THE FLOPPY CHILD CLINICAL APPROACH TO THE FLOPPY CHILD

The floppy infant syndrome is a well-recognised entity for paediatricians and neonatologists and refers to an infant with generalised hypotonia presenting at birth or in early life. An organised approach is essential when evaluating a floppy infant, as the causes are numerous.

A detailed history combined with a full systemic and neurological examination are critical to allow for accurate and precise diagnosis. Diagnosis at an early stage is without a doubt in the child’s best interest.

HISTORY

The pre-, peri- and postnatal history is important. Enquire about the quality and quantity of fetal movements, breech presentation and the presence of either poly- or oligohydramnios. The incidence of breech presentation is higher in fetuses with neuromuscular disorders as turning requires adequate fetal mobility. Documentation of birth trauma, birth anoxia, delivery complications, low cord R van Toorn pH and Apgar scores are crucial as hypoxic-ischaemic encephalopathy remains MB ChB, (Stell) MRCP (Lond), FCP (SA) an important cause of neonatal hypotonia. Neonatal seizures and an encephalo- Specialist pathic state offer further proof that the hypotonia is of central origin. The onset of the hypotonia is also important as it may distinguish between congenital and Department of Paediatrics and Child Health aquired aetiologies. Enquire about consanguinity and identify other affected fam- Faculty of Health Sciences ily members in order to reach a definitive diagnosis, using a detailed family Stellenbosch University and pedigree to assist future genetic counselling. Tygerberg Children’s Hospital

CLINICAL CLUES ON NEUROLOGICAL EXAMINATION Ronald van Toorn obtained his medical degree from the University of Stellenbosch, There are two approaches to the diagnostic problem. The first is based on identi- and completed his paediatric specialist fying the neuro-anatomical site of the lesion or insult. The second is to determine whether or not the hypotonia is accompanied by weakness. Careful neurological training at both Red Cross Children’s examination should, in most cases, localise the site of the lesion to the upper Hospital in Cape Town and the Royal motor neuron (UMN) or lower motor neuron (LMN) unit. Useful clues are listed in College of Paediatricians in London. One Fig. 1. of his interests is in the field of neuromus- cular medicine. His working experience Next assess whether the hypotonia is accompanied by weakness. Weakness is includes the neuromuscular clinics attached uncommon in UMN hypotonia except in the acute stages. Hypotonia with pro- found weakness therefore suggests involvement of the LMN. Assessment of muscle to Birmingham Children’s, Red Cross power of infants is generally limited to inspection. Children’s, Guy’s and St Thomas’ hospitals.

Useful indicators of weakness are: • Ability to cough and clear airway secretions (‘cough test’). Apply pressure to the trachea and wait for a single cough that clears secretions. If more than one cough is needed to clear secretions, this is indicative of weakness.2 • Poor swallowing ability as indicated by drooling and oropharyngeal pooling of secretions. • The character of the cry — infants with consistent respiratory weakness have a weak cry. • Paradoxical breathing pattern — intercostal muscles paralysed with intact diaphragm.

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Floppy weak Hypo- to areflexia Floppy strong Selective motor delay Normal head circumference Increased tendon reflexes and growth Extensor plantar response Preserved social interaction Sustained ankle clonus Weakness of antigravitational Global developmental delay limb muscles Microcephaly or suboptimal Low pitched weak cry head growth Tongue fasciculations Obtundation convulsions Paradoxical chest wall Axial weakness a significant movement feature

Upper motor neuron Lower motor neuron disorder disorder Central hypotonia Peripheral hypotonia

Creatine kinase assay EMG Nerve conduction studies

Genetic studies CT/MRI DNA-based mutation Muscle or nerve Karotyping analysis if available biopsy FISH methylation studies VLCFA

Hypoxic ischaemic Spinal muscuar Congenital Triosomy 21 encephalopathy dystrophy structural Prader-Willi syndrome Cerabral malformations Congenital myotonic myopathies Zellweger syndrome dystrophy Congenital muscular dystrophies

