Flat baby
Further neurological investigations are indicated when the aetiology is not clearly asphyxia, trauma, infection or poisoning.
Contributory causes include myotonic dystrophy and some congenital myopathies, glycine encephalopathy, mitochondrial derangements, Aicardi-Goutieres syndrome and the central hypoventilation syndrome.
Apnoeic baby
Apnoea could be feature of subtle neonatal epileptic seizures
Myasthenia
A response to edrophonium or neostigmine or a positive result on stimulation single fibre EMC (stimSFEMG) should confirm this.
Hyperekplexia
Hyperekplexia may present predominantly as episodes of severe apnoea with high-voltage rhythmic 8-30 CMAP (compound muscle action potential) superimposed on ictal EEG and ECG traces: if there is auditory startle and head retraction without habituation on tapping the tip of the nose then it is permissible to go straight to analysis of hyperekplexia genes (GLRA1 and GlyT2).
Brainstem malformations
Central hypoventilation (Ondine's curse)
Although apnoea is more likely to occur in sleep with most causes, in congenital hypoventilation it exclusively does so. This disorder of autonomic regulation may be associated with Hirschsprung disease and later neural crest tumours. Polyalanine repeats are found in the paired homeobox gene PHOX2b.
Floppy baby
The clinical distinction should be attempted between non-paralytic hypotonia which tends to be axial hypotonia, and weakness which tends to affect preferentially the head and the limbs.
Ill floppy baby
Investigations will include microbiological tests, CSF examination, brain ultrasound (± MRI), blood ammonia and lactate, plasma and urine amino acids and urine organic acids. Dysmorphism will lead to chromosome analysis as well as determining copper, copper oxidase, very long chain fatty acids (VLCFAs) and sialotransferrin status.
Axial hypotonia without limb weakness
Prader-Willi syndrome
Prader-Willi syndrome would be suggested by the need for tube feeding, cat-like cry, Micky saliva, extreme poverty of movement and a combination of axial hypotonia and limb dystonia. FISH (fluorescent in situ hybridization) testing should be conducted for deletion on chromosome 15ql3 and, if negative, MLPA (multiplex ligation-dependent Probe amplification - see Chapter 2.13).
Peroxisomal Disorders
see Peroxisomal Disorders
Brain malformations
Brain malformations shown on imaging may be associated with metabolic disorders
Generalized weakness
Myasthenia
When maternal myasthenia is present little difficulty arises. In the absence of maternal myasthenia various congenital myasthenic syndromes (CMS) should be considered in any infant with stridor, respiratory (including apnoeic attacks or 'infantile syncope') and feeding difficulties. Eye signs such as ptosis may be minimal or absent and a high index of suspicion of CMS is needed to allow directed investigations.
The intravenous edrophonium (Tensilon) test may not give a clear-cut response, and the use of neostigmine before feeds or a trial of pyridostigmine may be preferable . Trials of such acetylcholinesterase inhibitors may be hazardous in certain kinds of CMS and should always be performed in hospital with resuscitation facilities on hand and under video surveillance. There are several types of CMS for which molecular genetic tests are available: the number of genes involved is still expanding. Such testing is usually performed at a national myasthenia reference laboratory. Stimulation single fibre EMC (stimSFEMC) may be helpful if a decremental response is detected following repetitive nerve stimulation, and in the diagnosis of CMS has good sensitivity (0.88) and specificity (0.79).
Unlike myasthenia, in neonatal botulism the weakness will not develop until the age of 10 days or later. In contrast to myasthenia, there is an incremental response to repetitive nerve stimulation, and microbiological evidence of infection with Clostridium will confirm the diagnosis.
