Pediatric Annals

Approach to Diagnosis in the Child With Muscle Weakness

Alfred J Spiro, MD

Abstract

Brased on experience accumulated from studies of large numbers of patients with muscle diseases, a fivepronged approach has been considered necessary to arrive at a correct diagnosis in most instances. The five categories of this approach are (1) interpretation of clinical signs and symptoms, (2) genetic study of the patient's family, (3) appropriate biochemical studies, (4) electrodiagnostic studies, and (5) pathologic studies (Table 1). Investigations usually proceed smoothly when carried out in that order, and a fitting diagnosis is reached by incorporating the results of all of the above-mentioned studies. These categories, generally necessary in the investigation of patients with weakness, and ancillary studies will be considered separately.

INTERPRETATION OF SYMPTOMS AND SIGNS

Symptoms. Careful clinical assessment, although frequently neglected, can prove very important in deciding which studies, if any, are needed to afford the patient the correct diagnosis (Table 2).

The parents should be questioned about various manifestations of the child's weakness; these may include a history of trouble walking up or down stairs, difficulty in running, a peculiar gait in which the child appears to waddle, or difficulty in arising from a low chair. All these features should indicate to the pediatrician that the patient has proximal muscle weakness in the lower extremities. It is less common for the parents to be aware of weakness in the upper extremities when this weakness is mild. Primarily proximal muscle weakness is often associated with muscular dystrophy and with progressive spinal muscular atrophy; it is observed in most of the muscular disorders of childhood. When the history of weakness is primarily manifested in the hands and feet, the clinician must be on the lookout for a peripheral neuropathy or for myotome dystrophy. Toe-walking, a common presenting complaint, may be an early manifestation of neuromuscular disease. It is noted in Duchenne muscular dystrophy and in spinal muscular atrophy, but the pediatrician must differentiate this from mild spastic diplegia and from the toe-walking associated with mental retardation or infantile autism or observed as a mannerism of early childhood.

Table

1. Worden, K. D.. and Vignos. P. J., Jr. Intellectual function in childhood progressive muscular dystrophy. Pedatrics 29 (1962), 968.

2. Spiro, A. Unusual myopathies. In Swaiman, K. F.. and Wright, F. S. (eds.). The Practice of Pediatric Neurology, Volume 2. St. Louis: C. V. Mosby Company, 1975, pp. 1008-1021.

3. Rowland, L P., et al. The clinical diagnosis of McArdte's disease: Identification of another family with deficiency of muscle Phosphorylase. Neurology 16 (1966). 93.

4. Layzer. R. B.. Rowland, L. P.. and Ranney, HM. Muscle phosphof ructokinase deficiency. Aren. Neurol. 17 (1967), 512.

5. Savage. D. C. L. Forbes. M . and Pearce. G. W. Idiopathic rhabdomyoiysis. Arch. Dis. Child. 46 (1971). 594.

6. Swaiman. K. F. Diseases of the neuromuscular junction. In Swaiman. K. F., and Wright. F. S. (eds). The Practice of Pediatric Neurology, Volume 2. St. Louis: C. V. Mosby Company. 1975. pp. 978-989.

7. Armstrong. R. M. et al Central core disease with congenital hip dislocation: Study of two families. Neurology21 (1971). 369.

8. Spiro, A, J., Prineas, J. W., and Moore. C. L. A new mitochondrial myopathy in a patient with satt craving. Arch. Neurol. 22 (1970), 259

9. Spiro, A. J.. Shy, G. M., and Gonatas. N. K. Myotubular myopathy. Arch. Neurol. 14 (1966). 1.

10. Aides to the Investigation of Peripheral Nerve Injuries. London: Her Majesty's Stationery Office. 1943.

11. Dubowitz, V-. and Hersov. L. Management of children with non-organic (hysterical) disorders of motor function. Dev. Med. Child Neurol. 18 (1976), 358.

12. Spiro. A. J. Minipolymyoclonus: A neglected sign in childhood spinal muscular atrophy. Neurology…

Brased on experience accumulated from studies of large numbers of patients with muscle diseases, a fivepronged approach has been considered necessary to arrive at a correct diagnosis in most instances. The five categories of this approach are (1) interpretation of clinical signs and symptoms, (2) genetic study of the patient's family, (3) appropriate biochemical studies, (4) electrodiagnostic studies, and (5) pathologic studies (Table 1). Investigations usually proceed smoothly when carried out in that order, and a fitting diagnosis is reached by incorporating the results of all of the above-mentioned studies. These categories, generally necessary in the investigation of patients with weakness, and ancillary studies will be considered separately.