Fig. 1. Clinical clues on neurological examination (EMG = electromyogram: CT= computed tomograph; MRI = magnetic resonance imaging; VLCFA = very long-chain fatty acids; FISH = fluorescent in situ hybridisation)

•Frog-like posture and quality of Further confirmation of the last indica- support with a sensation of ‘slipping spontaneous movements — poor tor can be obtained by means of infor- through he hands’ during vertical sus- spontaneous movements and the mal neurological examination in the pension testing and inverted U posi- frog-like posture are characteristic test positions. Excessive head lag will tion on ventral suspension are further of LMN conditions. be evident on ‘pull to sit’. Minimal indicators (Fig. 2.1 and 2.2).3

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THE FLOPPY WEAK INFANT The presence of a facial diplegia (myopathic facies) suggests either a Table I gives a comprehensive congenital structural myopathy or approach to the clinical clues and myasthenia gravis. Respiratory and investigations for the more common bulbar weakness can accompany phenotypes of the weak floppy infant. both conditions. Fluctuation in strength would favour myasthenic syndromes Once the lesion has been localised to (Fig. 6). the LMN proceed with further neu- roanatomical localisation according to Fig. 2.1. A 12-week-old male infant with the compartments of the LMN. The excessive headlag evident on ‘pull-to-sit’. compartments and disease associa- Note the hypotonic posture of the legs tions are listed in Fig. 3. with external rotation. Examine the tongue for size and fasci- culations. Fasciculations, irregular twitching movements, generally indi- cate an abnormality of the anterior horn cells (Fig. 4). Do not examine the tongue while the infant is crying. The co-existence of atrophy would strongly favour a denervative aetiology. An ECG may be helpful in demonstrating baseline fasciculations of the inter- costal muscles (Fig 5). Enlargement of Fig. 2.2. The same infant in horizontal the tongue may suggest a storage dis- suspension. Note the inverted U posture. order such as Pompe’s disease.

A distinct pattern of weakness may Fig. 6. Ptosis and external ophthalmo- favour certain aetiologies: plegia in a floppy weak child sugges- • Axial weakness is a significant fea- tive of myasthenia gravis. ture in central hypotonia. • Generalised weakness with sparing of the diaphragm, facial muscles, Where clinical evaluation suggests pelvis and sphincters suggests ante- complex multisystem involvement (i.e. rior horn cell involvement. hypotonia plus) inborn errors of •With myasthenic syndromes, the metabolism should be excluded. bulbar and oculomotor muscles Referral to a tertiary centre for meta- exhibit a greater degree of involve- bolic investigations would then be ment. indicated. •Progressive proximal symmetrical Fig. 4. Tongue fasciculations in a child weakness suggests a dystro- with spinal muscular atrophy. The com- THE FLOPPY STRONG CHILD phinopathy. Signs of proximal bination of fasciculations with atrophy weakness in the older infant is strongly indicative of muscle dener- The presence of facial dysmorphism include a lordotic posture, vation. should alert the doctor to the possibili- Trendelenburg gait and Gower ty of an underlying syndrome or genet- sign. •A striking distribution of weakness of the face, upper arms and shoul- ders suggests fascioscapulohumeral muscular dystrophy. • Distal muscle groups are predomi- nantly affected with peripheral neu- ropathies. Signs suggesting distal weakness in an older infant would include weakness of hand grip, Fig. 5. ECG of a floppy infant with spinal muscular atrophy demonstrating base- foot drop and a high stepping, line fasciculations arising from the underlying intercostal muscles. slapping gait.

