JICNA^R○| Journal of the International

Child Neurology Association

A peer reviewed open access e-journal in Child Neurology

INVITED REVIEW

Expected future developments in child neurology

123

Ingrid Tein

¹Division of Neurology, Dept. of Pediatrics and²Genetic and Genome Biology Program,The Research

Institute, The Hospital for Sick Children,and³Dept. of Laboratory Medicine and Pathobiology, The

University of Toronto, Toronto, ON, Canada M5G 1X8

Corresponding author:Ingrid Tein, The University of Toronto, Toronto, ON, Canada M5G 1X8; Email:

ingtein@sympatico.ca; Tel: +1-416-813-5668.

https://doi.org/10.17724/jicna.2019.158

Received: 18 Feb 2018

Accepted: 21 July 2019

Published 18 Nov 2019

Abstract

We stand on the shoulders of giants on the threshold of many new exciting developments in the field of child neurol-

ogy due to innovations in clinical approach, diagnostic technologies and treatment strategies. There are many exciting

new technologies, but we must never forget the power of clinical medicine which allows us to interpret and use these

tools with precision and with clinical wisdom. Strong collaborations continue to be needed: between clinicians for the

meticulous clinical phenotyping, expansion of the range of phenotypic expression, and the entry of patients into interna-

tional RCTs (randomised controlled trials); between the biochemists for the biochemical phenotyping and understanding

of the basic pathophysiology of the underlying dysregulations and disease mechanisms arising from the protein dysfunc-

tions and the development of robust biomarkers, to evaluate disease severity and response to therapies; and between the

geneticists for the understanding of the impact of the exonic or intronic mutations, roles of other regulatory genes on

the affected pathway, and epigenetic factors. These collaborations in the aggregate will lead the field forward in terms

of increased insight into disease pathophysiology for the development of targeted precision medicine treatment strate-

gies and effective preventative measures. This review is meant to highlight certain selected areas of future development

and is not meant to be a comprehensive survey beyond the scope of this review. The subspecialty areas which will be

highlighted will include intellectual disability, epilepsy, neuroprotection, neonatal and fetal neurology, CNS infections,

headache, autoimmune/inflammatory disorders, demyelinating disorders, stroke, movement disorders, neurotransmitter

defects, neuromuscular diseases, neurometabolic disorders, neurogenetic diseases, neuropsychiatry/autism, and neuroon-

cology. In each subspecialty area, I will endeavor to identify emerging diseases, new specific diagnostic technologies and

novel therapeutic approaches, but will need to be selective. This review is the culmination of a literature survey for current

developments, discussions with leaders in each of the subspecialty fields, who I will acknowledge at the end, and certain

personal projections.

Keywords: child neurology; precision medicine; whole exome sequencing; randomised controlled trials

tain significance (VUS) be identified, the need then arises to

General approach: The way forward

determine whether these same variants are carried by the

parents of a given child and whether they are symptomatic,

As we open Pandora’s box in all fields of medicine, we are

particularly in the case of autosomal dominant genes. In the

faced with a ‘tsunami ‘ of genetic information arising from

case of autosomal recessive disorders in which two VUS’s

the powerful new genetic technologies of whole exome ( 1%

are identified in a target gene in any given child, it becomes

of the genome) and whole genome sequencing. In the case

critical to determine whether the VUS’s are in cis or in trans,

of the identification of known pathogenic variants in the in-

to decide whether they may predispose to a given pheno-

terrogation of genes targeted for a given clinical phenotype,

type. This may be further complicated, as in the case of

the interpretation of the results will be relatively straight-

the common nuclear mitochondrial gene POLG (polymerase

forward. Should previously unidentified variants of uncer-

TEIN I. JICNA 2019;1(1)

gamma) which may account for up to 25% of mitochondrial

block/dysfunction, modify ‘loss of function’ or ‘gain of func-

disorders, in that any given child may have both dominant

tion’ mutations, reduce secondary downstream effects, em-

and recessive variants, which in the aggregate lead to a mi-

ploy the use of small molecule chaperone therapies to refold

tochondrial phenotype (Chinnery and Zeviani, 2008). The

misfolded proteins, etc.

analysis of whether the VUS’s are pathogenic if previously

With this explosion of new genetic information, the role

not identified as pathogenic in an affected individual, would

of the skilled clinician in identifying and defining the range

require biochemical or proteomic evaluation, either in vitro

of the clinical phenotypes, as well as the role of the bio-

in human cells or in vivo in an animal model, to confirm

chemist in ascertaining the effect of the mutation on protein

pathogenicity. There are also several bioinformatics compu-

structure and function, will therefore become even more im-

tational programs, such as SIFT (Ng and Henikoff, 2001),

portant in order to interpret the significance of the results of

Polyphen-2 (Adzhubei et al., 2010) and Mutation taster

WES and WGS. International collaborations and databases

(www.mutationtaster.org), which may be used to predict the

(e.g. Leiden Open Variation Database 3.0, etc.) to com-

pathogenicity of the variation, based upon the significance

bine clinical, biochemical, proteomic and genetic informa-

of the nucleotide change. For example, whether it changes

tion, and to define genotype-phenotype correlations, will

an amino acid residue and if so, whether the change is sig-

become essential to move all fields of medicine forward.

nificant (e.g. causing a change in charge, polarity, bending

New genetic technologies will routinely involve computa-

of the secondary structure of the protein, etc.) and does it

tional biology, epigenetic studies, genome-wide association

occur in a residue that is highly conserved throughout the

studies (GWAS), DNA microarray technology and whole ex-

species? Additional challenges to interpretation may arise

ome sequencing.

from conditions in which a pathogenic variant in an auto-

Computational biology includes areas of molecular cell bi-

somal recessive condition may lead to a clinical phenotype

ology with the application of mathematical theory to char-

when combined with a disease susceptibility polymorphism,

acterise the principles underlying biology at cellular, molec-

such as in short-chain acyl-CoA dehydrogenase (SCAD) de-

ular and genetic levels to advance discovery, and includes

ficiency (Zolkipli et al., 2011). With whole exome sequenc-

foundations in computer science, applied mathematics, bio-

ing (WES), the cDNAs encoding the expressed proteins is

statistics, biochemistry, chemistry, biophysics, molecular bi-

elucidated, which covers

1% of the genome. It is only

ology and genetics.

with whole genome sequencing (WGS) that intronic muta-

Epigenetics is the study of changes in gene activity that do

tions, which may for example affect the splicing of a protein,

not involve alterations to the genetic code, but are inherited

that the entire gene can be interrogated. Thus there may

and are governed by the cellular material, the epigenome,

be eloquent exonic as well as intronic mutations in a given

that overlies the genome, e.g. DNA methylation and his-

gene, contributing to the clinical phenotype. The resulting

tone modification, both of which serve to upregulate gene

phenotypes may be further complicated by the presence of

expression without altering the underlying DNA sequence.

promoter regions of the gene and epigenetic modifiers that

The various techniques to identify epigenetic modifications

lower the threshold for disease expression. To further com-

to DNA may include mapping locus-specific differences in

plicate the picture, disease phenotypes may also arise from

DNA modification, using enzymes that recognise the same

multiple partial defects in one or more metabolic pathways,

target sequence in DNA but are either sensitive or insen-

leading to the phenomenon of synergistic heterozygosity

sitive to its modification, exposing DNA to bisulphites and

(Vockley et al, 2000). These patients show clinical symp-

then sequencing, to allow methylated sites to be identified,

toms consistent with a defect in the affected pathway even

and using chemical approaches or antibodies, targeted to

though they do not have a complete deficiency in any one

specific modifications.

given enzyme.

Genome-wide association studies (GWAS) will enable re-

In the case of the identification of new genes of which

searchers to identify genes involved in human illnesses and

the function is not clearly known, the interpretation of the

search the genome for small variations, called single nu-

results becomes even more challenging, particularly if the

cleotide polymorphisms (SNPs) that occur more frequently

protein product is not known. This may then require site-

in individuals with a particular illness than those without

directed mutagenesis or CRISPR/Cas9 genome-editing tech-

the illness. Once identified, this ideally allows clinicians to

nology, and in vivo animal models and in vitro human cell

develop better strategies to detect, treat and prevent the dis-

cultures, to ascertain clinical and biochemical phenotype(s)

ease, e.g. in complex diseases, such as neuropsychiatric dis-

arising respectively. In most cases, the most severe pheno-

eases and cancer.

types for a given gene disorder are elucidated first. Over

DNA microarray technology allows the measurement of

time, as more variants and/or mild disease-causing muta-

the expression levels of large numbers of genes simultane-

tions are identified, there is often an expansion of the clin-

ously, to detect SNPs or to genotype multiple regions of a

ical phenotype from mild to severe. Using these technolo-

genome. Since an array can contain tens of thousands of

gies, pathways can be interrogated to understand the patho-

probes, a microarray experiment can accomplish many ge-

physiologic mechanisms of specific mutations, which will

netic tests simultaneously and accelerate investigations, es-

provide the basis for the development of targeted therapeu-

pecially in complex illnesses, such as neuropsychiatric dis-

tic strategies, e.g. to push through or bypass a biochemical

orders.

TEIN I. JICNA 2019;1(1)

Whole exome sequencing (WES) selectively sequences

ability and also other subspecialties of child neurology may

the coding regions of the genome, the regions in genes that

include pharmacoimaging, high-resolution in vivo spec-

are translated into proteins. In the human genome there

troscopy, and metabolomics for individual metabolic pro-

are about 180,000 exons which represent 1% of the entire

files.

genome. It is estimated that most disease-causing mutations

(a) Pharmacoimaging is the union between imaging and

are found in the regions of the genome that encode proteins.

pharmacology that provides additional information that

could not otherwise be obtained using traditional tech-

niques. It allows for a more precise, faster and direct

translation of data from a preclinical to a clinical context.

Precision Medicine

Evidence has now been accumulated, pointing to the po-

Precision medicine will be the next major paradigm shift

tential role of imaging in mitigating risk and cost during

in medicine. In the past we had symptom-based data

drug development. This is done by validating targets, ob-

with clinical intuition, which today has become pattern and

taining early indicators of bioactivity, assessing pharma-

evidence-based medicine. Our next move will be toward

cokinetic profiles, confirming mechanism(s) of action, pro-

consensus algorithmic approaches and reference databases,

viding prognostic indicators and supporting regulatory fil-

and we will use personal genetic information and biochem-

ings. Molecular imaging, using a variety of targeted probes

ical/biophysical profiling to design targeted therapies for

such as quantum dots, and instrumentation such as opti-

specific mutations. These may be gain or loss of func-

cal magnetic resonance (MR) and positron emitting tomog-

tion and will dictate precision medicine for the treatment

raphy (PET) methods, provides insights into target valida-

and prevention of specific diseases. There will be personal

tion and disease mechanism issues that are critical in pre-

molecular fingerprinting and molecular imaging which will

clinical studies. It is hoped that greater use of imaging dur-

be interpreted in the context of big data analytics and ref-

ing pre-clinical stages will facilitate more effective transla-

erence databases. Mobile information communication tech-

tion from animal models to human subjects, by minimising

nologies will be used to provide a precision medicine ap-

changes in experimental paradigms while the model organ-

proach targeted at disease prevention, diagnosis and treat-

ism is changed. In addition, imaging can frequently provide

ment.

critical supportive data for regulatory approval. Pharma-

Intellectual Disability

coimaging may also be useful for optimising combination

New diseases

treatments of novel compounds or compounds already in

We will be looking at the further expansion of new cat-

clinical trials.

egories of diseases, such as:

