystrophy, it is present in the muscles of hands, face, and tongue, and, rarely, of the limbs. When myotonic dystrophy is manifest in infancy, there are hypotonia, poor sucking ability, feeding problems, and delayed progression of motor development. Mental retardation of variable degree becomes obvious as the infant grows older. Some of these patients have feeble facial movements, ptosis, and a high-arched palate. The urinary creatine is often increased and the creatinine excretion is low. T h e electromyographic pattern of myotonia can be detected as early as 9 months of age. Clinically myotonia is not usually detected before the child is 3 to 6 years of age. As these children grow older, atrophy of the muscles of the face and the distal muscles of the extremities slowly appears. In some documented cases, the intelligence quotient was measured repeatedly; it declined progressively. 63 Muscle biopsies are difficult to interpret. Abnormal findings are not obvious in the young infant, but, when present, they consist of an increase in the number of sarcolemmal nuclei which appear in chains plus

March 1964

an unusually high incidence of circumfibril. lar striated fibers or "ringbinden. T M Polymyositis. Polymyositis is a rare cause of hypotonia and weakness in the infant. Walton described one case with symptoms appearing soon after birth. This child was both weak and hypotonic. The disease was progressive, and by the age of 8 years, this child could not walk because of contractures and weakness. Muscle biopsy at this time revealed changes characteristic of chronic polymyositis. 2G In this same report, one other case is alluded to in which an infant with the clinical picture of "amyotonia congenita" was proved by muscle biopsy to have microscopic evidence of polymyositis. Type I I glycogen storage disease. The clinical picture of congenital hypotonia may also be produced by Type I I glycogen storage disease (Pomp6's) 6~-6~ which is also known as the cardiomuscular form of glycogen storage disease. Affected infants have muscular weakness at birth which often progresses. In addition, enlargement of the tongue and of the heart may result in feeding difficulty and in cardiac failure. The muscular weakness is often quite marked and the muscles may feel unnaturally firm and rubbery. Deep tendon reflexes are usually preserved. Muscle biopsy is diagnostic in this disease. 66 If the biopsy material is fixed in alcohol and not in formalin, muscle fibers show vacuoles as well as basophilic degeneration in the sarcoplasm. When vacuolization is marked, t h e ' muscle fibers are swollen and large, These patients often succumb before the age of 9 months, and complete postmortem examinations have shown that all other body tissues contain variable amounts of glycogen. The motor neurons of the cerebrospinal axis contain swollen cytoplasm with an eccentrically placed nucleus; the cytoplasmic bulging apparently is due to glycogen2 6 One observer has reported glycogen in Schwann cells, dorsal root ganglia, and even in the astrocytes of the brain. 6s The basic pathologic physiology of the enzyme deficiency noted in Pomp6's disease has not yet been deter-

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mined. 69 Although a deficiency of maltase has been discovered in muscle of patients with Pompf's disease, it is not entirely clear how this finding is r e l a t e d to the large accumulation of glycogen in the muscle of these patients. 7~ SPECIFIC DIAGNOSTIC M E T H O D S USED IN EVALUATING INFANTS WITH HYPOTONIA--MUSCLE BIOPSY

One of the most valuable aids in determining the cause of hypotonia in infants is the examination of stained fixed tissue obtained by muscle biopsy. T h e value of the muscle biopsy can be enhanced by close cooperation between the pediatric neurologist and the surgeon who performs the biopsy. It is most important t ~ take specimens from areas of clinical involvement, from more than one site, in adequate amount, and from the belly of the muscle. It is also important to have the specimen properly mounted and gently handled before and during fixation. In the process of interpretation, it is important to have in mind clearly the variations of normal fiber size according to age as well as to he aware of the existence of the normally large "B" fibers of Wohlfart. TM 71 By using muscle biopsies, especially in infants, one will usually be able to differentiate between myelopathic or neural atrophy with compensatory hypertrophy of unaffected muscle fibers and a primary myopathy. Although some claim to be able to differentiate between myelopathic atrophy and neural atrophy by the pattern of distribution of the atrophic fibers and by the appearance of atrophy and fibrosis of intramuscular sensory organs, i.e., muscle spindles, 72 these findings are generally difficult to recognize and the differentiation by this means is therefore difficult. By using appropriate stains, one can see in a muscle biopsy the terminal nerve fibers as well as small nerves between muscle fascicles in the perimysium and thus one can find some clues as to the presence of neuropathy in the muscle specimen. The histologic picture in a muscle biopsy

