A Schematic Approach to Hypotonia in Infancy

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NEUROLOGY SUBSPECIALTY ARTICLE

A schematic approach to hypotonia in infancy

JoAnna Leyenaar MD MPH, Peter Camfield MD FRCPC, Carol Camfield MD FRCPC

J Leyenaar, P Camfield, C Camfield. A schematic approach Une démarche schématique envers l’hypotonie to hypotonia in infancy. Paediatr Child Health 2005; pendant la première enfance 10(7):397-400. L’hypotonie peut être le signe révélateur de nombreuses maladies Hypotonia may be the presenting sign for many systemic diseases and systémiques ou du système nerveux. Le présent article traite d’une diseases of the nervous system. The present paper discusses a rational, démarche diagnostique rationnelle, simple et précise envers l’hypotonie simple and accurate diagnostic approach to hypotonia in infancy, pendant la première enfance, illustrée par le cas d’une fillette de cinq mois illustrated by the case of a five-month-old infant girl recently referred récemment aiguillée vers le IWK Health Centre de Halifax, en Nouvelle- to the IWK Health Centre in Halifax, Nova Scotia. Key points in the Écosse. Les principaux points de l’anamnèse et de l’examen physique sont history and physical examination are outlined to allow a tailored exposés afin de permettre une exploration personnalisée de la patiente et investigation both for the patient and for other hypotonic infants. A des autres nourrissons hypotoniques. Un exposé sur une importante discussion of an important neuromuscular disease, diagnosed in the maladie neuromusculaire, diagnostiquée chez la patiente, conclut l’article. present patient, concludes the paper.

Key Words: Hypotonia; Infant; Spinal muscular atrophy

nfants with hypotonia pose challenges for clinicians respiratory syncytial virus-positive bronchiolitis. The family Ibecause hypotonia may be the presenting sign of both history was unremarkable and there was no consanguinity. benign and serious conditions. On first glance, the magni- The infant’s mother had antiphospholipid syndrome. There tude of the differential diagnosis, the rarity of associated ill- was a seven-year-old, healthy male sibling. nesses, and the ongoing advances in diagnosis and On examination, the infant looked well, with no dys- management may appear overwhelming. morphic features. Height, weight and head circumference The present paper discusses a practical approach to were between the 75th and 90th percentiles. She had a hypotonia in infancy. Key elements in the child’s develop- strong cry and no fasciculations of the tongue were noted. mental and medical history and physical examination are Respiratory, cardiovascular and abdominal examinations outlined. The case of a five-month-old infant girl, recently were normal. Cranial nerves were normal, including seen at the IWK Health Centre in Halifax, Nova Scotia, extraocular movements. She had marked hypotonia on hor- provides a basis for discussion. izontal and vertical suspension. Tightness of the hip adduc- tors and knee extensors was noted. She had a weak grasp CASE PRESENTATION and was unable to reach forward. Primitive reflexes were A five-month-old infant girl was brought to her family absent. Deep tendon reflexes could not be elicited. physician after a family friend expressed concern that she was unable to raise her upper body when lying prone. Her Step 1: Understanding the terminology parents stated that she had made no attempts to roll over, A key distinction is to determine whether the infant has rarely moved her legs and made no attempts to push with low tone with or without muscle weakness. Tone is her feet when held upright. She put toys into her mouth defined as the resistance of muscles to stretch (1); there- using both hands but did not reach farther than 10 cm for fore, hypotonia is diminished resistance of muscles to pas- objects before her. She laughed and interacted with those sive stretching. With respect to infantile hypotonia, it around her and became excited at the sight of food. She may be considered the “least resistance that an alert (but breastfed well and seemed to have tolerated the recent not overstimulated) infant generates while opposing pas- introduction of rice cereal without coughing, choking or sive movement” (2). In contrast, weakness is diminished vomiting. She often squealed and seemed to respond to her muscle power or strength. While weak infants are always name. No loss of milestones was reported. hypotonic, hypotonia is often present with normal She had been born at 38 weeks by spontaneous vaginal strength (2). delivery with no prenatal or postnatal concerns. Apgar Hypotonia is caused by disorders that affect any level of scores were 8 at 1 min and 5 min, with points lost for colour the nervous system – brain, brain stem, spinal cord, periph- and tone. At three months, she had been hospitalized for eral nerves, neuromuscular junction and muscle. Figure 1 Department of Pediatrics, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia Correspondence: Dr Peter Camfield, IWK Health Centre, 5850 University Avenue, PO Box 3070, Halifax, Nova Scotia B3J 3G9. Telephone 902-470-8479, fax 902-470-8486, e-mail [email protected]