Congenital dystrophies and myopathies
Maternal examination and EMG, followed by molecular genetic analysis for trinucleotide repeats will confirm congenital myotonic dystrophy. While creatine kinase may be elevated in some congenital myopathies and dystrophies, the confirmatory test is needle biopsy of muscle. A specific myopathy (centronuclear, nemaline, etc.) may be confirmed on muscle biopsy, while, if a congenital dystrophy is found, further immunohistochemical staining (for merosin) in conjunction with brain imaging and ophthalmological evaluation will assist in clarifying the type of congenital dystrophy syndrome.
Weakness sparing the face
While facial weakness may not be very obvious in some of the above congenital muscular disorders, weakness above the neck is more often absent in the following lour conditions.
Spinal muscular atrophy (SMA or Werdnig-hoffmann disease)
Molecular genetic testing for the typical SMN gene deletion confirms the clinical diagnosis. Findings on EMC and muscle biopsy are nonspecific and mainly allow the exclusion of other disorders pending the results of the molecular genetic studies.
| Congenital myasthenic syndromes | |||
| Condition (including usual gene/s) | Age at onset | Clinical features | Response to AChE inhibitors |
| CHAT | Birth or infancy | Bulbar weakness. Episodic apnoea, less with time | ↑ |
| D0K7 | Mostly 2nd year | Often normal motor milestones. Waddling 'limb-girdle' weakness ± ptosis ± respiratory crises. May improve with ephedrine or albuterol | Usually → or ↓. Rarely ↑ briefly |
| COLQ | Birth or later if milder | Severe progressive weakness, scoliosis, chronic respiratory failure, bulbar weakness, ptosis and ophthalmoplegia ± slow light pupil response. May improve with ephedrine or albuterol | Usually → or ↓ |
| Acetylcholine receptor deficiency (CHRNE, CHRNA1, CHRND, CHRNB1) | <2 years="" mostly="" at="" birth="" td=""> | Choking, feeding difficulties; ptosis in most; ophthalmoplegia; delayed motor milestones | ↑ |
| AChR deficiency [RAPSNl | Birth, infancy and much later | Arthrogryposis frequent in early-onset phenotype. Episodic apnoea: may be relatively well between crises and improve over time | ↑ |
| Slow channel | Variable | Selective weakness ± multiple CMAPs. Quinidine or fluoxetine may help | ↓ |
| Fast channel | <2 years="" td=""> | Ptosis, ocular bulbar and limb weakness | ↑ |
| Key: ↑ = improved; ↓ = worse; → = no change. | |||
SMARD1
Spinal muscular atrophy with respiratory distress (SMARD) may present with respiratoryfailure due to diaphragmatic paralysis. Mutations in the immunoglobulin μ-binding protein gene (1GHMBP2) lead to SMARD1, in which there is usually respiratory failure with onset between 6 weeks and 6 months and the presence of diaphragmatic eventration or preterm birth.
Cervical CORD DAMAGE
Pre- or intrapartum injury or cervical cord developmental abnormalities are possible. Neonates with intrapartum cervical cord damage will be ill at birth and with temporan generalized oedema. Congenital Horner syndrome might be seen. Birth asphyxia may coexist and lead to diagnostic confusion. MRI of the cervical cord and nerve routes is the definitive investigation in this situation.
PERIPHERAL NEUROPATHY
Demyelinating peripheral neuropathy is extremely rare in the neonate. Congenital hypomyelinating neuropathy may present with severe hypotonia, feeding and respiratory difficulties and limb deformities. Motor nerve conduction velocity will be profoundly delayed (<5m /s), while CSF protein is elevated. Sural nerve biopsy will show virtual absence of myelin and molecular genetic testing for this disorder will confirm the diagnosis (see http://neuromuscular.wustl.edu/time/hmsn.html).
Stiff baby
Hyperekplexia
Stiffness or hypertonia in the newborn infant is usually due to hyperekplexia. Clues on history include startle disease in a parent or the recognition of 'jumps' in the latter part of the pregnancy. The stiffness will be increased on stimulation and diminished or abolished by sleep.