(a) disorders of complex

(b) High-resolution in vivo spectroscopy in the brain us-

lipid synthesis and remodeling, of which there are now

ing

1H-MRS (proton magnetic resonance spectroscopy)

at least

100 subtypes, including pathways for phospho-

may be useful for screening for specific disorders and

lipid and sphingolipid synthesis; (b) disorders of subcellu-

also for evaluating the effect of treatments by measur-

lar transport and trafficking, such as the class III phospho-

ing specific biomarkers, e.g. elevated N-acetyl-L-aspartate

inositide 3 kinase (PI3K), which synthesises phosphoinosi-

(NAA) in Canavan’s disease, elevated lactate peaks in mi-

tide 3 phosphatase (PI3P), regulating endosome-lysosome

tochondrial disorders, decreased creatine peaks in the cre-

trafficking and the induction of autophagy, pathways in-

atine deficiency disorders (creatine transporter defect, argi-

volved in pathogen killing, antigen processing and immune

nine:glycine amidinotransferase (AGAT) and guanidinoac-

cell survival (Hawkins and Stephens, 2015). Phosphoinosi-

etate methyltransferase

(GAMT) deficiencies), increased

tides (PIs) are a group of key signaling and structural lipid

guanidinoacetate (GAA) peaks in GAMT deficiency and de-

molecules involved in a myriad of cellular processes. PI

creased choline peaks in disorders of myelin. These MRS

phosphatases, together with PI kinases, are responsible for

profiles may undergo further resolution and expansion in

the conversion of PIs between distinctive phosphorylation

the future.

states (Hsu and Mao, 2015), and (c) disorders of the cellu-

lar cytoskeleton, such as the ‘tubulin code’ disorders which

chemical fingerprints that specific cellular processes leave

have the potential to modulate microtubule structure, dy-

behind, namely the study of their small-molecule metabo-

namics and interactions with associated proteins in neurons,

lite profiles. The metabolome represents the collection of all

and which have become increasingly important in both neu-

metabolites in biological cells, tissues, organs or organisms,

rodegenerative and neurodevelopmental disorders, such as

which are the end products of cellular processes. Metabolic

lissencephaly (Chakraborti et al., 2016). The tubulin code

profiling can give an instantaneous snapshot of the physi-

is believed to regulate microtubule functions on a cellular

ology of that cell. One of the challenges of systems biol-

and subcellular level. Current advances in knowledge of

ogy and functional genomics is to integrate proteomic, tran-

the tubulin code on the molecular and functional level will

scriptomic, and metabolomic information to provide a bet-

increase understanding of the process of complex signaling

ter understanding of cellular biology. Metabolomics, partic-

events in controlling microtubule function, particularly in

ularly in small molecule diseases such as the use of tandem

the central nervous system.

mass spectrometry (MS/MS) in fatty acid oxidation disor-

ders allows a snapshot of the physiology of the cell in a given

Novel Diagnostics Novel diagnostics in intellectual dis-

TEIN I. JICNA 2019;1(1)

disease (e.g. used in newborn screening) and can be used to

2015).

The epileptic encephalopathies include many

monitor the impact of therapies. The Human Metabolome

age-related electroclinical syndromes with specific seizure

Database (HMDB 4.0) for 2018, using in silico approaches,

types and EEG features. There may be evolution from

along with more traditional manual curation, has expanded

one age-related epilepsy syndrome to another, e.g. Ohta-

to 114,000 metabolites (Wishart et al., 2018).

hara syndrome (early infantile epileptic encephalopathy)

Novel Therapies In intellectual disability, as well as in

beginning in the first two months of life, evolving into

all other subspecialties of child neurology, novel therapies

infantile spasms and later into Lennox-Gastaut syndrome

may include (a) cell-based and gene-based therapies, (b)

(Ohtahara,

1977).

The number of known monogenic

small molecule chaperone therapies for misfolded proteins,

determinants underlying the epileptic encephalopathies

e.g. in lysosomal storage disorders, and (c) stop codon

is growing rapidly with the identification of molecular

readthrough therapies for missense and nonsense muta-

mutations. De-novo dominant mutations are frequently

tions (Keeling et al., 2014). Nonsense suppression ther-

identified, along with somatic mosaicism and recessive

apy encompasses approaches aimed at suppressing transla-

disorders. Mosaicism in both the somatic and germline cells

tion termination at in-frame premature termination codons

is becoming increasingly important in order to understand

(PTCs), also known as nonsense mutations, to restore defi-

pathophysiology, particularly in patients in whom exome

cient protein function. The approaches include readthrough

and gene panel sequencing is negative. Whole genome

drugs, suppressor tRNAs, PTC pseudouridylation, and in-

sequencing may be needed to identify intronic mutations

hibition of nonsense-mediated mRNA (messenger ribonu-

and regulatory components of the genome. Furthermore,

cleic acids) decay. A further therapy, (d) antisense oligonu-

epigenetic regulation

(including methylome) may also

cleotide (AON) therapy, corrects splicing defects through

need investigation and may help to explain phenotypic

exon skipping (e.g. Duchenne dystrophy) (Aartsma-Rus et

pleiotropy. One gene might be associated with phenotypic

al., 2007; van Roon-Mom and Aartsma-Rus, 2012). AONs

pleiotropy and conversely, several genes can cause one

are short synthetic modified nucleic acids that bind RNA

electroclinical syndrome. As more genes are identified, spe-

through base-pairing, and enable modulation of its expres-

cific genetic epileptic encephalopathies are being identified

sion (Southwell et al., 2012; Siva et al., 2014). The design

with distinctive electroclinical features and comorbidities,

of AONs that can bind to splice sites or to exonic- or intronic-

allowing classification of disorders in patients which was

enhancing cis-regulatory sequences in the pre-mRNA (ex-

not previously possible (Thomas et al., 2015; Howell et al.,

onic splice enhancers (ESEs) or intronic splice enhancers

2015).

(ISEs)) leads to the masking of these regions and the in-

Diverse genetic causes and molecular pathways have been

ability of trans-splicing regulatory factors to bind effectively,

implicated, which may involve ion channels and proteins

thus inducing switching between alternative splice isoforms

needed for synaptic, regulatory and developmental func-

via exon skipping. In the same way, by the masking of cryp-

tions. Gene discovery provides the basis for neurobiological

tic splice sites, AONs have been used for the correction of

insights, often showing convergence of mechanistic path-

cryptic splicing. With their diverse functionality, high target

ways (McTague et al., 2015). These findings will underpin

specificity, and the relative ease of central nervous system

the development of targeted therapies, essential to improve

(CNS) delivery, they are uniquely positioned as potential

the outcome of these severe neurological disorders. In the

therapies for neurological diseases.

future, models of network dysfunction in a given individual

will require the development of sophisticated in silico

models in addition to in vitro models from patient-derived

stem cells, in order to understand the pathomechanisms

Epilepsies

of dysfunction (McTague et al., 2015). In the case of early

onset epileptic encephalopathies (e.g. serine deficiency due

New Diseases In the future, epileptic encephalopathies will

to 3-phospoglycerate dehydrogenase deficiency) (de Koning

be thought of as ‘developmental’ epileptic encephalopathies

et al., 2004), effective therapy may require prenatal admin-

in order to encapsulate the developmental aspects of the

istration to reduce the effects of these devastating disorders.

child in addition to the epileptic component. The epilepsies

will be classified according to the genetic mutations,

e.g. STXBP1 encephalopathy, which may present with an

Further expansion of knowledge In the future, there

early infantile epileptic encephalopathy, characterised by

will be a further expansion of the knowledge related to the

infantile spasms or myoclonic, atonic or absence seizures

neurobiology of severe epilepsies. The disease mechanisms

due to syntaxin-binding protein 1 mutations. There will

may include synaptic dysfunction, channelopathies, trans-

also be an increased understanding of immune-mediated

porter defects, dysregulation of transcription, impaired re-

epilepsies, e.g. anti-GAD (glutamic acid decarboxylase)

pair of DNA and the remodeling of chromatin as well as

65 antibody-mediated epilepsy. Epileptic encephalopathies

metabolic disorders (McTague et al., 2015). Bioinformatic

of infancy and childhood comprise a large, heterogeneous

approaches with computer modeling and in vitro and in vivo

group of severe epilepsies characterised by several seizure

models of epilepsy will be used to identify links between dif-

types, frequent epileptiform activity on EEG, and often

ferent disease mechanisms, which may show convergence of

developmental slowing or regression

(McTague et al.,

disease pathways (Noebels 2015; Oliver et al., 2014). Pat-

TEIN I. JICNA 2019;1(1)

terns of spatial expression, including certain cell types, brain

terference - to specifically target mutated rather than wild-

regions or networks may also be important in epileptic en-

type alleles, e.g. in KCNQ2 encephalopathy (Matsa et al.,

cephalopathies, e.g. abnormalities of interneuron develop-

2014).

ment, migration or function, are associated with the ARX

Novel Diagnostics It must be kept in mind that each gene

and SCN1A genes (Yu et al., 2006; Kitamura et al., 2002).

may show phenotypic pleiotropy and that each epilepsy syn-

In addition, the temporal expression of genes may predict

drome may show genetic heterogeneity (McTague et al.,

the timing of the onset of the epilepsy, e.g. KCNQ2 and

2015). The phenotypic heterogeneity may arise from the

GRIN2A-related epilepsies will typically present around the

type and timing of the mutations during development, the

age when gene expression is needed for the normal physio-

timing and location of the gene expression, epigenetic fac-

logical development of neurons (Carvill et al., 2013; Lesca

tors as well as modifier genes. In the future, there will be

et al., 2013; Weckhuysen et al., 2012). Furthermore, ge-

an expansion of non-invasive evaluation of structural fo-

netic causes of severe epilepsy may also affect neuronal

cal epilepsies for seizure surgery using a combination of

function through mechanisms different from the seizure dis-

technologies, e.g. cEEG, MEG, PET, etc. Genetic technolo-

order, such as abnormal neuronal migration or abnormal

gies such as WES will amplify the genetic heterogeneity for

network formation, which may lead to abnormal cognitive

the given mutation. Currently there are > 22,000 variants

development (Bender et al., 2013). Novel Therapeutics (a)

now identified which will be incorporated into expanded

Pharmacologic approaches that directly target the abnormal

epilepsy gene panels. One gene may be associated with phe-

protein or disrupted pathways: (i) Mutations in the sodium-

notypic pleiotropy and there will be a need for functional

gated potassium channel gene KCNT1 may present with

validation of mutation pathogenicity. Techniques such as

epilepsy of infancy with migrating focal seizures (EIMFS)

single cell sequencing will provide insight into somatic mo-

with five times the gain of function over the wild type, which

saicism. WGS has 5 million estimated variants, allowing

begins in early infancy (< six months of age), or with auto-

for the identification of novel mutations or novel genes in

somal dominant nocturnal frontal lobe epilepsy (ADNFLE)

a large group of unsolved epilepsies covering the remain-

with three times the gain of function, which begins much

ing 99% of the genome and including intronic splice sites,

later in mid-childhood. The phenotypes can be reversed

regulatory regions, etc.

(McTague et al., 2015). Modeling

with quinidine which crosses the blood-brain barrier and re-

of epilepsy, using patient-derived stem cells or animal mod-

versibly blocks the channel in humans and rodents (Milligan

els, will facilitate the study of epigenetics, gene-interactions,

et al.,

2014).

(ii) Retigabine opens Kv7 potassium chan-

and environmental factors.

nels consisting of KCNQ2 and KCNQ3 subunits and restores

normal channel function of KCNQ2 encephalopathy muta-

tions in vitro (Orhan et al., 2014). (iii) NMDA (N-methyl-D-

Neuroprotection in Hypoxic Ischemic

aspartate) receptor antagonists, e.g. memantine, have been

Encephalopathy

suggested for GRIN2A- or GRIN2B-related diseases (Pierson

et al., 2014).