Leyenaar et al

difficulties and failure to thrive. Therefore, a detailed feeding history from birth may provide valuable diagnostic clues. A Nerve • Congenital diagnosis of infantile botulism may be prompted by a history hypomyelinating neuropathy of honey or corn syrup consumption; contamination of these • Familial dysautonomia • Infantile neuraxonal products with Clostridium botulism may account for up to 20% Central Nervous degeneration of botulism cases during infancy (1). The family history may System • Chromosome be very revealing: a history of repeated abortions may suggest disorders (ie. Prader-Willi) . a variety of disorders with prenatal onset, developmental • Metabolic diseases . Muscle • Spinal cord injuries • Muscular delay (a chromosomal abnormality), delayed motor mile- dystrophies • Cerebral Motor stones (a congenital myopathy) and premature death (meta- dysgenesis • Metabolic Neuron myopathies • Hypoxic-ischemic bolic or muscle disease). injuries • Spinal • Central core muscular disease/fibre atrophies myopathies • Other Step 3: The physical examination Neuromuscular Junction congenital myopathies • Congenital and transient The physical examination typically narrows the differential myasthenia gravis • Infantile botulism diagnosis markedly. The degree of hypotonia may be initially inferred by assessing the infant’s posture while supine; truly Figure 1) Anatomical-clinical correlation illustrating differential diag- hypotonic infants may lie ‘frog-legged’, with hips adducted nosis of hypotonia in infancy and knees flexed. A lack of spontaneous movement suggests weakness. illustrates common diseases with hypotonia as a prominent In assessing tone, the child should be alert but not cry- feature and their anatomical correlates. ing. Extremity tone is readily assessed by passive movements. The term ‘benign congenital hypotonia’ was historically Truncal and nuchal tone may be best examined using tests of used as a diagnosis for infants who were hypotonic in the horizontal and vertical suspension. On vertical suspension, a absence of other signs and symptoms, and who had normal healthy infant should maintain the head upright and mid- tone in later childhood. We urge caution in the use of this line without slipping through the examiner’s hands. On ‘diagnosis of exclusion’, especially because it requires many horizontal suspension, the infant should maintain a straight months of follow-up for confirmation. One author argues back with the head upright and limbs flexed. In contrast, that benign congenital hypotonia has not been an appropri- hypotonic infants may wrap over the examiner’s arms. ate diagnosis since the 1960s, when central core disease and While strength may be measured in adults and older a number of other congenital myopathies were described (3). children using a standardized five-point scale, the ability to point, reach and lift may provide more helpful information Step 2: Key elements in the patient’s history in infants (1). Encouraging the caregiver to become Although the list of conditions to be considered in the dif- involved in this portion of the examination may provide ferential diagnosis of hypotonia in infancy is long, the valuable information. Abilities will need to be compared patient’s history may narrow the possibilities significantly. with age-appropriate developmental norms. Details of the pregnancy, delivery and postnatal period are The deep tendon reflexes are likely the most valuable important – a history of preterm delivery; toxoplasmosis, aspect of the physical examination. Brisk reflexes or clonus other infections, rubella, cytomegalovirus infection and indicate CNS dysfunction, while diminished or absent herpes simplex; neonatal seizures; drug and alcohol use; or reflexes point strongly to disorders of the lower motor unit. other pre- or postnatal insult increases the probability of Dysmorphic features sharply increase the likelihood of central nervous system (CNS) dysfunction as the underly- CNS dysfunction as an explanation for hypotonia, although ing etiology for low tone. A history of hip subluxation or a long, narrow face may indicate muscle weakness. Anterior arthrogryposis increases the likelihood of hypotonia in horn cell disease usually spares extraocular muscles, while utero (1). Inborn errors of metabolism should be suspected diseases of the neuromuscular junction may be characterized in an infant with a normal pregnancy and delivery and the by ptosis and extraocular muscle weakness (2). Attention to development of hypotonia after the first day or two of life. the quality of the cry is important because a high-pitched or A developmental assessment is useful. Motor delay with unusual-sounding cry suggests CNS pathology, a weak cry normal social and language development decreases the like- may reflect diaphragmatic weakness, and a fatigable cry may lihood of brain pathology. In contrast, loss of milestones suggest a congenital myasthenic syndrome. increases the index of suspicion for neurodegenerative disor- A head-to-toe physical examination is required to assess ders. A dietary/feeding history may point to diseases of the for potentially associated organ dysfunction and to recog- neuromuscular junction, which may present with sucking nize existing syndromes. Abnormalities of internal organs and swallowing difficulties that ‘fatigue’ or ‘get worse’ with such as the heart or liver are more likely to be associated repetition. Several genetic disorders may present with hypo- with a number of metabolic diseases. In the presence of tonia, including Prader-Willi syndrome, which in later hypotonia, signs of cardiac failure suggest muscle or mito- childhood shows hypotonia, obesity, mental retardation and chondrial disease. Hepatosplenomegaly suggests a lysosomal hypogonadism but is characterized in infancy by feeding or glycogen storage disease (4).