INTERPRETATION OF SYMPTOMS AND SIGNS

Symptoms. Careful clinical assessment, although frequently neglected, can prove very important in deciding which studies, if any, are needed to afford the patient the correct diagnosis (Table 2).

The parents should be questioned about various manifestations of the child's weakness; these may include a history of trouble walking up or down stairs, difficulty in running, a peculiar gait in which the child appears to waddle, or difficulty in arising from a low chair. All these features should indicate to the pediatrician that the patient has proximal muscle weakness in the lower extremities. It is less common for the parents to be aware of weakness in the upper extremities when this weakness is mild. Primarily proximal muscle weakness is often associated with muscular dystrophy and with progressive spinal muscular atrophy; it is observed in most of the muscular disorders of childhood. When the history of weakness is primarily manifested in the hands and feet, the clinician must be on the lookout for a peripheral neuropathy or for myotome dystrophy. Toe-walking, a common presenting complaint, may be an early manifestation of neuromuscular disease. It is noted in Duchenne muscular dystrophy and in spinal muscular atrophy, but the pediatrician must differentiate this from mild spastic diplegia and from the toe-walking associated with mental retardation or infantile autism or observed as a mannerism of early childhood.

Table

TABLE 1APPROACH TO THE CHILD WITH MUSCLE DISEASE

TABLE 1

APPROACH TO THE CHILD WITH MUSCLE DISEASE

Table

TABLE 2CHECKLIST FOR HISTORY TAKING

TABLE 2

CHECKLIST FOR HISTORY TAKING

It is at times difficult for parents to assess the age at onset of a muscular disorder, but this is sometimes important to estimate in coming to a correct conclusion about the diagnosis. Most patients with congenital myopathies are hypotonic as infants. Duchenne muscular dystrophy, on the other hand, does not manifest itself generally until the child begins to walk; the parents frequently realize at about two years of age that the child's gait is odd or that he is unable to run. In a family in which there is a member with a muscular disorder, observant members will usually be able to detect other affected members earlier in the course of the disease than in families in which no members with muscular disorders are known.

In many instances, parents are initially aware of a potential problem because the child does not attain his motor landmarks at the appropriate time. The pediatrician should have a high index of suspicion for a muscular disorder if the gross motor function lags despite the normal progression of fine motor function and adaptive and language behavior. The presence of mental retardation, however, does not exclude the coexistence of a muscular disorder, because Duchenne muscular dystrophy and myotonic dystrophy, for example, are very commonly associated with mental retardation1 or abnormal behavioral manifestations. Overt deterioration of mental function, when coupled with muscle weakness, should alert the physician to the possibility of a progressive central nervous system disorder rather than a primary muscle disorder. It is of interest that patients with spinal muscular atrophy are almost always of normal or above-normal intelligence.

It is sometimes difficult to assess progression or lack of progression of a muscular disorder unless the deterioration is rapid. If progression or worsening of the disease is slow and the child is in the period in which he normally attains motor landmarks rapidly, worsening disease may not be recognized. Many of the congenital myopathies,2 such as nemaline myopathy or central core disease,* may remain static or only slowly progressive throughout the patient's life. Other disorders, such as spinal muscular atrophy, may reach a stage in which there is no further progression after a period of rapid advancement. Such disorders as Duchenne muscular dystrophy, although relentlessly progressive, may appear to be stationary in the early school years.

When muscle pain or tenderness is a prominent feature, the clinician should be aware of the possibility of an inflammatory myopathy, especially when the pain is associated with weakness and a rash. On the other hand, it is important for the physician to realize that inflammatory myopathies may not be accompanied by pain. Muscle cramping on exertion should alert the physician to the possibility of McArdle's disease3 or phosphofructokinase deficiency of muscle,4 although the pathogenesis of muscle cramping, despite extensive evaluations, remains primarily unknown. Patients with disorders of the glycolytic chain may have a peculiar feeling in their muscles on exertion. Myoglobinuria is rarely a presenting complaint in childhood, but it is less uncommon in adolescence; this may be associated with McArdle's disease, phosphofructokinase deficiency, or idiopathic rhabdomyoly sis . 5

The mode of onset of weakness is also helpful in reaching a correct diagnosis. Sudden onset of weakness may be associated with either hypoor hyperkalemia2 or with the Guillain-Barré syndrome. Similarly, weakness after effort may be associated with disorders of the glycolytic chain or with idiopathic rhabdomyoly sis. In inflammatory myopathies the onset of weakness is usually over a period of days or weeks. In the genetic myopathies, such as the various types of muscular dystrophy, and in progressive spinal muscular atrophy, the onset is usually insidious. In the neonatal period the clinician must be alerted to the possibility of myotonic dystrophy, myasthenia gravis, or one of the other congenital myopathies when the newborn has difficulty swallowing or sucking or has respiratory difficulties not easily explainable on the basis of pulmonary disease.