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Anterior horn cell: Spinal muscular atrophy Poliomyelitis

Nerve fibre: neuropathies (Demyelinating or axonal) Acquired: Guillain-Barré syndrome Infectious: diphtheria, syphilis, coxsackie, HIV Toxic: drugs, heavy metals Nutritional: Vit B1, B6, B12, E, folate Endocrine: Diabetes, uraemia Metabolic neurodegenerative causes Hereditary: Charcot-Marie-Tooth disease

Neuromuscular junction Myasthenia gravis Botulism

Muscle Dystrophinopathies (lack of specific muscle protein): Duchenne, Becker’s fascioscapular humeral, limb gir- dle and congenital muscular dystrophies Congenital myopathies (abnormal muscle structure) Muscle membrane disorders: congenital myotonias, congenital myotonic dystrophies Inflammatory myopathies: dermatomyositis, poliomyositis Metabolic myopathies: lipid glycogen storage dis- eases

Endocrine myopathies: hypothyroidism Energy depletion within muscle: mitochondrial, free- fatty acid oxidatation and carnitine disorders

Fig. 3. LMN comportments and disease associations.

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Table I. Clincical clues and investigations of the more common phenotypes of the floppy weak infant

Condition Clinical clues Investigations

Spinal cord transection or Haemangioma or tuft of hair in midline MRI spinal cord disease Scoliosis Syringomyelia or other forms Evidence of bladder or bowel dysfunction of spinal dysraphism Mixed deep tendon reflexes with absent abdominal and anal reflexes Spinal muscular atrophy Tongue atrophy and fasciculations ECG: Baseline fasciculations Paradoxical breathing pattern Deletion of the survival motor Severe proximal muscle weakness with neuron (SMN) gene by PCR absent tendon reflexes testing Preserved social interaction Peripheral neuropathy Weakness predominantly distal Motor nerve conduction In most cases absent deep tendon reflexes studies Pes cavus Sural nerve biopsy Molecular DNA testing is available for specific demyelinating disorders Myasthenia gravis Greater involvement of oculomotor and Response to acethylcholine bulbar muscles esterase inhibitors True congenital myasthenia due to receptor Single-fibre EMG defects is rare Serum antibodies to Exclude transient neonatal form from acethylcholine receptors maternal history Electrodiagnostic studies not universally positive in young patients Infantile botulism Acute onset descending weakness, Isolation of organism from cranial neuropathies, ptosis, stool culture unreactive pupils, dysphagia, Presence of toxin in the stool constipation Congenital muscular Hypotonia, weakness and contractures Creatine kinase usually dystrophy at birth elevated Associated brain and eye problems Brain MRI for structural and white matter abnormalities Muscle biopsy: merosin stain Congenital myotonic Polyhydramnios with reduced fetal Molecular DNA testing by dystrophy movements determining number of CTG Inverted V-appearance of the mouth repeats (normal range 5 - 39 Examination of mother’s face shows inability repeats) to bury her eyelashes and grip myotonia EMG of the mother Premature cataract surgery in the mother Congenital structural Slender stature CK and EMG usually not myopathy Hypotonia with feeding problems at birth helpful Weakness that is often non-progressive Muscle biopsy is critical for Nemaline myopathy: often associated with definitive diagnosis. feeding problems ECG when nemaline and Central core: most often associated with desmin myopathies are malignant hyperthermia suspected Myotubular myopathy: Ptosis and The genetic basis for several extraocular palsies consistent of the congenital myopathies clinical features has now been determined Glycogen storage disease Enlarged heart in a very floppy weak Blood smear vacuolated Pompe’s disease newborn lymphocytes Unexplained cardiac failure Urine oligosaccharides Tongue may appear large Typical ECG and ECHO changes Acid maltase assay in cultured fibroblasts Muscle biopsy usually not necessary

