DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY

REVIEW

Neonatal hypertonia – a diagnostic challenge ANTHONY R HART 1

| RUCHI SHARMA 2 | CHRISTOPHER D RITTEY 1 | SANTOSH R MORDEKAR 1

1 Department of Paediatric Neurology, Sheffield Children’s Hospital NHS Foundation Trust, Sheffield; 2 Department of Paediatric Neurodisability, Sheffield Children’s Hospital NHS Foundation Trust, Ryegate Children’s Centre, Sheffield, UK. Correspondence to Santosh R Mordekar at Department of Paediatric Neurology, Sheffield Children’s Hospital NHS Foundation Trust, Ryegate Children’s Centre, Sheffield, S10 5DD, UK. E-mail: [email protected]

PUBLICATION DATA

Accepted for publication 3rd November 2014. Published online 12th December 2014. ABBREVIATIONS

AGS CSF EME HIE ICP PDH

Aicardi–Goutieres syndrome Cerebrospinal fluid Early myoclonic encephalopathy Hypoxic-ischaemic encephalopathy Intracranial pressure Pyruvate dehydrogenase

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested.

Hypertonia is defined as abnormally increased resistance to externally imposed movement around a joint.1 It is less common in neonates than hypotonia, and its neuronanatomical site can be central, spinal, or peripheral. Central aetiologies may develop antenatally, intrapartum, or postnatally. Clinicians should not assume all neonatal hypertonia is hypoxic-ischaemic encephalopathy (HIE) or they may miss important conditions with treatments and recurrence risks. Clues to the aetiology of, and diagnostic approach towards, neonatal hypertonia can be gained through careful history and examination of both the neonate and parents. This article reviews the causes of neonatal hypertonia and suggests an algorithm for an investigative approach.

HYPERTONIA – A VARIETY OF MOVEMENT DISORDERS Neonatal hypertonia can be caused by dystonia, spasticity, or rigidity,1 or a combination thereof. Determining a predominant movement disorder in a neonate can be difficult. In our experience, repeated assessment over time helps determine the predominant movement disorder, severity, and affected parts of the body because this changes quickly and markedly in the neonatal period. Data on the incidence of hypertonia and the relative frequencies of the predominant movement disorders and aetiologies are lacking. Hypertonia, however, should be distinguished easily from the contractures seen in arthrogryposis. 600 DOI: 10.1111/dmcn.12658

THE NEUROANATOMICAL SITE AND TIMING OF NEONATAL HYPERTONIA Hypertonia can result from central, spinal, or neuromuscular disorders, of which central pathologies are the most common. Central causes may result from developmental abnormalities or injury to the cortex, white matter, and/or basal ganglia and thalami. Scher reviewed the literature on structural and functional correlates of central neonatal hypertonia.2 We have not found it possible to determine the neuroanatomical site of injury based on neonatal examination alone. The causes of central hypertonia include those with antenatal onset (such as developmental structural abnormalities to the brain, intrauterine infection, intracerebral haemorrhage, or ischaemic stroke), perinatal onset (such as ischaemic brain injury), and postnatal acquired brain injury. Together, these conditions would fulfil the diagnostic classification of cerebral palsy (CP) if they are non-progressive.3 The American College of Obstetrician and Gynecologists’ Task Force on Neonatal Encephalopathy highlights that combinations of distal and proximal risk factors both play a role in the development of CP.4 Distal factors include genetic abnormalities (e.g. COL4A1 gene mutations) or environmental (e.g. placental abnormalities or maternal drug use). Figure 1 summarizes the timing of some of the aetiologies of neonatal hypertonia. By definition, progressive causes of central hypertonia, such as mitochondrial disorders, should not be diagnosed as CP, nor should conditions without evidence of brain injury, such as neurotransmitter disorders. © 2014 Mac Keith Press

The timing of the appearance of neonatal hypertonia may help determine the timing of the development of brain abnormalities/injury and aetiology. Hypotonia typically follows an acute cerebral insult, following which hypertonia develops over the ensuing weeks, months, or years.5 However, we have seen transient increases in tone, sometimes alongside other movement disorders such as myoclonus or jitteriness, in neonates with hypoxic brain injury receiving hypothermia treatment. This usually resolves. Chronic hypertonia may or may not evolve weeks or months later. Of course, neonatal hypotonia that evolves later into hypertonia is not always HIE, and a careful review of the pregnancy and family history is important in identifying other potential causes. On the other hand, persistent hypertonia from birth is unusual and usually indicative of a distant acquired or developmental abnormality, especially if no encephalopathy, seizure activity, or systemic features are seen. Arthrogryposis, facial abnormalities, or a high-arched palate may result in secondary to reduced fetal movements in these cases. A review of the pregnancy, maternal, and family history is mandatory, alongside placental examination.6

• • •

What this paper adds Neonatal hypertonia within 24 hours is unlikely to be caused by hypoxicischaemic encephalopathy. Hypertonia with a sub-acute presentation later has many possible aetiologies and may represent central or peripheral pathology. Some conditions have treatments or genetic implications. A diagnostic approach to the neonate with hypertonia is suggested.