It is often difficult for parents to describe hypotonicity in the neonatal period. However, some parents will describe their babies as feeling like "wet sponges" or "rag dolls." This, obviously, should alert the physician to the possibility of one of the floppy-baby syndromes.

When fatigability is the presenting symptom, the physician should be aware of the possibility of hyperthyroid myopathy,2 especially in an older child. When fatigability is associated with diplopia or when diplopia is the presenting complaint, the diagnosis of myasthenia gravis must be considered.6 Diplopia is not a presenting complaint in ocular muscular dystrophy.

Observant parents sometimes report that their children have difficulty letting go of objects once they have grabbed hold of them - for instance, in letting go of the door knob after opening the door. This should alert the physician to the possibility of myotonia, the inability to relax after a voluntary muscular contraction. Garbled speech noted after eating iced foods (associated with myotonia of the tongue induced by cold) may be one of the presenting complaints of patients with paramyotonia congenita or myotonia congenita.2 Reduced intrauterine movements in the third trimester are sometimes reported by mothers of babies with spinal muscular atrophy or arthrogryposis.

Congenital hip dislocations, espedally when noted in more than one member of the family, and other orthopedic abnormalities - such as scoliosis, flat feet, pes cavus, and sloping of the shoulders - should alert the physician to the possibility of an underlying neuromuscular disorder. For example, central core disease is frequently associated with congenital hip dislocation.7 Sloping of the shoulders may be one of the early presenting symptoms of facioscapulohumeral muscular dystrophy, and young women patients may complain that their brassiere straps constantly fall over their shoulders.

An unusual craving for table salt or salty foods is sometimes associated with one of the mitochondrial myopathies.8

Signs. It goes without saying that a general physical examination should not be excluded when the patient has one of the above symptoms, but certain features of the examination should be emphasized (Table 3). For example, when a patient has as his major symptom a subacute onset of weakness in his extremities, a subtle rash, indicating dermatomyositis, should be carefully sought. The rash may be most clearly visible over the eyelids and cheeks, on the extensor surfaces of the knees and elbows, and over the knuckles and dorsal surfaces of fingers immediately proximal to the nail beds. Special attention must also be paid to the presence of musculoskeletal abnormalities. An increase in the lumbar lordosis, for example, is seen rather early in various types of muscular dystrophy. Pes cavus is sometimes associated with hereditary peripheral neuropathies. The presence of scoliosis should always alert the physician to the possibility of an underlying muscular disorder. Congenital hip dislocations are observed in central core disease and nemaline myopathy, among other congenital myopathies.

Absent muscles, although sometimes present as an isolated abnormality (especially pectoralis and sternocleidomastoid muscles), are sometimes associated with a muscular disorder such as myotubular myopathy.9 Absence of the pectoralis muscles is sometimes associated with absence of other muscles of the same extremity, occasionally with syndactyly, and more rarely with leukemia. Long tapering fingers and toes are occasionally associated with congenital myopathies, such as nemaline myopathy.

It is also important to examine the patient for mental retardation. Patients with Duchenne muscular dystrophy, Becker's muscular dystrophy, and myotonic dystrophy are frequently overtly retarded. Becker's muscular dystrophy is sometimes associated with color blindness.

Table

TABLE 3CHECKLIST FOR EXAMINATION

TABLE 3

CHECKLIST FOR EXAMINATION

Of paramount importance, obviously, is the examination of the motor system. Methods vary with the age of the patient. The infant patient should first be observed in both the prone and the supine position for paucity of movements of the extremities. Then evaluation of muscle tone and assessment of muscle strength can be performed. The physician should acquaint himself with the normal tone of infancy, but we do not put a great deal of emphasis on the so-called quantitative methods. The physician should also be careful in evaluating tone solely on the basis of a single examination, as tone may change considerably with changes in the baby's sleeping or waking state and may vary with his degree of hunger. In older infants and younger children, strength is generally assessed on the basis of functional examination, such as watching the baby creep and attempting to sit up, stand, or walk. Certainly, under any circumstances, the physician should determine whether there is a great deal of gross motor lag compared with normal adaptive, fine motor, and language development. The quality of head control can be assessed by performing the traction response (attempting to pick the child up by his arms when he is in the supine position).