New Therapies Hypoxic-ischemic encephalopathy in term

(b) Nanotherapies function at an atomic, molecular or

infants occurs at a rate of about three per 1000 live-born

macromolecular level (McTague et al., 2015). An example

infants in resource-rich countries and at higher rates in

would be the proposed development of a protein-protein in-

resource-limited countries (Kurinczuk et al.,

2010; Ellis

teraction inhibitor that disrupts the helical interaction be-

et al.,

2000). Asphyxia can lead to hypoxic-ischemic en-

tween syntaxin-1A molecules, thus mimicking the action of

cephalopathy and cerebral palsy. Cerebral palsy is one of the

STXBP1 (Hussain et al., 2014).

most costly neurologic disabilities because of its frequency

(2/1000 births) and persistence over the life span (John-

novel compounds in neurons derived from fibroblasts of pa-

ston and Hoon, 2006). Knowledge of the nature, prognosis,

tients with specific mutations, e.g. SCN1A (McTague et al.,

and ways to treat brain lesions in neonatal infants has in-

2015).

creased remarkably over the past decade. Neonatal hypoxic-

(d) Gene therapy with delivery or expression of a wild-

ischaemic encephalopathy (HIE) in term infants involves a

type gene or modification of a transcription of a mu-

progressive cascade of excito-oxidative events that unfold

tant gene may constitute future therapies

(McTague et

in the brain after an asphyxial insult. In the laboratory,

al., 2015). Examples may include (a) an aminoglycoside-

this cascade can be blocked to protect brain tissue through

induced readthrough of a premature truncation codon of

the process of neuroprotection. The interval between the

GABRG2 to rescue the cellular phenotype (Huang et al.,

initial hypoxic-ischemic insult and delayed energy failure

2012). The effect, following the introduction of a gene,

includes the latent period after resuscitation when the in-

would however be permanent, which may interfere with

fant appears more active for 8-24 hours but then devel-

normal temporal expression patterns and have side effects.

ops seizures and signs of encephalopathy (Tan et al., 1996;

This might be mitigated by the use of optogenetics - light-

Thoresen et al., 2000). The experimental evidence sug-

sensitive proteins which can be used to activate channels

gests that activation of excitatory glutamate receptors, espe-

and lasers to induce excitation or inhibition (McTague et al.,

cially NMDA receptors, occurs very early during the initial

2015). Another approach would be allele-specific RNA in-

HIE insult and then oxidative stress associated with worsen-

TEIN I. JICNA 2019;1(1)

ing mitochondrial dysfunction and mitochondrial failure be-

jury. The sub-acute response to injury was driven by as-

come important factors, which determine whether neurons

trocytes. Within five days of injury, microglial prolifera-

and glia survive or die by apoptosis or necrosis (Ferriero,

tion and migration occured, along with limited differenti-

2004; Johnston, 2005; Johnston et al., 2001). Inflamma-

ation of oligodendrocytes and oligodendrocyte death. From

tion plays an important role in the excito-oxidative cascade

one day to five days after injury, a shift in dendrimer co-

of injury (Hagberg et al., 2009), in which lipopolysaccha-

localisation occurred. Initially, dendrimers predominantly

ride has been shown to sensitise the perinatal brain to HIE

co-localised with astrocytes, with a subsequent shift to-

and worsen injury (Wang et al., 2009), which can be re-

wards microglia. Co-localisation with oligodendrocytes re-

duced by administration of the antioxidant N-acetylcysteine

duced over the same period of time, demonstrating a region-

(Wang et al., 2007). Proof of a clinical effect was lacking

specific uptake based on the progression of the injury. They

until three landmark positive RCTs of moderate hypother-

further showed that systemic administration of a single dose

mia for term infants with HIE were published from 2005 to

of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either

2009

(Gluckman et al., 2005; Shankaran et al., 2005; Az-

sub-acute or delayed time points after injury, resulted in sus-

zopardi et al., 2009). These results have greatly improved

tained attenuation of the ’detrimental’ pro-inflammatory re-

treatment prospects for babies with asphyxia and showed

sponse up to nine days after injury, while not impacting the

that moderate hypothermia within six hours of asphyxia im-

’favourable’ anti-inflammatory response. The D-NAC ther-

proves survival, without cerebral palsy or another disability,

apy also led to improvement in myelination, suggesting re-

by about 40% and reduces death or neurological disability

duced white matter injury. Demonstration of treatment ef-

by nearly 30% (Johnston et al., 2011). The search is cur-

ficacy at later time points in the postnatal period provides

rently underway to discover adjuvant treatments that can

a greater understanding of how microglial activation and

further enhance the effects of hypothermia. Sex differences

chronic inflammation can be targeted to treat neonatal brain

should also be taken into consideration when designing and

injury and may also provide a longer therapeutic window.

testing new therapies, as preclinical testing has shown that

There is also potential for cell-based therapy in perinatal

treatments may be protective in one sex but ineffective in

brain injuries in the future using stem cells, including cord

another (Johnston et al., 2011).

blood and mesenchymal stem cells which have a neuropro-

Extreme prematurity is a major risk factor for perina-

tective effect in neonatal HIE in animal studies (Phillips et

tal and neonatal brain injury, and can lead to white mat-

al.,

2013). The mechanisms of action are diverse and in-

ter injury that is a precursor for a number of neurologi-

clude anti-apoptotic effects, release of growth factors, im-

cal diseases, including cerebral palsy (CP) and autism. Be-

munomodulation and activation of endogenous stem cells.

cause neuroinflammation, mediated by activated microglia

and astrocytes, is implicated in the pathogenesis of neona-

tal brain injury, targeted drug delivery to attenuate neu-

roinflammation may greatly improve therapeutic outcomes

Fetal and Neonatal Neurology

in models of perinatal white matter injury. Kannan et al.,

(2012) have demonstrated that systemically administered

In fetal neurology, there will be increasing diagnostics in

dendrimer-based N-acetyl-L-cysteine therapy in the postna-

utero to diagnose fetal diseases that may benefit from

tal period for a prenatal insult in a newborn rabbit model

early interventions. Examples of this would include early

of brain injury, suppressed neuroinflammation and led to a

ventriculo-amniotic shunt insertions (24 to 32 wks ges-

dramatic improvement in motor function, suggesting a new

tation) for progressive, non-infectious, obstructive hydro-

window of opportunity for treatment in CP after birth in hu-

cephalus (Cavalheiro et al., 2003), maternal hyperoxygena-

mans.

tion to promote early brain development in fetuses with

Dendrimers are man-made, nanoscale compounds with

congenital heart disease (Poryaette et al., 2016; Co-Vu et

unique properties that make them useful to the health and

al.,

2017), and metabolic therapies for inborn errors of

pharmaceutical industry as both enhancements to existing

metabolism, such as maternal high dose serine therapy to

products and as entirely new products. Dendrimers are con-

promote normal brain growth in utero in fetuses with a de-

structed by the successive addition of layers of branching

fect in serine biosynthesis, who would otherwise be born

groups and each new layer is called a generation. The fi-

with microcephaly (de Konig et al., 2004).

nal generation incorporates the surface molecules that give

In neonatal neurology, there will be an increasing fo-

the dendrimer the desired function for pharmaceutical, life

cus on the recognition of the daily medical care needed

science, chemical, electronic and materials applications.

by neonates in terms of nutritional requirements at differ-

Nance et al.,

(2015) have used a mouse model of

ent stages of gestation, particularly on neurodevelopmental

ischemia-induced neonatal white matter injury to study

outcomes and nutritional strategies in very low birth weight

the biodistribution of generation 4, hydroxyl-functionalised

infants (Belfort and Ehrenkranz, 2017). There will also

polyamidoamine dendrimers. Following systemic adminis-

be an increasing focus on reducing pain in neonates, given

tration of the Cy5-labeled dendrimer (D-Cy5), they demon-

the studies demonstrating that early procedural pain (skin-

strated dendrimer uptake in cells involved in ischemic in-

breaking events) in very preterm infants may contribute to

jury, and in ongoing inflammation, leading to secondary in-

impaired brain development (Brummelte et al., 2012).

TEIN I. JICNA 2019;1(1)

autoimmune complications may include GBS or transverse

CNS Infections

myelitis (Smith and Mackenzie, 2016; Mecharles et al.,

2016), whereas the prenatally acquired ZIKV manifests with

Perhaps one of the most devastating congenital neurotropic

devastating severe congenital microcephaly, placental loss

viruses in the past 100 years has been the Zika virus and

and IUGR (Rasmussen et al., 2016; Mlakar et al., 2016). In

its extremely deleterious effect on intrauterine fetal brain

a Task Force study by the Brazil Ministry of Health, as part

development. Historically, the Zika virus (ZIKV), which is

of the work of the Global Health Workforce Alliance, ZIKV

a neurotropic flavivirus carried mainly by mosquitoes of

was identified in the amniotic fluid of two women with fe-

the genus Aedes, was discovered in Uganda in 1947. Be-

tal microcephaly (Millichap, 2016). In this study, 35 infants

tween the 1960’s and the 1980’s, human infections related

with microcephaly were born during the period from Au-

to ZIKV in Africa and Asia were typically mild. In 2007,

gust to October 2015. All of the mothers had lived in or vis-

the first large outbreak of disease was reported from the

ited ZIKV-affected areas during pregnancy. Of these infants,

Island of Yap (one of the federated states of Micronesia)