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ic disorder. Conditions that need to be VALUE AND CHOICE OF means that most neuromuscular condi- excluded include trisomy 21, Prader- DIAGNOSTIC MODALITIES tions can now be diagnosed by molec- Willi and Zellweger syndrome. At ular testing. Examples include spinal birth the facial anomalies in Prader- Special investigations should be guid- muscular atrophy which can now be Willi syndrome are often insignificant ed by clinical findings. Evaluation of confirmed by polymerase chain reac- and the diagnosis is usually only tone and power should be delayed in tion (PCR) testing for a deletion of the established after onset of obesity. the systemically unwell nutritionally survivor motor neuron (SMN) gene Useful early markers include the pres- compromised child. Infective and bio- and congenital myotonic dystrophy ence of feeding difficulties, small chemical parameters should first be which can be diagnosed by demon- hands and feet, almond shaped eyes, normalised before attempts are made strating an expansion of cytosine narrow bifrontal diameter and hypogo- to examine tone and power. thymine guanine (CTG) triplet repeats. nadism (Fig. 7). Failure to identify Hypokalaemia and hypophospha- electrophysiological abnormalities in a taemia in particular will cause DNA Xp21 deletion testing (PCR neonate with profound hypotonia reversible weakness. Serum albumin, assays) can confirm the diagnosis in should prompt testing for Prader-Willi calcium, phosphorus, alkaline phos- 65% of males with Duchenne muscular syndrome. This can be done by a phatase and thyroxine levels will pro- dystrophy and 80% of males with DNA methylation study which will vide confirmation of clinical suspicion Becker’s muscular dystrophy. Only in detect 99% of cases. in malnutrition, ricketts and hypothy- the remaining cases is muscle biopsy roidism. still advocated. Muscle enzymes levels (creatine kinase assay) are rarely help- ful in the floppy infant, with the excep- SUSPECTED CENTRAL CAUSE tion of muscle disorders where crea- For infants with central hypotonia, ini- tine kinase values are elevated, such tial investigations include karyotype as congenital muscular dystrophies and neuroimaging (CT or MRI scan). A and in some of the congenital structur- karyotype is a must in the dysmorphic al myopathies. hypotonic child. This can be combined with FISH testing if Prader-Willi syn- Electromyography (EMG) should not drome is suspected. Cranial MRI will be performed in isolation. It does not identify patients with structural CNS allow for a definitive diagnosis as malformations, neuronal migration there are virtually no waveforms that defects and those with white matter are pathognomonic for specific dis- changes (congenital muscular dystro- ease entities. In the floppy child, EMG phies in particular). Hypotonia may is indispensable in deciding whether also be prominent in connective tissue there is true weakness due to neuro- diseases such as Ehlers Danlos or muscular disease, or merely hypotonic- Marfan’s syndrome. An excessive ity from causes in other systems or range of joint mobility, unusual joint other parts of the nervous system. The postures, the ability to do various con- abnormalities detected may then assist in localizing the disease process to the Fig. 7. A 1-year-old girl with Prader- tortions of the limbs and/or hyperelas- neuron, neuromuscular junction or Willi syndrome. Marked hypotonia ticity of the skin are important diag- muscle. EMG is also useful to confirm and feeding difficulties were evident nostic clues. Although metabolic disor- a clinical suspicion of myotonia in the during the first few months of her life. ders are well recognised as the cause for central hypotonia, because of the older child. rarity of the conditions, the diagnostic Zellweger syndrome presents in the yield is low. Very long-chain fatty Nerve conduction studies are useful in newborn with typical facial dysmor- acids (VLCFA) testing should be per- the investigation of hereditary motor phism including high forehead, wide formed if a peroxisomal disorder such sensory neuropathies and distinguish- patent fontanelles and sutures, shallow as Zellweger is suspected. ing axonal from demyelinating disor- orbital ridges, epicanthus and microg- ders. Molecular DNA testing can then nathia. Neurological manifestations be used for specific demyelinating dis- are dominated by severe hypotonia SUSPECTED PERIPHERAL orders. Commercial testing is not yet with depressed or absent tendon CAUSE available for most axonal forms of reflexes, and poor sucking and swal- hereditary neuropathies. Major discoveries have been made in lowing. Hepatomegaly and liver dys- the genetic analysis of the muscular function are consistent findings. Muscle biopsy remains the investiga- dystrophies, spinal muscular atrophies tion of choice in an infant with a sus- and hereditary neuropathies. This