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of myelopathic or neural atrophy can be indicative of Werdnig-Hoffman's disease, congenital or infantile poliomyelitis, or peripheral polyneuropathy. Myelopathic atrophy may also be demonstrated at times in arthrogryposis. The diagnosis of the patient with hypotonia due to peripheral nerve disease will depend not only upon the appearance of the nerves in the muscle, but also upon the concentration of protein in the cerebrospinal fluid, and the presence of abnormalities of nerve conduction time. 'Patients with hypotonia and a histologic diagnosis of primary myopathy will include children with infantile muscular dystrophy with or without arthrogryposis, dystrophica myotonica, central core disease, and rod body myopathy. T h e histologic picture of glycogen storage disease is not likely to be confused with other forms of primary myopathy. The microscopic picture of polymyositis when well developed is unmistakable, but otherwise it can be difficult to interpret even in a patient who is severely ill clinically. Patients who are weak and in Whom the muscle mass seems small but in whom there is no family history of muscle disease, in whom cerebrospinal fluid and nerve conduction times are normal, and in whom muscle biopsy shows no discernible abnormality must of necessity be categorized as cases of "benign congenital hypotonia" and must be followed clinically at periodic intervals. It thus becomes apparent that a close correlation of both clinical and histologic observations concerning a case will be needed to arrive at a reasonable diagnostic conclusion. The histologic findings are sometimes difficult to interpret but a description of the pitfalls" and the advantages in the use of muscle biopsy in the study of the hypotonic infant can be found in articles by Adams 7~ and by Greenfield. TM Two other methods used in the histologic examination of muscle should be mentioned. The first is supravital staining of muscle with methylene blue before its removal; the second, intravital staining with the same substance immediately after surgical removal. 7s This method enables one to view

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the intramuscular nerve fibers and end plates with great clarity. The difficulty of the method plus the absence of its clear advantage over good conventional methods have precluded its widespread use. 7~, 77 An even more difficult method of examining muscle biopsy specimens is the technique which uses histochemical stains tO show the presence or absence of enzymes within muscle. These techniques have been revised so that it is now apparent that in some diseases of muscle there m a y be generalized changes in the enzyme content (for example, in McArdle's phosphorylase deficiency) or localized changes in only certain fibers (as in rod body myopathy).Ts This technique at present is mainly a research tool. ELECTROMYOGRAPHY THE DETERMINATION NERVE CONDUCTION

AND OF TIMES

Electromyography and the concomitant measurement of nerve conduction velocity are techniques of some value in determining the cause of hypotonia in infants. In electromyography the usual technique is to insert a No. 24 needle, shielded save for the tip, into the muscle. Differences in the electrical potential are measured between the tip of the needle and an indifferent electrode placed on the skin surface. Observations are made of the potential differences following insertion, at rest, and with spontaneous movement. Abnormalities in the pattern of electrical discharges following insertion of the needle into muscle may be seen in patients with congenital myopathies. An abnormality of insertional activity whereby there is a persistent discharge with a constant decrease both in voltage and in duration of potentials is seen in myotonia. Abnormalities of the resting electromyogram are observed in myelopathic disease. In infants with a thick subcutaneous fat layer, fasciculations, or contraction of a motor unit, which accompany disease of the anterior horn cells, are not visible to the eye but they can be seen in the electromyogram. These are often present in Werdnig-Hoffman's disease. The assessment of the pattern and voltage

of spontaneous activity in the infant is very difficult and when a peculiarity in the interference pattern of spontaneous activity is noted and is the only abnormality found, it should be viewed with suspicion. When fibrillation potentials are seen either with spontaneous activity or at rest, disease of the anterior horn cells, nerve roots, plexus, peripheral nerves, or muscle can be suspected. T h e lack of specificity of some of the findings of electromyography must be appreciated. The most diffficult yet the most useful part of the electrical examination is the measurement of the nerve conduction time. Stimulating electrodes are placed at two sites over a peripheral nerve, and a recording electrode is placed in a muscle innervated by this nerve. A single pulse of electricity is applied consecutively at the two sites of stimulation and by proper recording devices the time lag between stimulus and muscle response is determined. The differences in the conduction times between the two points and the distance between them are used to determine the conduction time of that nerve. Rates of conduction vary according to age, the nerve tested, and the temperature of the limb. In peripheral neuropathy, a significant decrease in the speed of nerve conduction time is found. 7~ The combination of electromyography and the measurement of nerve conduction times are helpful in diagnosing diseases of the anterior horn cells (as in Werdnig-Hoffman's disease), peripheral nerves (as in chronic peripheral polyneuropathy), and muscles (as in myotonia). These tests are less helpful in diagnosing primary myopathy without myotonia in infants. The prime requisites for useful testing are experience in the technique of performing the test and knowledge of the patterns in normal children at various ages.79, so SERUM ENZYME DETERMINATIONS

The determination of the concentration of certain enzymes in serum is of use in the differential diagnosis of hypotonia in infants.