(71%) had severe microcephaly (HC (head circumfer-

as the virus moved from South-east Asia across the Pacific

ence) > 3 SD (standard deviations) below normal) and 17

(Hills et al.,

2017; Talero-Gutierrez et al., 2018). From

(49%) had at least one neurological abnormality, including

2013 to 2014, there was an outbreak in French Polyne-

hypertonia/spasticity in 37% and seizures in 9%. Of the 27

sia with cases of Guillain-Barre syndrome (GBS), related

infants who underwent neuroimaging, all had abnormali-

to the ZIKV. In May 2015, the first reports of local trans-

ties with brain calcifications in 74%, ventricular dilatation

mission in Brazil were apparent. In July 2015, cases of

in 44% and neuronal migration disorders in 33%. Tests for

GBS related to ZIKV were reported in Brazil and in Oc-

other congenital infections were negative. In another study

tober 2015, cases of congenital microcephaly arising from

of 42 pregnant women in Rio de Janeiro who were positive

devastating intrauterine ZIKV exposure were reported. In

for ZIKV, fetal ultrasound demonstrated abnormalities in 12

February 2016, the WHO declared ZIKV associated micro-

(29%) with two fetal deaths at 36 and 38 weeks gestation,

cephaly and other neurological disorders as a Public Health

five with IUGR, with or without microcephaly, seven with

Emergency of International Concern. The ZIKV has been

ventricular calcifications or other brain lesions, and seven

carried worldwide by international travel. Cases were re-

with abnormal amniotic fluid volumes or cerebral or umbil-

ported in Central America and the Caribbean, with some

ical artery flows (Brasil et al., 2016). Pathophysiologically,

cases in North America (Chen and Hamer 2016; Kind-

the ZIKV has been shown to target and infect human em-

hauser et al., 2016). The primary vector Aedes aegypti has

bryonic cortical neural progenitor cells (hNPCs) and to dys-

been recorded across all continents, including North Amer-

regulate the cell cycle and transcription which leads to cell

ica, Madeira, the Netherlands and the northeastern Black

death (Tang et al., 2016). The diagnosis of ZIKV infection

Sea coast, signifying adaptation to colder climates. As of

can be done by RT-PCR (reverse transcription polymerase

March 2016, all six major geographic regions confirmed

chain reaction) during the first week of illness. The viremia

local transmission including South America (Chile, Brazil,

occurs from days 0-11 after symptom onset. Serologic test-

Colombia, Suriname, Venezuela, French Guyana, Bolivia,

ing can be done by measurement of IgM (immunoglobu-

Argentina, Ecuador, Paraguay); the Caribbean (Martinique,

lin) by ELISA (enzyme-linked immunosorbent assay), how-

Puerto Rico, Saint Martin, Haiti, Barbados, US Virgin Is-

ever there may be false positives with cross-reacting Dengue

lands, Dominican Republic, Jamaica, Curacao, Trinidad and

virus (Musso and Gluber, 2016). Confirmation can be done

Tobago, Aruba, Bonaire, St. Vincent and the Grenadines,

by plaque reduction neutralisation assays. The ZIKV may

Sint Maarten, Cuba, Dominica); Central America (Mex-

be detectable in blood, saliva, urine, sperm and amniotic

ico, Panama, Honduras, El Salvador, Nicaragua, Costa Rica,

fluid. At present, there are still no effective vaccines against

Guatemala); North America (USA*, Canada*, Hawaii), Eu-

the ZIKV, although many efforts are currently underway

rope (France*, Italy* (+ travelers in Germany, Finland, UK,

to accelerate the development of ZIKV vaccines using var-

Denmark)), Africa (Cape Verde), and South-East Asia (New

ious platforms, including live attenuated virus, inactivated

Caledonia, Laos, Philippines, Bangladesh, Tonga, American

virus, DNA and RNA, viral vectors, and in silico-predicted

Samoa, Fiji, Marshall Islands, Thailand (+ Japanese trav-

immunogenic viral epitopes (Makhluf and Shresta, 2018).

elers*)). Transmission is through the bites of the Aedes

There is promising news from phase I, randomised, double-

species mosquitoes, blood transfusion and sexual transmis-

blind, placebo-controlled clinical trials on aggregate safety

sion, and the ZIKV can be found in blood and urine. The

and immunogenicity results from three trials of a purified,

clinical incubation period following the bite of a ZIKV in-

inactivated ZIKV vaccine which appeared to be well tol-

fected mosquito is two to seven days. The clinical manifes-

erated and elicited robust neutralising antibody titres in

tations of post-natally acquired ZIKV are usually mild and

healthy adults (Modjarrad et al., 2017). The mainstay of

include a maculopapular rash at two to 14 days (median

therapy is prevention and symptomatic treatment. Symp-

of six days), arthralgia (at one to 14 days with a median

tomatic treatment includes antipyretics for fever and anal-

of three and a half days), and conjunctivitis, and may in-

gesics for headache and myalgia, and avoidance of nons-

variably include myalgia, headache, retroorbital pain, joint

teroidal anti-inflammatory drugs if there is thrombocytope-

swelling, vertigo and vomiting, and are self-resolving in

nia. Prevention rests on the avoidance of mosquito exposure

approximately one week (Musso and Gubler, 2016). The

TEIN I. JICNA 2019;1(1)

with DEET or picaridin repellants to minimise day-biting

is evidence that this involves axonal transport via sensory fi-

Aedes, drainage of mosquito-breeding sites, application of

bres (Gooriah and Ahmed, 2015).

insecticides and avoidance of contact with infected body flu-

Other new non-medicinal modalities include the use of

ids. Questions that still remain to be answered include the

transcutaneous supraorbital nerve stimulation (tSNS) by

effect of ZIKV on the postnatally infected developing brain.

the Cefaly device. In a double-blind, randomised sham-

controlled trial of tSNS, the device was found to be effective

and safe as a preventive therapy for migraine, with a ther-

apeutic gain of 26% which was within the range of those

Headache

reported for other preventative drug and nondrug antimi-

The management of headache has several exciting new

graine treatments (Schoenen et al., 2013). Monthly mi-

modalities of treatment on the horizon. Non-medicinal ther-

graine attacks, monthly headache days, and monthly acute

apies such as cognitive behavioural therapy (CBT) are show-

antimigraine drug intake were also significantly reduced. In

ing promise. A randomised clinical trial of 135 youths aged

a survey of 2,313 headache sufferers in the general pop-

10 to 17 years, diagnosed with chronic migraine and a Pe-

ulation, tSNS was a safe and well-tolerated treatment for

diatric Migraine Disability Assessment Score > 20 points,

migraine headches that provided satisfaction to a majority

were assigned to CBT plus amitriptyline or to headache ed-

of patients who tested it for 40 days with adverse events

ucation plus amitriptyline (Powers et al., 2013). The use

in only 4.3%, which were minor and fully reversible (Magis

of CBT plus amitriptyline resulted in greater reductions in

et al., 2013). The Cefaly (Cefaly Technology sprl, Herstal,

days with headache and migraine-related disability com-

Belgium) device has obtained approval from the American

pared with the use of headache education plus amitripty-

Food and Drug Administration under prescription for the

line. These findings supported the efficacy of CBT in the

prevention of episodic migraine (Riederer et al., 2015). In

treatment of chronic migraine in children and adolescents.

an open-label preliminary trial of 23 consecutive headache

centre patients with chronic migraine, over half of the pa-

Encouraging results are also being found with onabo-

tulintoxin A. In a double-blind placebo-controlled trial of

tients had a greater than 50% reduction in acute medica-

onabotulinumtoxin A versus placebo for migraine prophy-

tion consumption (Di Fiore et al., 2017). The Cefaly is po-

laxis, there was no between-group difference for headache

sitioned on the forehead using an adhesive electrode and

episodes. There were however significant reductions from

precise impulses are produced during a 20 minute program,

baseline for headache and migraine days, cumulative hours

which act on the trigeminal nerve in order to prevent mi-

of headache on headache days and frequency of moder-

graine attacks.

ate/severe headache days, which in turn reduced the bur-

A second non-medicinal device which has been recently

den of illness in adults with disabling chronic migraine (Au-

approved by the FDA for patients with migraine with aura is

rora et al., 2010). In a second double-blind randomised

the Cerena Transcranial Magnetic Stimulator, a single pulse

placebo-controlled PREEMPT (Phase III Research Evaluat-

TMS stimulator which can be used as an effective preventa-

ing Migraine Prophylaxis Therapy) clinical program study

tive or abortive therapy (Zhu and Marmura, 2016).

of 1,384 adults, pooled analyses demonstrated a large mean

Currently there is a focus on the development of cal-

decrease from baseline in frequency of headache days, with

citonin gene-related peptide (CGRP) antagonists (human

statistically significant between-group differences favouring

monoclonal antibodies to CGRP or its receptor, or CGRP

onabotulinumtoxin A over placebo at week 24 (-8.4 vs -6.6;

receptor antagonists) as a preventative treatment for mi-

P < .001) and at all other time points. Significant differ-

graine. In the trigeminal vascular system, the cell bodies

ences favouring onabotulinumtoxin A were also observed

on the trigeminal ganglion are a main source of CGRP, a

for all secondary efficacy variables at all time points, with

neurotransmitter involved in pain and vasodilation which

the exception of frequency of acute headache pain medica-

is believed to play a role in migraine. The role of CGRP in

tion intakes (Dodick et al., 2010). The pooled PREEMPT

migraine is likely mediated by modulating nocioception and

results demonstrated that onabotulinumtoxin A was an ef-

sustaining neurogenic inflammation that leads to further pe-

fective prophylactic treatment for chronic migraine and re-

ripheral and central pain sensitisation (Yuan et al., 2017).

sulted in significant improvements compared with placebo

Multiple pharma companies are developing CGRP biolog-

in multiple headache symptom measures, significantly re-

icals (humanised monoclonal antibodies) to be used in the

ducing headache-related disability and improving function-

treatment of migraine. In a phase III placebo-controlled trial

ing and overall health-related quality of life. In a retro-

of fremanezumab (humanised monoclonal antibody target-

spective chart review of the efficacy of botulinum toxin

ing CGRP) in 1,130 patients, there was a lower frequency of

type A therapy in 10 pediatric patients with chronic daily

headache (Silberstein et al., 2017). Phase II and III studies

headaches, 40% reported subjective but clinically meaning-

have been promising with favourable safety profiles mak-

ful relief, consisting of a decrease in headache intensity, and

ing CGRP antagonists a major potential new therapy for the

two patients additionally noted a decrease in headache fre-

management of migraine (Yuan et al., 2017). These studies

quency and thus an improvement in quality of life (Ahmed

have been done in adults. The applicability to children will

et al., 2010). The mechanism of action of onabotulinum-

require future pediatric clinical trials.

toxin A in chronic migraine is not fully understood, but there

Within the clinical entity of idiopathic intracranial hy-

TEIN I. JICNA 2019;1(1)

pertension (IIH), there are now revised diagnostic criteria

evidence for autoimmune encephalitis (possible, probable,

for elevated opening pressures on lumbar puncture (LP)

or definite) are achieved, which can lead to prompt im-

which are > 250 mm CSF in adults and > 280 mm CSF

munotherapy. As the repertoire of autoimmune encephali-

in children (250 mm CSF in children if not sedated and not

tis in children is different from that in adults, in that the

obese) in properly performed LPs (Friedman et al., 2013).

younger the child the more difficult it is to recognise spe-

The additional required criteria for a diagnosis of IIH are

cific syndromes, the guidelines for pediatric autoimmune

papilledema, normal neurological exam except for cranial

encephalitis may be more dependent on antibody identifi-

nerve abnormalities, normal brain MRI without evidence of

cation and other ancillary tests (Graus et al., 2016). Thus

hydrocephalus or structural lesion or abnormal meningeal

there will need to be testing of this protocol for applicability

enhancement, and normal CSF composition. These inves-

to the pediatric neurology cohort.

tigators also provided criteria for IIH without papilledema.

In a two-year, single centre prospective study of CSF open-

ing pressure in 472 children undergoing LP as part of their

routine clinical care, the reference range for the 90th per-

Demyelinating disorders

centile was 28 cm of water and for the 10th percentile was

11.5 cm of water (Avery et al., 2010). Subjects placed under

moderate to deep sedation during LP had a slightly higher

Similarly in the demyelinating disorders, autoimmune de-

opening pressure as compared with those not receiving any

myelination will be divided into recognised autoantibody

sedatives. The patient’s depth of sedation, body mass index,

positive disorders

(e.g. aquaporin

4 antibody in neu-

and sedation medication could sometimes result in small

romyelitis optica spectrum disorder (NMOSD) and MOG

increases in opening pressure, whereas age and leg posi-

antibody in acute disseminated encephalomyelitis (ADEM)

tion (flexed vs extended) in the lateral decubitus position

and NMOSD) versus disorders that are autoantibody nega-

did not seem to significantly impact opening pressure (Av-

tive (e.g. monophasic demyelination and relapsing chronic

ery, 2014). In a large retrospective, multisite cohort study

demyelination or multiple sclerosis (MS)). Novel diagnos-

of pediatric idiopathic intracranial hypertension with up-

tics will expand through immunophenotyping to distinguish

dated diagnostic criteria and pediatric-specific assessments,

between different neuroinflammatory demyelinations. In

three subgroups were identified; a young group that was

the autoantibody associated demyelinations, the data is

not overweight, an early adolescent group that was either

currently limited to retrospective and observational cohort

overweight or obese, and a late adolescent group that was

studies. The natural history and treatment of subgroups

mostly obese (Sheldon et al., 2016).

should be better defined in the next two to five years and

this will be facilitated through the IPMSSG (International

Pediatric MS Study Group). MS in childhood manifests most

frequently as a relapsing-remitting MS phenotype (RRMS)

