approach to a floppy infant- for post graduates

its a presentation helpful for post gradutes of pediatrics

1. Dr. Preeti Lata Rai

2. Sign of both benign and serious conditions Exhaustive differential diagnosis Rare disorder Overwhelming advances in diagnosis and management

3. Differential diagnosis of hypotonia in infants. Describe the differences between central and peripheral causes of hypotonia. Evaluation of hypotonia in infants.

4. Tone is the resistance of muscle to stretch. Clinicians test two kinds of tone: phasic and postural. Phasic tone - The rapid contraction in response to a high-intensity stretch , as in tendon reflex response . Postural tone - It is the prolonged contraction of antigravity muscles in response to the low-intensity stretch of gravity. When postural tone is depressed, the trunk and limbs cannot maintain themselves against gravity and the infant appears floppy.

5. The maintenance of normal tone requires intact central and peripheral nervous system . Hence hypotonia is a common symptom of neurological dysfunction and occurs in diseases of the brain, spinal cord, nerves, and muscles.

6. Motor unit - One anterior horn cell and all the muscle fibers that it innervates make up a motor unit . The motor unit is the unit of force. Therefore, weakness is a symptom of all motor unit disorders.  Neuronopathy - A primary disorder of the anterior horn cell body Neuropathy - a primary disorder of the axon or its myelin covering Myopathy - a primary disorder of the muscle fiber

7. Two categories - Central and peripheral disorders . Peripheral causes include abnormalities in the motor unit , specifically in the anterior horn cell (ie, spinal muscular atrophy), peripheral nerve , neuromuscular junction , and muscle Central causes account for 60% to 80% of hypotonia cases and the peripheral causes occur in 15% to 30%. Considerable overlap of involvement and clinical manifestations

8.  Cerebral insult – Hypoxic ischemic encephalopathy , intracranial haemorrhage  Brain malformations  Chromosomal disorders – Praderwilli syndrome , Down syndrome Peroxisomal disorders – cerebrohepatorenal syndrome ( Zellweger’s syndrome) , Neonatal adrenoleukodystrophy Other genetic defects – familial dysautonomia , oculocerebrorenal syndrome ( Lowe syndrome ) Neurometabolic disorders – Acid maltase deficiency , infantile GM1 gangliosidosis Drug effects ( ex Maternal Benzodiazepines ) Benign congenital hypotonia

9. Infantile spinal muscular atrophy Traumatic myelopathy ( esp following breech delivery ) Hypoxic ischemic myelopathy Infantile neuronal degeneration

10. Congenital hypomyelinating neuropathy Giant axonal neuropathy Charcot marie tooth disease Dejerine sottas disease

11. Myasthenia gravis ( Transient acquired neonatal myasthenia ,congenital myasthenia ) Infantile botulism Magnesium toxicity Aminoglycoside toxicity

12. Congenital myopathy Nemaline myopathy Central core disease Myotubular myopathy Congenital fiber type disproportion myopathy Multicore myopathy

13. Congenital muscular dystrophy with merosin deficiency Congenital muscular dystrophy without merosin deficiency  Congenital muscular dystrophy with brain malformations or intellectual disability Dystrophinopathies Walker Warburg disease Muscle – eye – brain disease Fukuyama disease  Congenital muscular dystrophy with cerebellar atrophy / hypoplasia  Congenital muscular dystrophy with occipital agyria  Early infantile facioscapulohumeral dystrophy Congenital myotonic dystrophy

14. Disorders of glycogen metabolism ( ex Acid maltase deficiency ) Severe neonatal phosphofructokinase deficiency Severe neonatal phophorylase deficiency Primary carnitine deficiency Peroxisomal disorders Neonatal adrenoleukodystrophy Cerebrohepatorenal syndrome ( zellweger ) Disorders of creatine metabolism Cytochrome c oxidase deficiency

15. The most common central cause of hypotonia is hypoxic encephalopathy / cerebral palsy in the young infant. However, this dysfunction may progress in later infancy to hypertonia. The most common neuromuscular causes , although still rare, are congenital myopathies, congenital myotonic dystrophy, and spinal muscular atrophy. Disorders with both central and peripheral manifestations ex acid maltase deficiency (Pompe disease).

