DNB PEDIATRIC

1. Gopakumar.H
Specialist Neonatology Trainee
Adelaide

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

8.  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

9.
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

10.
Infantile spinal muscular atrophy
Traumatic myelopathy ( esp following breech
delivery )
Hypoxic ischemic myelopathy
Infantile neuronal degeneration

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

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

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

14.  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

15.  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

16. 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).

19.  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

20.  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

21. 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.

22. 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.

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

24.  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


25. 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.

26. 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 .

27. 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.

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

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

30.
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.

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

32. 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

33.  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.

34.  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.

35.  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

36.  Decreased resistance to flexion and extension of
the extremities
 Exaggerated hip abduction & ankle dorsiflexion
 Oral-motor dysfunction
 Poor respiratory efforts
 Gastroesophageal reflux
 Note the distribution of weakness ex .face is
spared versus the trunk and extremities.

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

38. 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

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

41.  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

43.  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

44. 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

45.  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.

46.  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

47. 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.

49.  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

50.  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.

51. 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.

52.  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)

53.  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.

54.  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

55.  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

56.  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

57. 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

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