Neuroimmunology

(Brenton and Banwell, 2016). As in all neurological subspe-

Advances in autoimmune encephalitis research in the past

cialties, multicentre collaborative RCTs (randomised con-

10 years have led to the identification of new syndromes

trolled trials) should be the goal in order to evaluate the

and biomarkers that have transformed the diagnostic ap-

true efficacy and safety of different treatment strategies,

proach to these disorders. These newly identified forms of

given the rarity of pediatric MS. Novel therapies will rest

autoimmune encephalitis may be associated with antibod-

on immunophenotyping to determine the optimal therapies

for individual patients within diagnostic categories. There

ies against neuronal cell-surface or synaptic proteins, and

will be increasing RCTs for new immunomodulatory agents

can resemble infectious encephalitis and have neurological

in pediatric MS. Data on the efficacy of the first oral agent

and psychiatric manifestations without fever or CSF pleocy-

for pediatric MS, fingolimod, should become available in

tosis (Leypoldt et al., 2015). However, existing criteria for

the next few years through a prospective, double-blind, ran-

autoimmune encephalitis are too reliant on antibody test-

domised, active-controlled study that has begun to evalu-

ing and response to immunotherapy, which might delay the

ate the efficacy and safety of fingolimod versus IFN-ß1a in

diagnosis.

pediatric patients with MS (PARADIGMS), with a primary

In the field of neuroimmunology, a major breakthrough

endpoint of annualised relapse rate reduction (Brenton and

moving forward is the development of the first multicentre,

Banwell, 2016). Fingolimod is the first oral drug to receive

consensus definition of autoimmune encephalitis by a team

FDA approval in North America and Europe for adults with

of experts, designed for both adults and children and allow-

relapsing-remitting MS and is a sphingosine-1-phosphate re-

ing the clinician to navigate through the differential diag-

ceptor modulator that prevents T-cell egress from peripheral

nosis to make a suspected clinical diagnosis and to initiate

lymphoid tissue into the peripheral and central circulation

treatment while awaiting antibody testing, in order to avoid

(Pelletier and Hafler, 2012). There will also be a focus on

critical delays in immunotherapy (Graus et al., 2016). This

the development of neuroprotective strategies to improve

initial diagnostic approach is based upon neurological as-

remyelination.

sessment and conventional tests that are accessible to most

clinicians. Through logical differential diagnosis, levels of

TEIN I. JICNA 2019;1(1)

(29 days to 18 years of age) and 354 stroke-free controls.

Stroke

Infection in the week prior to stroke was reported in 18% of

Arterial ischemic stroke in newborns, young children and

cases versus 3% of controls, conferring a 6.3-fold increase

adults may appear the same on neuroimaging, but the out-

risk of AIS (p< 0.0001), with upper respiratory infections

come in terms of neurologic morbidity and mortality is

being the most common, followed by gastroenteritis, fol-

markedly different due to the tremendous capacity for plas-

lowed by otitis media (Fullerton et al., 2015). Of note, chil-

ticity in the developing child’s brain. Neocortical devel-

dren with some/few/no routine vaccinations were at higher

opment is characterised by an extended period of synap-

stroke risk than those receiving all or most, suggesting that

tic proliferation that peaks in mid-childhood, with subse-

routine vaccinations appeared to be protective. These stud-

quent pruning through early adulthood, as well as relatively

ies have been greatly facilitated by the International Pedi-

delayed maturation of neuronal arborisation in the pre-

atric Stroke Study Group which runs multicentre (> 55 ac-

frontal cortex compared with sensorimotor areas (Bianchi

tive IPSS centres in 2016), multinational consecutive cohort

et al., 2013). In studies of human cortical development by

studies with the objective to develop multicentre clinical tri-

anatomic brain MRI scans, between ages four to 21 years,

als.

the higher-order association cortices were shown to ma-

In the future, there may be a role for thrombectomy in pe-

ture only after lower-order somatosensory and visual cor-

diatric stroke in highly selected cases, in centres with a full

tices, the functions of which they integrate were developed,

complement of pediatric anesthesia and a fully equipped pe-

and the phylogenetically older brain areas matured earlier

diatric stroke team with interventional neuroradiology and

than the newer ones (Gogtay et al., 2004). The sequence

a set of well-developed institutional guidelines. Initial case

in which the cortex matured involved an early maturation

selection would likely involve teenagers and adhere to the

of the more basic functions: motor and sensory brain areas

criteria for benefit from RCTs in which diagnosis is made

matured first, followed by areas involved in spatial orienta-

well within six hours of stroke onset, the preceding IV tPA

tion, speech and language development, and attention (up-

has been unsuccessful, there is occlusion of the proximal

per and lower parietal lobes). Later to mature were areas

Circle of Willis, and the infarct core is small. To date there

involved in executive function, attention and motor coordi-

have been only a few reported cases of pediatric thrombec-

nation (frontal lobes). The frontal pole, involved in taste

tomy in AIS and the safety and efficacy of thrombectomy

and smell processing and the occipital pole containing the

in children is currently unknown (Buompadre et al., 2017).

primary visual cortex, also matured early. This sequence

Moving forward, there will need to be a registry of compli-

of cortical maturation agreed with regionally relevant mile-

cations and outcomes of treated cases to determine efficacy.

stones in cognitive and functional development. There was

a progressive loss of grey matter volume with maturation,

the exact process of which is unknown, but may be partially

explained by synaptic pruning (Huttenlocher, 1979) in com-

Movement Disorders

bination with trophic glial and vascular changes and/or cell

shrinkage (Morrison and Hof, 1997).

In the field of movement disorders, as in other subspecial-

There are novel technologies being developed and tested

ties, it is becoming clear that the genotype is not necessarily

to modulate plasticity in the developing brain with the aim

the final answer in defining the clinical phenotype which

of enhancing rehabilitation in children with perinatal in-

may be modified by other genes and epigenetic factors and

juries or infantile strokes. One of these is the use of tran-

will therefore require further analysis. A clear example of

scranial direct-current stimulation (tDCS), which has been

mutations in a single gene that may lead to multiple phe-

shown to enhance motor-learning in healthy school-aged

notypes are mutations in ATP1A3, which may present with

children and which was well-tolerated and safe with no ad-

rapid-onset dystonia-parkinsonism, alternating hemiplegia

verse events (Ciechanski and Kirton, 2017). Another modal-

of childhood, or ataxia with dystonia (Boelman et al., 2014;

ity with promise is that of combined repetitive transcranial

Termsarasab et al., 2015; Panagiotakaki et al., 2015; Swead-

magnetic stimulation (rTMS) and constraint-induced move-

ner et al.,

2016). Other examples include mutations in

ment therapy (CIMT) which has been shown to enhance

PRRT2 which may present with diverse clinical phenotypes

therapy-induced functional motor gains persisting to six

such as paroxysmal kinesigenic dyskinesia or benign familial

months in children with stroke-induced hemiparetic cere-

infantile convulsions (Chen et al., 2011; Wang et al., 2011;

bral palsy (Class II evidence in the PLASTIC CHAMPS Trial)

Meneret et al., 2012; Schubert et al., 2012). Similarly, mu-

(Kirton et al., 2016).

tations in TUBB4A may present with autosomal dominant

In the analysis of risk factors in pediatric arterial ischemic

torsion dystonia/whispering dysphonia (DYT4) (Lohmann

stroke (AIS), the Vascular Effects of Infection In Pediatric

et al., 2013) or hypomyelinating leukoencephalopathy with

Stroke (VIPS) study tested the hypothesis that infection

atrophy of the basal ganglia and cerebellum (HABC) (Si-

transiently increases the risk of AIS in children, regardless

mons et al., 2013). New therapeutic approaches These

of stroke subtype (arteriopathic, cardioembolic and idio-

will focus on improved medication options based upon a

pathic). This was an international case-control study that

better understanding of the neurobiology of the specific

prospectively enrolled 355 centrally confirmed cases of AIS

movement disorder, e.g. therapies may be directed, as ap-

TEIN I. JICNA 2019;1(1)

propriate, toward subtype specific anti-muscarinic medica-

cortical, mesolimbic and nigrostriatal) (San Sebastian et

tions, vesicular dopamine uptake inhibitors or may use gene

al.,

2014).

(See www.aadcresearch.org/page/aadc-gene-

modification approaches, such as anti-sense oligonucleotide

therapy-trials-usa-uk/).

therapy. There may also be advances in neuromodulation

therapies, such as more specific deep brain stimulation tar-

gets, patient-specific stimulation paradigms, or non-invasive

Neuromuscular Disorders

methods for neuromodulation.

In the field of neuromuscular disorders, the Treat-NMD Al-

liance (www.treat-nmd.eu) has provided an important in-

frastructure and highly informative website for clinicians,

Neurotransmitter disorders

researchers, families and patients, to ensure that the most

promising new therapies reach patients as quickly as pos-

New diseases In the field of neurotransmitter disorders,

sible, and to provide state-of-the-art standards of care for

emerging new diseases are being recognised, including dis-

common neuromuscular disorders, such as muscular dys-

orders of serotonin deficiency as well as novel monoamine

trophies and spinal muscular atrophy (SMA).

neurotransmitter disorders that involve defects in dopamine

Novel diagnostics

transport and monoamine vesicle packaging (Ng et al.,

In neuromuscular disorders, novel diagnostics will in-

2015). There will also be increasing recognition of sec-

creasingly use qualitative and quantitative muscle and nerve

ondary neurotransmitter disorders where the CSF profile

ultrasound techniques (Connolly et al., 2015; Jongloed et

does not fit a known primary neurotransmitter defect. Most

al., 2016). There will also be an increasing trend toward the

of the secondary neurotransmitter disorders have been sep-

identification of robust biomarkers for different disorders,

arated into those associated with abnormal levels of HVA

in order to evaluate the efficacy of therapies in randomised

or with abnormal levels of

5-HIAA (selective serotonin

clinical trials.

deficiency) (Ng et al.,

2015). In these conditions, dis-

ruption of monoamine metabolism may be secondary to

Identification of pathophysiologic mechanisms will be

dopaminergic and serotonergic tract degeneration or defec-

aided by CRISPR/Cas9 gene editing which has been use-

tive monoamine metabolism. Disorders with low HVA and

ful for DMD mouse models. Gene-edited Zebra fish have

normal 5-HIAA include mitochondrial disorders, Rett syn-

also become a very valuable model for understanding the

drome, CACNA1A mutations with ataxia, NKH, etc.; disor-

impact of mutations in congenital myopathies and muscular

ders with low HVA and low 5-HIAA include ADEM, GBS,

dystrophies (Raeker et al., 2014). The Treat-NMD network

urea cycle disorders, mitochondrial disorders, encephalitis,

has also provided standard operating procedures (SOPs) to

etc.; disorders with low HVA and low methyltetrahydrofo-

unify experimental protocols used to test new therapies in

late include leukodystrophy, hypomyelination, demyelina-

animal models and cells, allowing direct comparisons be-

tion, etc.; disorders with high HVA and normal 5-HIAA in-

tween studies.

clude Angleman syndrome, HIE, stroke, urea cycle disor-

Novel therapies

ders, etc.; disorders with low 5-HIAA only include autism,

Internationally, novel therapies are now listed on

idiopathic adult-onset dystonia, etc. and those with high

www.clinicaltrials.gov to allow clinicians and patients to as-

neopterin include EIEE, HIV infections, CNS infections, etc.