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It has been repeatedly shown that in a patient with muscular dystrophy, the serum concentration of glutamic oxalacetic transaminase (SGOT) and glutamic pyruvic transaminase (SGPT) are elevated. Lactic dehydrogenase ( L D H ) , aldolase, and creatine kinase are elevated concomitantly. TM 82 The earliest and most consistently elevated values in muscle dystrophy are those of aldolase and creatine kinase, a2 Elevated concentrations of S G O T , SGPT, aldolase, and LDH have been noted in children before clinical evidence of dystrophy appears, sl These observations have been made principally in patients who developed clinical manifestations of pseudohypertrophic muscular dystrophy between the ages of 189 and 4 years. The mechanisms whereby patients with dystrophy develop elevations in their serum enzyme concentrations is not clear. Patients with muscular weakness and wasting due to neurogenic atrophy do not have elevated serum enzyme concentrations. Since patients with heart disease or l i v e r disease can have elevated S G O T , SGPT, serum aldolase, and serum L D H concentrations, it is important tO be certain that these diseases are absent before interpreting the results of serum enzyme tests w i t h reference to the existence of muscle disease. Patients with acute polymyositis have been reported to have elevations of serum aldolase 8a and S G O T . s~ In children with muscular weakness and the diagnosis of "amyotonia congenita" (presumably nonmuscular causes), the S G O T levels have been normal. 8~ In summarizing the information concerning serum enzymes in the diagnosis of the hypotonic infant, it can be said that elevated S G O T , SGPT, serum aldolase, or serum L D H m a y occur in children with classical muscular dystrophy and with polymyositis. Serum enzyme values have not been reported in a large number of patients with congenital infantile muscular dystrophy so that one may only speculate that these values should be elevated in children with this disorder. In one patient (followed by us) who exhibits the clinical course, familial

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incidence, and biopsy findings of an infantile congenital myopathy, SGOT, SGPT, and serum aldolase concentrations were elevated. 86 Children with hypotonia secondary to myelopathic or neurogenic atrophy or with dystrophica myotonica are likely not to have elevated concentrations of these serum enzymes. CREATINE AND CREATININE EXCRETION IN THE HYPOTONIC INFANT

The value of measurements of the 24 hour urinary excretion of creatine and creatinine is limited in the differential diagnosis of hypotonia in infants. Certain basic tenets should be reviewed to understand this statement. Creatine is normally formed by the liver, the precursor amino acids being glycine, alanine, and methionine. Creatine is then transported to the muscle where it is found as phosphocreatine and where it serves as a reservoir for and donor of high energy phosphate. 87 Creatine is found in variable quantities in the urine of infants and children, the amount seeming to vary to some extent with age. The creatine coefficient (milligrams of creatine excreted per 24 hours per kilogram of body weight) ranges from 0.08 to 1.0 in premature infants, 88 0.12 to 5.15 in full-term infants (birth to 2 years),Ss, s9 and 0.7 to 9.2 in children 2 to 13 years of age. ss Why children have creatinuria "physiologically," and normal adults, have it only when the serum creatine concentration exceeds 0.58 mg. per cent 9~ is not known. Creatinine, the anhydride of creatine, presumably formed in normal muscle is excreted in the urine constantly. There is an apparent relation between the muscle mass and the 24 hour urinary excretion of creatinine at all ages21 The creatinine coefficient (milligrams of creatinine excreted per 24 hours per kilogram of body weight) varies according to age and in the premature infant averages 12 (range 9.9 to 14.0); in the full-term infant (birth to 24 months), 22.0 (range 14.2 to 32.0); and in children from 2 to 18 years of age, 25 (range 16.3 to 36.2).ss, ~2