16. Identify cause and the timing of onset Maternal exposures to toxins or infections suggest a central cause Information on fetal movement in utero, fetal presentation, and the amount of amniotic fluid. Low Apgar scores may suggest floppiness from birth Breech delivery or cervical position – cervical spinal cord trauma

17. A term infant who is born healthy but develops floppiness after 12 to 24 hours – suspect inborn error of metabolism Infants suffering central injury usually develop increased tone and deep tendon reflexes. Central congenital hypotonia does not worsen with time but may become more readily apparent

18. Motor delay with normal social and language development decreases the likelihood of brain pathology. Loss of milestones increases the index of suspicion for neurodegenerative disorders.

19. A dietary/feeding history may point to diseases of the neuromuscular junction, which may present with sucking and swallowing difficulties that ‘fatigue’ or ‘get worse’ with repetition.

20. Developmental delay (a chromosomal abnormality) Delayed motor milestones (a congenital myopathy) and Premature death (metabolic or muscle disease).

21.  Any significant family history – affected parents or siblings, consanguinity, stillbirths, childhood deaths Maternal disease – myotonic dystrophy Pregnancy and delivery history – drug or teratogen exposure Decreased fetal movements Abnormal presentation Polyhydramnios/ oligohydramnios Apgar scores Resuscitation requirements Cord gases History since delivery Respiratory effort Ability to feed Level of alertness Level of spontaneous activity Character of cry 

22. When lying supine, all hypotonic infants look much the same, regardless of the underlying cause or location of the abnormality within the nervous system. Lack spontaneous movement Full abduction of the legs places the lateral surface of the thighs against the examining table, and the arms lie either extended at the sides of the body or flexed at the elbow with the hands beside the head.

23. Hip dislocation - The forceful contraction of muscles pulling the femoral head into the acetabulum is a requirement of normal hip joint formation.  Pectus excavatum indicates long standing long-standing weakness of the chest wall muscles  Infants who lie motionless eventually develop flattening of the occiput and loss of hair on the portion of the scalp that is in constant contact with the crib sheet.  Hip subluxation or arthrogryposis suggest hypotonia in utero .

24. Arthrogryposis varies in severity from clubfoot, the most common manifestation, to symmetrical flexion deformities of all limb joints. Joint contractures - a nonspecific consequence of intrauterine immobilization. As a rule, newborns with arthrogryposis who require respiratory assistance do not survive extubation unless the underlying disorder is myasthenia.

25. High-pitched or unusual-sounding cry - suggests CNS pathology A weak cry - diaphragmatic weakness Fatigable cry - congenital myasthenic syndrome.

26. A comprehensive neurologic evaluation Assessment for dysmorphic features Evaluation of the parents – may point towards specific diagnosis as in myotonic dystrophy .

27. Detailed neurologic assessment - tone, strength, and reflexes Assessment of tone – begin by examining posture, and movement. A floppy infant often lies with limbs abducted and extended.

28. Traction response Vertical suspension Horizontal suspension Further evaluation Of Hypotonia

29. Normal infant - keeps the head erect, maintains the back straight, and flexes the elbow, hip, knee, and ankle joints Baby suspended in the prone position with the examiner’s palm underneath the chest Hyptonia - infants drape over the examiner's hands, with the head and legs hanging limply

30. The most sensitive measure of postural tone Grasp the hands and pull the infant toward a sitting position A normal term infant lifts the head from the surface immediately with the body When attaining the sitting position, the head is erect in the midline for a few seconds. During traction, the examiner should feel the infant pulling back against traction and observe flexion at the elbow, knee, and ankle.

31. The traction response is not present in premature newborns of less than 33 weeks' gestation The presence of more than minimal head lag and of failure to counter traction by flexion of the limbs in the term newborn is abnormal and indicates hypotonia. By 1 month , normal infants lift the head immediately and maintain it in line with the trunk.

