1. health and fitness
2. disease
3. epilepsy

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12th Asian & Oceanian Congress of Child Neurology
(AOCCN), Riyadh, Saudi Arabia
14-18 September 2013
Suad Al-Yamani, MD.
Department of Neurosciences, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
The 12th Asian & Oceanian Congress on Child Neurology was hosted by King Faisal Specialist Hospital &
Research Centre in Riyadh, Saudi Arabia on 14-18 September 2013. The latest biennial congress of the Asian
Oceanian Child Neurology Association (AOCNA), this was the first time for this prestigious international congress
to be brought to the Middle East. The rich scientific program was spread over 5 days with 3 parallel tracks and 8
pre-congress workshops. The congress discussed a broad range of topics in the field of child neurology with a focus
on Epilepsy, Metabolic Disorders, Neuromuscular Disorders, Pediatric Stroke, Critical Care, Movement Disorders
and Neurodevelopmental Disorders.
In recognition of this important international Neurosciences event in the region, the Neurosciences journal welcomes the
opportunity to publish the highlights from the prestigious 12th Asian & Oceanian Congress of Child Neurology.
Plenary Sessions
Cerebellar malformations: An overview and classification
Joseph G. Gleeson, University of California, San Diego, CA, United States of America
The classification of cerebellar malformations was largely ignored until recently due to difficulty in imaging of the posterior
fossa and lack of correlation with clinical outcomes. However, with improved MRI-based imaging and the realization that the
cerebellum plays major roles in cognition and motor functions, detailed classifications have emerged. Cerebellar malformations
are generally divided into 2 major groups: cerebellar hypoplasia and dysplasia. Cerebellar hypoplasias are further divided
into focal and generalized. While isolated vermis and one hemisphere hypoplasias make up the focal subgroup, DandyWalker continuum, pontocerebellar hypoplasias, and congenital muscular dystrophies comprise the generalized subgroup.
Cerebellar dysplasias are also grouped according to whether they are focal or generalized. Molar tooth malformations and
rhombencephalosynapsis represent the major isolated vermian dysplasias whereas focal cerebellar hemispheric dysplasias/
heterotopia are also observed. Generalized dysplasias, however, can be a result of congenital cytomegalovirus infections,
lissencephalies either associated with RELN mutation, congenital muscular dystrophies, or with agenesis of corpus callosum.
My talk will focus on the hypoplastic and dysplastic cerebellar anomalies, providing information on clinical presentation, MRI
findings, and molecular characterization of this class of disease.
Correcting human mitochondrial mutations
G. Wang, E. Shimada, C. M. Koehler, M. A. Teitell, University of California at Los Angeles, Los Angeles, CA, United States of
America
Numerous disease causing mutations have been identified within the mitochondrial genome. A functional decline due to
mtDNA mutations could lead to reduced oxidative phosphorylation and other untoward effects on mitochondrial activities.
Mutations in mtDNA have been implicated in neuromuscular diseases, metabolic defects, and aging. Strategies that restore
mitochondrial function could potentially offset key aspects of mitochondrial-related diseases. The RNA import into
mammalian mitochondria is considered essential for replication, transcription, and translation of the mitochondrial genome,
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but the pathway(s) and factors that control this import are poorly understood. Previously, polynucleotide phosphorylase
(PNPASE), a 3’ to 5’ exoribonuclease and poly-A polymerase, was localized in the mitochondrial intermembrane space, a
location lacking resident RNAs. In recent studies, we have shown a role for PNPASE in regulating the import of nuclearencoded RNAs into the mitochondrial matrix. PNPASE reduction impairs mitochondrial RNA processing, and polycistronic
transcripts accumulate. Augmented import of nuclear-encoded RNAs depends on PNPASE expression and PNPASE RNA
processing and import activities are separable. A mitochondrial RNA targeting signal was identified that enables the import of
heterologous RNAs in a PNPASE-dependent manner. An efficient and simple mechanism for neutralizing deleterious mtDNA
alterations has unfortunately remained elusive. Recently, we devised a promising approach for transferring non-coding RNAs,
such as tRNAs, and coding mRNAs into mitochondria to compensate for mtDNA alterations and showed that functional
defects in mtRNA translation and cell respiration were partially reversed in 2 human disease lines. Combined, our studies
show an unanticipated role for PNPASE in mediating the translocation of RNAs into mitochondria and provide a potential
therapeutic route for halting or reversing the decline in mitochondrial function in human disease.
Metabolic diseases in muscle
Ichizo Nishino, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan
Although rare, metabolic myopathy is an important topic as many of these conditions are treatable. There are 2 major
myopathic conditions due to lipid dysmetabolism: rhabdomyolysis, and lipid storage myopathy. Determining the cause of
rhabdomyolysis is often not easy as clinical and pathological features are usually nonspecific. Of note, however, very-long-chainacyl-CoA dehydrogenase (VLCAD) deficiency, which is probably the most common b-oxidation defect, may be diagnosed by
immunohistochemistry. Lipid storage myopathy is a condition diagnosed by its characteristic finding on muscle pathology.
There are only 4 genetically diagnosable diseases: primary carnitine deficiency (PCD), multiple acyl-CoA dehydrogenase
deficiency (MADD), neutral lipid storage disease with ichthyosis, and neutral lipid storage disease with myopathy. In our
study, 3/4 of cases had no mutations in any of known causative genes, indicating that cause is still unknown in most cases.
Nevertheless, treatment is available for PCD and some cases of MADD: oral high-dose carnitine supplementation, and
riboflavin treatment, respectively. I will also touch on some of glycogen storage diseases including Pompe disease for which
enzyme replacement therapy is available. Knowledge about these genetically identifiable and potentially treatable diseases is of
relevance.
Epilepsy
Benign epilepsy syndromes
Generoso G. Gascon, Clinical Neuroscience and Pediatrics, Brown University, Providence, Rhode Island, United States of America
Benign epilepsy syndromes carry a benign prognosis, meaning normal development, no structural lesions, prompt response to
antiepileptic drugs, or high likelihood of seizure remission by a certain age. The 1989 ILAE classification lists more than 25
epilepsy syndromes. The benign syndromes have usually been based on clinical-electrical correlations. Since 1989, several new
syndromes have been described. In addition with longer follow-up on previously described syndromes, published reports of the
evolution into, or the addition of, co-morbidities necessitate modification of our conception of what is “benign”. This talk will
discuss the clinical-electrical correlations, genetics, and management of: benign familial and non-familial neonatal convulsions,
benign familial and non-familial infantile epilepsy, benign myoclonic epilepsy, GEFS + (generalized epilepsy febrile seizures
plus), Panayiotopoulos syndrome, benign Rolandic epilepsy, late onset benign occipital epilepsy (Gastaut type), childhood
absence epilepsy, juvenile myoclonic epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, autosomal dominant lateral
temporal lobe epilepsy, other familial temporal lobe epilepsies, and familial focal epilepsy with variable features.