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In patients with a disease which produces muscular wasting, such as muscular dystrophy, poliomyelitis, dermatomyositis, and dystrophica myotonica, 91, 92 as well as malnutrition with steatorrhea and hypotonia, "4 there occurs an increase in the urinary creatine coefficient and a decrease in the urinary creatinine coefficient. Studies with labeled amino acid in adult patients with muscular dystrophy 9s have shown that creatine is formed from ingested amino acids in the anticipated pattern but that the newly formed creatine is then excreted in the urine and that little labeled creatinine is to be found in the urine. This is evidence that creatinuria in muscular dystrophy is due to creatine being formed by the liver normally but not being "accepted" by the decreased muscle mass. The decrease in urinary creatinine is apparently related to the decrease in normal muscle secondary to the disease. 9s It is possible but not proved that creatinuria in other pathologic conditions is due to a similar mechanism. I t is, therefore, apparent that increased creatine coefficients and decreased creatinine coefficients are not specific for any disease causing hypotonia but are found in a number of pathologic conditions manifested clinically by hypotonia, for example, in muscular wasting due to primary muscle disease, myelopathic disease, or malnutrition. CLINICAL ASSESSMENT OF D E V E L O P M E N T A L

LEVEL

One of the most important diagnostic procedures in the evaluation of the etiology of congenital hypotonia is the estimation of the developmental level of tire infant. Because of the necessity to determine the level primarily from motor performance, and to a lesser degree from social and adaptive response in the infant under 6 months of age, methods of assessing the developmental level of these children are not as reliable as they are in the older childP 6 Also among infants with hypotonia, mental retardation may not appear until a later age and even then will do so gradually, for example, in Tay-Sachs disease or in dystrophica myotonica. It is

obvious, therefore, that in infants with hypotonia, failure to reach the motor performance schedule on time as outlined by Gesell and Amatruda ~7 does not carry the same prognosis in all infants. Thus, the patient with "benign congenital hyp0tonia" m a y not sit unsupported until 16 months, use 2 word phrases until 22 months, walk until 36 months, but can be normal in all respects at 48 months. On the other hand, a child with dystrophica myotonica who shows myotonia and facial diplegia m a y not sit with support until 18 months, m a y say'only single words at 24 months, walk at 36 months, and be obviously retarded in speech and adaptive behavior at 48 months. What is most important is to determine the existence of significant cerebral damage which can affect motor function, speech, and adaptive behavior. T o this end, repeated observations of the same child at 6 to 9 month intervals are needed over a 2 to 4 year period of time. In conclusion, it seems pertinent to mention the relative incidence of the various causes of hypotonia in the infant as seen in the practice of pediatric neurology. Our clinical experience has shown that the commonest cause of hypotonia in the infant is Werdnig-Hoffman's disease, followed in order of decreasing incidence by benign congenital hypotonia, congenital encephalopathy with either atonic diplegia or cerebellar ataxia, acute infective polyneuropathy , and congenital infantile myopathy. The remaining clinical syndromes are not commonly seen. SUMMARY

(TABLE

I)

I. The factors concerned in maintaining normal muscle tone have been described in detail as a background to the understanding of the possible sites of pathology which can lead to hypotonia. II. The causes of hypotonia in children under 24 months of age have been discussed from the point of view of the presumed site of pathology. The classification which has evolved from this approach is as follows: A. Hypotonia due to diseases of the central nervous system:"

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1. Atonic diplegia 2. C o n g e n i t a l c h o r e a a n d athetosis 3. Congenital c e r e b e l l a r a t a x i a 4. K e r n i c t e r u s 5. M o n g o l i s m 6. T a y - S a c h ' s disease B. H y p o t o n i a due to diseases of the spinal cord: 1. W e r d n i g - H o f f m a n ' s disease (infantile progressive m u s c u l a r atrophy) 2. M y e l o p a t h i c artl!rogryposis multiplex congenita 3. C o n g e n i t a l a n t e r i o r poliomyelitis C. H y p o t o n i a due to diseases of the spinal roots or p e r i p h e r a l nerves: 1. A c u t e a n d chronic p o l y n e u r o p athy D. H y p o t o n i a d u e to a b n o r m a l i t i e s of the m y o n e u r a l j u n c t i o n : 1. C o n g e n i t a l m y a s t h e n i a gravis 2. N e o n a t a l ( t r a n s i e n t ) m y a s t h e n i a gravis E. H y p o t o n i a d u e to diseases of the muscle: 1. Benign congenital h y p o t o n i a 2. Universal m u s c u l a r hypoplasia 3. C o n g e n i t a l infantile m u s c u l a r d y s t r o p h y w i t h or w i t h o u t a r t h r o gryposis m u l t i p l e x congenita 4. D y s t r o p h i c a m y o t o n i c a 5. C e n t r a l core disease 6. R o d b o d y m y o p a t h y 7. Polymyositis 8. Glycogen storage disease I I I . T h e value of a n c i l l a r y aids in the diagnosis of the etiology o f h y p o t o n i a in infants has beer/ discussed. T h e s e have ineluded muscle biopsy, e l e c t r o m y o g r a p h y , m e a s u r e m e n t of the nerve c o n d u c t i o n time, d e t e r m i n a t i o n of s e r u m enzyme c o n c e n t r a tions, u r i n a W creatine and c r e a t i n i n e excretion coefficients, a n d the assessment of the d e v e l o p m e n t a l level of the infant.