32. The examiner places both hands in the infant's axillae and, without grasping the thorax, lifts straight up The muscles of the shoulders should have sufficient strength to press down against the examiner's hands and allow the infant to suspend vertically without falling through Normal response – Head erect in the midline with flexion at the knee, hip, and ankle joints. When a hypotonic infant is suspended vertically, the head falls forward, the legs dangle, and the infant may slip through the examiner's hands because of weakness in the shoulder muscles

33. Decreased resistance to flexion and extension of the extremities E xag g era t e d hip ab d uction & ankle dorsiflexion Oral-motor dysfunction Poor respiratory efforts Gastroesophageal reflux Note the distribution of weakness ex .face is spared versus the trunk and extremities.

34. Deep tendon reflexes (DTRs) often normal / hyperactive in central conditions Clonus and primitive reflexes may persist DTRs - normal, decreased, or absent in peripheral disorders

35. Course of hypotonia - fluctuating, static, or progressive discriminates between a static encephalopathy (as is seen in intellectual disability) and a degenerative neurologic condition (eg, spinal muscular atrophy). Distribution of hypotonia – Ex Face involvement Distribution of hypotonia Ex facial involvement

36. Usually spares extraocular muscles, while diseases of the neuromuscular junction may be characterized by ptosis and extraocular muscle weakness .

37. Hepatosplenomegaly – storage disorders, congenital infections Renal cysts, high forehead, wide fontanelles – Zellweger’s syndrome Hepatomegaly, retinitis pigmentosa – neonatal adrenoleukodystrophy Congenital cataracts, glaucoma – oculocerebrorenal (Lowe) syndrome Abnormal odour – metabolic disorders Hypopigmentation, undesceded testes – Prader Willi

38. Dysmorphic features Depressed level of consciousness or lethargy Abnormal eye movements or inability to track visually Early onset seizures Apnea Exaggerated irregular breathing patterns. Predominant axial weakness Normal strength with hypotonia scissoring on vertical suspension Fisting of the hands Hyperactive or normal reflexes Malformations of other organs

39. Hypoxic ischemic encephalopathy, teratogens, and metabolic disorders may evolve into hyperreflexia and hypertonia, but most syndromes do not. Infants who have experienced central injury usually develop increased tone and deep tendon reflexes

40. Hypotonia, Generalized weakness Absent reflexes, Feeding difficulties Classic infantile form of spinal muscular atrophy Fasciculations of the tongue as well as an intention tremor. Affected infants have alert, inquisitive faces but profound distal weakness.

41. Alert infant and appropriate response to surroundings Normal sleep-wake patterns Associated with profound weakness Hypotonia and hyporeflexia / areflexia Other features - muscle atrophy, lack of abnormalities of other organs, the presence of respiratory and feeding impairment, and impairments of ocular or facial movement

42. A systematic approach to a child who has hypotonia, paying attention to the history and clinical examination, is paramount in localizing the problem to a specific region of the nervous system.

43. Rule out sepsis first - complete blood count , (blood culture, urine culture, cerebrospinal fluid culture and analysis); Measurement of serum electrolytes – calcium and magnesium Liver function tests Urine drug screen Thyroid function tests TORCH titers (toxoplasmosis, rubella, cytomegalovirus infection, herpesvirus infections) and a urine culture for cytomegalovirus ( hepatosplenomegaly and brain calcifications ) Karyotype – Dysmorphism EEG – helps in prognostication Genetic studies - Array comparative genomic hybridization study, methylation study for 15q11.2 (Prader-Willi/Angelman) imprinting defects, and testing for known disorders with specific mutational analysis

44. Complex multisystem involvement on clinical evaluation suggests - inborn errors of metabolism Presence of acidosis - plasma amino acids and urine organic acids (aminoacidopathies and organic acidemias) Serum lactate in disorders of carbohydrate metabolism, mitochondrial disease Pyruvate and ammonia in urea cycle defects Acylcarnitine profile in organic acidemia, fatty acid oxidation disorder Very long-chain fatty acids and plasmalogens - specific for the evaluation of a peroxisomal disorder.