Classification of seizures and epilepsies
Weiping Liao, Institute of Neuroscience and The Second Affiliated Hospital of Guangzhou Medical University; Key Laboratory
of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China
The dichotomous classification of seizures and epilepsies, namely, generalized or partial (focal), is an essential concept in
epileptology. Such a dichotomous classification was questioned in recent years. Generalized epilepsy differs from partial epilepsy
in many clinical and EEG aspects, but there are also cases with features of both generalized and partial epilepsies. Recent
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studies have demonstrated their differences in genetics, and these findings have provided molecular bases for classification of
seizures and epilepsies. It has been demonstrated that pure epilepsies are generally associated with abnormalities of channels
or channel-regulatory genes and appear to be either generalized epilepsies or partial in the majority. In contrast, genetic
epilepsies that are associated with cellular dysfunction or structure malformations are commonly accompanied by other
manifestations of dysfunctions of the CNS, among these, distinct generalized epilepsies or partial epilepsies are less common.
Generalized epilepsy, partial epilepsy, and epilepsy with both generalized and partial features are potentially associated with
distinct underlying mechanisms. From an etiological point of view, epilepsies can be classified into genetic, acquired, and
undetermined; whereas the classification of epilepsies into idiopathic or symptomatic refers to mechanism rather than etiology.
Clinically, classifications of seizures and epilepsies are important in serving as indicators of prognosis, for selecting antiepileptic
drugs (AEDs), and for evaluating surgical options. For example, generalized epilepsy can be aggravated by GABA receptoracting antiepileptic drugs (AEDs). The AEDs with sodium channel-blocker properties aggravate seizures in patients with
partial epilepsy and loss of function of Nav1.1. Therefore, understanding the molecular bases and underlying mechanism
associated with epilepsy classification will help physicians in the management of epilepsy.
Development of individualized medicine for epilepsy based on genetics information
Yuwu Jiang, Department of Pediatrics, Peking University First Hospital, Beijing, China
Epilepsy is one of the most common chronic neurological disorders during childhood. There are many challenges not only in
the diagnosis, but also in the treatment for epilepsy, because of the significant diversity in the disease etiology and drug response
(including efficacy and adverse effect). Therefore, individualized diagnosis and treatment strategies are urgently needed for
better management of epilepsy patients. The recent rapid advances in genetic analysis give us an exciting chance to develop
individualized medicine for epilepsy based on genetic information. In this topic, we will review what the new genetic analysis
techniques bring us, such as the next generation sequence based disease causing gene variation analysis and array CGH based
copy number variation detection. We will also discuss usage of the new genetic analysis methods in pharmacogenetic studies
for anti-epileptic drugs.
Dravet syndrome and febrile seizure plus
I-Ching Chou, Wei-De Lin, Fuu-Jen Tsai, China Medical University Hospital, Taichung, Taiwan
Febrile seizures (FS) affect 2-5% of all children younger than 6 years. A small proportion of children with febrile seizures later
develop epilepsy, ranging from relatively mild phenotypes found in families with generalized epilepsy with febrile seizures plus
(GEFS+), to severe phenotypes of Dravet syndrome (DS). The syndrome of GEFS+ is a heterogeneous disorder characterized
by FS that may persist beyond age 6 years or nonfebrile seizures. Dravet syndrome typically presents around 6 months of
age in previously well children with prolonged, febrile and afebrile, generalized clonic, or hemiclonic epileptic seizures. The
treatment and prognosis usually depend on the individual child. Several studies demonstrate that some gene mutations and
submicroscopic copy number variations (CNV) are highly consented with epilepsy. In our previous studies, we investigated
that several ion channel genes have been implicated in the susceptibility to febrile seizures. Our genetic study of DS revealed
that when mutation was found, the sensitivity of SCN1A was 55.6% of DS phenotype. In addition, their DNA samples also
underwent whole genome CNV analysis using SNP microarray; a novel duplication region, 4q13.1-q13.2, was detected in one
case. This variant region contained a gene, EPHA5, which is correlated with cerebral neuron-development. Future studies with
a large sample size will be helpful in explaining the role of the novel region on the pathogenesis of DS phenotype, which will
focus on the relationship of genotype with cognitive outcome, seizure control, and the degree of defects.
EEG in epilepsy diagnosis
Hoon-Chul Kang, Severance Children’s Hospital, Yonsei University, Seoul, Korea
The EEG helps determine seizure type and epilepsy syndrome in patients with epilepsy, and thereby choice of antiepileptic
medication and prediction of prognosis. The EEG findings contribute to the multi-axial diagnosis of epilepsy, in terms of
whether the seizure disorder is focal or generalized, idiopathic or symptomatic, or part of a specific epilepsy syndrome. Many
of the epilepsy syndromes associated with specific EEG features present in early life or childhood. Some syndromes are well
accepted; others are controversial or may not be included in current International League Against Epilepsy classification
systems because of insufficient data. Here, I intend to review the usefulness of EEG in epilepsy diagnosis and review the specific
EEG findings in specific epilepsy syndromes.
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Epilepsy surgery outcome - seizures and cognitive
Heung D. Kim, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
Approximately 20-30% of pediatric epilepsy patients continue to have seizures even with adequate anti-epileptic drug (AED)
treatment. Many forms of drug-resistant epilepsy in the pediatric age frequently combine progressive developmental deficits
from epileptic insults to the developing brain; especially the various forms of epileptic encephalopathy. Theoretically, shortening
the duration of an epileptic insult would be beneficial in preventing developmental decline from epilepsy. Epilepsy surgery
is one important option for treating intractable pediatric epilepsy. Although there is significant benefit with early surgery,
the surgical risk is higher in younger aged children with immature brains. A careful diagnostic evaluation is mandatory to
localize the epileptogenic zone, but the immature brain shows less sensitive findings in many imaging tools even with MRI
and electrophysiological findings. Recent development and more active application of various diagnostic tools including ictal
SPECT with computer analysis technique, PET, functional MRI, magnetoencephalography (MEG), or magnetic resonance
spectroscopy (MRS) may provide additional information to localize underlying epileptogenic focus even in MRI negative
cases. Our recent experiences suggest that epilepsy surgery is successful in obtaining a seizure free outcome and improving
developmental progress in selected intractable pediatric epilepsy patients, even in the generalized forms of epilepsy with
epileptic encephalopathy such as Lennox-Gastaut Syndrome, even without focal brain MRI lesions. We will discuss the
benefits, potential risks, and appropriate timing to move to more aggressive and difficult interventions such as surgery.
Genetics of early onset epilepsy with encephalopathy
Masashi Mizuguchi, Makiko Saitoh, Department of Developmental Medical Sciences, Graduate School of Medicine, the
University of Tokyo, Tokyo, Japan
Acute encephalopathy refers to severe and prolonged impairment of consciousness that usually occurs during an acute febrile
illness. Its pathologic substrate is diffuse or widespread, non-inflammatory brain edema. Acute encephalopathy is classified
into several distinct syndromes, such as Reye’s syndrome, acute necrotizing encephalopathy (ANE), acute encephalopathy
with biphasic seizures and late reduced diffusion (AESD), and acute encephalitis with refractory, repetitive partial seizures
(AERRPS). Patients with AESD and AERRPS are often left with severe neurologic sequelae including intractable epilepsy. On
the other hand, epileptic syndromes, in particular Dravet syndrome, are occasionally complicated by AESD and other types
of acute encephalopathy, often leading to death or worsening of motor and intellectual deficits. Except for the familial and
recurrent variant of ANE, most acute encephalopathies do not show Mendelian inheritance. However, ethnic preponderance
for AESD and ANE, as well as occasional familial cases, suggests the involvement of multiple genetic predispositions. Our
genetic studies in Japanese patients have identified mutations and polymorphisms of many genes as risk factors of acute
encephalopathy. Mutations of SCN1A, a subunit of a voltage-gated sodium ion channel, are responsible for AESD, AERRPS,
and other types of acute encephalopathy, with or without underlying Dravet syndrome. Thermolabile variations of CPT2, a
mitochondrial enzyme, are risk factors for AESD and other encephalopathies. Polymorphisms of ADORA2A, an adenosine
receptor that enhances excitatory neurotransmitter release, predispose children to AESD. Polymorphisms of other genes that
regulate natural immunity have recently been identified as risk factors for AESD. Elucidation of genetic factors may lead to the
development of new therapeutic interventions for these devastating encephalopathies with epilepsy.
