Hypotonia: The Floppy Infant

Hypotonia: The Floppy Infant
Felicia Gliksman , DO, MPH Pediatric Neurology Joseph M. Sanzari Children’s Hospital Hackensack University Medical Center Assistant Professor Seton Hall University-Hackensack Meridian SOM

Disclosures none

Objectives Identify an infant with hypotonia
Become familiar with the possible etiologies of hypotonia Diagnostic tests used to identify causes of hypotonia Treatment of hypotonia

Case 1 Patient is a 3 month old male, born FT, via NSVD with no significant medical history who was in his USOH until 2 days prior to admission. He had decreased PO intake, “moaning”, and while breastfeeding seemed “lethargic” and “poorly latching on”. No fever, vomit, diarrhea Patient was given Motrin and teething tablets without relief Seen by PMD at home who found patient in a “lethargic state” ROS- lethargy, decreased urine output, decreased movement of extremities

PMHx-none BHx-11lb 2oz, FT, NSVD,no complications Imm-UTD FamHx- parents and 7 siblings all healthy SocHx- lives w/parents and siblings in a house. No pets, no smokers Devp- no reported delays

Case continued Neurological Exam- Awake, weak cry
CN: tracking but slow-180 degrees, pupils nonreactive, mild right esotropia, head lag, mild b/l facial weakness, absent gag, poor suck MOTOR: decreased tone throughout with slight movement of extremities SENS: responds to painful stimuli with weak cry DTRs: 0/4 throughout

Case continued Labs-nl CBC, D-stick 20 SMAC- bicarb- 18, anion gap 16 Lactate- 1.17, ammonia 32 CSF- WBC 1, RBC 4, gluc 64, prot 30, gram stain- no organisms CXR-nl, CT-nl, MRI brain-nl

Case 2 3 week old child referred for hypotonia
Infant was born at 36 weeks, via C/S secondary to breech Mother reports poor fetal movements throughout pregnancy Exam: Awake, weak cry CN: +tracking , PERRL 4mm to 2mm, head lag, no evidence of facial asymmetry, +gag, +tongue fasciculations MOTOR: decreased tone throughout with slight movement of extremities SENS: responds to painful stimuli with weak cry DTRs: 0/4 throughout

Hypotonia Definition Symptoms of diminished tone of skeletal muscle associated with decreased resistance of muscles to passive stretching. Phasic tone Rapid contraction in response to a high-intensity stretch (ie tendon reflex Postural tone Prolonged contraction of antigravity muscles in response to the low- intensity stretch of gravity When hypotonia is present, the truck and limbs cannot maintain themselves against gravity and infant appears floppy. Maintenance of tone requires intact central and peripheral nervous system

Exam findings in a hypotonic infant
When supine, there is usually: Lack of spontaneous movement Legs are abducted (frog-legged appearance) Arms are extended at sides of body or flexed at elbow with hands beside head May have pectus excavatun Plagiocephaly (particularly flattening of the occiput) When sitting Head control may be poor or absent, with the head falling to the side, backward, or forward. Shoulders droop and limbs hang limply

Exam findings Traction response Present starting at 33weeks
Initiate by grasping hands of the infant and pulling to a sitting position A normal infant lifts head from the surface immediately with the body and while sitting will keep head erect for a few seconds During traction the infant should pull back against traction and flex elbows, and legs By 1 month, an infant should lift head immediately and keep in line with trunk

Vertical Suspension Place both hands in axilla and without grasping lift straight up Shoulder musculature should have sufficient strength to press down against examiners hands and suspend without slipping through Head should be midline with flexion of the legs

Horizontal Suspension
A normal infant keeps head erect, maintains back straight, and flexes arms and legs A healthy infant will make intermittent efforts to maintain this position

Approach to diagnosis: localization
Central Cerebral Spinal cord Peripheral peripheral nerves (including AHC) neuromuscular junction muscle

Is the hypotonia static or progressive?
Is there regression?