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The onset of the hypotonia mal tendon reflexes IN A NUTSHELL is also important as it may • normal or mild motor retardation that distinguish between improves later on When evaluating a floppy infant, • normal muscle enzymes, EMG, congenital and aquired the first goal should be to distin- motor nerve conduction studies aetiologies. guish whether the disorder is cen- (MNCS) and histology. tral or peripheral in origin.

PRINCIPLES OF Hypotonia with weakness suggests There are two approaches MANAGEMENT a lower motor neuron lesion, where- to the diagnostic problem. as weakness is uncommon in disor- Regular physiotherapy will prevent con- The first is based on identi- ders affecting the upper motor neu- tractures. Occupational therapy is ron except during the acute stage. fying the neuro-anatomical important in facilitating activities of site of the lesion or insult. daily living. Vigorous treatment of respi- Evaluation of tone and power The second is to determine ratory infections is indicated. Annual flu should be delayed in the unwell, whether or not the hypoto- vaccination is necessary. Annual nutritionally compromised child. nia is accompanied by orthopaedic review is required to moni- Muscle enzymes are rarely helpful weakness. tor for scoliosis and to exclude hip dislo- in the floppy child, with the excep- cation/subluxation. tion of the congenital muscular dys- Feeding intervention by nasogastric tube trophies and some of the structural Children with neuromuscu- or gastrostomy will benefit the under- congenital myopathies. lar disorders deserve spe- nourished child. Maintenance of ideal weight is important, as excessive weight EMG does not allow a definitive cial attention when it gain will exacerbate existing weakness. diagnosis but is indispensable in comes to anaesthesia. Children with neuromuscular disorders deciding whether there is weakness deserve special attention when it comes due to neuromuscular disease, or pected congenital structural myopathy, to anaesthesia. The anaesthetist should merely hypotonia from causes in as none of the clinical features are be forewarned about the possibility of other systems or parts of the nerv- truly pathognomonic. Even a CK with- an underlying muscle disease even if the ous system. in the reference range and normal child has very mild or non-existing The most common of the neuromus- EMG does not exclude the presence of symptoms. A family history of muscle cular disorders, spinal muscular a myopathy. Muscle biopsy is also disease or mild hyper-CK-aemia may be atrophy (SMA), is now diagnosable indicated in infants with suspected of importance. Muscle relaxants should by molecular genetic analysis limb-girdle muscular dystrophies only be used if essential because of (PCR). (LGMD). their more profound and prolonged effect in myopathic children. All children Where clinical evaluation suggests complex multisystem involvement The term ‘benign essential hypotonia’ with (i.e. hypotonia plus) inborn errors or ‘hypotonia with favourable outcome’ neuromuscular disease should also be of metabolism should be excluded. should be used with caution since considered potentially susceptible to newer investigative techniques have malignant hypothermia (the strongest Children with neuromuscular disor- resulted in most previously labelled correlation is with central core disease) ders deserve special attention when cases being classified into specific disor- and implicating agents should therefore it comes to anaesthesia. ders. There are however many benign be avoided. The term ‘benign essential hypoto- congenital hypotonia cases that remain nia’ or ‘hypotonia with a unclassified, even with detailed exami- Ethical considerations such as the favourable outcome’ should be used nation of the muscles. Patients labelled appropriateness of cardiopulmonary with caution and only after compli- as ‘hypotonia with favourable outcome’ resuscitation in the event of cardiac ance with strict diagnostic criteria. should fulfil all of the following criteria1: arrest or acute respiratory failure need to be addressed sensitively. • early hypotonia, usually since birth References available on request. • active movements of limbs and nor-

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