DETERMINING THE AETIOLOGY OF NEONATAL HYPERTONIA Hypertonia obvious from birth Hypertonia from birth is rare and central in origin. Potential causes include: (1) developmental structural abnormalities or injury to the brain; (2) meningoencephalitis; (3) raised intracranial pressure (ICP), for example caused by congenital tumours, obstructive hydrocephalus, or antenatal stroke; and (4) metabolic abnormalities. In our experience, antenatal brain injuries are most likely, such as secondary to antenatal hypoxic brain injury, congenital infection, fetal intracranial haemorrhage such as in neonatal alloimmune thrombocytopenia or collagen IV A1 gene mutations (OMIM 120090),7–11 trauma to the fetus, maternal illness, placental/umbilical abnormalities, septicaemia, cardiac arrest, or drug use. Muscle atrophy,

Risk factors / events leading to neonatal hypertonia and childhood hypertonia





Maternal Drug use Incomplete vaccination Genetic condition / carrier status Genetic abnormalities in fetus: Conditions leading to developemental structural barin abnormalities or biochemical / metabolic disease Hyperekplexia Neuromyotonia disorders







Genetic / conception

Maternal Drug use (illicit or prescribed) Infection e.g. CMV Trauma Hypoxia (including cardiac arrest) / haemorrhage Hyperparathyroidism III health e.g. hypertension, diabetes, immune disorders



Maternal Drug use (illicit or prescribed) Infection e.g. CMV Trauma Hypoxia / haemorrhage



Perinatal / Neonatal Transient hypertonia secondary to HIE, particularly with hypothermia therapy Epileptic seizures / syndromes Brainstem movements / tonic stiffening Perinatal stroke / cerebral venous sinus thrombosis Intracerebral haemorrhage Meningo-encephalitis / cerebral abscess Raised ICP e.g congenital hydrocephalus / stroke / tumour Metabolic disease including those associated with seizures / stroke, such as kernicterus, maple syrup disease, mitochondrial disease, molybdenum cofactor disorder, serine deficiency Neurotransmitter disorders Spinal trauma during delivery Spinal infarction e.g. in preterm infants with umbilical catheters Hyperekplexia Neonatal tetanus Neonatal neuromyotonia conditions

Placental / umbilical abnormalities e.g. poor development / growth, abnormal umbilical bloody flow, chorioamnioitis, fetal thrombotic vasculopathy Fetal Intrauterine infection Ischaemic stroke / hypoxic brain injury Metabolic disease Neurotransmitter disorders Intracerebral haemorrhage e.g. COL4A1 mutations, neonatal alloimmune thrombocytopenia, pyridoxine deficiencis Genetic abnormalities leading to acquired in-utero brain abnormalities e.g. COL4A1, Aicardi-Goutieres syndrome Congenital hydrocephalus leading to raised ICP

Pregnancy

Chronic hypertonia

Resolution, if transient

Developing or continuing into infancy / childhood (with or without the development of neonatal hypertonia)

Neonatal hypertonia

Birth

Neonatal

Childhood

Figure 1: The timing of risk factors and events leading to neonatal hypertonia. Risk factors and events may be present at conception or shortly afterwards, during pregnancy, a result of birth or perinatal factors. More than one risk factor may be present in each or all of these epochs. The result may be neonatal hypertonia with chronic hypertonia continuing beyond the neonatal period (solid arrows), or relatively normal or low tone in the neonatal period with hypertonia emerging later (dotted arrows). CMV, cytomegalovirus; HIE, hypoxic-ischaemic encephalopathy; ICP, intracranial pressure. Review

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contractures, and dysmorphic features secondary to fetal akinesia may be present if the condition is long-standing.