I wish to thank Miss Betty Kuusisto, research assistant, for her invaluable aid in locating and translating much of the foreign literature used in

T h e hypotonic in/ant

4 37

this article and to acknowledge the helpful criticism concerning the physiologic mechanism of hypotonia given by Dr. Thomas TwitchelI.

REFERENCES

1. Oppenheim, H.: ~ber alIgemelne und tokatisierte Atonie der Muskulatur (Myatonie) im friihen Kindesalter, Monatsschr. Psychiat. u. Neurol. 8: 232, 1900. 2. Werdnig, G.: Zwei frfihinfantile hereditire FS.11e yon progressiver Muskelatrophie unter dem Bilde der Dystrophie ober auf neurotischer Grundlage, Arch. f. Psychiat. 22: 437, 1891. 3. Hoffman, J.: t)ber chronische spinale Muskelatrophie im Kindesalter auf famili~irer Basis, Deutsche Ztschr. Nervenh. 3: 427, 1893. 4. Adams, R. D., Denny-Brown, D., and Pearson, C. M.: Diseases of muscle: A study in pathology, ed. 2, New York, 1962, Harper Brothers, p. 544. 5. Rushworth, G.: Muscle tone and the nmscle spindle in clinical neurology, 3rd series, Williams, Denis, editor: in Modern trends in neurology, Washington, 1962, Butterworth & Co., Ltd., pp. 36-56. 6. Paillard, J.: Reflexes et regulations d'origine proprioeeptive chez l'homme, in Etude neurophysiologique et psychologique, Paris, 1955, Arnette. (Cited by Rushworth,~ p. 52.) 7. Payne, W. W.: Calcium. and phosphorus metabolism in nervous disorders, in Cumings, J. N., and Kremer, M., editors: Biochemical aspects of neurological disorders, Oxford, 1959, Blaekwell Scientific Publications, chap. 7, pp. 73-85. 8. Norman, R. M.: Malformations of the nervous system, birth injury, and diseases of early life, in Greenfield, J. G.: Neuropathology, London, 1958, Edward Arnold & Co., chap. 5, p. 352. 9. Polani, Paul E.: Cytogenics of Down's syndrome (mongollsm), Pediat. Clin. North America 10: 423, 1963. 10. Foerster, O.: Der atonische-astatische Typus der infantilen Cerebrall~ihmung, Deutsches Arch. klin. Med. 98: 216, 1909. 11. Clark, L. P.: Infantile cerebro-cerebellar diplegia, of flaccid atonic astasic type, Am. J. Dis. Childhood 5: 425, 1913. 12. Yannett, H., and Horton, F.: Hypotonic cerebral palsy in mental defectives, Pediatrics 9" 204, 1952. 13. Ford, F. R.: Diseases of the nervous system in infancy, childhood, and adolescence, ed. 4, Springfield, Ill., 1960, Charles C Thomas, Publisher, pp. 193-194. 14. J e l l s , G. A.: Early familial cerebellar degeneration, J. Nerv. &Ment. Dis. 111: 398, 1950.