When a patient is able to walk, it is always mandatory to observe his gait. Waddling, for example, is an indicator of a proximal muscle weakness. Toe-walking, seen commonly early in Duchenne muscular atrophy, is also observed in the other disorders listed in the previous section. Foot drop may be one of the early manifestations of hereditary peripheral neuropathies; in this situation, the front portion of the soles of the shoes may be extensively worn. Weakness of the upper extremities can also be observed when attempting to wheelbarrow the child - that is, holding him by his legs and asking him to walk on his hands. The child should also be observed while running and hopping and while walking up and down stairs. His need for holding on to a bannister while ascending stairs should be observed. The patient's ability to push himself up after a deep knee bend should also be watched, as should his ability to rise from a supine position on the floor; during the latter movement, if he has to hold on to another object to pull himself up or climb up on his own body using his hands to push himself up (Gower's maneuver), this usually indicates proximal muscle weakness in the lower extremities. The need for the patient to overextend (lock) his knees during walking usually also points to the presence of quadriceps muscle weakness.

Generally, in children over three or four years of age, manual muscle testing can be used to assess strength.10 At least the deltoid, biceps, and triceps should be assessed, as well as wrist extensors and hand grasp, in the upper extremities, and the quadriceps muscles, hamstrings, and dorsiflexors of the feet in the lower extremities. From this brief assessment the physician can determine whether the weakness is generalized, proximal, or distal, and he can also tell whether the weakness is symmetrical or asymmetrical. Certain muscles, such as the brachioradialis and the anterior tibialis, are involved early in Duchenne muscular dystrophy. Flexor muscles of the neck are involved early (frequently) in inflammatory myopathies and only late in genetic myopathies, such as muscular dystrophy.

While the patient's strength is being assessed, attention should be paid to the presence or absence of muscle wasting. As a general rule, in the early stages of polymyositis and dermatomyositis, the muscles are not wasted despite the weakness. In an obese child or a young infant it may be difficult, because of large amounts of subcutaneous tissue, to assess muscle wasting. Muscle mass should also be assessed; isolated large muscles, sometimes firm and sometimes rubbery to palpation, are noted most commonly in the calf in Duchenne muscular dystrophy and Becker's muscular dystrophy. Large calves may also be seen in juvenile progressive muscular atrophy and in hyperkalemic periodic paralysis. An anterior sloping of the shoulders, associated with an elevation of the scapula, is seen in patients with facioscapulohumeral muscular dystrophy, especially when their arms are abducted. In myotonia congenita, in some hypothyroid infants, and, at times, in the early stage of Duchenne muscular dystrophy, the muscle mass may be enlarged throughout.

When the patient's gait is bizarre and when the functional disabilities are far out of proportion to what could be explained on the basis of manual muscle testing, the physician should consider an inorganic disorder.11

Fasciculations in muscles are not commonly seen in children, but they should be sought when the child is at rest. The ability of the child to relax his muscles after voluntary contraction is best looked for after allowing him to grasp the examiner's extended index and middle fingers; delayed relaxation is indicative of myotonia (reflex myotonia). The examiner should also look for percussion myotonia, elicited by a rapid percussion of the thenar mass; the contraction in the percussed muscle will be followed by a markedly delayed relaxation in patients with myotonia. At times this response is accentuated by immersing the hand in ice water. The ability of the child to hold his outstretched hands still should be observed. A peculiar movement disorder (minipolymyoclonus), characterized by tremulousness, has been observed in children with the rather slowly progressive form of spinal muscular atrophy12 or in Charcot-Marie-Tooth disease. This movement is not observed in muscular dystrophy and can sometimes be used to differentiate these disorders.

Assessment of the patient's deep tendon reflexes is obviously part of every examination. These reflexes are commonly lost early in progressive spinal muscular atrophy. As a general rule, the deep tendon reflexes are also lost in Duchenne muscular dystrophy, with one glaring exception: the ankle jerks are well preserved until the disease becomes markedly advanced. The same holds true for Becker's type of muscular dystrophy. In peripheral neuropathies, the reflexes are generally lost. It must be remembered that the presence of normal reflexes, or occasionally of hyperactive reflexes, does not preclude the diagnosis of a muscle disease. Reflexes, for example, in dermatomyositis are frequently preserved despite the presence of weakness. In hypothyroid myopathy, the reflexes may be "hung up." Pathologic reflexes are not observed in muscular diseases. At times, because of severe muscle wasting and weakness, there will be no response to a noxious stimulus of the sole of the foot.

A careful sensory assessment is also performed routinely, although sensory perception is not disturbed in muscle diseases. The loss of central recognition of pain, detected in infants by the lack of crying after the skin is stimulated by a needle, can sometimes assist the clinician to distinguish infantile progressive spinal muscular atrophy, in which there are no sensory abnormalities, from a transection of the cervical cord, as is occasionally seen following a breech delivery. In this condition there is a sensory level. Reduced vibratory and touch perception may be observed in peripheral neuropathies.