Hypertonia appearing acutely, including within the first day after birth A number of conditions can cause hypertonia relatively quickly within the first few days after birth (Table I). The central causes predominate. Aetiologies include: (1) the transient increase in tone in neonates with HIE, particularly those receiving hypothermia treatment; (2) a predominately near-total asphyxia close to delivery affecting deep grey matter structures with no or minimal cortical involvement can present with rapid conversion to hypertonia from hypotonia after resuscitation; however, this presents within 3 to 7 days following asphyxia; (3) brain stem release phenomenon in a child with acute brain injury, often related to hypoxia, extensive perinatal stroke or meningitis, or intracranial haemorrhage; (4) tonic seizures, which may be secondary from HIE, perinatal stroke, and the neonatal epilepsy syndromes, including Ohtahara syndrome (OMIM 308350), early myoclonic encephalopathy (EME), or migrating partial seizures of infancy;12 (5) infective aetiologies, including meningoencephalitis and cerebral abscess; (6) intracranial haemorrhage; (7) raised ICP, such as from extensive perinatal stroke, congenital tumours13 or congenital hydrocephalus, which rarely lead to uncal or temporal lobe herniation;14,15 (8) hyperekplexia; (9) metabolic conditions, particularly if associated with a neonatal epilepsy syndrome or stroke, examples include non-ketotic hyperglycinaemia, molybdenum cofactor, and serine deficiencies; and (10) the evolution of neonatal hypertonia from an antenatal structural developmental abnormality or injury. We have seen a neonate with molybdenum cofactor deficiency secondary to a mutation in the MOCS1 gene. He presented with hypertonia, jitteriness, startling, and seizures that did not appear classic of HIE and mimicked hyperekplexia. He had a persistent lactic acidosis, raised cerebrospinal fluid (CSF) lactate and had bilateral infarctions in the middle cerebral artery territories. Mitochondrial gene testing was negative. These clinical findings have been described in hyperekplexia by others, and neonates may subsequently develop porencephalic cysts.16,17 The clue to diagnosis was sulphites and sulphocysteine in the urine with low serum uric acid. Hyperekplexia is a relatively benign disorder comprising exaggerated startle response (elicited by the glabellar tap) and hypertonia. Hyperekplexia is associated with mutations on chromosome 5 in genes encoding the alpha – one subunit of the GLRA1 glycine receptor (OMIM 138491) or in the glycine transporter GLYT2 (OMIM 604159). Other genetic associations with neonatal hyperekplexia are very rare and include ARHGEF9 (OMIM 300429), GLRB (OMIM 138492), GPHN (OMIM 603930), and SLC6A5 (OMIM 604159) mutations.18,19 Treatment is with clonazepam. The hypertonia gradually subsides and, in general, normal development ensues, although persistent hypertonia may be an issue. 602 Developmental Medicine & Child Neurology 2015, 57: 600–610

Neonatal hypertonia persisting beyond a few days of age or of subacute onset Persistent neonatal hypertonia presenting on the first day after birth, or slowly emerging thereafter is a diagnostic puzzle. Although central causes predominate, it is worth asking whether the features are consistent with a central or peripheral disorder at the outset (Table II). Central causes The transient increase in tone seen in neonates with HIE usually settles within a few days. The typical picture of HIE is of hypotonia and encephalopathy early on, with dystonia or spasticity emerging over weeks or months if the basal ganglia, thalami, or cerebral white matter are affected.5 Therefore, neonates who are born with or become rapidly and persistently hypertonic within the first day after birth do not have HIE, even if encephalopathy is a feature of their illness. Structural abnormalities, such as those caused by developmental abnormalities, stroke, placental pathology, maternal drug use, and congenital infections, are possibilities that should be identified with magnetic resonance imaging (MRI). Maternal medical and pregnancy history and antenatal imaging should be reviewed. The placenta should also be studied, where possible. Where congenital infection looks likely but no viruses are isolated, the congenital-like infections disorders, such as Aicardi–Goutieres syndrome (AGS), should be considered. AGS is a genetic syndrome mimicking congenital viral infections and is associated with intracranial injury and characteristic patterns of intracranial calcification involving the basal ganglia, thalami, and dentate nucleus.20,21 Other features include acquired microcephaly, epileptic seizures, poor feeding, eye movement abnormalities, myoclonic jerks, jitteriness, white matter abnormalities, chronic CSF lymphocytosis, and raised CSF interferon-alpha (INF-alpha).22 AGS is associated with a number of mutations in several genes, including TREX1 (OMIM 225750), RNASEH2A (OMIM 610333), RNASEH2B (OMIM 610181), RNASEH2C (OMIM 610329), SAMHD1 (OMIM 612952), and ADAR1 (OMIM 615010). Spinal trauma during delivery can be associated with a cervical and high thoracic myelopathy or haemorrhage compressing the spinal cord. Preterm infants can have spinal infarctions. The initial features are hypotonia and flaccid paresis, with hypertonia developing later.13 If the injury is associated with hypoxic brain injury or the need for sedation, these features can easily be missed. Metabolic causes should be considered if other diagnoses have been ruled out. These include: (1) bilirubin encephalopathy (kernicterus) which is rare in the UK (1 per 100 000 live births);23 (2) maple syrup urine disease (OMIM 248600) which leads to dystonic posturing following a period of stupor, poor feeding, vomiting, fluctuating ophthalmoplegia alongside the characteristic urine smell, although this may not be present in the initial stages;24

Table I: Aetiology of neonatal hypertonia presenting in the first day after birth Aetiology

Presentation

Key investigations

Treatment

Meningitis/meningoencephalitis

Encephalopathy, irritability, or signs of sepsis. May have evidence of meningism on examination and bulging fontanelle

Blood and CSF biochemistry and microbiological studies

Antibiotic therapy Treat raised ICP as necessary

Cerebral abscess

Encephalopathy, irritability, signs of history of sepsis, bulging fontanelle, raised ICP

Cranial ultrasound, MRI, lumbar puncture

Antibiotic therapy Treat raised ICP as necessary

Acute intracranial haemorrhage

Encephalopathy, irritability, signs of sudden collapse, apnoea, bulging fontanelle, sudden drop in haemoglobin, raised ICP. Preterm infants may have no clinical features.