Clues to Cerebral Hypotonia
Abnormalities of other brain functions (lethargy, seizure) Dysmorphic features Fisting of the hands Malformations of other organs Postural reflexes are generally preserved despite a paucity of spontaneous movements. Normal or brisk tendon reflexes Scissoring on vertical suspension

Clues to Spinal Hypotonia
Intact mental status DTRs may be brisk or depressed (ie spinal shock) No dysmorphic features Constipation or urinary retention

Clues to Peripheral Hypotonia
Spontaneous movement is lacking Legs are fully abducted (frog legged) Arms are extended at sides of body or elbows flexed with hands beside head Pectus excavatum when long-standing Flattening of occiput, loss of hair Sitting position causes head to fall forward, shoulders droop & limbs hang limply May have weakness of facial muscles DTRs ↓ or absent Muscle atrophy +/- tongue fasciculations (esp. if AHC involved)

Additional History Any significant family history Maternal disease
Affected parents Siblings Consanguinity Stillbirths Childhood deaths Maternal disease Diabetes Epilepsy Myotonic dystrophy

Additional History 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

Evaluation of hypotonia
Mental status (awake vs. lethargic) Physical exam Labs CBC (r/o infection) CMP (r/o metabolic derangement) TFTs (r/o hypothyroidism) LP Toxicology (esp. in a newborn with poor prenatal care) CK Neurology/Genetic/Metabolic consult→→→PAA, UOA, ammonia, lactate, pyruvate, chromosome analysis

Evaluation of hypotonia
Imaging HUS, MRI Ancillary testing infant: EMG/NCS, muscle biopsy, nerve biopsy, tensilon test (r/o LMN lesion, NMJ, or muscle etiology) Other findings in exam may warrant optho or cardiology consult

Differential of central hypotonia in a newborn/infant
“benign” congential hypotonia Inborn errors of metabolism Chromosome disorders/genetic defects Prader- Willi Trisomy 21 Familial dysautonomia (Riley Day syndrome) Lowe syndrome (oculocerebrorenal syndrome) Peroxisomal Disorders (i.e. Zellweger and Neonatal adrenoleukodystrophy Mg Demerol/Stadol Chronic nonprogressive encephalopathy Cerebral malformations HIE TORCH infections Acquired infections (meningitis) Other metabolic defects Infantile GM1 gangliosidosis Acid maltase deficiency

Central Causes of Hypotonia
Benign congenital hypotonia Diagnosis of exclusion Usually hypotonic at or shortly after birth, then later have normal tone May have increased incidence of MR or LD despite recovery

Inborn errors of metabolism ????? Hyperammonemia Progressive lethargy, vomiting, and hypotonia within a day of delivery (even before initiation of protein feeding) Progressive LOC, and seizures on subsequent days Causes: liver failure primary enzyme defects in urea synthesis Argininosuccinic acidemia Carbamoyl phosphate synthetase deficiency Citrullinemia Ornithine transcarbamoylase deficiency disorders of amino acid metabolism Glycine encephalopathy Isovaleric acidemia Methylmalonic acidemia Multiple carboxylase deficiency Proprionic acidemia Transitory hyperammonemia of prematurity

Chromosomal Abnormality Trisomy 21 Prader Willi Hypotonia, ↓DTRs, feeding difficulties, hypogenitalism (100%) , cryptorchidism (84%), dysmorphic facies, MR, short stature, obesity Dx: DNA methylation detects the absence of the PATERNALLY contributed proximal long arm of chromosome 15 Angelman Syndrome Delayed development, intellectual disability, severe speech impairment, and(ataxia). Most have epilepsy and microcephaly “happy puppet” Dx: DNA methylation detects the absence of the MATERNALLY contributed proximal long arm of chromosome 15 (inherits 2 copies of chromosome 15 from father)

Familial Dysautonomia (Riley Day) AR, Ashkenazi Jews, chromosome 9q31-33 Meconium aspiration, no or poor suck, hypotonia Causes of hypotonia are due to disturbance in brain, DRG, and peripheral nerves Feeding difficulty (lack of coordination of suck and swallow) Pallor, temperature instability, lack of papillae on tongue, diarrhea, and abdominal distention Poor weight gain, lethargy, no corneal reflexes, labile BP, failure to produce tears DX: optho exam

Lowe (oculocerebrorenal syndrome) X-linked recessive Hypotonia, hyporeflexia Congenital cataracts and glaucoma MR Disorder of renal tubules Usually die from FTT MRI-diffuse demyelination

Peroxisomal disorders (leukodystrophies) Neonatal adrenaleukodystrophy Infantile refsum disease Zellweger (cerebrohepatorenal) Poorly responsive, severe hypotonia w/arthrogryposis Dysmorphic features (pear-shaped head, widened sutures, micrognathia, hypertelorism) Suck and cry are weak Organ abnormalities: Biliary cirrhosis Polycystic kidneys Retinal degeneration Cerebral malformations from migrational defects →seizures Bony stippling of long bones and patella Death usually within first year of life DX: VLCFA increased, elevated pipecolic acid, urine contains excessive bile acid intermediates