Non-habituating head retraction on tapping the tip of the nose and/or auditory startle support the diagnosis. If EEG, ECG and EMG are recorded during an apnoeic episode, high-voltage repetitive and rhythmic CMAP 'spikes' at 8-30Hz are characteristic.
Other investigations are not indicated before proceeding directly to gene analysis focusing on mutations in the gene for the α-1 subunit of the glycine receptor (GLRA1) or in the glycine transporter GlyT2. Other genetic associations with neonatal hyperekplexia are very rare.
Prenatal thalamic injury
Neonatal hypertonia of a degree greater than that found in hyperekplexia is seen after thalamic injury earlier in the pregnancy. A history of maternal cardiac arrest might occasionally be obtained but usually lesions are 'silent'. Investigation is by brain MRI it may be prudent to test blood and CSF lactate in case this is a manifestation of a mitochondrial disorder.
Other stiff babies
Not all stiff babies have hyperekplexia or prenatal thalamic injuries. Swartz-Jampel syndrome is obvious, but KCNA1 -related neuromyotonia/myokymia has not been reported at such an early age. Dentato-olivary dysplasia might be missed on brain MRI.
Congenital absence of the pyramidal tracts is difficult to diagnose in life. Those with neonatal stiffness and epileptic seizures may have a serine synthesis deficiency syndrome hut in general have so far not been well characterized, so in this phenotype there is scope for further thoughtful investigations.
Increased movements
In particular, some degree of tremulousness or jitteriness is very common in normal healthy newborn infants and in those with hypoglycaemia and hypocalcaemia.
Jitteriness
Despite what we just said about jitteriness in normal newborn infants, lymphocytic choriomeningitis virus (LCMV) infection is one of the causes - all with LCMV-related jitteriness have cerebellar hypoplasia that will be apparent on imaging.
Neonatal abstinence syndrome
The diagnosis of drug ingestion by the mother during pregnancy will usually be obvious but if need be urine toxicology should clarify. Around 70% have benign neonatal sleep myoclonus.
Transient biochemical disturbances
Hypoglycaemia, hypocalcaemia and hypomagnesaemia will be recognized on routine blood examination.
Urea cycle defects
Investigation will include plasma urea, ammonia, amino acids and urine amino acids and orotic acid.
GLUT1 deficiency
If symptoms persist and GLUT1 deficiency seems possible, then blood and CSF glucose estimation (blood immediately before lumbar puncture) are indicated.
Brain malformation, etc.
Persisting symptoms would also prompt brain ultrasound or MRI.
Aicardi-Goutieres syndrome
Reduced movement (hypokinesia)
In contrast to the overdiagnosis of jitteriness or hyperkinesia in newborn infants, reduced movements or hypokinesia tend to be under-recognized and diagnosed late.
Prader-Willi syndrome
Extreme poverty of movements, axial hypotonia and some degree of limb dystonia, together with a difficult to elicit and peculiar cry with a need for nasogastric feeding characterize Prader-Willi syndrome. No ancillary investigations are indicated before going direct to genetic analysis.
Myopathies
Creatine kinase elevation should distinguish congenital muscular dystrophies from connatal spinal muscular atrophy and congenital myopathies. Examination of the mother (including BMC if possible) will allow the provisional diagnosis of congenital myotonic dystrophy, which will be confirmed by finding the trinucleotide repeats. In the weak immobile newborn infant with facial sparing, DNA will be investigated for a deletion in the survival motor neuron gene (SMN) on chromosome 5q 12-13.
Brain malformations including chromosome abnormalities
Brain MRI and chromosome karyotyping should clarify.
Thalamic infarctions
As well as being stiff, such infants with prenatal symmetrical thalamic damage may be immobile. Brain MRI will clarify the thalamic lesions. Increased lactate levels and the lack of any antecedent during the pregnancy would point to possible pyruvate dehydrogenase deficiency, which is confirmed by fibroblast enzyme analysis and then testing for the specific mutations.