Cranial ultrasound

None. Treat any relevant clotting defects May consider neurosurgical intervention (e.g. large compressive extradural haemorrhage or hydrocephalus) Treat raised ICP as necessary

Arterial ischaemic stroke/cerebral venous sinus thrombosis

Focal seizure disorder Encephalopathy, irritability, evidence of meningism, bulging fontanelle and/or evidence of raised ICP

Neuroimaging (MRI better than cranial ultrasound) Discussion with haematologists about haematological investigations

Nil routinely – controversy exists about anti-coagulation48 Treat raised ICP and seizures as necessary

Tonic seizures

May be encephalopathic with unilateral/asymmetric tonic stiffening associated with eye deviation, apnoea, or autonomic features and EEG/aEEG changes. Can be generalized tonic stiffening, but most cases of generalized tonic stiffening are not associated with EEG changes and are likely to be brainstem release phenomena rather than seizures Consider neonatal epilepsy syndrome

Amplitude integrated EEG and standard EEG

Phenobarbital Phenytoin Pyridoxal phosphate Biotin Follinic acid Other antiepileptics depending on cause of seizure Treat causes of acute symptomatic seizures (e.g. electrolyte imbalance, hypoglycaemia)

Hydrocephalus

Large head circumference, bulging/wide fontanelle, prominent scalp veins, sunset eye sign, opistotonic posturing. May occur following intraventricular haemorrhage

Neuroimaging

Neurosurgical review for consideration of reservoir/ventriculoperitoneal shunt or endoscopic third ventriculostomy

Antenatal brain injury Example aetiologies: Antenatal hypoxia Fetal intracranial haemorrhage Vascular phenomena trauma Chorioamnioitis maternal septicaemia Maternal cardiac arrest Maternal systemic illness Maternal drug side effects Fetal metabolic conditions such as mitochondrial defects Fetal genetic disorders such as mutations in the collagen IV A1 gene (OMIM 120090)7–11

Shortly after birth up to later in childhood with hypertonia If injury occurred shortly before birth, encephalopathy may be present Alert child with hypertonia/ contracture/arthrogryposis if distant to insult Seizures Drug withdrawal (if antenatal drug use has caused a structural abnormality)

Cranial ultrasound MRI Check blood and CSF lactate in case this is a manifestation of mitochondrial dysfunction Consider COL4A in cases of unexplained porencephaly or ante/intrapartum intracranial haemorrhage Urine toxicology screen (if drug use suspected)

Symptomatic

Congenital tumours

Macrocephaly, bulging fontanelle, hydrocephalus, signs of raised ICP, herniation, seizures, cranial nerve involvement, central respiratory drive abnormalities, abrupt intracranial haemorrhage

Cranial ultrasound and MRI. Specialist investigations directed by oncology department

Neurosurgical intervention and review by oncologists for further treatment

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Table I: Continued Aetiology

Presentation

Key investigations

Treatment

Hyperekplexia

Infants present with being stiff and irritable. Startle disease in a parent

EMG, ECG, EEG, genetics (see Table II)

Clobazem/clonazepam

CSF, cerebrospinal fluid; ECG, electrocardiogram; EEG, electroencephalography; aEEG, amplitude-integrated EEG; EMG, electromyography; ICP, intracranial pressure; MRI, magnetic resonance imaging.

(3) mitochondrial disorders, such as pyruvate dehydrogenase (PDH) deficiency (OMIM 312170), can present rapid onset hypertonia following a period of hypotonia, irritability, poor suck, along with derangements of liver and renal function, and lactic acidosis. Basal ganglia or thalami injury on MRI can mimic HIE; (4) serine deficiencies; (5) GTP cyclohydrolase deficiency caused by a novel mutation in the GCH1 gene (OMIM 600225) can present with neonatal hypertonia within a few weeks of birth and responds to LDOPA. MRI in this condition can show mild periventricular leukomalacia, which may be confusing. A normal cognitive outcome is possible with treatment;25 and (6) other neurotransmitter defects include secondary deficiencies in mitochondrial DNA depletion syndrome and reduced complex IV activity,26 sepiapterin reductase deficiency (OMIM 182125),27 and autosomal recessive holocarboxylase synthetase deficiency.28 It may be impossible to find a diagnosis in some neonates. We have seen a case with blindness, optic nerve hypoplasia, early onset epileptic spasms, and low CSF homovanillic acid; and another four cases in which no diagnosis was made, despite extensive investigations. Sometimes, the abnormalities can only be found post-mortem, such as dentate-olivary dysplasia,29 and olivopontocerebellar atrophy.30 Other rare central causes include prenatal cocaine exposure;31 neuroaxonal dystrophy, which is associated with mineralization and widespread neuronal loss in the basal ganglia and thalami;32 congenital absence of the corticospinal tracts33 seen at postmortem; neuronal loss in the lateral thalami of no known cause;34 and an unknown syndrome associated with severe growth retardation, microcephaly, obesity, hypogenitalism, and characteristic amphora facies.35