Spinal Cord Causes of Hypotonia
Acute causes Hypoxic Ischemic Myelopathy (can been seen in conjunction with HIE) Spinal Cord Injury Traction injury to lower cervical and upper thoracic regions in breech presentation Twisting injury of neck in forceps delivery causes high cervical cord injuries in cephalic presentation Erb’s palsy

Peripheral Causes of Hypotonia
SMA (Spinal Muscular Atrophy) ↓fetal movements, weak cry, IUGR, respiratory distress, foot deformities, arthrogryposis Tx:Spinraza (Nusinersen):MOA-antisense oligonucleotide designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron protein deficiency. ?Newborn State Screen? Polyneuropathies (rare in infancy) Axonal familial dysautonomia Hereditary motor-sensory neuropathy II Demyelinating Guillain Barre Syndrome Krabbe Disease (mean range of onset 1mo-7mo) HMSN I/III Metachromatic leukodystrophy

Disorders of Neuromuscular Junction Infantile Botulism Familial Infantile Myasthenia Transitory Myasthenia Gravis

Disorders of Neuromuscular Junction
Infantile Botulism Ingestion of Clostridium botulinum colonizes the intestinal tract and produces toxin in situ (as opposed to ingestion of the preformed exotoxin) Exotoxin prevents release of acetylcholine in the NMJ

Disorders of Neuromuscular Junction
AFFECTS ALL MUSCLES Hx of poor feeding, constipation, weakness/malaise CRANIAL NERVES ARE AFFECTED (as opposed to SMA) extraocular muscle weakness or paresis causing ptosis and/or blurred vision, diplopia fixed/dilated pupils, dysarthria, dysphagia, suppressed gag reflex Diffuse weakness decreased/absent DTRs Tx: Baby BIg Dx:stool sample

Familial Infantile Myasthenia Presynaptic defect in Ach resynthesis and packaging, postsynaptic defect in kinetics of AchR, or congenital acetylcholineesterase deficiency Respiratory insufficiency and feeding difficulty at birth Ptosis and generalized weakness Within weeks get stronger, may not need ventilation but can continue to have attacks of apnea.

Transitory myasthenia gravis Within hours to 2-3 days after birth  eager to feed but difficult due to early fatigue, hypotonia (diffuse) 50% has weak cry w/o facial expression Only 15% with limited EOM and ptosis Respiratory distress is rare. Duration mean: 18days Maternal AChR antibody (IgG)  fetal transfer with symptoms (10-20% of cases) Tensilon test If severe case: plasmaphoresis Less impaired case: .1% Neostigmine IM before feeding

Congenital Myopathies Developmental disorders of the skeletal muscle Main clinical feature is hypotonia Muscle biopsy for diagnosis Shows Type I fibers are greater in number but smaller in size , than type II fibers These patients commonly have cerebellar aplasia CK may be normal or only slightly elevated

Congenital Myopathies Along with Type I predominance, may have unique histological features Central core disease (ryanodine receptor mutation and malignant hyperthermia) Multiminicore disease (multiple small zones lacking oxidative activity) Myotubular myopathy (may require ventilation at birth) Nemaline (rod) myopathy (severe, intermediate,typical) Independent ambulation by 18months predictive of survival

Metabolic myopathies Acid-maltase deficiency (Pompe Disease) Lysosomal defect, AR Profound hypotonia and CHF are initial symptoms Cardiomegaly is almost diagnostic Muscle biopsy establishes diagnosis (large vacuoles) Cytochrome C oxidase deficiency Deficiency of mitochondrial electron transfer chain and oxidative phosphorylation

Congenital Muscular Dystrophy
Muscular dystrophies Congenital Muscular Dystrophy Hypotonia, early joint contracture, diffuse weakness, and atrophy AR Syndromic: muscle and brain are abnormal Nonsyndromic : muscle disease without cerebral involvement Merosin-linking protein for dystroglycan complex Primary merosin defiency –affect only muscle Hypotonia, arthrogryposis, and respiratory insufficency at birth Secondary merosin deficiency- syndromic CMD

Congenital myotonic dystrophy
Muscular Dystrophies Congenital myotonic dystrophy Multisystem disorder AD Symptoms usually after 10yo May have h/o reduced fetal movements and polyhydraminios 50% premature, prolonged labor sec. to weak uterine contraction Infant may have inadequate diaphramatic and intercostal muscle funstion and need intubation after birth Many die immediately after birth Facial diplegia, hypotonia, joint deformaties, GI dysfunction, choking DX: made by examining mother- see clinical features and EMG, DNA amplification of ch. 19