sess eligibility of patients for new or ongoing clinical tri-

(Ng et al., 2015). The importance of the recognition of

als. The major breakthrough in the treatment of SMA is the

these patterns lies in the potential for treatment interven-

intrathecal anti-sense oligonucleotide therapy (Nusinersen)

tion, even in cases of secondary deficiencies. Enhanced

that modulates pre-messenger RNA splicing of the survival

understanding of novel disease mechanisms will be aided

of motor neuron 2 (SMN2) gene. This has shown great

by current technologies, such as induced pluripotent stem

promise in clinical trials of children with type 1 SMA and

cells (iPSC) which may be used to understand pathophysi-

later-onset SMA and has generated a number of immediate

ology of disease in the appropriate neuronal subtypes and

and substantial medical, ethical and financial implications

may form the basis for development of therapies (Rein-

(Chiriboga, 2017; Messina et al., 2017; Paton, 2017; Groen

hardt et al., 2013). Another powerful new technology is

et al., 2018; Mercuri et al., 2018).

the development of CRISPR/Cas9 models in animals and

Treatments for Duchenne muscular dystrophy (DMD), the

cell lines, leading to further understanding of pathophys-

most common of the muscular dystrophies, which leads to

iologic disease mechanisms. Novel diagnostics may in-

a shortened life span and considerable disability, are util-

clude metabolomics approaches through the use of mass

ising new gene therapies such as exon skipping (exon 44,

spectrometry profiles, to develop biomarkers, both for di-

45, 51, and 53) and stop mutation readthrough strategies.

agnosis and for monitoring of treatment efficacy. Novel

Other strategies include the use of monoclonal antibody

therapies may include gene therapy approaches as in the

to connective tissue growth factor (CTGF) (Morales et al.,

aromatic amino acid decarboxylase (AADC) gene therapy

2013). In terms of organ complications, carvedilol has been

trial, using delivery of the AAV2-hAADC by a stereotac-

found to be protective for cardiac function (Matsumura et

tically inserted canula into the midbrain into the site of

al., 2010). Targets for experimental treatments for DMD in-

origin of the three major dopaminergic pathways (meso-

clude strategies for cell membrane repair, gene repair (as in-

TEIN I. JICNA 2019;1(1)

dicated above and including morpholino oligonucleotides to

autophagosome formation, maturation or autophagosome-

block translation or gene splicing) and gene transfer, muscle

lysosome fusion. Examples include the EPG5-related Vici

or stem cell therapy, myostatin inhibition and utrophin up-

syndrome, the beta-propeller protein-associated neurode-

regulation (Guiraud and Davies, 2017; Mishra et al., 2017).

generation due to mutations in WDR45, SNX14-associated

Among the novel approaches to corticosteroid treatment in

autosomal recessive cerebellar ataxia and intellectual dis-

DMD, these have focused on the development of dissocia-

ability syndrome, and three forms of hereditary spastic para-

tive steroids such as VBP15 which retain membrane and

plegia, SPG11, SPG15, SPG49, caused by SPG11, ZFYVE26

anti-inflammatory subactivities associated with clinical effi-

and TECPR2 mutations, respectively. There are also as-

cacy, but do not retain the glucocorticoid response element-

sociations between defective autophagy and other inborn

mediated transcriptional activities with the associated ad-

errors of metabolism, such as the lysosomal storage dis-

verse side effects of gluconeogenesis, muscle catabolism and

eases and neurodevelopmental diseases associated with the

adrenal suppression (Hoffman et al., 2012; Heier et al.,

mTOR pathway. The modulation of autophagy may serve

2013). VBP15 has been shown to improve muscle strength

as a therapeutic target for pathway-specific drug develop-

in DMD mice independent of hormonal, growth or immuno-

ment. The neuronal pathways of protein and cargo degra-

suppressive effects (Heier et al., 2013).

dation are well outlined (Ebrahimi-Fakhari et al., 2014).

Novel therapies for limb girdle muscular dystrophy in-

Novel diagnostics Novel diagnostics will increasingly in-

clude gene transfer for LGMD2D (alpha-sarcoglycan de-

volve metabolomic profiles to distinguish between clinical

ficiency), using scAAVrh74 by intramuscular transfer, re-

and biochemical phenotypes within a given disorder, as well

sulting in long-term, sustainable gene expression of alpha-

as response to therapies. There will also be increasing use

sarcoglycan (Mendell et al., 2010). In the dysferlinopathies,

of 1H-MRS brain metabolite profiles, which are already use-

novel therapy may include intramuscular gene transfer of

ful for the non-invasive diagnosis and assessment of thera-

the dysferlin gene by AAV5 (Grose et al., 2012).

peutic responses in a number of disorders, including mito-

chondrial disorders, white matter diseases, Canavan’s dis-

ease, and creatine deficiency syndromes, but which may be-

come further expanded with finer resolution of MRS peaks.

Neurometabolic Disorders

There may also be increasing use of 31P-MRS protocols of

exercising muscle using an MR-compatible cycle ergometer

Neurometabolic disorders, given the understanding of dys-

and different exercise protocols to distinguish between dif-

regulation of metabolic pathways, have become a model for

ferent metabolic pathway defects (e.g. use of high energy

pathophysiology-driven therapies. On the initial characteri-

phosphagens assessed with a short burst of maximal in-

sation of a neurometabolic disorder, the most severe of the

tense activity, glycolytic/glycogenolytic defects assessed by

phenotypes is usually first recognised and described, fol-

sustained intense exercise at 85% maximal exercise repre-

lowed by an expansion of the phenotypes based on milder

senting primarily anaerobic exercise, and of mitochondrial

mutations in a given gene. In addition, many disorders

disorders assessed with repeated bouts of moderate inten-

once considered rare are becoming increasingly recognised

sity activity at 65% of maximal work, representing primar-

by improved clinical recognition, as well as through new-

ily aerobic exercise) (Rodan et al., 2015). In mitochondrial

born screening, allowing for more accurate predictions of

disorders, the delay in the rate of phosphocreatine recovery

prevalence, and through the application of WES and WGS.

post-aerobic exercise is the most sensitive abnormality on

New disease categories New disease categories are show-

31P-MRS of mitochondrial function, since it is purportedly

ing an ever increasing number of newly recognised path-

entirely achieved through oxidative phosphorylation (Mat-

way defects, including the expanding spectrum of congeni-

tei et al., 2004). This technique will also be useful for the

tal disorders of glycosylation (now > 100 known disorders),

evaluation of interventional therapies and their impact on

which are multisystemic and can involve every organ sys-

exercise performance. Another diagnostic modality, namely

tem. They often include intellectual disability, epilepsy, hy-

BOLD-MRI, may become of increasing interest in the eval-

potonia, muscle and nerve disease, and multiorgan involve-

uation of vascular disorders (e.g. Moya moya for vascular

ment due to cell signaling, cell to cell interaction or cell

reserve) and metabolic disorders (e.g. MELAS syndrome).

migration abnormalities (Peanne et al., 2017). Other cate-

In a pilot study, MELAS disease severity and mutation load

gories of disorders that are expanding include the congen-

were found to be inversely correlated with interictal cere-

ital disorders of autophagy (Ebrahimi-Afkhari et al., 2016)

brovascular reactivity (CVR) on BOLD-MRI and directly cor-

and the CNS transporters. The congenital disorders of au-

related with frontal cerebral blood flow (on arterial spin la-

tophagy are an emerging novel class of inborn errors of

beling) which may serve as noninvasive prognostic markers

neurometabolism. They affect the CNS at various stages of

to stratify risk for stroke-like episodes (Rodan et al., 2015).

development and may lead to brain malformations, devel-

Novel therapies

opmental delay, intellectual disability, epilepsy, movement

disorders and neurodegeneration (Ebrahimi-Fakhari et al.,

These will include mutation-based precision medicine

2016). Mutations in key autophagy genes map to differ-

approaches. There will also be a number of novel ther-

ent stages of this highly conserved pathway and may lead

apies including new target-based pharmacotherapeutic

to impairment in the isolation membrane (or phagophore),

approaches in mitochondrial disorders, small molecule

TEIN I. JICNA 2019;1(1)

chaperone therapies for misfolded proteins, in utero fetal

piratory chain function with vitamins and cofactors, elim-

therapy for identified metabolic disorders

(e.g. serine

ination of noxious compounds, shifting of heteroplasmy to

deficiency due to 3-phosphoglycerate dehydrogenase defi-

lower the mutation load in mtDNA-related disorders and,

ciency) (de Konig et al., 2004), new ergometric therapies

most recently, cytoplasmic transfer in mtDNA-related dis-

for

‘gene shifting’ in mitochondrial disorders (Taivassalo

eases. In cytoplasmic transfer, the nucleus of an in vitro-

et al.,

1999; Tarnopolsky, 2014), novel in vitro fertilisa-

fertilised oocyte from a carrier is transferred to an enucle-

tion genetic therapies in mitochondrial genetic disorders

ated oocyte from a normal donor, whereby the embryo will

(three-parent embryo) (Tavare, 2012; Liu and Chu, 2015),

have the nDNA of the biological parents but the mtDNA of a

and international RCTs to determine drug efficacy in rare

healthy female mitochondrial donor (DiMauro et al., 2013).

disorders. Mitochondrial disorders as a group are the most

Currently, we stand at the threshold of novel pharmaco-

common inborn errors of metabolism. The new generation

logic approaches to restore mitochondrial function, includ-

of highly potent antioxidants, such as EPI-743, may hold

ing agents to stimulate and/or restore mitochondrial bio-

new promise in mitochondrial Leigh syndrome (Martinelli

genesis, mitochondrial dynamics (fusion and fission), mi-

et al., 2012; Pastore et al., 2013). Resistance training of 12

tophagy and the mitochondrial unfolded protein response

weeks in patients with single, large-scale deletions of mito-

(Andreux et al., 2014). Mitochondrial biogenesis agents

chondrial DNA led to increased muscle strength, myofibre

may include NAD+ boosters, sirtuins, PPAR and PCGC1 lig-

damage and regeneration, increased proportion of neural

ands; targets for mitochondrial fusion may include MFN1,

cell adhesion molecule-positive satellite cells and improved

MFN2, and OPA1; targets for mitochondrial fission may in-

muscle oxidative capacity, supporting the hypothesis of

clude dynamin-related protein 1; targets of mitophagy may

resistance exercise-induced mitochondrial gene-shifting

include Parkin and PINK1 genes; and targets of protein-

in muscle containing satellite cells with low or absent

folding homeostasis may include the mitochondrial un-

levels of deleted DNA (Murphy et al., 2008). Alternating

folded protein response (UPR) which reduces the amount

endurance exercise training (which increases VO2 max and

of unfolded proteins by stimulating mtHSP70 and HSP60

respiratory chain enzyme activity, and improves quality of

(Andreux et al., 2014). New and powerful phenotypic as-

life) with resistance training (which increases strength and

says in cell-based models, as well as multicellular organ-

may lower mutation burden in patients with mitochondrial

isms, have been developed to explore different aspects of

DNA deletions) and beginning an exercise program at a low

mitochondrial function that may serve to test and ascertain

intensity and duration, gradually increasing duration and

the efficacy of novel pharmacotherapies. Target-based ap-

intensity, tempered with abstaining from exercise on days

proaches enable structure-activity relationship optimisation

with stressors, such as fever, infection, muscle pain, or fast-

of hits from primary screens (e.g. estrogen-related receptor

ing, should prove a useful therapeutic strategy for children

ligands, PPAR ligands, SIRT1 activators such as sirtuin 1,

with mitochondrial disorders using play-based exercises

AMP-activated protein kinase). The disadvantage is that the

(Tarnopolsky, 2014). Exercise prescriptions should become

target is a small part of the regulatory networks. Phenotype-

a part of future therapy. There is also promising preliminary

based approaches in different model systems (yeast, im-

data on the therapeutic effects of L-arginine and L-citrulline

mortalised cell lines, primary cells) allow identification of

supplementation in reducing the frequency, duration and

novel drugs that modulate a more global phenotype, with-

severity of stroke-like episodes in MELAS syndrome (Koga

out knowing the specific target, and may identify novel

et al.,

2007; Siddiq et al., 2015; El-Hattab et al., 2016).