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A schematic approach to hypotonia in infancy

Physical examination of the parents may also provide History: important diagnostic information, especially because a par- Prenatal History: TORCH infections? Drugs or alcohol? Maternal illness? Fetal movements? Neonatal History: Delivery complications? Preterm delivery? Seizures? Initial presentation of ent may have very mild symptoms of a serious disorder. For hypotonia? Past Medical History: History of presenting symptoms? Associated symptoms? Symptoms of systemic example, transitory neonatal myasthenia may be suspected disease? Rate of symptom progression? Developmental History: Delayed milestone attainment? Loss of milestones? Motor, social and language if the mother displays fatiguability of the eyelids with incongruence? Feeding History: Stamina with feeding? Choking or aspiration? Constipation? Honey or corn syrup? upward gaze or fatiguability of the arms with sustained for- Family History: Other children? Consanguinity? Developmental delay? Neurological disease? ward extension. Infants with congenital myotonic dystro- Premature death? Metabolic or genetic diseases? phy have severe hypotonia but their mothers are typically General Physical Examination: only mildly affected and unaware of their disorder. Mothers Head and neck: Microcephaly? Dysmorphic features? Ptosis? Facial expression? Nutritional wasting? with myotonic dystrophy may show grip myotonia, percus- Systems: Cardiovascular findings? Liver enlargement? Splenomegaly? sion myotonia, ptosis and/or distal weakness that they were Skeletal abnormalities? Arthrogryposis? unaware of. Although myotonic dystrophy is inherited as an Neurological Examination: autosomal dominant disorder, when a newborn inherits the Objective – Localize the lesion. gene and shows the striking weakness and bulbar difficulties Cranial nerves: Extraocular movements? Muscles of facial expression? Fasciculations of tongue? of congenital myotonia, the mother, not the father, is nearly Tone: Posture? Horizontal and vertical suspension? Scissoring or spasticity? Strength: Proximal versus distal weakness? Symmetry? always affected (5,6). Reflexes: Hyperactive? Symmetry? Readily elicited? Clonus? Muscles: Atrophy? Symmetry?