Helpful Hints Physical Examination Clues Hepatosplenomegaly
Storage disorders Congenital infections Renal cysts High forehead Wide fontanelles Zellweger’s syndrome

Helpful Hints Physical Examination Clues Abnormal odor Hepatomegaly
Metabolic disorders (MSUD) Hypopigmentation, undesceded testes Prader Willi Hepatomegaly Retinitis pigmentosa Neonatal adrenoleukodystrophy

Helpful Hints Physical Examination Clues Examination of the mother
Congenital myotonic dystrophy Myasthenia gravis Facial weakness, +extremity weakness, no DTRs Botulism No facial weakness, +extremity weakness, no DTRs SMA (there is a treatment as of Dec 2016!!)

Neonatal Hypotonia Peripheral Causes CK EMG/NCS
acetylcholine receptor Abs muscle biopsy Whole exome sequencing

Treatment Depends on underlying condition
i.e. MG- mestinon, Botulism- Big, SMA- Spinraza Mostly it is supportive Ventilation, NGT/GT Physical therapy To improve motor control and overall strength Occupational therapy To improve fine motor control Speech therapy Extra help/Special Education

The Floppy Infant: Retrospective Analysis of Clinical Experience (1990—2000) in a Tertiary Care Facility Birdi et al. J Child Neurol.2005; 20:

The Floppy Infant Retrospective study Selected population of infants with hypotonia who underwent genetic/neurologic evaluation over 11 yrs ( ) at the Childrens’ Hospital in Winnepeg, Canada All infants who were evaluated for generalized hypotonia by genetics and metabolism and neurology as well as infants who had EMG requests

The Floppy Infant 89 infants (42F:47M) 60 definitive diagnoses
24/60 on purely clinical grounds 36/89 needed additional testing Genetic disorders (18/60) CNS (cong/acquired) disorders (22/60) LMN disorders (9/60) Of the 61 that survived >1yr: 38 (62.3%) were globally delayed 30 (49.2%) achieved independent ambulation

The Floppy Infant Family history of neurologic or NM problems in 32/89
D/D, epilepsy, ALS, opthomologic(strabismus and cataracts), and other unidentified NM disorder 5/89-polyhydraminios, 3/89- oligohydraminios 11/89- abnormal fetal movements 51.7% were vaginal deliveries and FT, Average APGARS 6,8,~ 1/3 required intubation or PPV

Physical Findings Craniofacial dysmorphic features in 55.1%
Multiple congenital anomalies -27% Arthrogryposis of multiple joints -10.1%

Mode of diagnosis

The Floppy Infant The most valuable information came from those that had abnormalities on imaging and DNA- based diagnostic studies (statistically significant) Interestingly, metabolic workups (CK, lactate, ammonia, AA/OA and LCFA) were done in 72% of cases but most abnormalities were nonspecific or non-diagnostic Of those with diagnoses, there was a genetic defect or structural brain abnormality

Diagnosis of 60/69 floppy infants
Benign neonatal hypotonia 9 Hypoxic-ischemic encephalopathy 5 Genetic/syndrome/chromosomal Prader-Willi syndrome 5 Cardiofaciocutaneous syndrome 1 Pallister-Killian syndrome 1 Rubinstein-Taybi syndrome 1 Kabuki syndrome 1 Marden-Walker syndrome 1 Sotos syndrome 2 X-linked mental retardation syndrome 1 Duplication of band q23 on the long arm 1 of chromosome 1 Craniosynostosis 1 Prenatal exposures Fetal alcohol effect 1 Fetal alcohol syndrome 1 Congenital cytomegalovirus infection 1 Structural CNS malformations Agenesis of corpus callosum 4 Holoprosencephaly 3 Lissencephaly 1 Dandy-Walker malformation 3 Communicating hydrocephalus 1 Early myoclonic encephalopathy 1 Connective tissue disorders Ehlers-Danlos syndrome, type III 1 Ehlers-Danlos syndrome, type VI 1 Brain tumor Desmoplastic meduloblastoma 1 SMA type I (Werdnig-Hoffmann) 2 Congenital muscular dystrophies Muscle-eye- brain disease 1 Congenital myotonic dystrophy 2 Congenital myopathies Myotubular myopathy 1 Nemaline rod myopathy 3