pathways (Andreux et al., 2014). Given the marked vari-

Randomised, placebo-controlled clinical trials to assess the

ability in mitochondrial phenotypes for a given genotype

therapeutic efficacy of both on clinical complications of

and the different genotypes that may share a similar clin-

MELAS are needed.

ical phenotype, as well as the unpredictable variability in

individual clinical courses, compounded by the relative rar-

ity of each etiology or subtype of mitochondrial disease even

Therapy in mitochondrial disorders has been largely pal-

within a given genetic mutation, this underlines the critical

liative and inadequate. Therapeutic trials in mitochondrial

importance of international collaborations for large-scale

disorders to date have been disappointing. In a Cochrane

randomised double-blind placebo-controlled clinical trials.

review of 1,335 studies of therapeutic interventions, includ-

In developing children, evaluation is further complicated as

ing pharmacologic agents, dietary modification, nutritional

improvements may be a function of their normal develop-

supplements and exercise therapy, only 12 studies fulfilled

mental profile rather than the therapeutic strategy, in which

the entry criteria of randomised controlled trials (including

case repeat crossover trials, allowing for the comparison of

cross-over studies) (Pfeffer et al., 2012). On review of these

the individual child both ‘on’ and ‘off’ the intervention at

studies, it was concluded that there was no clear evidence

several timepoints, may help to clarify treatment efficacy.

supporting the use of any intervention in mitochondrial dis-

In mitochondrial disorders there will be an increasing fo-

orders. However, the studies were conducted with different

cus on international prospective randomised, double-blind,

agents in clinically heterogeneous populations with evalu-

placebo-controlled trials of well-characterised clinically ho-

ation of different primary and secondary endpoints, mak-

mogeneous phenotypic populations using international reg-

ing comparisons difficult. The therapeutic strategies to date

istries and clinical consortia

(e.g. North American Mi-

have included supportive measures, enhancement of res-

TEIN I. JICNA 2019;1(1)

tochondrial Disease Consortium (NAMDC)) with common

atric disorders peak at different stages of development,

protocols and measurement of clinically relevant primary

e.g. ADHD/conduct disorders peak at around 10 years of

endpoints. In 2005, the National Institute of Neurological

age (range of five to 14 years), anxiety disorders around

Disorders and Stroke (NINDS) initiated the development of

12-13 years of age (range five to 18 years), schizophre-

Common Data Elements (CDEs) to assist NINDS-funded in-

nia around 17 years of age (range 13-20 years), substance

vestigators in collecting neuroscientific clinical trial research

abuse around 18-20 years (range 13-25 years), and mood

data in a standardised and consistent fashion (Grinnon et

disorders around 25 years of age (Kessler et al.,

2005;

al.,

2012). In 2016, an international group of mitochon-

Kessler and Wang, 2008). An understanding of the devel-

drial clinicians and scientists assembled a series of tests into

opmental course of these changes may inform which treat-

a toolkit for use in future mitochondrial clinical trials. There

ments are best at different ages. By understanding sensitive

will be increasing use of a comprehensive set of CDEs, rec-

windows of development when the brain is particularly re-

ommendations, data definitions, CRFs (case report forms),

ceptive to the environment, we may be better able to under-

and guidelines for use in mitochondrial clinical research as

stand shifts and early closures of these windows due to envi-

developed by the NINDS (Karaa et al., 2017) to offer use-

ronmental or genetic factors, allowing us to potentially ex-

ful frameworks for standardisation of mitochondrial clinical

pand them behaviourally and/or pharmacologically (Casey

trials. Such trials will also facilitate the validation of tests in

et al., 2015). Targeting more developed or dynamic/plastic

this population. The widespread use of CDEs is intended to

circuitry may enhance treatment efficacy. Novel interven-

enhance mitochondrial clinical research endeavors, includ-

tions would be based on bridging information from humans

ing natural history studies, clinical trial design, and data

and animal models at the genetic, molecular, circuit and be-

sharing, and to harmonise collected data in different re-

havioural levels and would allow a precision medicine ap-

search studies in order to allow comparisons of results in

proach, based on the age and genetic makeup of the indi-

relatively rare phenotypes. Ongoing international collabora-

vidual and environmental factors (Casey et al., 2015). For

tion will facilitate regular review, updates and online publi-

example, treatments for fear-related disorders such as post-

cation of mitochondrial CDEs, and support improved consis-

traumatic stress disorder, might be tailored as a function of

tency of data collection and reporting. The North American

age to use specific interventions at a developmental stage

Mitochondrial Disease Consortium (NAMDC) provides a na-

when they may be most effective (Hartley and Lee, 2015).

tional registry of patients with mitochondrial disorders. This

The attenuation of fear-extinction associated with adoles-

resource, along with other national registries, will hopefully

cent development may hinder responses to traditional psy-

provide adequate patient numbers with homogeneous phe-

chotherapy, such as cognitive behavioural therapy (CBT),

notypes for study and for clinical trials in order to advance

because CBT densensitises an individual to anxiogenic stim-

a better understanding of the specific disease pathogenesis,

uli through repeated exposures (e.g. extinction-learning).

and to ultimately allow for the development of much needed

This is particularly topical in our current age where chil-

evidence-based protocols and treatments.

dren in many regions of the world are exposed to significant

emotional trauma through the devastation of war, poverty,

illness, and separation from parents. Attention must also

be paid to the constant, often unfiltered and traumatic, and

Neuropsychiatry

age-inappropriate information intrusion/overload from the

media, cell phones, iPads, etc. and the effects of these reg-

Neurobiological studies have demonstrated that behaviours

ular interruptions on attention, focus and learning. Autism

and underlying brain circuits and neural growth factors

There are major advances occurring in the field of autism.

(brain-derived neurotrophic factor (BDNF)) show charac-

Autism is now recognised as a complex multifactorial de-

teristic changes across the life-span that produce ‘sensitive

velopmental disorder arising from polygenic (‘autism-risk’

windows of vulnerability or heightened plasticity’ to partic-

genes) and epigenetic factors, as well as non-genetic envi-

ular experiences or ‘resilience to psychopathology’ (Casey et

ronmental risk factors (e.g. prenatal teratogens in utero,

al., 2015). Inhibitory neurotransmission peaks early within

congenital viral infections, maternal anticonvulsants, post-

the amygdala (during childhood), whereas increases in the

natal autoimmune diseases, as well as viral infections, hy-

prefrontal cortex begin during adolescence and do not peak

poxia and CNS toxins, etc.) and their interaction. ASD

until adulthood (Hartley and Lee, 2015). The gonadal hor-

(autism spectrum disorder) demonstrates high heritability

mones and BDNF levels peak during adolescence. Myelina-

and familial clustering, yet the genetic causes remain only

tion increases gradually from childhood to adulthood. Fear-

partially understood due to extensive clinical and genomic

learning, extinction, and reconsolidation exhibit qualitative

heterogeneity. Novel diagnostics Novel diagnostics include

maturational changes across the lifespan from childhood

the detection of clinically relevant genetic variants in ASD

to adolescence to adulthood. Cued and contextual fear-

by whole-genome sequencing. In the study by Jiang et al.

learning emerge during childhood, but the memories are la-

(2013), WGS was used to examine 32 families with ASD and

bile. Contextual fear expression and extinction-learning are

deleterious variants were found in four unrecognised, nine

attenuated during adolescence, whereas in adulthood, ex-

known, and eight candidate ASD risk genes. Identification

tinguished fear recovers, but can be attenuated persistently

of biomarkers in infants at high risk for ASD, such as eye fix-

through reconsolidation (Hartley and Lee, 2015). Psychi-

TEIN I. JICNA 2019;1(1)

ation, which is present but in decline in two- to six-month-

200 kilobases, through transcription elongation (King et al.,

old infants later diagnosed with ASD, provides a chance for

2013). Many high-confidence ASD candidate genes are ex-

early intervention (Jones and Klin, 2013). There is a ma-

ceptionally long and were found to be reduced in expres-

jor effort underway to identify novel mechanisms leading to

sion after topoisomerase 1 inhibition (King et al., 2013).

ASD in order to develop better therapies in the future. Ge-

This would suggest that chemicals and genetic mutations

netic studies have identified mutations in genes that inter-

that impair topoisomerases could contribute to ASD and

fere with typical neurodevelopment in utero through child-

other neurodevelopmental disorders which may inform fu-

hood. Studies employing exome and genome-wide sequenc-

ture therapies.

ing have identified nine high-confidence ASD genes (ANK2,

b) Microbiotica: in the maternal immune activation (MIA)

CHD8, CUL3, DYRK1A, GRIN2B, KATNAL2, POGZ, SCN2A,

murine model that displays GI barrier defects, microbiota

TBR1) (Buxbaum et al., 2012; Willsey et al., 2013), but oth-

alterations and features of ASD, oral treatment of MIA

ers are likely to be identified.

offspring with the human commensal Bacteroides frag-

Many genes discovered to date are involved in multiple bi-

ilis corrects gut permeability, alters microbial composition

ological processes at multiple points during development,

and ameliorates defects in communication, stereotypy and

and identical mutations in the same gene can lead to wide

anxiety-like and sensorimotor behaviours, consistent with

variability in psychiatric and neurological syndromes (Mal-

ASD features supporting a brain-gut-microbiome connec-

hotra and Sebat, 2012). Investigators using coexpression

tion in a mouse model of ASD (Hsaio et al., 2013). The

networks based on these high-confidence ASD ‘seed’ genes,

MIA offspring display an altered metabolomics profile and

leveraging a rich expression data set, including multiple

B. fragilis modulates the levels of several of these metabo-

human brain regions across human development and into

lites. These findings support a potential probiotic therapy

adulthood, have demonstrated a key point of convergence

for GI and for behavioural symptoms in human neurodevel-

in midfetal layer 5/6 cortical projection neurons (Willsey

opmental disorders, which may provide the basis for future

et al.,

2013). The complexes of genes identified have

therapeutic interventions.

been involved in synaptogenesis and axon motility (Park

c) Though < 5% of ASD has been found to be related to

et al., 2016). It is felt that the resultant microstructural,

metabolic disorders (Park et al., 2016), the identification of

macrostructural and functional abnormalities that emerge

potentially treatable etiologies is important. These would

during brain development lead to a pattern of dysfunctional

include the creatine deficiency disorders, PKU (phenylke-

neural networks involved in socioemotional processing. Mi-

tonuria), the CNS folate transporter (FOLR1), adenylosuc-

crostructurally, there is an altered ratio of short- to long-

cinate lyase deficiency, disorders of purine metabolism and

diameter axons and disorganisation of cortical layers and,

mitochondrial disorders. d) Another randomised, placebo-

macrostructurally, MRI studies of brain volume in ASD in-

controlled trial of methyl B12

in children with autism

dividuals have consistently shown cortical and subcortical

demonstrated improved clinician-rated symptoms of ASD

grey matter overgrowth in early brain development (Park et

that were correlated with improvements in measures of

al., 2016). Pathological changes have been noted on neu-

methionine metabolism and cellular methylation capacity

roimaging and neuropathological studies in the prefrontal

(Hendren et al., 2016). e) Autism spectrum disorder, ADHD,

cortex, amygdala and Nucleus acumbens (Park et al., 2016).