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15. Rubenstein, H. S., and Freeman, W.: Cerebellar agenesis, J. Nerv. & Ment. Dis. 92: 489, 1940. 16. Ford, F. R.: Diseases of the nervous system in infancy, childhood, and adolescence, ed. 4, Springfield, Ill., 1960, Charles C Thomas, Publisher, p. 197. 17. Gerrard, J.: Kernicterus, Brain 75: 526, 1952. 18. Haymaker, W., et aI.: Pathology of kernicterus and posticteric encephalopathy, in Kernicterus and its importance in cerebral palsy, Springfield, Ill., 1961, Charles C Thomas, Publisher, pp. 21-228. 19. Zuelzer, W. W., and Brown, A. K.: Neonatal jaundice, A. M. A. J. Dis. Child. 101: 87, 1961. 20. Windle, W. F.: Neuropathology of certain forms of mental retardation, Science 140: 1186, 1963. 21. Rothstein, J. L., and Welt, S.: Infantile amaurotic familial idiocy, Am. J. Dis. Child. 62: 801, 1941. 22. Brandt, S.: Hereditary factors in infantile muscular atrophy, Am. J. Dis. Child. 78: 226, 1949. 23. Byers, R. K., and Banker, B. Q.: Infantile muscular atrophy, A. M. A. Arch. Neurol. 5: 140, 1961. 24. Walton, J. N.: The amyotonia congenita syndrome, Proc. Roy. Soc. Med. 50: 301, 1957. 25. Woolf, A. L.: Muscle biopsy in the diagnosis of the "floppy baby": Infantile hypotonia, Cerebral Palsy Bull. 2: 19, 1960. 26. Walton, J. N.: Amyotonia congenita; a followup study, Lancet 1: 1023, 1956. 27. Drachman, D. B., and Banker, B. Q.: Arthrogryposis multiplex congenita, A. M. A. Arch. Neurol. 5" 89, 1961. 28. Adams, R. D., Denny-Brown, D., and Pearson, C. M.: Diseases of muscle: A study in pathology, ed. 2, New York, 1962, Harper Brothers, pp. 310-314. 29. Whittem, J. H.: Congenital abnormalities in calves: Arthrogryposis and hydranencephaly, J. Path. & Bact. 73: 375, 1957. 30. Drachman, D. B., and Coulombre, A. J.: Experimental clubfoot and arthrogryposis multiplex congenita, Lancet 2: 523, 1962. 31. Shelokov, A., and Weinstein, L.: Poliomyelitis in the early neonatal period: Report of a case of possible intra-uterine infection, J. PEDrAT. 38: 80, 1951. 32. Horn, P.: Poliomyelitis in pregnancy: A 20 year report from Los Angeles County, California, Obst. & Gynec. 6: 121, 1955. 33. Baskin, J. L., Soule, E. H., and Mills, S. D.: Poliomyelitis in the newborn: Pathologic changes in 2 cases, Am. J. Dis. Child. 80: 10, 1950. 34. Peterman, A., et al.: Infectious neuronitis (Guillain-Barrfi syndrome) in children, Neurology 9: 533, 1959. 35. Chambers, R., and MacDermot, V.: Po/yneuritis as a cause of "amyotonia congenita," Lancet 1: 397, 1957.

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36. Byers, R. R., and Taft, L. T.: Chronic multiple peripheral neuropathy in childhood, Pediatrics 20: 517, 1957. 37. Grob, D., and Johns, R. J.: Disorders of the motor unit which may produce transient paralysis in Adams, R. D., Eaton, L. M., and Shy, G. M., editors: Neuromuscular disorders, ARNMD, Vol. 38, Baltimore, 1960, Williams & Wilkins Company, pp. 601-623. 38. Millichap, J. G., and Dodge, P. R.: Diagnosis and treatment of myasthenia gravis in infancy, childhood, and adolescence, Neurology 10: 1007, 1960. 39. McRae, D.: Myasthenia gravis in early childhood, Pediatrics 13: 511, 1954. 40. Kibrick, S.: Myasthenia gravis i n the newborn, Pediatrics 14: 365, 1954. 41. Grob, D., and Johns, R. J.: Disorders of the motor unit which may produce transient paralysis, in Adams, R. D., Eaton, L. M., and Shy, G. M., editors: Neuromuscular disorders, ARNMD, Vol. 38, Baltimore, 1960, Williams & Wilkins Company, pp. 607-612. 42. Strickroot, F. L., Schaeffer, R. L., Bergo, H. L.: Myasthenia gravis occurring in an infant born of a myasthenic mother, J. A. M. A. 120: 1207, 1942. 43. Moore, H.: Advantages of pyridostigmine bromide (Mestinon) and edrophonium chloride (Tensilon) in the treatment of transitory myasthenia gravis in the neonatal period, New England J. Med. 253: 1075, 1955. 44. Walton, J. N.: The limp child, J. NeuroL, Neurosurg. & Psychiat. 20: 144, 1957. 45. Krabbe, K. H.: Congenital generalized muscular atrophies, Acta psychiat, et neurol. 33: 94, 1958. 46. Krabbe, K. H.: Kongenit. generaliseret muskelaplasi, 338 Meeting of the Danish Neurological Society, Feb. 26, 1946, pp. 264, 274. 47. Schreier, K., and Huperz, R.: tJber die hypoplasia musculorum generalisata congenita, Ann. Pediat. 186: 241, 1956. 48. Gibson, A.: Muscular infantilism, Arch. Int. Med. 27: 338, 1921. 49. Van Wisselingh, C. J.: Een geval van congenitale gegeneraliseerde spierhypoplasie, Maandschr. v. kindergeneersk. 24: 234, 1956. 50. Ford, F. R.: Diseases of the nervous system in infancy, childhood, and adolescence, ed. 4, Springfield, Ill., 1960, Charles C Thomas, Publisher, pp. 1258-1260. 51. Councilman, W. T., and Dunn, C. H.: Myotonia congenita: a report of a case with autopsy, Am. J. Dis. Child. 2: 340, 1911. 52. DeLange, C.: Studien iiber angeborene Liihmungen bzw. angeborene Hypotonie, Acta. pediat. 20 (suppl. 3): 5, 1937. 53. Banker, B. Q., Victor, M., and Adams, R. D.: Arthrogryposis multiplex due to congenital muscular dystrophy, Brain 80: 319, 1957. 54. Short, J. K.: Congenital muscular dystrophy: A case report with autopsy findings, Neurology 13: 526, 1963. 55. Pearson, C. M., and Fowler, W. G., Jr.: Hereditary non-progressive muscular dys-