Is prevention of epilepsy possible?
Motohiro Okada, Graduate School of Medicine, Mie University, Tsu City, Mie, Japan
Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. In the past 2 decades, genetic and neuroscience
studies demonstrated that genetic susceptibility played important roles in pathogenesis and/or pathophysiology of various
types of epilepsy syndromes. Most conventional anticonvulsants have been developed by standard screening tests, including
maximal electroshock seizure and pentylenetetrazole induced seizure tests. Therefore, present anticonvulsants medications
can reduce/control recurrent unprovoked epileptic seizures; however, it is unknown whether conventional anticonvulsants
can affect epileptogenesis or ictogenesis. Recently, we have succeeded in the generation of a genetic rat model of frontal lobe
epilepsy namely, S286L-TG, which harbors transgenes with a rat mutant a4 subunit of nicotinic acetylcholine receptor that
corresponds to the human S284L CHRNA4 mutation identified in pedigrees of patients with autosomal dominant (ADNFLE)
and sporadic nocturnal frontal lobe epilepsy (NFLE). After the onset of NFLE, the abolishment of the transgene could not
affect NFLE seizures of S286L-TG. Thus, the genetic abnormality of CHRNA4 plays important a role in the development
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of pathogenesis of ADNFLE and NFLE as a trigger, but cannot be targeted regarding complete remission. On the contrary,
neither BSAM-1117 nor BSAM-1118 affected NFLE seizures of S286L-TG after onset; however, before onset of NFLE, the
chronic administration of these 2 agents could prevent the NFLE onset. Additionally, BSAM-1211 could inhibit the NFLE
seizure and prevent onset. Therefore, BSAM-1211 is an anti-epileptogenesis and anti-ictogenesis drug against NFLEs, whereas
both BSAM-1117 and BSAM-1118 are anti-epileptogenesis drugs, but are not anti-ictogenesis drugs against NFLEs.
Neonatal seizures
Hitoshi Yamamoto, Akihisa Okumura, Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki,
Japan
The underlying etiologies of neonatal seizures (NSs) are diverse, and NSs have generally been identified in most NICUs
only by direct clinical observation. There is usually a lack of objectivity about whether seizures in the newborn are diagnosed
as epileptic of cortical origin or non-epileptic of non-cortical origin. A common and important feature of NSs is electroclinical dissociation with some electrographic seizures showing subtle seizures (subclinical seizures) or no clinical symptoms
(electrographic seizures). Recent studies have revealed that ictal EEG recording is essential for the identification of true NSs of
cortical origin. We will emphasize the importance of ictal EEGs for diagnosis and management of NSs in NICUs. We will also
propose a new classification of clinical features and symptoms of NSs, which can be classified objectively by any neonatologist.
Treatments for NSs must be aimed at treating both the seizures and their underlying etiologies. There are few reports that show
obvious evidence for the efficacy of antiepileptic drugs for NSs. Based on past literature and recommendations, we suggest that
phenobarbital is the best first-line option, and that midazolam and lidocaine are best second-line agents as anticonvulsants for
the treatments of NSs. We will also emphasize the importance of other treatments, such as brain hypothermia, anti-oxidative
stress agents, zonisamide or topiramate for the underlying disorders that are associated with NSs.
Neuroimaging in epilepsy diagnosis
Hyang W. Lee, Department of Neurology, Epilepsy and Sleep Center, Ewha Womans University School of Medicine, Seoul,
South Korea
Neuroimaging is one of the most important diagnostic methods for epilepsy, with tremendous achievements in recent decades.
It provides better understanding of the etiology and valuable information to decide the best therapeutic strategy for patients
with epilepsy. Neuroimaging can contribute to the proper classification of certain epileptic disorders, and can delineate the
genetics underlying some syndromes. Neuroimaging techniques include CT and MRI, although CT has been replaced in many
situations because of the diminished role for diagnosis. By providing excellent structural information, MRI is the technique
of choice in the initial investigation of patients with epilepsy. The MRI is also critical for neurosurgical planning. Advances
in technology to localize focal epileptogenic lesions, especially those of high-resolution structural MRI, have substantially
improved the success of surgical treatment. The MRI is the most sensitive technique for the diagnosis of hippocampal sclerosis,
tumors, and malformations of cortical development. Advances in radionuclide-based techniques such as positron emission
tomography (PET) and single photon emission computed tomography (SPECT) are reserved for patients with intractable
epilepsy when surgery is contemplated. New developments such as magnetic resonance spectroscopy (MRS), receptor PET,
magnetic source imaging (MSI) with magnetoencephalography (MEG), and functional MRI (fMRI) are providing new
insights into the pathophysiology of epilepsy, which permits noninvasive assessment of the epileptic substrate, its functional
status, and alteration in neuroreceptors.
Resective epilepsy surgery for malformation of cortical development in infancy and early childhood
Taisuke Otsuki, Epilepsy Center, National Center of Neurology and Psychiatry, Tokyo, Japan
Frequent epileptic seizures in infants cause severe epileptic encephalopathy associated with progressive developmental delay.
Cortical dysplasia (CD) is increasingly recognized as a cause of intractable epilepsy in infancy. Among CD, focal cortical
dysplasia (FCD), and hemimegalencephaly (HMC) are the 2 most frequent types in reported surgical series. Histologically,
FCD is sub classified as FCD type I, type IIA, and type IIB. A contemporary series of resective surgery for CD reports that
more than 60% of patients are seizure free, with higher rates for complete removal of the lesion. Morbidity (<3%) and
mortality (0.2%) are low for patients with CD undergoing epilepsy neurosurgery. Moreover, patients operated on at younger
ages reportedly show larger increases in developmental quotient (DQ) after surgery. Attention, therefore, is now focused
on early surgery to avoid the negative influence of frequent intractable seizures on the immature brain causing epileptic
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encephalopathy in early life. In our institute, 56 consecutive children (less than 6 years old) underwent resective epilepsy
surgery for CD from December 2000 to August 2011. Seizure free (ILAE class I) outcome was obtained in 66% of the cases
(class Ia; 55%): 85% with focal resection (n=13), 50% with lobar resection (n=18), 71% with multilobar disconnection (n=7),
and 67% with hemispherotomy (n=18). Early surgical intervention in children with CD and intractable seizures in infancy
and early childhood can yield favorable seizure outcome without mortality or severe morbidities although younger children
often need extensive surgical procedures.