In the assessment of a patient with weakness, special attention is also paid to the muscles supplied by the cranial nerves. Extraocular muscles are involved in only a few muscle diseases, such as myasthenia gravis, ocular dystrophies, myotubular myopathy, and Möbius syndrome.13 A lid lag is sometimes seen in myotonia congenita and can also be seen in hyperthyroid myopathy. Facial muscles are involved rather early in facioscapulohumeral muscular dystrophy, and they may be involved in the later stages of other types of muscular dystrophy. In facioscapulohumeral muscular dystrophy, this is demonstrated by the inability of the patient to whistle, blow up a balloon, or close his eyelids against resistance- In myotonic dystrophy the face has a peculiar blank appearance, which may be coupled with ptosis. Facial muscle weakness, coupled with external ophthalmoplegia, is also seen in Möbius syndrome. Facial muscle weakness is also seen in GuillainBarré syndrome but not as an isolated finding. Hearing is generally not affected in muscular diseases, but in myotonic dystrophy the patients may have a high-frequency deficit when tested.

Muscles of mastication are involved rather early in myotonic dystrophy, and a temporal hollowing can be observed and felt. Sternocleidomastoid muscle weakness and wasting are also observed in myotonic dystrophy, sometimes early in the disease, and can easily be identified by asking the patient to push his chin to the side against resistance. Normally the sternocleidomastoid muscle is an easily observed thick muscle. The tongue should be carefully observed for wasting and for fasciculations. Fasciculations are seen in infantile progressive spinal muscular atrophy and in some of the more benign types of spinal muscular atrophy. At times it is difficult to assess small movements of the tongue, which are normally seen in infancy, and to differentiate them from the fasciculations seen in spinal muscular atrophy. Tongue myotonia is seen in myotonic dystrophy and in myotonia congenita, and it can be elicited by asking the patient to stretch his tongue out while the examiner covers the patient's bottom teeth with a tongue depressor. A second tongue depressor is then held perpendicularly over the patient's outstretched tongue and percussed. A rapid contraction of the muscles of the tongue and a markedly delayed relaxation (myotonia) can readily be observed.

GENETIC STUDIES

A careful genetic history, which may entail actual examination of many members of the patient's family, is often of great help, in either a positive or a negative sense, in establishing a correct diagnosis. For example, the finding of muscular dystrophy in more than one member of a family, although not precluding the diagnosis of an inflammatory myopathy in an individual member, makes it unlikely. Consanguinity in parents may suggest autosomal recessive disease. Either conscious or subconscious denial of illness is very common in certain muscular disorders, such as myotonic dystrophy and facioscapulohumeral muscular dystrophy. The proband under investigation may, for example, be a child with minimum facial muscle weakness and winging of the scapula; in taking a family history, one may receive negative answers about other members' being affected. Examination of other members of the family may reveal sloping shoulders, weakness of eye closure, or inability to whistle - problems that are often overlooked and not recognized as being abnormal - and even overt weakness that has been denied. These findings may enable the clinician to establish the true autosomal dominant nature of the disorder and, thus, the correct diagnosis.

Similarly, in myotonic dystrophy, some members of the family minimally or moderately affected with this likewise autosomal dominant disease may not be aware that they actually have a disorder but suffer from a "family trait." Several of the congenital myopathies, such as nemaline myopathy, and central core disease are frequently autosomal dominant, but some members of the family may be only minimally affected. The importance in determining the mode of inheritance of these and other disorders is to enable the physician to provide appropriate genetic counseling to family members.

Questioning about genetic disorders in the family must be done rather gingerly, not to enhance existing guilt feelings in the family. Many families are willing to discuss the presence of a serious disorder among their members, and many are willing to discuss the question of consanguinity; but others are not, at least during the initial interview. In X-linked diseases, such as Duchenne muscular dystrophy and Becker's muscular dystrophy, the revelation to the family of the X nature of the genetic inheritance may add special guilt feelings to the patient's mother and evoke a great deal of anxiety in the patient's female relatives. For this reason, it may be wise for the clinician to refer the family with a muscular disorder to a genetic counseling program, available in many institutions, where more sophisticated studies may be available.

BIOCHEMICAL STUDIES

A standard battery of serum "muscle enzymes" may be very helpful in ascertaining whether a patient has a muscle disease or not and in ascertaining the nature of the disorder.14 These enzymes include creatine Phosphokinase (CPK), serum glutamic oxaloacetic and serum glutamic pyruvic transaminases (SGOT and SGPT), lactate dehydrogenase (LDH), and aldolase. The CPK determination has proved over the years to be the most valuable of the enzymes listed. The value for CPK is virtually always very high in Duchenne and Becker's muscular dystrophy, even before the onset of overt muscular weakness, but the clinician should be aware that in the other forms of muscular dystrophy the values for CPK may be within normal limits or only moderately elevated. Similarly, in inflammatory myopathies, although the values for at least one of the serum muscle enzymes are usually high, it must be remembered that there are isolated cases in which the values are normal. In spinal muscular atrophy, most prominently in the juvenile type or in the protracted infantile type, values of CPK may be moderately elevated, making the distinction between "myopathy" and "neuropathy" difficult on a biochemical basis alone.