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62.

63. 64.

65. 66. 67. 68.

69.

70. 71.

72. 73. 74.

trophy inducing arthrogryposis syndrome, Brain B6: 75, 1963. Turner, J. W. A.: The relationship between amyotonia congenita and congenital myopathy, Brain 63: 163, 1940. Turner, J. W. A.: On amyotonia congenita, Brain 72: 25, 1949. Turner, J. W. A., and Lees, F.: Congenital myopathy: A 50-year follow-up, Brain 85: 733, 1962. Shy, G. M., and Magee, K. R.: A new congenital non-progi'essive myopathy, Brain 79: 610, 1956. Dowben, R. M.: Treatment of muscular dystrophy with steroids, New England J. Med. 268: 912, 1963. Engel, W. K., Foster, J. B., Hughes, B. P., Huxley, H. E., and Mahler, R.: Central core disease: An investigation of a rare muscle cell abnormality, Brain 84: 167, 1961. Shy, G. M., Engel, W. K., Sommers, J. E., and Wanko, T.: cited by Engel, W. K.: in The essentiality of histo-and-cytochemical studies of skeletal muscle in the investigation of neuromuscular disease, Neurology 12: 778, 1962. Vanier, T. M.: Dystrophica myotonica in childhood, Brit. M. J. 2: 1284, 1960. Adams, R. D., Denny-Brown, D., and Pearson, C. M.: Diseases of muscle: A study in pathology, New York, 1962, Harper Brothers , pp. 334-337. Cori, G. T.: Biochemical aspects of glycogen deposition disease, Mod. Prob. Pediat. 3: 344, 1957. Clement, D., and Godman, G.: Glycogen disease resembling mongolism, cretinism , and amyotonia congenita, J. PEmAT. 36:11, 1950. Friedman, S., arid Ash, R.: Glycogen storage disease of the heart, J. P~D~AT. 52: 635, 1958. Schnabel, R.: l~ber die neuromuskulare Form der Glykogen-speieherungskrankheit (neuromuscular form of glycogen storage disease), Virchows Arch. f. path. Anat. 331: 287, 1958. Field, R. A.: Glycogen deposition diseases, in Stanbury, J. B.,-Wyngaarden, J. B., and Fredrickson, D. S., editors: The metabolic basis of inherited disease, New York, 1960, McGraw-Hill Book Company, pp. 156-207. Her, H. G.: Alpha-glucosidase deficiency in generalized glycogen storage disease (Pompfi's disease), Biochem. J. 86: 11, 1963. Wohlfart, G.: l~ber das Vorkommen verschiedener Arten yon Muskelfasern in der Skelettmuskulatur der Menschen und einlger S~iugetiere, Acta psychiat, et neurol, suppl. 12: 119, 1937. Wohlfart, G.: Muscular atrophy in diseases of the lower motor neuron, Arch. Neurol. & Psychiat. 61: 599, 1949. Adams, R. D.: The histopathology of human muscle disease, neuromuscular disorders, Research Publication A R N M D 38: 318, 1960. Greenfield, J. G., Cornman, T., and Shy, G. M.: The prognostic value of the muscle

The hypotonic infant

75. 76.