Semiology in epilepsy diagnosis
Hirokazu Oguni, Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Epileptic syndrome classification provides useful information for the treatment of children with epilepsy in daily clinical
practice. The first step that needs to be performed is a precise seizure diagnosis. In the outpatient clinic, the confirmation and
diagnosis of seizure types rely heavily on the history taken from the parents or caregivers. Detailed history taking, interictal
EEG findings, and neuroimaging can lead us to a proper seizure type diagnosis as well as syndromic classification. When
difficulties are encountered in making a seizure diagnosis and seizure control, long-term ictal video-polygraphic recording
may help when the seizure frequency is on a daily or weekly basis. Several specific seizure patterns have been linked to
corresponding specific epilepsy syndromes. Ictal vomiting followed by long-lasting focal or secondary generalized seizures may
lead practitioners to suspect Panayiotopoulos syndrome. Epilepsia partialis continua occurring in previously normal children
may indicate Rasmussen syndrome. The presence of myoclonic seizures, which we should distinguish from epileptic spasms,
suggests benign myoclonic epilepsy in infants, Dravet syndrome, and juvenile myoclonic epilepsy, depending on the age of
onset and associated seizure types. Epileptic drop attacks occurring in previously normal young children may suggest Doose
syndrome. However, we should know the semiological characteristics of each ILAE-recognized seizure type because history
taking is frequently insufficient when the seizures are brief in duration and infrequent in occurrence. I would like to present
ictal video-polygraphs of various seizure types often seen in children with refractory epilepsy and illustrate the semiological
approach used to make a proper seizure diagnosis.
Treatment of intractable epilepsy based on mechanism of action of antiepileptic drugs
Kenji Sugai, Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo,
Japan
The major mechanisms of action (MOA) of antiepileptic drugs (AEDs) include inhibition of Na channel, Ca channel, K
channel, glutamates system or carbonic anhydrase, inhibition of release of presynaptic vesicles by binding SV2A, enhancement
of the GABAergic system, and postsynaptic hyperpolarization. In the treatment of intractable epilepsies, MOA can be applied
to select effective AEDs and predict side effects. The latter is important for treatment with a sufficient tolerated dose as well
as efficacy. 1) Rational polytherapy by combination of AEDs with different MOA, 2) Change to AEDs with MOA different
from that of the previous ineffective AEDs, 3) Prediction of efficacy of AEDs: for partial tonic seizures, AEDs with MOA of
inhibition of both Na channel and Ca channel (ZNS, LTG, PB, PHT, TPM) show a high responder rate. However, AEDs with
either Na channel or Ca channel (VPA, CBZ, CLB, CZP, AZM, LEV, GBP) have a low responder rate. 4) Prediction of side
effects: AEDs that enhance the GABAergic system (CLB, CZP, PB, VPA, ZNS, bromide, GBP, TPM, LEV) inevitably produce
sedative side effects in moderate or high dose, but AEDs without this MOA (PHT, LTG, ESM) yield no sedative side effects,
and AEDs that inhibit carbonic anhydrase (AZM, ZNS, TPM) may produce urinary stones. 5) When one AED is effective
but side effects occur, effective and safe AEDs can be changed to other AEDs with similar MOA. 6) AEDs that enhance the
GABAergic system may be avoided in young infants because the GABAergic system works not as inhibitory, but excitatory in
young infants.
Treatment strategies for refractory epilepsy of childhood
Hirokazu Oguni, Department of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan
Refractory epilepsy of childhood comprises certain types of ILAE-recognized epileptic syndromes, for which various specific
treatments have been successfully attempted, including ACTH for West syndrome and stiripentol for Dravet syndrome. Thus,
the first step that needs to be performed is a proper syndromic diagnosis based on clinical and EEG findings. If they do not fit
a known epilepsy syndrome, a neurobiological approach utilizing genetic, neurophysiological, and pharmacological knowledge
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that alternatively provides useful information to the specific treatment should be undertaken, such as ethosuximide for epileptic
negative myoclonus. When all available antiepileptic drugs fail to control the seizures, we have to consider the next nonpharmacological approach. A ketogenic diet and ACTH therapies can be attempted if the seizures are generalized, and epilepsy
surgery should be considered if the seizures arise from a well-delineated cortical focus. Recent advances in neuroimaging can
help to identify the responsible localized cortical lesions in children with refractory focal epilepsy, and a good surgical outcome
has been increasingly reported throughout the world. The ACTH or steroid therapy may be successful for those with epileptic
spasms, atonic seizures, and myoclonic seizures. Ketogenic diet therapy is also effective for myoclonic seizures and generalized
tonic or tonic-clonic seizures, and may also be beneficial for those with Lennox-Gastaut syndrome and Dravet syndrome. In
conclusion, the treatment strategy can be better determined based on the syndromic classification and presence of a resectable
epileptogenic focus on neuroimaging if epilepsy has been diagnosed as symptomatic focal.
Metabolic disorders
Approach to neurometabolic disorders
Zuhair A. Rahbeeni, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
The inherited metabolic diseases (IMDs), as an example of genetic diseases, are individually rare, however, they are collectively
numerous. They are considered a major component of mortality and morbidity, particularly in the pediatric population. The
inherited metabolic diseases are transmitted mainly by autosomal recessive inheritance, which makes it more prominent in
Arab countries, in general, and in the Kingdom of Saudi Arabia in particular due to first and second degree cousin marriages.
Our neonatal screening program data showed that the incidence among 16 diseases that are screened, is one affected among
1000 newborns. Other statistical data from our medical records showed that we are following at least 3,500 patients with
different genetic disorders. Approximately one half of those are related to inherited metabolic disorders, and 30% of them
exceeded the age of 14 years. These statistical figures make genetic disorders a major health problem that needs to be resolved.
Most IMDs disorders afflict the nervous system. Neurometabolic diseases are defined as hereditary conditions, which are
characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected
central or peripheral structures of the nervous system. They include diseases such organic acidemias, amino acids disorders,
lysosomal disorders, and many others. In my talk I will discuss our approach to neurometabolic disorders, simplifying these by
clinical classifications, which include 3 groups. Group 1 - The complex molecule. Group 2 - The toxic. Group 3 - The energy
deficiency. At the end, I would like to emphasize that genetic disorders are relatively common in this region of the world, and
early diagnosis and preventive methods should be established to decrease the incidence of these disorders.
Congenital disorders of glycosylation
Osama Y. Aldirbashi, Department of Pediatrics, University of Ottawa, Ontario, Canada
Glycosylation is a complex process that involves binding of sugar chains to proteins or lipids. Congenital disorders of
glycosylation (CDGs), formerly called carbohydrate-deficient glycoprotein syndrome is a heterogeneous group of inherited
metabolic disorders caused by impaired glycosylation. Glycoconjugates including glycoprotein and glycolipids occur in
all human cells. Approximately half of our proteins are glycosylated, and this modification plays a crucial role in cell-cell
interaction, adhesion, protein folding, stability, trafficking, antigenicity, and intracellular signaling. Genes responsible for
glycosylation represent a significant fraction (1-3%) of the translated human genome. In general, genetic mutations in these
genes result in deficient enzymes or transporters and lead to CDGs. To date, approximately 70 disorders are known to be
associated with impaired glycosylation. Defective glycosylation often results in a multisystem disease. The large number of
affected organ systems illustrates the imperative role of glycosylation machinery in health and disease. Some organs such as
the brain and liver have higher demand for glycoconjugates, and thus are more commonly affected. The clinical spectrum can
range from severe hydrops fetalis to a relatively mild disease. Most patients, however, present in infancy with a multisystem
disorder and neurological involvement. With the exception of a few, CDGs are mostly untreatable. This presentation will
outline the basic principles of glycobiology and the clinically relevant CDGs with a special focus on the N-linked protein
glycosylation pathway. It will also summarize the established investigational approaches and how to interpret the results.