It must be remembered that although muscle enzyme determinations, particularly CPK, are very useful in diagnosing asymptomatic carriers of X-Iinked disease, such as Duchenne and Becker's muscular dystrophy, less than two-thirds of known carriers have high CPK values. Female relatives of patients with these disorders should have CPK determinations performed at the earliest age possible, since the values - and thus the yield - may diminish with advancing age.

In many of the congenital myopathies, the values for muscle enzymes may be normal or just minimally elevated. In rhabdomyolysis, malignant hyperpyrexia, and other disorders in which muscle destruction is acute, the enzyme values may be strikingly elevated and the patient may have pigmenturia. The presence of myoglobinuria in these disorders (and in McArdle's disease and phosphofructokinase absence of muscle, both rare) can be suspected when the standard test for blood in the urine is positive in the absence of red blood cells. This screening test should always be confirmed with electrophoretic or immunologic methods. When these disorders are suspected and the patient is old enough to cooperate, he should be asked to perform ischemic work (opening and closing his hand forcefully for as long as he can while a blood pressure cuff on his arm is inflated to a value above the systolic pressure). At the end of the period of ischemic work, the venous pyruvate and lactate values should rise appreciably above baseline values; in the absence of this rise, a defect in glycogen breakdown should be considered. Myoglobinuria has also been described in an unusual lipid storage disease.

Isoenzyme studies of CPK and LDH have some clinical usefulness, but they are not part of the routine diagnostic program. Similarly, determination of urinary excretion of creatinine and creatine have no major diagnostic usefulness; abnormal values may be indicative of diminished muscle mass.

ELECTRODIAGNOSTIC STUDIES

There are two major categories of studies that are performed in the electrodiagnostic laboratory: (1) nerve conduction velocity determinations, which may be either motor or sensory, performed with surface electrodes; (2) electromyography, performed with needle electrodes. We perform these studies without sedation, but some investigators believe that sedation is necessary. Slow nerve conduction velocities may be extremely useful in diagnosing peripheral nerve involvement, such as that seen in hereditary peripheral neuropathies. These studies may also be useful in distinguishing infantile progressive spinal muscular atrophy from the much rarer peripheral neuropathy of infancy. Repetitive stimulation of peripheral nerves may also be helpful in the clinical diagnosis of myasthenia gravis, but it must be remembered that in a small child this is a very difficult test to interpret.

One of the most useful purposes for electromyography in children is in confirming the presence of myotonia; this can usually be accomplished using a single electrode in the thenar muscle mass, and in just a few seconds the diagnosis can be established. In patients in whom reflex and percussion myotonia is only minimal, this test can be ven,' helpful; it must be remembered, however, that in infants and young children with myotonic dystrophy, the electrical myotonic response may be absent.

In routine diagnostic electromyography, muscles are sampled first at rest; no electrical activity should be recorded. Fibrillations and positive sharp waves may indicate denervation, but these are occasionally recorded in distal muscles in normal young infants. Muscles are then tested during minimal volitional activity; an analysis of recorded single motor unit potentials with respect to duration and amplitude may be helpful in distinguishing myopathies from neuropathies. (Recent studies, however, have emphasized the difficulties encountered in this analysis.) Muscles are then tested at maximum volitional contraction, which may be painful; the patterns thus obtained may also be useful in attempting to distinguish neuropathic from myopathic processes.

Electromyography is very helpful in helping the clinician to establish a diagnosis of polymyositis. Several areas can be sampled with the needle electrode, and the finding of fibrillations, short-duration single motor unit potentials, and bizarre highfrequency potentials can be interpreted as suggesting an inflammatory myopathy.

It must be remembered that in many of the congenital myopathies, results of electrodiagnostic studies may be completely normal.

In attempting to diagnose asymptomatic carriers of X-linked muscular dystrophy, detailed electromyographic study may add slightly to the yield of positivity over the biochemical studies.