Peripheral causes Neonatal tetanus is common in middle- and low-income countries because of incomplete maternal vaccination and poor hygiene, such as cutting the umbilical cord with dirty scissors.36,37 Maternal vaccination state should be sought. Hypocalcaemia and/or hypomagnesaemia occur in maternal hyperparathyroidism leading to neonatal hypertonia/tetany,38,39 although this is rare in our experience. Myotonia is the sustained contraction of the muscles leading to stiffness/hypertonia. This can be seen in the autosomal recessive Schwartz–Jampel type 1b syndrome (OMIM 255800), caused by mutations to the HSPG2 gene on the 604 Developmental Medicine & Child Neurology 2015, 57: 600–610

short arm of chromosome 1 (OMIM 142461). Hypertonia can present shortly after birth, but the characteristic facial and skeletal abnormalities will be obvious earlier. Electromyography (EMG) reveals excessive muscle contraction. Unlike in true myotonia, the muscle contraction does not wax and wane, and appears as complex, repetitive discharges on EMG. The condition previously called type 2 Schwartz– Jampel syndrome is now called Stuve–Wiedemann syndrome (OMIM 601559) caused by mutations in the LIFR gene on chromosome 5p13,40 and has similar phenotype to Type 1b Schwarz–Jampel syndrome. However, neonates are more frequently hypotonic than hypertonic. Another peripheral cause is neuromyotonia or Isaacs syndrome. This condition usually affects older children and adults in whom it can be acquired, paraneoplastic, or hereditary. It is marked by continuous muscle contraction not stopped by spinal or general anaesthetic nor peripheral nerve block. In neonates, congenital Isaacs syndrome may not present until a few weeks of age.41 The most likely aetiology is a mutation in the KCNA1 gene (OMIM 176260) which codes for a potassium ion channel associated with autosomal dominant hereditary myokymia. The EMG shows continuous motor unit activity and persists during sleep.42 Some success has been reported with treatment using phenytoin and carbamazepine.41,43 Paramyotonia congenita caused by mutations in the sodium channel SCN4A gene (OMIM 603967) can present in the neonatal period with sustained stiffness, recurrent laryngospasm, and stridor.44,45 EMG is helpful in making the diagnosis.27 Treatment options include carbamazepine and mexiletine.45

THE DIAGNOSTIC APPROACH A suggested diagnostic approach is presented in Figure 2. A detailed history is the starting point. Features to seek include: (1) When the hypertonia started, which parts of the body are affected, whether it is intermittent or continuous, and the presence of epileptic seizures and degree of consciousness. (2) Family history/tree of at least three generations to identify: (a) learning difficulties, epilepsy, skeletal dysplasia, cataracts, or other illnesses that may represent a genetic or mitochondrial condition; (b) muscle aches and cramps that could be caused by a familial myotonia; (c) porencephaly, ante/perinatal intracerebral haemor-

Table II: Aetiology of neonatal hypertonia presenting after the first day after birth Condition

Age of presentation and mode of inheritance

Central aetiologies Acute onset/illness – see Table I Subacute/gradual onset Hypoxic-ischaemic Early onset encephalopathy encephalopathy with evolving movement disorder over weeks to months

Antenatal brain injury (e.g. hypoxic, sepsis, maternal drug use, maternal cardiac arrest, intracranial haemorrhage)

At birth or shortly after Usually sporadic

Spinal trauma/ haemorrhage/ cervical myelopathy

Sporadic

Bilirubin encephalopathy

Within few days after birth Sporadic

Metabolic disturbance (e.g. organic aciduria, maternal hyperparathyroidism)

Dependent on cause

Mitochondrial disorders (e.g. pyruvate dehydrogenase deficiency)

Can present in neonatal period

Presentation

Key investigations

Treatment

Neonatal encephalopathy with possible multi-organ failure, seizures and initial hypotonia leading to hypertonia. A convincing history of asphyxial injury should be sought If hypertonia presents early, consider other diagnoses Shortly after birth up to later in childhood with hypertonia. If injury occurred shortly before birth, encephalopathy may be present Alert child with hypertonia/ contracture/ arthrogryposis if distant to insult Seizures Drug withdrawal

History of perinatal period, review of CTG, cord gas results MRI of the brain (before day 5 for diffusionweighted imaging or after day 14 when both T1w and T2w changes visible)

Therapeutic hypothermia treatment

Cranial ultrasound MRI Check blood and CSF lactate in case this is a manifestation of mitochondrial dysfunction Consider COL4A in cases of unexplained porencephaly or ante/ intrapartum intracranial haemorrhage Urine toxicology screen (if drug use suspected) Spinal MRI

Symptomatic

Serum bilirubin MRI

Prevention by avoiding hyperbilirubinaemia; phototherapy, exchange transfusion

Renal, liver function Calcium, phosphate, magnesium, lactate, ammonia Maternal examination and biochemical profile Urine for organic acids (e.g. where maple syrup urine disease suspected) MRI altered signal in globus pallidus; low CSF lactate/pyruvate ratio; fibroblast PDH Muscle biopsy for histology and respiratory chain enzyme analysis