Motor Neuron Nerve NM Junction Muscle Step 4: Investigations Tone* normal/ Strength normal/ The history and physical examination should guide the Reflexes absent absent normal/ absent/ Muscle Atrophy normal/ normal/ investigations. If there is good evidence for CNS dysfunction, brain imaging may be the first step. Suspicion of meta- Investigations: General Investigations: TSH, free T4, electrolytes (including calcium) bolic disease will trigger the appropriate tests; an immediate CNS Dysfunction Suspected: CT/MRI head, consider EEG, consult neurology, and consider karyotype search for disorders of energy metabolism, amino acid Metabolic Disease Suspected: Urine and serum amino acids, urine organic acids, blood gas, serum ammonia, liver function tests metabolism, fatty acid metabolism and urea cycle function Lower Motor Neuron Disease Suspected: Creatine kinase, referral to neurology for should be undertaken immediately if the child presents in specialized tests metabolic crisis. These types of disorders may be more read- Figure 2) Schematic approach to hypotonia in infancy. Pertinent posi- ily detected during metabolic crisis than once the child has tives, highlighted in italics, raise suspicion of central nervous system and been stabilized. The presence of particular dysmorphic fea- metabolic diseases. ↑ Increased; ↓ Decreased; CNS Central nervous tures may prompt karyotype testing. Screening for hypothy- system; CT Computed tomography; EEG Electroencephalography; MRI Magnetic resonance imaging; NM Neuromuscular; TORCH roidism should be performed in all infants for whom an Toxoplasmosis, other infections, rubella, cytomegalovirus infection and etiology is not clear. If a disorder of the muscles, nerves or herpes simplex; TSH Thyroid-stimulating hormone. *Adapted from ref- neuromuscular junctions seems likely, a creatine phospho- erence 2 kinase (CPK) test may be useful, keeping in mind that most congenital myopathies are associated with a normal CPK level, while anterior horn cell disease may be associated relevant. First, the infant’s social and communication skills with mild increases. A significant increase in CPK suggests were age-appropriate, while her hypotonia was associated a form of congenital muscular dystrophy. primarily with marked gross motor delay. This increases the Following initial screening tests and noninvasive inves- likelihood of a disorder of the lower motor neuron unit. A tigations, electromyography (EMG), nerve conduction diagnosis of lower motor neuron disease is also supported by studies and muscle biopsy may be considered. If muscle the unremarkable pregnancy and early postnatal course. biopsy or EMG are considered, blood for a CPK test should The physical examination provides further support: absent be drawn before these procedures because the procedures reflexes with decreased strength points decisively to dis- may cause a short-term elevation of the CPK level (1). eases of the motor unit. The absence of ptosis, early severe Given the advances in genetic testing, muscle biopsies are feeding difficulties and extraocular muscle weakness suggests not performed with the same frequency as they were in the that problems in the neuromuscular junction are unlikely past. Specific genetic tests are available for such disorders as and increases the likelihood of motor neuron disease. Prader-Willi and the spinal muscular atrophies (SMAs). Given the results of the history and physical examina- However, many muscular disorders that present with hypo- tion, a diagnosis of SMA seemed very likely. EMG con- tonia in the newborn or infancy period can only be diag- firmed dysfunction in the anterior horn cells, and blood sent nosed specifically using a muscle biopsy. Processing of the for genetic testing confirmed a diagnosis of SMA type 1. biopsy must include sophisticated electron microscopy and Parents were counselled regarding the nature of the disease special staining – a ‘routine’ biopsy may miss significant and the value of supportive care. pathology (7). DISCUSSION REVIEW OF THE CASE The SMAs are a group of diseases characterized by a pro- Reviewing our case presentation in the context of the gressive loss of spinal anterior horn cells, leading to muscu- above discussion and Figure 2, a number of points become lar denervation, atrophy and weakness. It is the second most