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Energy and health: The many faces of mitochondrial diseases
Majid Alfadhel, Department of Pediatrics, Genetics Division, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Mitochondrial disorders are a heterogeneous subgroup of disorders that result from defects in the mitochondrial respiratory
chain. They can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). Several mitochondrial disorders affect
a single organ only, while others involve multiple organ systems and often present with prominent neurologic and myopathic
features. Mitochondrial disorders may present at any age. Many affected individuals display a cluster of clinical features that
fall into a discrete clinical syndrome, such as the Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia
(CPEO), mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with
ragged-red fibers (MERRF), neurogenic weakness with ataxia and retinitis pigmentosa (NARP), or Leigh syndrome (LS).
However, significant clinical variability exists and several patients do not fit into one particular category. Common clinical
features of mitochondrial disease include ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance,
cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus. Common CNS findings
are fluctuating encephalopathy, seizures, dementia, migraine, stroke-like episodes, ataxia, and spasticity. In the lecture, we
highlighted the basic biology, genetics, classification, investigations, cases scenarios, and diagnostic approach of mitochondrial
disorder.
Expanding newborn screening
Osama Y. Aldirbashi, Department of Pediatrics, University of Ottawa, Ontario, Canada
Newborn screening (NBS) is a public health service aimed at identifying a group of rare, but serious inherited or congenital
disorders. This service is in place to detect pre-symptomatic babies so that proper interventions to prevent mortality or
ameliorate physical or mental disability can be implemented. Targeted conditions are selected based on availability of suitable
screening and diagnostic methods as well as treatability. Driven by the availability of a test applicable to dried blood spot
samples (DBS), NBS was introduced around 50 years ago to detect PKU. The application of tandem mass spectrometric
methods to the DBS in the 1990’s shifted the paradigm in NBS from one test, one disease, to multiplex testing in which
large numbers of disease markers are detected in a single test. The recommended DBS-based uniform panel encompasses 28
metabolic, endocrine, and other disorders. The recent development in high throughput DNA analyses on DBS allowed the
inclusion of severe combined immune deficiencies into the screening panel of several programs. Expanding NBS is triggered by
further understanding the target disorder and development of new testing technologies and treatment modalities. Lysosomal
storage diseases including Hurler, Gaucher, Pompe and others for which treatment exists are being considered. Other expansion
targets include X-linked adrenoleukodystrophy, creatine deficiency syndromes, Wilson disease, and a number of metabolic and
non metabolic disorders. This presentation will review the current status of expanded NBS, and discuss future expansion in the
context of natural history, test technology, and the relative merits of treatment amongst these disorders.
Genetic diseases in Saudi Arabia
Zuhair Al-Hassnan, Department of Medical Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi
Arabia
Certain population indicators have had a significant impact on genetic diseases in Saudi Arabia. The high consanguinity rate,
tribal structure, and demographic characteristics of the Saudi population have dramatically influenced the incidence, type,
and distribution of recessively inherited genetic diseases in the country. In normal clinical service for genetic diseases in Saudi
Arabia, rare disorders are more commonly observed; and novel entities are continually described. The regional distribution
of genetic diseases mirroring the tribal structure of the population is clearly recognized. Founder mutations, which are in
some diseases tribe-specific while in others are pan-tribe, have been identified in many recessive disorders. The medical,
social, and economic burdens of genetic diseases are nowadays more appreciated in the country. The importance of preventive
interventions is recognized at the national level with the implementation of premarital and newborn screening programs.
With the advances in technology, the molecular diagnosis of genetic disease is becoming less challenging. Consequently, in
many disorders, it is possible to offer preventive interventions to families through at-risk carrier screening, prenatal diagnosis,
and preimplantation genetic diagnosis. Through several illustrative examples, we show in this presentation how the clinical
approach to neurogenetic diseases is changing with advances in technology. We also demonstrate how understanding the
inherent demographic characters of our population facilitate the diagnosis of disorders that are less recognized in the literature.
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Imaging diagnosis of congenital metabolic disorders
Hiroshi Oba, Department of Radiology, Teikyo University Hospital, Tokyo, Japan
Metabolic disorders are difficult to diagnose because there are hundreds of them, and symptoms can mimic more common
diseases or conditions. The MRI plays an important role in the assessment of leukoencephalopathies and other metabolic
disorders. However, findings obtained with conventional MRI may often be lacking in specificity. In this lecture, I will highlight
10 specific key findings in which characteristic MRI findings are read to reach the proper diagnosis of metabolic disorder.
Key findings include: “tiger stripes” (metachromatic leukodystrophy), “optic optic nerve enlargement and leukodystrophy”
(Krabbe disease), “we can see the rosenthal fibers on both CT and MRI” (Alexander disease), “low signal white matter on
FLAIR sequence” (leukoencephalopathy with vanishing white matter; VWM and megaloencephalic leukoencephalopathy
with subcortical cysts; MLC), “micro cyst effect” (VWM, MLC, progressive cavitating leukoencephalopathy), “calcification
and cysts” (cerebroretinal microangiopathy with calcification and cysts; CRMCC, Aicardi-Goutieres syndrome), “cyst-like
sylvian fissure” (Glutaric aciduria type 1), “cortical dysgenesis and leukodystophy” (Zellweger syndrome and Fukuyama
congenital muscular dystrophy; FCMD), “T1 high stripes of substantia nigra” (static encephalopathy with neurodegeneration
in adulthood; SENDA), “Occipital horn” (occipital horn syndrome). I believe this knowledge will reduce the difficulty in
diagnosis of metabolic disorders.
Mechanism and physiologic function of mitochondrial fission
Katsuyosh Mihara, Kyushu University, Fukuoka, Japan
Mitochondria frequently change their morphology by fusion and fission, and these dynamic morphology changes are essential
for maintaining both mitochondrial and cellular functions. (1) Identification of Drp1 receptor. The dynamin-related GTPase
Drp1 (Dnm1 in yeast) is recruited from the cytoplasm to mitochondrial fission sites and severs mitochondria in a GTP
dependent manner. Although the mitochondrial outer membrane protein Fis1 is thought to be a Drp1 receptor, this has not
been confirmed. We showed that (i) mitochondrial fission factor (Mff)-knockdown released the Drp1 foci from mitochondria
accompanied by the network extension, while Mff-overexpression stimulated mitochondrial recruitment of Drp1 accompanied
by mitochondrial fission; (ii) Mff-dependent mitochondrial fission proceeded independent of Fis1; (iii) Mff and Drp1
physically interacted both in vitro and in vivo; (iv) proapoptotic stimuli-triggered mitochondrial fission and apoptosis were
compromised by knockdown of Drp1 and Mff, but not Fis1. Thus, Mff acts as a bona fide Drp1 receptor. (2) Tissue-specific
Drp1-KO mice. Whole tissue Drp1-KO mice exhibit developmental abnormalities, particularly in the forebrain, and die after
embryonic day 12.5. Neural cell-specific (NS) Drp1-KO mice die shortly after birth due to brain hypoplasia. Primary culture
of NS-Drp1-KO mouse forebrain showed a decreased neurite number and defective synapse formation due to aggregated
mitochondria that failed to properly distribute within the cell processes, thus highlighting the importance of Drp1-dependent
mitochondrial fission within highly polarized cells such as neurons. Phenotypes of Drp1-KO mice specific for several other
tissues will be discussed.