Dependent on cause

History of difficult delivery with hyperextension of the neck. May have encephalopathy. Bladder and bowel dysfunction (e.g. urinary retention). May initially present with flaccid paresis of lower limbs before hypertonia emerges Initial stupor, hypotonia, weak suck, high pitched cry changing to cerebral irritability and stimulus-induced hypertonia 2–3d later Encephalopathy, may have multi-organ dysfunction. Raised lactate should raise suspicion of mitochondrial disorders Maternal history and signs of hyperparathyroidism Mitochondrial presentations, episodic ataxia, dystonia

If haemorrhage causing compression, discuss with neurosurgical team. Otherwise, conservative

As directed by metabolic team

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Table II: Continued Condition

Age of presentation and mode of inheritance

Presentation

Key investigations

Treatment

Can present in neonatal period AR

Early epileptic seizures, microcephaly Combination of truncal hypotonia and limb spasticity

CSF amino acids for low serine and glycine Low CSF pterins

Serine and glycine supplements Levodopa

AR, SPR gene on chromosome locus on 2p14-p12

‘Cerebral Palsy’ oculogyric crises, dystonic episodes, learning disability

Levodopa, carbidopa, 5-hydroxytryptophan +/ BH4

Congenital infection

Not applicable

Congenital infection-like syndromes

Neonates

May present with sepsis/other organ involvement (e.g. liver enzyme abnormalities and thrombocytopenia), seizures May present with dystonia or seizures from antenatally acquired structural brain abnormalities Constellation of neurologically abnormal infant, hepatosplenomegaly, abnormal liver functions

Normal blood phenylalanine. CSF neurotransmitters reveal low level of HVA and 5-HIAA and high levels of biopterin and dihydrobiopterin. Diagnosis confirmed by enzyme assay in cultured fibroblasts. Congenital viral screen

res Aicardi–Goutie syndrome

Neonatal period in one third. Gene identified as TREX1, RNASEH2A, RNASEH2B, RNASEH2C, and SAMHD1

Clinical features include irritability, poor feeding, ocular jerking, hypertonia more than hypotonia, dystonia and occasional seizures

Congenital absence of the pyramidal tracts

Neonatal period or later

Dentate–olivary dysplasia

Can present in neonatal period or later

Delayed motor development, head lag, and spasticity of the limbs Rigidity and hypokinesia

Hereditary myokymia

Ion channelopathy, may present within a few weeks of age

Congenital stiffness and flexor posturing Unequivocal extensor plantar responses May be associated with neonatal epilepsy syndrome (e.g. Ohtahara syndrome or EME)

Sporadic Presents after 3d of age

No maternal immunization. Neonatal fever, rigidity, posturing, opisthotonus, risus sardonicus, rigid abdomen

Serine synthesis deficiency syndrome Neonatal dopa-responsive extra pyramidal syndrome with recessive GTPCH deficiency Sepiapterin reductase deficiency

Peripheral aetiologies Neonatal tetanus

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Screen for infections like HIV, TORCH. Might have cerebral white matter abnormalities on MRI. Basal ganglia or white matter calcification Genetic analysis. Increased CSF lymphocytes and interferon alpha. Distinctive brain imaging including cerebral calcification and white matter changes. Cerebellar atrophy is common MRI

Antiviral treatments, where appropriate Symptomatic

According to cause

Symptomatic

Symptomatic

Normal CSF metabolites, MRI, confirmed on post mortem neuropathological examination Normal MRI Obvious on surface EMG

Symptomatic

History including maternal immunization.

Early muscular paralysis and ventilation to prevent hypoxic brain injury and muscle relaxants Penicillin therapy for 10d Tetanus immunoglobulin

Some success with carbamazepine

Table II: Continued Condition Schwartz–Jampel syndrome type 1B and 2

Hereditary hypertonia/Isaac syndrome

Paramyotonia congenita

Age of presentation and mode of inheritance

Presentation

Key investigations

Treatment

AR; neonatal period. Mutations in the HSPG2 gene on chromosome 1 (type 1B) Mutations in the LIFR gene on chromosome 5p13 (type 2) At birth or within a few weeks after birth. AD. Gene locus on chromosome 5 or KCNA1 gene on chromosome 12

Characteristic facies, skeletal abnormalities

Obvious on surface EMG. Brain MRI normal

Procainamide hydrochloride produces symptomatic relief

Hypertonicity with rigidity of all voluntary muscles

Symptomatic

Can present in neonatal period. AD. Mutation in SCN4A gene

Sustained stiffness with activity

Continuous electromyographic activity even at rest (with absence of fasciculation) improves after intravenous diazepam EMG