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common hereditary neuromuscular disease, with a carrier (11,12). Cerebral causes predominate and one series (12) frequency of one in 50 to one in 80 and an incidence of one suggested that this group of disorders might explain up to in 10,000 to one in 25,000 (8). The most common forms of 88% of cases. Prader-Willi syndrome was particularly SMA are transmitted by autosomal recessive inheritance, important. Paro-Panjan and Neubauer (12) suggested a with the gene defect localized to the motor neuron survival six-step approach to diagnosis. Step 1 was simply the clini- gene (SMN gene) on chromosome 5q. Rare X-linked and cal examination, which allowed a successful diagnosis in autosomal dominant forms have been recognized. 50% of 138 cases. Step 2 was neuroimaging, which diag- SMA type 1, also known as Werdnig-Hoffman disease, is nosed 13% of cases. Step 3 involved a search for dysmor- most commonly described as the acute, infantile form of the phic syndromes, which diagnosed 9%. Step 4 involved disease, with symptoms recognized within the first six karyotyping and fluorescence in situ hybridization tests, months of life. Patients with SMA type 1 rarely develop the which diagnosed an additional 6.5%. Step 5 was made up of ability to sit unassisted and usually die by two years of age biochemical testing, which diagnosed 6%. Step 6 involved (9). SMA type 2 has intermediate severity, often following a muscle and/or nerve biopsy, which diagnosed 6%. The more chronic course. Patients may be able to sit unassisted, remaining patients were only diagnosed with prolonged are generally unable to stand or walk without assistance, but follow-up. Clearly, a careful history and physical examina- may survive well into adolescence or young adulthood (10). tion will provide most of the clues. SMA type 3, Kugelberg-Welander disease, generally mani- fests after 18 months of age and follows a slower disease pro- REFERENCES 1. Fenichel GM. The hypotonic infant. In: Fenichel GM, ed. Clinical gression, with survival into adulthood. Pediatric Neurology: A Signs and Symptoms Approach, 4th edn. Children with SMA type 1 are most frequently per- Philadelphia: WB Saunders Company, 2001:149-69. ceived by parents to be normal during the first months of 2. Crawford TO. Clinical evaluation of the floppy infant. Pediatr Ann 1992;21:348-54. life, with subsequent development of dramatic hypotonia, 3. Thompson CE. Benign congenital hypotonia is not a diagnosis. proximal muscle weakness and absent deep tendon reflexes. Dev Med Child Neurol 2002;44:283-4. The disease is not associated with sensory loss or intellectual 4. Crumrine PK. Degenerative disorders of the central nervous system. Pediatr Rev 2001;22:370-9. impairment. Like our patient, most infants presenting with 5. Darras BT. Neuromuscular disorders in the newborn. Clin Perinatol SMA type 1 appear normal on first glance because extraoc- 1997;24:827-44. ular movements are spared and muscles of facial expression 6. Dubowitz V. The floppy infant syndrome. In: Dubowitz V, ed. Muscle Disorders in Childhood, 2nd edn. London: WB Saunders Company, relatively so. As weakness develops, fasciculations of the 1995:457-72. tongue and fingers may be noted. With disease progression, 7. Johnston HM. The floppy weak infant revisited. Brain Dev feeding and swallowing are compromised, and death usually 2003;25:155-8. 8. Menkes JH, Sarnat HB. Diseases of the motor unit. In: Menkes JH, results from aspiration and respiratory insufficiency. Sarnat HB, eds. Child Neurology, 6th edn. Philadelphia: Lippincott Treatment of SMA type 1 is supportive. Although the Williams & Wilkins, 2000:1027-40. disease is generally described as rapidly progressive, the 9. Markowitz JA, Tinkle MB, Fischbeck KH. Spinal muscular atrophy in the neonate. J Obstet Gynecol Neonatal Nurs 2004;33:12-20. course may be quite variable. Counselling, respite care, 10. Andersson PB, Rando TA. Neuromuscular disorders of childhood. physiotherapy, occupational therapy and other necessary Curr Opin Pediatr 1999;11:497-503. supports should be made available. 11. Richer LP, Shevell MI, Miller SP. Diagnostic profile of neonatal hypotonia: An 11-year study. Pediatr Neurol 2001;25:32-7. Several studies have addressed the relative frequency of 12. Paro-Panjan D, Neubauer D. Congenital hypotonia: Is there an the various causes of neonatal/infantile hypotonia algorithm? J Child Neurol 2004;19:439-42.

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