New treatment option for mitochondrial fatty acid oxidation defect: Bezafibrate, a PPAR agonist
Seiji Yamaguchi, Department of Pediatric, Shimane University School of Medicine, Izumo, Japan
The number of patients with mitochondrial fatty acid beta-oxidation (FAO) disorders is becoming larger with the spread of
newborn mass screening using tandem mass spectrometry (MS/MS). The clinical presentation of FAO disorders includes
lethargy, hypotonia, myopathy-like illness, and acute encephalopathy, or even sudden death due to energy production
insufficiency. The treatments such as avoiding long starvation, early infusion of glucose during sick days, or carnitine therapy
for some cases has been described for FAO disorders. It is claimed that bezafibrate (BEZ), an agonist of peroxisome proliferating
activator receptor (PPAR), can restore the FAO activity of some FAO related enzymes. Bezafibrate facilitated transcription of
genes encoding FAO enzymes, and subsequently induces FAO enzyme production. We used an in vitro probe (IVP) assay,
which can evaluate FAO capacity using cultured cells and MS/MS to evaluate the effect of BEZ. Consequently, accumulated
acylcarnitine specific for all FAO diseases in culture medium significantly decreased by the presence of BEZ in the IVP assay.
Moreover, the clinical trial of BEZ treatment for a 2-year-old boy with glutaric academia type 2 (GA2) showed dramatic
improvements in his muscle strength, and motor, and cognitive skills, accompanied by sustained reduction of accumulated
acylcarnitine in the blood, and normalization or urinary organic acids. No major adverse effects were observed. Hence, BEZ
can be a new treatment options for many of the FAO disorders.
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Newborn screening
Ali Alodaib, Department of Genetics, Research Centre, King Faisal Specialist Hospital & Research Centre, Kingdom of Saudi Arabia
The Saudi newborn screening program is a public health program implemented to detect and prevent selected congenital and
metabolic disorders. If not detected and treated early in life, these disorders cause severe mental retardation, illness, or death.
The detection of pre-symptomatic babies improves the clinical outcome and reduces morbidity and mortality. The newborn
screening program was launched in 2005 and targets all babies born in the Kingdom of Saudi Arabia. The program includes
screening dried blood spots from newborns at 24-72 hours after birth for 16 inherited metabolic and endocrine disorders.
Peroxisomal disorder
Nobuyuki Shimozawa, Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan
Peroxisomal diseases are categorized into 3 large groups – peroxisome biogenesis disorder (PBD), single enzyme deficiencies
(SED), and contiguous gene syndrome. Thirteen complementation groups and PEX genes responsible for all subgroups of
PBD, plus 10 diseases and their responsible genes in SED have been identified. We have established a diagnostic system for
peroxisomal diseases in Japan, and identified more than 50 Japanese patients with PBD, 13 patients with beta-oxidation
enzyme deficiencies, and more than 100 patients with adrenoleukodystrophy (ALD). It is important for effective therapy of
the cerebral form of ALD to diagnose earlier after onset, and pre-symptomatic diagnosis is also valuable. Furthermore, we have
diagnosed 22 patients with peroxisomal diseases in Saudi Arabia by a collaborative study with King Faisal Specialist Hospital
& Research Centre. The division of the diagnostic system into several specified centers of peroxisomal diseases in the whole
world should be functional for overcoming these rare inherited neurometabolic diseases.
Recent advances in lysosomal storage disease
Rose-Mary Boustany, American University of Beirut Medical Center, Beirut, Lebanon
The lysosome turns 58 years this year (DeDuve 2005). The concept of lysosomal storage diseases (LSDs) was developed in
Pompe’s disease (Hers 1965). Great strides have been made in the understanding of the pathology of LSDs and neuronal
ceroid lipofuscinoses (NCLs). The LSDs are due to protein defects resulting in lysosomal storage in the reticuloendothelial
system, brain, bone, skeletal, and cardiac muscle. All are autosomal recessive except for X-linked Hunter’s, Fabry’s, and Danon
disease. Defects of integral/lysosome associated membrane proteins and novel NCLs are now described. Good animal models
and mass enzyme production have resulted in enzyme replacement (ERT) for 6 LSDs with more in clinical trials, and presymptomatic hematopoietic stem cell treatments for 3 others. Neural/non-neural stem cell therapies and enzyme delivery
into the brain of animals/humans are under investigation. Creative treatments of substrate reduction diminishing substrate
burden, and chaperone therapies raising enzyme activities are approved or in clinical trials. Gene replacement using viral
vectors and combination therapies are encouraging in animal models. Inflammation, endoplasmic reticulum (ER) calcium
homeostasis, the unfolded protein response (UPR), apoptosis and autophagy are promising targets for emerging therapies.
Recently materialized treatments are far from perfect as many challenges remain. Screening programs, genetic counseling, and
prenatal diagnosis remain the mainstays of prevention.
Update on Krabbe disease
Hiroshi Kobayashi, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
Krabbe disease (Globoid Cell leukodystrophy, GLD) is a progressive demyelinating disorder due to genetic deficiency of
b-galactocerebrosidase (GALC), which results in the degeneration of myelin-forming cells (oligodendrocytes and Schwann
cells) caused by an accumulation of galactosylsphingosine (psychosine). We paid attention to immaturity of the blood-brain
barrier and increased advantage in gene transfer into the hematopoietic stem cell in the neonatal period of the rodent, and
performed gene therapy for the neonatal model mice of GLD (twitcher mice). We constructed a recombinant lentiviral
vector to transduce cells with the normal human GALC cDNA, and have succeeded to improve the nutrition (body weight),
the accumulation of psychosine, and the pathology of sciatic nerve. By combination with substrate reduction therapy, we
have succeeded in delay of the onset time and extending their life span. Other groups reported the combination therapy of
neonatal gene therapy and hematopoietic stem cell transplantation (HSCT), or direct injection of adeno-associated virus
(AAV) vector into the brain and HSCT resulted in efficient improvement of life span. The other group reported that forced
GALC expression is toxic for hematopoietic stem cell (HSC) and early progenitor cells, and they performed successful exo vivo
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gene therapy using miRNA. We will discuss recent studies, mainly in the progress of curative therapy for Krabbe disease, with
the other points such as the pathological mechanism or clinical topics.
Neuromuscular
Congenital muscular dystrophies: An update
Carsten G. Bonnemann, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD,
United States of America
Congenital muscular dystrophies (CMD) are a genetically heterogeneous group of disorders of voluntary muscle presenting at
birth or in early infancy with weakness and evidence of dystrophic myopathy on muscle biopsy. Initially recognized more then
a hundred years ago, considerable progress in the elucidation of molecular mechanisms has occurred recently. An emerging
theme amongst gene products involved in the pathogenesis of CMD is their involvement with the extracellular matrix of
muscle. Three of the main forms affect molecular components that mediate the interaction of the muscle fibers with the
extracellular matrix: Merosin (laminin2) deficient CMD caused by mutations in LAMA2, the alpha-dystroglycanopathies
caused by mutations in genes involved in O-mannosyl linked glycosylation of alpha-dystroglycan, and the collagen VI related
muscular dystrophies, caused by mutations in COL6A1, A2, and A3. These CMDs of the extracellular matrix collectively
represent the most common forms. In addition, there are CMD forms resulting from mutations in intracellular components
of muscle, including SEPN1, LMNA, and RYR1 related forms. This presentation will highlight recent developments including
the discovery of novel genes, expanded clinical spectra, the definition of new syndromes, and the development of therapeutic
approaches.