Mexiletene may be useful

AD, autosomal dominant; CSF, cerebrospinal fluid; CTG, cardiotocography; EME, early myoclonic encephalopathy; EMG, electromyography; HIV, human immunodeficiency virus; MRI, magnetic resonance imaging; PDH, pyruvate dehydrogenase; TORCH, TOxoplasmosis, Rubella, Cytomegalovirus, HErpes simplex.

rhages, or recurrent strokes in children and young adults that may result from a COL4A1 mutation; (d) excessive startles secondary to hyperekplexia; and (e) dystonia resulting from neurotransmitter disorders. (3) Maternal/pregnancy history, including: (a) prescribed and illicit drug use; (b) sepsis during pregnancy; (c) viral illness during pregnancy; (d) trauma during pregnancy; (e) vaccine status; (f) maternal muscle cramps or aches during pregnancy which may be a feature of maternal hypoparathyroidism; (g) abnormal fetal movements and liquor volume suggesting an antenatal onset; (h) cardiotocography results, delivery history, resuscitation, and umbilical cord gases to identify infants with HIE; and (i) placental histopathology. An examination of the parents should identify dysmorphia, myotonia, and tetani (the Chvostek sign in mother). The first step in the neonatal evaluation is to determine whether the aetiology is central or peripheral. Central causes are suggested by features such as: (1) encephalopathy; (2) seizures; (3) meningism; (4) other organ involvement (e.g. liver, enzyme, and clotting abnormalties in HIE; hepatosplenomegaly and petechiae suggestive of congenital cytomegalovirus infection); (5) micro- or macrocephaly; (6) hyper-reflexia including ‘overflow’ to the contralateral limb and a positive jaw jerk; (7) signs of raised ICP such as loss of upgaze, a bulging fontanelle, and an increasing head circumference; (8) hyperalertness and a positive glabellar tap test suggestive of hyperekplexia; and (9) abnormal ophthalological findings such as cataracts or retinal abnormalities. Peripheral causes will usually be associated with a normal conscious level and the absence of other organ

involvement, unless the child has experienced an additional hypoxic insult. Usually, neonatal dysmorphia suggests a genetic condition and therefore a central aetiology. Because of the rarity of peripheral causes, this will be the case here too. However, one should be aware of the features of the Schwartz– Jampel syndromes with associated skeletal dysplasia. Similarly, stridor could suggest raised ICP and a central aetiology, or the peripheral paramyotonia congenita. Following initial assessment, the investigative approach should be directed by the differential diagnosis rather than a standard list of random tests. In acute and early onset hypertonia, we recommend: (1) treat as meningitis until proven otherwise, if acute onset; (2) electroencephalography (EEG); (3) neuroimaging (cranial ultrasound first, MRI when available); (4) biochemical investigations including serum calcium, magnesium, lactate, and paired CSF studies; (5) if no other causes found or the picture is of central origin but with unusual features, neurotransmitter disorders should be sought on CSF studies; and (6) if clearly hyperekplexia, genetic review/testing may be the only investigation required. Neonates with subacute/gradual onset central hypertonia should all be investigated with MRI unless the diagnosis is clearly hyperekplexia. If the history and neuroimaging is convincing of hypoxic injury, no further tests are required. Where history, examination, and neuroimaging do not reveal a diagnosis, other central aetiologies should be sought. Investigations could include: (1) electroencephalography; (2) serum lactate, liver and renal function, and clotting studies to identify systemic illness, such as mitochondrial disorders; (3) cerebrospinal studies for cell Review

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Neonatal hypertonia

History and examination History points:

• • • • • • •

Detailed family tree including learning difficulties, seizures, cataracts Maternal ethnicity, recent travel, tetanus vaccination status, and infection status Pregnancy history including evidence of chorioamnioitis / maternal sepsis Maternal cocaine use during pregnancy Birth history Resuscitation history Other signs of central causes - stupor, seizures, other organ dysfunction

Examination points: • Alert level (reduced suggesting central cause) • Dysmorphia (suggesting genetic condition) • Signs of sepsis / meningitis (dislike of light, Kernigs sign, neck stiffness) • Fontanelle appearance / level (bulging suggesting raised intracranial pressure / meningitis) • Head circumference (microcephaly suggesting genetic cause, macrocephaly suggesting possibly raised intracranial pressure) • Contractures • Jaw rigidity (suggesting tetanus) • Peripheral reflexes including cross overflow and jaw jerk (raised suggesting central origin, reduced or absent suggesting peripheral origin) • Startle including on nose tapping (suggestive of hyperekplexia) Myotonia • • Eye movement abnormalities (hydrocephalus. AGS, Sepiapterin reductase deficiency) • Paroxysmal episodes suggestive of epileptic seizures Parental examination • Myotonia / myokymia • Maternal Chvostek sign (hypocalcaemia / hypomagnesaemia)

Presentation within 24 h

Presentation after 24 h

Acute onset

Central

Subacute / gradual onset

Central

Unlikely to be HIE if persistent

If clear history of HIE, MRI only may be indicated. Ensure serum lactate settles. If not, consider metabolic condition

Initial possible investigations:

• Neuroimaging (cranial ultrasound first,

• • • • • • •

then MR imaging) to look for hydrocephalus, intracranial haemorrhage, tumour ECG for seizure activity Serum calcium, magnesium, biotinidase Serum lactate and amino acids Lumbar puncture for lactate, amino acids, neurotransmitters, infection screen Congenital infection screen (if suspected) Genetics referral(if dysmorphic or family history) Trial of benzodiazepines if startles to glabellar tap (hyperekplexia)

Consider starting antibiotics if infective aetiology possible.