77. 78.

79. 80.

81.

82.

83. 84.

85.

86. 87.

88.

8'9.

90.

439

biopsy in the "floppy infant," Brain 81: 33, 1958. CoOrs, C., and Woolf, A. L.: The innervation of muscle: A biopsy study, Springfield, Ill., 1959, Charles C Thomas, Publisher. Harriman, D.: The diagnostic value of motor point muscle biopsy, in Garland, H., editor: Scientific aspects of neurology, Baltimore, 1961, Williams & Wilkins Company, chap. 3, p. 37. Woolf, A. L.: Muscle biopsy in the diagnosis of the "floppy baby": Infantile hypotonia, Cerebral Palsy Bull. 2: 19, 1960. Engel, W. K.: The essentiality of histo- and cytochemical studies of skeletal muscle in the investigation of neuromuscular d!sease, Neurology 12: 778, 1962. Lambert, W. H.: Neurophysiological techniques useful in the study of neuromuscular disorders, A R N M D 38: 247, 1960. Eaton, L., editor: Electromyography and electric stimulation of peripheral nerves and muscle. Clinical examinations in neurology, Philadelphia, 1963, W. B. Saunders Company, pp. 311-341. Pearson, C. M., et al.: Studies of enzymes in serum in muscular dystrophy. II. Diagnostic and prognostic significance in relatives of dystrophic persons, Pediatrics 28: 962, 1961. Dreyfus, J. C., Schapira, G., and Demos, J.: Etude de la creatinekinase serique chez les myopathies et 1curs families, Revue Francaise l't~tudes Cliniques Biologiques 5: 384, 1960. Thompson, R. A., and Vignos, P. J.: Serum aldolase in muscle disease, Arch. Int. Med. 103: 551, 1959. Pearson, C. M.: Serum enzymes in muscular dystrophy and certain other muscular and neuromuscular diseases. I. Serum glutamic, oxalacetic transaminase, New England J. Med. 256: 1069, 1957. Murphy, E. G., and Cherniak, M.: Glutamic oxalacetic transaminase activity in the serum in muscular dystrophy and other neuromuscular disorders in childhood, Pediatrics 22: 1110, 1958. Rabe, E. F.: Personal observation. Peters, J. P.: Protein metabolism. Clinical physiology, in Grollman, A., editor: The functional pathology of disease, McGrawHill Book Co., Inc., New York, 1957, chap. 4, p. 126. Flood, R. G., and Pinelli, R. W.: Urinary glycocyamine, creatine and creatinine. I. Their excretion by normal infants and children, Am. J. Dis. Child. 77: 740, 1949. Marples, E., and Levine, S. Z.: Creatinuria of infancy and childhood. I. Normal variations, creatine tolerance tests and the effects of amino-acetic acid in normal infants, Am. J. Dis. Child. 51: 30, 1936. Tierney, N. A., and Peters, J. P.: The mode of excretion of creatine and creatine metabolism in thyroid disease, J. Clin. Invest. 22: 595, 1943.

44 0

Rabe

91. Milhorat, A. T.: Creatine and creatinine metabolism and diseases of the neuromuscular system, In Metabolic and toxic diseases of the nervous system, A R N M D vol. 32, Williams & Wilkins Company, Baltimore, 1953, chap. 21, pp. 400-421. 92. Clark, L, C., Jr., Thompson, H. L., Beck, E. I., and Jacobsen, W.: Excretion of creatine and ereatinine by children, A. M. A. Am. J. Dis. Child. 81: 774, 1951. 93. Shank, R. E., Gilder, H., and Hoagland, C. L.: Studies on diseases of muscle. I. Progressive muscular dystrophy, a clinical review of 40 cases, Arch. Neurol. & Psychiat. 52: 431, 1944.

March 1964

94. Powes, F., and Raper, H. S.: A study of the metabolism of a case of amyotonia congenita, Quart. J. Med. 10: 7, 1916-1917. 95. Benedict, J. D., et al.: The origin of urinary creatine in progressive muscular dystrophy, J. Clin. Invest. 34: 141, 1955. 96. Illingworth, R. S., and Birch, L. B.: The diagnosis of mental retardation in infancy. A follow-up study, Arch. Dis. Childhood 34: 269, 1959. 97. Gesell, A., and Amatruda, C. S.: Develop. mental diagnosis: Normal and abnormal child development, clinical methods and pediatric application, New York, 1951, Paul B. Hoeber, Inc.