45. MRI Delineate structural malformations Neuronal migration defects Abnormal signals in the basal ganglia (mitochondrial abnormalities) or brain stem defects (Joubert syndrome) Deep white matter changes can be seen in Lowe syndrome, a peroxisomal defect Abnormalities in the corpus callosum may occur in Smith- Lemli- Opitz syndrome Heterotopias may be seen in congenital muscular dystrophy. Magnetic resonance spectroscopy Magnetic resonance spectroscopy also can be revealing for metabolic disease.

46. Diagnosis mainly by history and clinical examination Molecular genetics – CTG repeats, deletions in SMN gene Nerve conduction studies and muscle biopsy (Depending on clinical situation, may be delayed until around 6 months of age as neonatal results are difficult to interpret)

47. Creatine kinase (levels need to be interpreted with caution in the newborn, as levels tend to be high at birth and increase in the first 24 hours, they also increase with acidosis). Repeat after few days , if initial value is elevated Elevated in muscular dystrophy but not in spinal muscular atrophy or in many myopathies.

48. Specific DNA testing - for myotonic dystrophy and for spinal muscular atrophy ( SMN gene ) Electrophysiological studies - Shows abnormalities in nerves, myopathies, and disorders of the neuromuscular junction Normal EMG usually suggest central hypotonia , with few exceptions

49.  Helps to differentiate a primary myopathy from a neurogenic disorder  Helps to differentiate myopathies from muscular dystrophies  Useful in the work-up of undiagnosed weakness  Provide the diagnosis of specific muscular conditions, such as a muscular dystrophy, metabolic or storage myopathies, and inflammatory myopathies. Helps to differentiate active from inactive and acute from chronic conditions. Additional clues can be derived from ultrastructural changes seen with the electron microscope. Various biochemical and genetic studies can be performed on fresh or frozen muscle tissue to measure enzyme levels and perform DNA studies for certain genetic diseases

50. Hematoxylin and eosin (H&E) Trichrome , PAS (for glycogen) Oil red O (ORO) (for lipids) Acid phosphatise (for lysosomal activity) Congo red and cresyl violet (for amyloid)  Myosin ATP ase Staining is useful for fiber-type differentiation Oxidative markers, such as nicotinamide adenine dinucleotide reductase (NADH), succinate dehydrogenase (SDH), and cytochrome C oxidase(COX), are most effective in the diagnosis of enzymatic deficiencies Myophosphorylase and myoadenylate deaminase (AMPAD) for enzyme deficiencies acetylcholinesterase silver stain, may be required in certain cases to show the motor endplates

51. Muscular dystrophy - subgroup of myopathies characterized by muscle degeneration and regeneration. Clinically, muscular dystrophies are typically progressive, because the muscles' ability to regenerate is eventually lost, leading to progressive weakness, often leading to use of a wheel chair and eventually death, usually related to respiratory weakness Congenital myopathies - do not show evidence for either a progressive dystrophic process (i.e., muscle death) or inflammation, but instead characteristic microscopic changes are seen in association with reduced contractile ability of the muscles. Muscle dystrophies Versus Congenital myopathies

52. Mainly supportive – feeding , neurodevelopment Physiotherapy Specific treatment – Pompe disease ( enzyme replacement therapy )

53. Scenario 2 day M in the NICU Poor feeding and “weakness” Not intubated Delivered 37 weeks by C/S – failure to progress Poor maternal pre-natal care HC ~50% Exam – axillary slippage, reduced spontaneous movements, +head lag, normal suck. +awake

54. Perkowski's top 5 not to miss causes of floppy baby Down's syndrome Prader Willi Pompe (have heart problems) Zellweger Spinal Muscular Atrophy However, most common is HIE

55. Question During the health supervision visit for a 6 week old boy, his father expresses concern that his son “doesn’t look like” his other children. Growth parameters are normal except for a head circumference of 35.5 cm (<5th percentile). On PE, you note that the infant does not appear to fixate or track your face visually. There is a “slip through” on vertical suspension and “draping over” on horizontal suspension. DTRs are brisk. Moro reflex is present and brisk. Of the following, the MOST likely cause of this infants hypotonia is:

56. Anterior horn cell disease Congenital brain malformation Congenital myasthenic syndrome Congenital myopathy Spinal cord disease