PATHOLOGIC STUDIES

As a general rule, a patient in whom muscle diseases is suspected (and in whom the diagnosis is not confirmed by other methods) should be subjected to a muscle biopsy, provided appropriate provisions can be made to study the morphology and histochemistry of the sections of muscle tissue.15 Valuable diagnostic information can be obtained only when an appropriate muscle is biopsied and only when the specimens are handled in the proper manner. A muscle that is severely wasted should not be selected for study. In an acute or subacute problem, such as polymyositis, it is best to select an involved muscle for biopsy in order to provide the highest yield. In a chronic problem, generally one of the proximal muscles (which can be removed without any technical difficulty) can be selected. The procedure should not be cosmetically harmful to the patient. It has become advisable to select a muscle in which there is a known proportion of histochemically defined fiber types; these include biceps, quadriceps, deltoid, and gastrocnemius muscles. Under no circumstances should a biopsy for diagnostic purposes be taken in a muscle that has undergone recent injections or trauma. It is advisable to avoid areas in which electromyography or acupuncture has been performed.

Before biopsy, the child can be sedated. Our routine for younger children is 1 mg. /kg. of meperidine (Demerol®) plus up to 8 mg./kg. of secobarbital (Seconal®), given intramuscularly in a site distant from the biopsy site one hour before the procedure. Older children can be given meperidine and diazepam (Valium®) intravenously immediately before the procedure, with the usual precautions. The area over the muscle, but not the muscle itself, is anesthetized with a local anesthetic not containing epinephrine. An incision approximately 1-1 V2 inches long is generally made over the muscle belly, and sections of muscle tissue are taken that preserve the normal orientation and stretch of the bundles. The surgeon should stay away from the myotendinous junction. Sections are fixed in formalin for routine studies and in glutaraldehyde for electron microscopic studies. Other sections are frozen rapidly in isopentane cooled to approximately -160° C. with liquid nitrogen. If facilities to perform this technique are not available in the institution in which the biopsy is being performed, the procedure may be delayed for several hours while the oriented specimen, kept slightly moist with a saline-soaked sponge at room temperature, is delivered to one of the recognized centers for histochemical studies.

Histochemical evaluation of a muscle biopsy is part of the essential diagnostic studies; this will permit demonstration of fiber typing and provide data about selective involvement of single fiber type and specific enzyme involvement. Excesses of intracellular glycogen or lipid can also be identified using appropriate studies. In addition, rods (as seen in nemaline myopathy), cores (as seen in central core disease), and targets (as noted in denervation) can be identified readily; they are, on the other hand, not readily identified when form a Ii ? -fixed, paraffinembedded tissue is used for diagnosis. When used for morphologic studies, tissue frozen in liquid nitrogen will provide clearly interpretable specimens, especially when accurate cross-sections are cut. Generally, the finding of groups of small fibers indicates a neuropathic process, whereas the finding of isolated architectural abnormalities, internally placed nuclei, an increased variation in fiber size, and an increase in endomysial connective tissue and fat indicates a myopathic process, such as that observed in muscular dystrophy. When cellular infiltrates are found, a diagnosis of inflammatory myopathy can be confirmed.

Ultrastructural analysis of muscle is not generally performed routinely for diagnostic purposes; at times it can provide details not seen with light microscopy, such as mitochondrial alterations.

At the time of biopsy, small sections may be taken and preserved for biochemical studies; in this way, definitive diagnosis can be made of some of the glycogen storage diseases and lipid storage myopathies. In specialized centers, mitochondrial studies can be performed on unfixed and unfrozen muscle tissue.

ANCILLARY STUDIES

The following studies are not necessarily performed as part of the routine examination of every patient with muscle weakness, but they can be performed when a high index of suspicion exists for an individual disorder. Appropriate skeletal x-rays can be ordered when an underlying osseous or cartilaginous disorder is suspected. An example of this is the mild form ot osteogenesis imperfecta, in which muscular hypotonia may be seen. In very acute and especially in periodic weakness, determination of serum electrolytes, with particular reference to potassium, should be made. In the hypokalemic form of periodic paralysis, one can readily identify the hypokalemia; the converse is not necessarily true in the hyperkalemic form of periodic paralysis, where a definite search for the hyperkalemia, using either serum electrolytes or electrocardiographic determinations, must be undertaken. Other electrolytes should be measured in the presence of acute weakness to rule out disorders that may simulate muscular disease.

The erythrocyte sedimentation rate (ESR) is sometimes elevated in dermatomyositis of childhood, but a normal ESR does not at all preclude this diagnosis.

Determination of an elevated cerebrospinal fluid protein can be helpful in substantiating the diagnosis of Guillain-Barré syndrome or other selected peripheral neuropathies. An electrocardiagram may reveal alterations in the wave forms or conduction abnormalities, common only in myotonic dystrophy and in Duchenne dystrophy (despite the absence of clinical symptoms). Other forms of muscular dystrophy and other disorders in which myotonia is a feature, such as paramyotonia and myotonia congenita, do not generally have accompanying electrocardiographic changes. In the form of infantile glycogen storage disease in which there is an acid maltase deficiency in muscle, cardiomegaly may be observed on chest x-ray; in the more benign form, however, an enlarged heart is not seen.