Considerations DNA based testing not available in earlier years of study Family history may suggest genetic component Advanced paternal age might be a factor b/c of known increased risk of new dominant inherited conditions and birth defects

Summary Etiology of the floppy infant accounted for by mostly genetic or dysmorphic syndromes and structural abnormalities in the CNS Less frequently localized to the lower motor unit No metabolic disorders- thought to be b/c they are less likely to present with isolated hypotonia and referred for more multisystem involvement CHROMOSOME ANALYSIS, DNA-BASED DIAGNOSTIC TESTS AND NEUROIMAGING are useful in establishing the diagnosis

Outcome Majority improved in tone and survived >12months but still delayed 62.3% -global developmental delay 11.5%- isolated motor delay 1 patient- isolated language delay 1 patient- autistic traits Only 9 (14.8%) were cognitively normal

Can clinical signs identify newborns with neuromuscular disorders?
Vasta et al. The Journal of Pediatrics, Volume 146, Issue 1, Pages

Identifying newborns with NM disorders
Prior to the availability of DNA testing, the etiology of hypotonia was based purely on recognition of specific syndrome based on dysmorphic features and clinical profile. If that wasn’t possible then more invasive procedures were employed such as electrophysiological tests and muscle biopsy.

Dubowitz in the 1980’s suggested that a clinical exam could help distinguish infants with primary NM disorders from those with CNS involvement Contractures or other signs of weakness with absent or reduced antigravity movt suggest NM Reduced visual alertness, convulsions, and abnormal movements usually suggest more global CNS involvement

Thus by using clinical signs and the ability to obtain a diagnosis using imaging, electrodiagnostics, metabolic, and genetic testing, we can use the clinical signs to target our specific investigations. Aim: 1) evaluate the prevalence of NM disorders in the population of infants referred to the tertiary care center with this suggested diagnosis. 2) establish the extent to which the clinical and instrumental signs can help with the DDx and reliably identify NM disorders

Consanguineous Found in 12/83 infants 3/39 of NM group 4/8 in those with metabolic disorder Family History 17/83 9/39 of NM group 5/7 –those with encephalopathy with neuropathy Antenatal Findings Decreased fetal movt 23/83 18/39 (46.1%) of NM (most freq ) Polyhydraminios 14/39 (35.8%) of NM (most freq)

IUGR/HC 16/83 9/39 of NM 25% of acq. Antenatal injury (none had HC<3%) Respiratory Problems 57/83 (int.>PPV>CPAP) 7/7-encephalopathy with neuropathy 27/39 of NM (46% required intub) Feeding difficulties (req. NGT) 75/83 34/39 in NM Freq in all groups Dysmorphic Features 35/83 More freq. encephalopathy with neuropathy and NM (long fingers, micrognathia, low set ears, high palate, absents dermatoglyphics)

Poor antigravity movt Reduced to absent 49/83 38/39 of NM had extremely reduced or absent movt Contractures 44/83 27/39 (69%) of NM (most freq) 57% of enceph with neuropathy Both isolated (mainly talipes) and multiple contractures can be found equally in NM and others Visual behavior (poor alertness and other signs of encephal) 31/83 2/39 of NM has seizures

HUS/MRI Performed in 73/83 Abnormal in 67% 100% infants with antenatal injury 48.7% of NM CK Available in all infants and elevated in 5 persistantly (all NM) Sensitivity and Specificity Absent/reduced movt Highest in NM but partial range antigravity were more freq. In other dx Reduced fetal movt and polyhydra High specificty but lower sens. Contractures: Mainly found in primary NM disorders but S/S were lower thank for weakness b/c contractures were relatively freq. In metbolic or gentic syndromes.

Conclusion of NM study Weakness +contractures, esp. when associated with reduced fetal movements and abnormal AF level are STRONGLY indicative of a NM disorder. Recognition of these signs are important when they are found in infants with signs of CNS involvement and brain lesions 19/39 (48%) with NM also had abnormal brain imaging (usually nonspecific periventricular changes), many had seizures or poor alertness

Question 1 Hypotonia + Decreased or diminished DTRs likely localizes to: a) central cause b) peripheral cause c) neither d) both

Question 2 If an infant with hypotonia infant has progressive poor spontaneous movement, poor feeding, poor gag, and dilated pupils, and constipation, one should be suspicious of: A) SMA B) botulism C)cerebral palsy D) none of the above

Infant with SMA

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Hypotonia: The Floppy Infant

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