Congenital myasthenic syndromes
Amina Chaouch, Hanns Lochmuller, Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, England,
United Kingdom
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders characterized by fatigable muscle
weakness secondary to abnormal function of the neuromuscular junction. So far, 15 genes have been shown to cause CMS,
most of which involve post-synaptic proteins. More recently, we have shown the importance of glycosylation defects in causing
a distinct pattern of limb girdle muscle weakness, sparing the ocular and bulbar muscles. We will cover the significant progress
made in understanding the molecular pathogenesis of CMS, which is important for both patients and clinicians in terms of
reaching a definite diagnosis and selecting the most appropriate treatment.
Genetic peripheral neuropathy
Garth A. Nicholson, University of Sydney, Sydney, Australia
Genetic neuropathies are the most common cause of neuropathy. Over 50 different genes with mutations have been found so
that making the precise diagnosis in an individual or family is a challenge. The CMT1A duplication accounts for some 60%
of cases. The remainder are relatively rare forms requiring DNA sequencing. This can be costly if a number of genes have to
be screened. Some clues to the specific genetic form can be found from the clinical presentation, age of onset, and the mode
of inheritance. New genetic technologies now may enable all gene coding DNA sequences (exons) to be sequenced rapidly
for a few thousand dollars (namely, for the same cost as sequencing 3-6 genes by traditional sequencing methods). By use of
appropriate informatics, genes known to cause neuropathies can be examined and normal variations can be excluded. We have
recently applied exome sequencing (sequencing all the exons in the human genome) to a cohort of 100 families with hereditary
neuropathies. The results will be presented for discussion.
Limb girdle muscular dystrophy
Eijiro Ozawa, National Institution of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
Limb girdle muscular dystrophy (LGMD) is a group of various kinds of muscular dystrophies, whose clinical symptoms
are roughly similar. Among them, sarcoglycanopathy (SGP) is special in that its onset is in childhood. Its symptoms are
similar to Duchenne muscular dystrophy (DMD), but SGP is inherited in an autosomal recessive manner. In this talk, the
pathomechanism of SGP is explained. The sarcoglycan (SG) complex is a transmembranous subcomplex of dystrophin-
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associated protein (DAP) complex, composed of 4 protein molecules, namely, a-, b-, g- and d-SGs. When anyone of their genes
is mutated and its protein product is lost, the whole SG complex is lost or greatly reduced from the DAP. In normal muscle,
the dystrophin-DAP complex serves to mechanically strengthen the protecting system of the cell membrane (lipid bilayer)
composed of the basal lamina and submembranous actin filament networks. The most important function of dystrophin-DAP
complex is to transmembranously connect the submembranous actin network and the basal lamina. Their principal structure
is dystrophin = b-dystroglycan (transmembranous) = a-dystroglycan, that is collectively called “dystrophin bolt”. When the
binding of dystrophin and b-dystroglycan is weakened or lost, DMD occurs. The role of SG complex is to strengthen this
binding. When the SG complex is lost, this binding is weakened and thus, the protection of the lipid bilayer is weakened and
the cell membrane is easily injured during repeated muscle contraction. Therefore, the pathomechanism of SGP is similar to
that of DMD. Although the cell membrane is equipped with a repairing system, its repeated injury would result in changes
that induce muscular dystrophy.
Critical care
Chemical chaperone therapy for neuronopathic Gaucher disease
Kousaku Ohno, Tottori University Hospital, Yonago, Japan
Enzyme replacement therapy has been developed as an effective treatment for Gaucher disease (GD), but the effects on
neurological symptoms are uncertain. We have reported that N-octyl-b-valienamine (2004, 2007) and bicyclic nojirimycin
(2009, 2010) enhance the enzyme activities and the protein levels of R120W, N188S, G202R, F213I, and N370S mutant
b-glucocerebrosidase (GBA) in cultured cells and in the tissues of normal mice (2010). The Toronto group (2009) screened
1040 FDA approved drugs and found ambroxol hydrochloride (ABX) has chaperone activity on N307S and F213I mutant
GBA. We confirmed ABX also enhances R120W, N188S mutant GBA activities, and enhances GBA activities significantly
in the cerebellum of normal mice fed with drinking water containing various concentrations of ABX ad libitum for 7 day
(Zhuo L, et al 2012). Three GD type 3 patients (30-, 15-, and 20-year olds) presenting with progressive myoclonic epilepsy
with N188S/G193W or N188S/? mutations have been placed on oral ABX treatment. The dose was graduated up to 25 mg/
kg over 6 months and maintained for more than 6 months. The GBA activity in lymphocytes enhanced to 60-70% levels of
controls at 25mg/kg/day. The ABX was detected in CSF at a 14% level of serum concentration. There were no clinical and
biochemical adverse effects. Myoclonus and seizures in all patients were ameliorated and ADL in 2 patients, except for one
patient with severe motor and intellectual disability, improved markedly. Ambroxol hydrochloride is a safe and effective drug
for neuronopathic Gaucher patients with N188S, F213I, G202R, and R120W mutations.
Hypothermia for hypoxic ischemia insults, stroke, and traumatic brain injury
John S. Beca, Pediatric Intensive Care Unit, Starship Children’s Hospital, Grafton, Auckland, New Zealand
Animal models clearly show the neuroprotective effects of hypothermia early after hypoxic ischemic insults. Clinical trials
have established hypothermia as a standard of care in newborn infants with birth asphyxia and in adults after cardiac arrest.
In contrast, the role of hypothermia after cardiac arrest in children is unproven. The mechanisms of cardiac arrest are different
in both neonates and adults and retrospective studies have not shown improved outcomes with hypothermia when compared
to normothermia. The optimal duration of hypothermia is also unknown. Despite this, hypothermia is now widely used in
children after cardiac arrest. A large multicenter randomized control trial is currently underway to address this question. Trials
of early hypothermia in traumatic brain injury, both in adults and children, have not shown improved outcome and some
have shown worse outcome. In contrast, delayed hypothermia to manage intracranial hypertension has consistently been
shown to reduce intracranial pressure. Current evidence would therefore support normothermia in traumatic brain injury and
hypothermia only as part of an algorithm to manage intracranial hypertension. Management of rewarming is complex and
may contribute to worse outcome if it leads to compromised cerebral perfusion. For stroke, animal and small series suggest a
possible benefit and support safety. There are no adequately powered randomized control trials completed, although several are
underway. Many stroke patients are not sedated in intensive care, raising additional challenges in the management of cooling.
Hypothermia for stroke is therefore not indicated outside of clinical trials.
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New approaches on refractory and non-convulsive status epilepticus
Ahmed Alrumayyan, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Refractory status epilepticus is defined as status epilepticus that continues or recurs 24 hours or more, including those with
non-convulsive status epilepticus. It is an uncommon, but important clinical problem with high mortality and morbidity rates.