An important pharmacologic test in the diagnosis of myasthenia gravis is the edrophonium (Tensilon) test, usually performed with intravenous administration of this drug.8 An easily established end point must be determined to evaluate the results of the test, such as the elimination of ptosis shortly after the drug is given. The effect of this drug is prompt and temporary, lasting generally not more than one-quarter hour. When the diagnosis of myasthenia gravis still remains in doubt, a regional curare test can be performed; but this must be done with caution, since patients with myasthenia gravis will at times become paralyzed from relatively small doses of curare.

Thyroid function studies may be performed when a dysthyroid state is suspected, and it should be remembered that hyperthyroidism may accompany myasthenia gravis. The hypothyroid state may be associated with weakness and enlargement of the muscles and, at times, with muscle pain. Hyperthyroid myopathy may present with easy fatigability and proximal muscle weakness.

When a mitochondrial myopathy is suspected, oxygen consumption studies can be performed to rule out an extrathyroidial hypermetabolic state, which is rarely seen.

When myotonic dystrophy is suspected, ophthalmologic examination, including a slit-lamp examination, can sometimes determine the presence of early lenticular opacities, commonly seen in this disorder.

In the presence of a painful weakness syndrome following a generalized gastrointestinal disorder, a trichina skin test can be performed and a white blood cell count for eosinophilia can be done.

CONCLUSION

Using the guidelines as outlined above, the clinician can usually formulate an accurate diagnosis, necessary for appropriate genetic counseling and management not only of the patient with muscle weakness but also of his entire family.

BIBLIOGRAPHY

1. Worden, K. D.. and Vignos. P. J., Jr. Intellectual function in childhood progressive muscular dystrophy. Pedatrics 29 (1962), 968.

2. Spiro, A. Unusual myopathies. In Swaiman, K. F.. and Wright, F. S. (eds.). The Practice of Pediatric Neurology, Volume 2. St. Louis: C. V. Mosby Company, 1975, pp. 1008-1021.

3. Rowland, L P., et al. The clinical diagnosis of McArdte's disease: Identification of another family with deficiency of muscle Phosphorylase. Neurology 16 (1966). 93.

4. Layzer. R. B.. Rowland, L. P.. and Ranney, HM. Muscle phosphof ructokinase deficiency. Aren. Neurol. 17 (1967), 512.

5. Savage. D. C. L. Forbes. M . and Pearce. G. W. Idiopathic rhabdomyoiysis. Arch. Dis. Child. 46 (1971). 594.

6. Swaiman. K. F. Diseases of the neuromuscular junction. In Swaiman. K. F., and Wright. F. S. (eds). The Practice of Pediatric Neurology, Volume 2. St. Louis: C. V. Mosby Company. 1975. pp. 978-989.

7. Armstrong. R. M. et al Central core disease with congenital hip dislocation: Study of two families. Neurology21 (1971). 369.

8. Spiro, A, J., Prineas, J. W., and Moore. C. L. A new mitochondrial myopathy in a patient with satt craving. Arch. Neurol. 22 (1970), 259

9. Spiro, A. J.. Shy, G. M., and Gonatas. N. K. Myotubular myopathy. Arch. Neurol. 14 (1966). 1.

10. Aides to the Investigation of Peripheral Nerve Injuries. London: Her Majesty's Stationery Office. 1943.

11. Dubowitz, V-. and Hersov. L. Management of children with non-organic (hysterical) disorders of motor function. Dev. Med. Child Neurol. 18 (1976), 358.

12. Spiro. A. J. Minipolymyoclonus: A neglected sign in childhood spinal muscular atrophy. Neurology 20(1970). 1124.

13. Pitner. S.. Edwards. J., and McCormick, W. Observations on the pathology of the Moebius syndrome. J. Neurol. Neurosurg. Psychiatry 28 (1965). 362

14. Munsat. L . et al. Serum enzyme alterations in neuromuscular disorders JAMA 226 (1973). 1536.

15 Dubowitz. V . Brooke. M. R. and Neville. H E Muscle Biopsy: A Modem Approach. Philadelphia: W. B. Saunders Company. 1973.

TABLE 1

APPROACH TO THE CHILD WITH MUSCLE DISEASE

TABLE 2

CHECKLIST FOR HISTORY TAKING

TABLE 3

CHECKLIST FOR EXAMINATION

10.3928/0090-4481-19770301-05

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