Prenatal cerebral infarction
While there may be hypokinesia (even ipsilateral if a thrombus is in the subclavian artery) this is not necessarily so; in any case, MRI with diffusion weighting will clarify. If there is porencephaly and/or a family history, consider COL4A1 and NAITP (neonatal thrombocytopenia).
Neurotransmitter disorders
Athough very rare, neurotransmitter disorders are important because they may be treatable.
In the past, although retrospectively symptoms may have begun in the neonatal period, most patients were not recognized until later in infancy. Features such as lack of movement, autonomic disturbances, oculogyric crises and dystonia will prompt CSF biogenic amine and pterin estimations . These studies are best done before levodopa trial
Arthrogryposis
The important point is not to imagine that arthrogryposis multiplex congenita is a diagnosis. Rather, it should be a trigger for further specific diagnostic investigations.
Maternal examination
Examine and/or investigate for myotonic dystrophy, myasthenia gravis and centronuclear myopathy.
Imaging
Brain in MRI may reveal primary malformation or ventricular dilatation in congenital myotonic dystrophy. Elevated right hemidiaphragm and thin horizontal ribs on chest radiograph suggest congenital myotonic dystrophy.
Other Investigations
Depending on the clinical appearances consider now or later creatine kinase, chromosomes, EMG/nerve conduction velocity, brain MRI, muscle biopsy, acetylcholine receptor antibodies (+ other antibodies), metabolic tests for mitochondrial and peroxisomal disorders and CDG, and CSF asialotransferrin.
Congenital infection-like syndrome
Clinical constellation of some or all of the following: a neurologically abnormal infant (feeding difficulty, jitteriness, seizures of some kind), hepatosplenomegaly, abnormal liver function tests, basal ganglia and/or white matter calcification, cerebral white matter abnormalities on MRI.
HIV infection in the mother will usually be already known. TORCH screen is too well known to require detailed description. Cytomegalovirus may be cultured from the urine or other body fluids, and for later retrospective diagnosis the Guthrie card will be stored. The increase in the incidence of syphilis makes this another diagnostic possibility.
AlCARDI-GOUTIERES SYNDROME
When the clinical picture is of congenital infection as described above but microbiological investigations are negative then Aicardi-Coutieres syndrome becomes highly likely (old names such as pseudo-TORCH and microcephaly-intracranial calcification syndrome are now obsolete except for occasional genetic rarities, and what used to be called Cree encephalitis is the same disorder as Aicardi-Goulieres syndrome).
It is permissible to go straight to genetic analysis for TREX1 without the need for CSF examination, but if the CSF is examined then Aicardi-Goulieres syndrome at this age will usually contain an excess of lymphocytes (>5/cm3) and always an increase in interferon-alpha.
Dysmorphic neonate
In several pans of the world newborn infants are misdiagnosed as 'abnormal' because of supposed dysmorphism of the fontanelle and such like. True dysmorphism is recognized when either the newborn infant has the same syndromic characteristics as one of the parents or is different in appearance from either of the parents or other members of the family. When dysmorphism is associated with neurological abnormality the yield from investigations (karyotype and brain imaging) is high.
If the karyotype is normal but an underlying brain malformation is found, specific genetic investigations may be indicated. Metabolic disorders with brain malformation include the following:
- peroxisomal disorders - elevated VLCFAs
- mitochondrial disorders - elevated plasma and CSF lactate
- carbohydrate deficient glycoprotein disorders - abnormal sialotransferrin
- glutaric aciduria type 2 - abnormal urine organic acids.
Source:
Mary D. King, 2009. A Handbook of Neurological Investigations in Children. 1 Edition. Mac Keith Press.
Cite this: ICNApedia contributors.Investigations of the baby with abnormal neurology. ICNApedia, The Child Neurology Knowledge Environment. 24 June 2024. Available at: https://icnapedia.org/knowledgebase/articles/investigations-of-the-baby-with-abnormal-neurology Accessed 24 June 2024.