If no diagnosis found, consider

First line, where diagnosis unclear: • MR imaging (if intracranial calcification likely, consider CT in addition) • Serum magnesium, calcium, lactate,liver function (including bilirubin), clotting, renal function • aEEG and, if abnormal, 12-lead EEG • Congenital viral screen • Urine organic acids and Guthrie test for maple syrup urine disease

Peripheral • • • • •

EMG Serum potassium, calcium, magnesium Skeletal survay (if dysplasia suspected) Genetics review Trial of carbamazepine of phenytoin

Possible second line tests, depending on differential • Paired serum and CSF lactate • Paired serum and CSF serine • CSF neurotransmitters • Muscle biopsy for histopathalogy and respiratory chain enzymes • Skin biopsy for culture and assessment of pyruvate dehydrogenase deficiency • CGH Microarray • Genetic review • Gene test of hyperekplexia • Gene tests for mitochondrial disease • Ophthalmology review • Trial of L-DOPA • Trial pyridoxal phosphate / biotin / follinic acid if refractory seizures present

Figure 2: A suggested algorithm for the investigation of neonatal hypertonia. AGS, Aicardi-Goutieres syndrome; CGH, comparative genomic hybridization; CSF, cerebrospinal fluid; EEG, electroencephalography; EMG, electromyography; HIE, hypoxic-ischaemic encephalopathy; MRI, magnetic resonance imaging. 608 Developmental Medicine & Child Neurology 2015, 57: 600–610

count, glucose, lactate, viruses, amino acids, and neurotransmitters. These should be taken with a paired serum sample for glucose, lactate, and amino acids before the lumbar puncture; (4) muscle and skin biopsy to identify respiratory chain enzyme defects and pyruvate dehydrogenase deficiency; (5) CT if intracranial calcification is possible; (6) ophthalmological review; and (7) genetic review. Despite this approach, an aetiological basis can be elusive. In these cases an empirical trial of L-DOPA (starting at 1mg/kg/d and gradually increasing to 3–4mg/kg/d divided into two divided doses) may be worthwhile, along with baclofen and benzodiazepines. In cases of tonic seizures which prove refractory to the standard anti-epilepsy treatment, we recommend a trial of pyridoxal phosphate (50mg/kg/d divided into four doses),46 biotin (5mg twice a day), and folinic acid (2.5–5mg twice a day).47 Peripheral aetiologies of neonatal hypertonia, could be investigated with: (1) an EMG in the awake and sleep state to look for myotonia; (2) serum potassium, calcium, and magnesium; (3) skeletal survey if a dysplasia is suspected; (4) genetics review; and (5) trial of carbamazepine or phenytoin if myotonia is confirmed.

TREATMENT The treatment depends on the cause, and some treatments can be used as a therapeutic trial during the investigative process. In children with known brain abnormalities, commencing baclofen followed by a benzodiazepine such as diazepam is our current first-line treatment. In neonates with refractory seizures, we trial vitamins. Where a central aetiology is expected and no neuroimaging abnormalities are found, a trial of L-DOPA is warranted following

sampling for CSF neurotransmitters. Central hypertonia worsens with pain or distress. Therefore, associated gastrooesophageal reflux disease, constipation, or other causes of pain should be addressed simultaneously. In peripheral causes, a trial of carbamazepine followed by phenytoin is warranted.

CONCLUSION Neonatal hypertonia is caused by a heterogeneous group of disorders. Hypertonia that presents at birth or within the first day after birth is not caused by HIE even if accompanied by encephalopathy, unless the raised tone is secondary to tonic seizures, brain stem release phenomena, or is transient and related to cooling. Subacute onset neonatal hypertonia is most often central in origin, but rare peripheral conditions do exist for which treatments are available. We have suggested a diagnostic approach to neonatal hypertonia but recommend early involvement of a paediatric neurologist and a clinical geneticist in difficult or atypical cases. A CK N O W L E D G E M E N T S All authors have read the manuscript and agreed to its submission for publication. All authors meet the criteria for authorship, and no one else qualifies for authorship to our knowledge. The authors’ roles were as follows: Dr Mordekar originated the concept and reviewed local experience of neonatal hypertonia; Dr Sharma collected the data and wrote the article; Dr Hart wrote the article, and added clinical experience and cases as a neonatal neurologist; and Dr Rittey reviewed and commented on the manuscript. No funding was received for this work. The authors have stated that they had no interests that might be perceived as posing a conflict or bias.

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Neonatal hypertonia - a diagnostic challenge.

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hyperton...
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