schizophrenia, major depressive disorder and bipolar disor-

The amygdala, which is a major component of the limbic

der have been shown to share genetic risk loci on genome-

system and the affective loop of the cortico-striatothalamo-

wide analysis, which showed SNPs at four loci in regions

cortical circuit, has roles in cognition and ASD, the Nucleus

on 3p21 and 10q24, and SNPs within two L-type voltage-

acumbens is a key structure in the social reward response,

gated calcium channel subunits, CACNA1C and CACNB2.

and the prefrontal cortex has roles in higher-level cogni-

Pathway analysis supported a role for calcium channel sig-

tive control processing. It also has reciprocal connections

nalling genes for all five disorders (Cross-Disorder Group

with brain regions involved in emotional processing (amyg-

of the Psychiatric Genomics Consortium, 2013). These risk

dala), memory (hippocampus) and high-order sensory re-

factor gene SNPs may serve to provide early identification of

gions (within the temporal cortex) (Park et al., 2016). Func-

ASD, and the dysregulated pathways may suggest targeted

tionally, resting-state fMRI (functional MRI) studies have

treatment interventions.

shown widespread global underconnectivity in the socioe-

Novel therapies

motional networks, and task-based fMRI have shown de-

The identification of pharmacogenomics indicators of

creased activation of networks involved in socioemotional

ASD subphenotypes and increased understanding of the

processing (Park et al., 2016). Future treatments may tar-

specific underlying pathophysiologic mechanisms contribut-

get the architecture of ASD development.

ing to ASD in a given child may enable targeted future ther-

Novel mechanisms for ASD

apies (e.g. antipsychotics, antidepressants, selective sero-

(a) Topoisomerases are expressed throughout the devel-

tonin reuptake inhibitors, adrenergic agonists, ß-adrenergic

oping and adult brain and are mutated in some individu-

antagonists, mood stabilisers, antiepileptic drugs, etc.).

als with ASD. Topoisomerases appear to be important in

In medically refractory cases with self-injurious behaviour,

the expression of extremely long genes in mouse and hu-

deep-brain stimulation of the amygdala, anterior limb of the

man neurons, including nearly all genes that are longer than

internal capsule or globus pallidus has been used with some

TEIN I. JICNA 2019;1(1)

benefit (Sturm et al., 2012; Stocco et al., 2014).

et al.,

2017). Another therapy for recurring tumours, or

Vaccines

ones difficult to reach surgically, is laser interstitial thermal

There has been enormous debate regarding the possibil-

therapy (LITT). This is a minimally invasive cytoreductive

ity of a link between childhood vaccinations and the subse-

treatment using a low voltage laser to induce hyperthermia

quent development of autism. In recent times this has be-

to destroy tumour cells. The extent of the thermal damage

come a major public health issue with vaccine preventable

is controlled through the use of real-time MR-thermography

diseases increasing in the community, due to the fear of a

guidance (clinicaltrials.gov) (Lagman et al., 2017). The

’link’ between vaccinations and autism. Taylor et al., (2014)

neurosurgeon visualises and controls the treatment proce-

performed a meta-analysis to summarise available evidence

dure in real-time with intraoperative MRI and a stereotacti-

from case-control and cohort studies on this topic (MED-

cally placed probe. The fibre optic probe heats the tissue

LINE, PubMed, EMBASE, Google Scholar up to April, 2014).

in the direction of the tumour while cooling in other di-

The meta-analysis findings suggested that vaccinations were

rections to protect the surrounding healthy tissue. There

NOT associated with the development of autism or ASD.

may also be increased use of robotics in stereotactic neu-

Furthermore, the components of the vaccines (thimerosal or

rosurgery and in rehabilitation. Robot-enhanced repetitive

mercury) or multiple vaccines (MMR) were not associated

treadmill (ROBERT) therapy is being used in children with

with the development of autism or ASD. Moving forward,

cerebral palsy (Schroeder et al., 2014).

it will be important to reinforce these findings within the

medical community, given the alarming rise of preventable

infectious diseases such as measles and the associated dev-

Stem Cell Therapy

astating subacute sclerosing panencephalitis (SSPE).

Continuing questions are being raised regarding the possi-

bility of stem cell therapy for neurodegenerative diseases.

Tuberous Sclerosis

This becomes even more complicated in the case of the de-

veloping nervous system in terms of bypassing the blood-

In tuberous sclerosis, the new diagnostics rest on under-

brain barrier and delivery of the cells to the needed loca-

standing phenotypic heterogeneity based upon genetic, bio-

tions, proliferation of the cells, self-renewal and differentia-

logic and environmental factors. There are improved TSC

tion of the stem cells into the appropriate neuronal or glial

disease models and increased understanding of the TSC

cell subtypes, developmental regulation of the expressed

signaling pathways and cellular consequences of TSC de-

cellular proteins and the formation of the appropriate path-

ficiency. TSC is a genetic disorder resulting from overacti-

way synaptic connections.

vation of the mTOR pathway, and pharmacologic inhibition

There have been very exciting new developments iden-

with mTOR inhibitors such as rapamycin have emerged as

tifying a drug that upregulates endogenous neurogenesis,

exciting viable target treatment options for the disease man-

thereby bypassing most of the issues raised above. Inves-

ifestations (Jeong and Wong, 2016). mTOR inhibition with

tigators have shown that metformin, a widely used FDA-

Everolimus has been shown to alleviate obstructive hydro-

approved diabetes drug, promotes neurogenesis and en-

cephalus due to subependymal giant cell astrocytomas in a

hances spatial memory formation (Wang et al.,

2012).

series of four patients, offering a significant therapeutic op-

Specifically, they have shown that an atypical PKC-CBP (pro-

tion to neurosurgical resection (Moavero et al., 2017).

tein kinase C-transcriptional coactivator) pathway is essen-

tial for the normal genesis of neurons from neural precur-

sors, and that metformin activates this pathway to promote

Neurooncology

rodent and human neurogenesis in culture. They have fur-

In neurooncology, there will similarly be more refined clini-

ther demonstrated that metformin also enhances neuroge-

cal diagnosis of brain tumours based on WGS. For example,

nesis in the adult mouse brain in a CBP-dependent fash-

medulloblastoma can be divided into a number of tumour

ion, and in so doing enhances spatial reversal-learning in

subtypes based upon molecular markers, which can predict

the water maze. By activating an aPKC-CBP pathway, met-

response to treatment in a precision medicine or person-

formin thus recruits neural stem cells and enhances neu-

alised medicine approach (Northcott et al., 2017).

ral function, thereby providing a candidate pharmacological

Novel therapies

approach for central nervous system therapy. Furthermore,

These may include convection-enhanced delivery (CED)

metformin has been shown to promote proliferation, self-

of novel compounds, including tumour-specific monoclonal

renewal and differentiation of adult neural precursor cells

antibodies for brain tumours that would not cross the

(NPCs) (Fatt et al., 2015). This study has shown that met-

blood-brain barrier and could be delivered by stereotactic

formin enhances adult NPC proliferation and self-renewal,

catheters placed within or around the tumour (e.g. molec-

dependent upon the p53 family member and transcription

ularly targeted cytotoxic drugs or immunotherapy in malig-

factor TAp73, while it promotes neuronal differentiation of

nant glioma (Shoji et al., 2016)). Other new agents will in-

these cells by activating the AMPK(AMP-activated protein

clude anti-angiogenesis agents targeting vascular endothe-

kinase)-aPKC-CBP pathway. Metformin thus represents an

lial growth factor and receptor signaling (Kalpathy-Cramer

optimal candidate neuroregenerative agent as it is capable

TEIN I. JICNA 2019;1(1)

of not only expanding the adult NPC population but also

site to provide access to all. There will be a focus on

subsequently driving them toward neuronal differentiation

evidence-based guidelines for best standards of care as

by activating two distinct molecular pathways.These find-

well as precision medicine approaches based on specific

ings have now been translated to a murine model of child-

individual mutations and profiles. These collaborations

hood hypoxic-ischemic injury. Investigators found that met-

in the aggregate will reduce the global burden of neuro-

formin administration activated endogenous NPCs, expand-

logic diseases, increasing cognitive potential and providing

ing the size of the NPC pool and promoting NPC migra-

a brighter and healthier future for our children.

tion and differentiation in the injured neonatal murine brain

in a hypoxia-ischemia (H/I) injury model (Dadwal et al.,

Abbreviations

2015). Importantly, metformin treatment following H/I re-

stored sensory-motor function and lineage tracking revealed

RCT Randomized controlled trial

that it also led to an increase in the absolute number of

POLG Polymerase Gamma

subependymal-derived NPCs relative to untreated H/I con-

trols in areas associated with sensory-motor function (Dad-

VUS variants of unknown significance

wal et al., 2015). Therefore, activation of endogenous NPCs

is a highly promising target for therapeutic intervention in

POLG Polymerase Gamma

childhood brain injury models.

POLG Polymerase Gamma

Conclusion

We now stand at the threshold of a brave new world with

Acknowledgments

many exciting new technologies, but we must never for-

get the power of clinical medicine which allows us to in-

The author would specifically like to gratefully acknowl-

terpret and use these tools with precision and with clinical

edge her colleagues who contributed their perspectives and

wisdom. In the aggregate, strong collaborations between

insights as follows: Brenda Banwell, Helen Cross, Rus-

clinicians for the meticulous clinical phenotyping, expan-

sell Dale, Bernard Dan, Linda De Meirleir, Gabrielle De

sion of the range of phenotypic expression and the entry

Veber, Michael Johnston, Manju Kurian, Kenneth Mack,

of patients into international RCTs, the biochemists for the

Steven Miller, Berge Minassian, Jonathan Mink, Francesco

biochemical phenotyping and understanding of the basic

Muntoni, Charles Newton, James Rutka, Ingrid Scheffer,

pathophysiology of the underlying dysregulations and dis-

Michael Shevell and Sylvia Stockler.

ease mechanisms arising from the protein dysfunctions, and

the development of robust biomarkers to evaluate disease

Competing interests

severity and response to therapies, as well as the geneti-

cists for the understanding of the impact of the exonic or

The author has declared that there are no competing inter-

intronic mutations, and the roles of other regulatory genes

ests.

on the affected pathway and epigenetic factors, will lead

The content of this article was delivered as a plenary

the field forward in terms of increased insight into disease

talk by author at the 14^th International Child Neurology

pathophysiology for the development of targeted precision

Congress (ICNC) held in Amsterdam May 1-5,2106.

medicine treatment strategies and effective preventative

measures. Enhanced diagnostics will be possible through

This is an Open Access article distributed under the terms of

metabolomic profiles, immunophenotyping, advanced neu-

the Creative Commons Attribution License which permits un-

roimaging techniques (1H-MRS, 31P-MRS, BOLD-MRI, ul-

restricted use, distribution, and reproduction in any medium,

trasound), algorithmic approaches and WES and WGS. Un-

provided the original work is properly credited. The Cre-

derstanding of disease pathophysiology will be enhanced

ative Commons Public Domain Dedication waiver applies to

through the development of in vitro and in vivo models,

the data made available in this article,unless otherwise stated.

including genetic manipulation through CRISPR/Cas9 tech-

nology in animal and cell models. Treatments may be mul-

Cite this article as:

tifaceted, including, as appropriate, pharmacotherapy, im-

Tein I. Expected future developments in child neurol-

munotherapy, physiologic therapy (e.g. ergometric therapy,

ogy. JICNA

[Internet].

2019;1(1). Available from:

deep brain stimulation), and genomic therapy (e.g. exon

https://jicna.org/index.php/journal/article/view/jicna-

skipping, stop codon readthrough therapies, viral vectors

2019-158

encoding genes or siRNA, etc.). Evaluation of treatment

efficacy will require, particularly in rare disorders, interna-

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