This presentation reviews various approaches to treatment. There are no controlled or randomized studies, and so therapy has
to be based on clinical reports and opinion. The published literature on the treatments will be evaluated: anesthetic agents,
anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency
resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain
stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid, and other older drug therapies. The importance
of treating the underlying etiology is stressed. A protocol and flowchart for managing refractory status epilepticus will be
suggested.
Neurodevelopment
Cognitive deficits in ADHD
Sadaaki Shirataki, Hakuai Research Institute of Developmental Disorders, Kobe Hakuai Hospital, Kobe, Japan
Cognitive deficits in ADHD are now acknowledged as very important factors, which are closely related both to the diagnosis
and to the interventions. Of course, ADHD is characterized by pervasive behavioral symptoms of hyperactivity, impulsivity,
and inattention. But, as far as we remain to be concerned only with the behavioral symptoms, we cannot be correct in
understanding the real causal relationship between behavioral symptoms and neural deficits. In other words, we should take
a more objective standpoint for relating the core symptoms of ADHD to the neural mechanisms by looking at the cognitive
deficits. We should also be aware of the developmental change of the cognitive functions, which go in parallel with the change
of the neural structure and function. Executive dysfunctions, for example, have been taken as the most pertinent cognitive
dysfunction, which can explain almost every difficulty the ADHD patient confronts. However, we know already that the age
at which the most primitive executive function can only start is at around 3-years-old. That means, if we meet a young infant
with inattention, we should not relate the responsibility for the symptom to the prefrontal cortex, which is almost non-existent
at such an early age. We are now conducting research on the improvements in both behavioral symptoms and cognitive deficits
after administration of methylphenidate or atomoxetine in ADHD children and adolescents. I assume the results from this
research will certainly be of value in understanding what is changing among the cognitive deficits of ADHD by means of
treatment with medication.
Developing language and functional skills for children with autism at home, in school, and in the community What works?
Heidi A. Alaskary, Persons with Disabilities Employment Program (Tawafuq) at Human Resources Development Fund
(HRDF), Riyadh, Saudi Arabia
Functional communication skills are one of the most important categories of skills that a person must possess to be able to
move from one stage of life to the next. From when an individual is a child these skills are developed in the home environment,
to the school, and then into the work environment. As communication skills are one of the core areas that are affected by ASD,
it is critical to be able to identify strengths and weaknesses in an individual, and work on developing skills that will serve them
throughout their life in the most functional way. This presentation will focus on the core communication challenges faced by
individuals with ASD, how to assess them, and present the most effective evidence-based programs out there that can be used
to develop functional communication. In addition, the key players in implementing these programs will be presented.
Genetics of attention deficit/hyperactivity disorder (ADHD)
Maximilian Muenke, National Human Genome Research Institute, National Institutes of Health, Department of Health and
Human Services, Bethesda, MD, United States of America
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental behavioral disorder, affecting
about 10% of children and adolescents worldwide. It frequently persists into adulthood and can have serious lifelong health
consequences. Attention-deficit/hyperactivity disorder increases the risk of substance use disorder (SUD) and disruptive
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(externalizing) disorders such as oppositional defiant disorder (ODD), conduct disorder (CD). Substance use disorder is
characterized by compulsive drug seeking behavior and drug use in the face of severe adverse consequences. We initiated a
clinical, neuropsychological, and molecular genetic study of ADHD. Our initial approach emphasized detailed phenotypic
and linkage studies in large families from a genetic isolate. This led to the identification of ADHD and comorbid disorder (for
example, substance use disorders) susceptibility loci, namely 4q13.2, 5q33.3, 8p23.1, 11q22, and 17p11 (Arcos-Burgos et al,
Am J Hum Genet 2004; Jain et al, Biol Psych 2007). We found and replicated the association between ADHD, including
treatment response, and LPHN3 variants (Arcos-Burgos et al, Mol Psych 2010). We then demonstrated that an interaction
between LPHN3 and a region on chromosome 11 (NCAM1, TTC12, ANKK1, and DRD2) doubles the risk for ADHD and
predicts severity and long-term outcome (Jain et al, Mol Psych 2011; Acosta et al, Transl Psych 2011). We are now generating
genotypes on samples already available in the lab as well as from samples from a cohort of individuals who have been followed
for 16 years as a part of the NIH MTA (Multicenter Treatment Assessment) study in order to define a genetics-symptomsfunction-treatment predictive framework as a step towards personalized medicine for children and adults who have ADHD.
Identifying and addressing microbial, immune, and hormonal imbalances in autism
Mady Hornig, Mallman School of Public Health, Columbia University, New York, NY, United States of America
Growing evidence suggests that the environment plays a role in autism pathogenesis. Diverse factors are implicated, ranging
from toxicants and dysnutrition to microbes. Explaining who gets sick, and when and why, is especially challenging when
exposures are ubiquitous. To account for variations in outcomes, we have proposed the “3 strokes” hypothesis, wherein disease
risk depends on the specific developmental age at which environmental exposure occurs and on intersection of this timed
exposure with genetic vulnerability factors. Inflammatory, autoimmune, and hormonal parameters may be persistently altered
in a subset of autism due to exposure to infectious or immunotoxic agents from the environment, before or after birth, and
susceptibility of the individual to these environmental challenges based on unfortunate genetics, bad timing, or prior harmful
exposures. Persistent elevation in levels of certain immune molecules can, in turn, compromise the integrity of the normally
protective blood-brain barrier, allowing both exogenous (infectious, xenobiotic) and endogenous (autoantibodies, cytokines)
substances to invade the brain from the blood. Immune molecules can also alter the microflora and disrupt intestinal function;
immune-triggered dysfunction of the intestines and of certain endocrine organs can negatively impact upon maturation and
function of the brain. We hypothesize that this dysregulation of brain-immune signaling is a critical component of the complex
mechanisms leading to the development of autism and to exacerbation of its clinical features. The evidence for immune and
hormonal dysregulation in autism and its potential role in development and maintenance of the disorder will be represented
along with implications for prevention and intervention.
Pearls, perils & pitfalls of treating ADHD
Susan S. Gau, Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with a high and complex genetic basis in its
etiology. Recent CNVs investigation for rare variants and GWA studies with endophenotype approaches for common variants
are promising strategies to identify common genetic variants for ASD. The presentation will focus on the imaging and genetic
research related socio-communication in ASD. We explored the relationship between runs of homozygosity (ROH) and
clinical heterogeneity in 315 Han Chinese with ASD, and 1,115 healthy controls in Taiwan, and investigated the involvement
of social deficits on semantic processing in 16 ASD with severe social deficit, 16 ASD with mild social deficits, and 16 age-,
gender-, and IQ-matched healthy controls. We found that one ROH region on chromosome 11 harboring 9 novel candidate
genes was significantly associated with risk of speech delay (unadjusted p=2.51 x 10-11). Regarding imaging results, both ASD
groups showed reduced activation in left anterior insula cortex (AIC), inferior frontal gyrus (IFG), and middle temporal gyrus
(MTG). There were negative correlations between AIC/IFG/MTG activations and social deficit across groups. In contrast,
the severe group showed greater activation in left superior temporal gyrus (STG) than the other groups. Left STG activation
positively correlated with social emotion deficit. These most recent findings suggest that extended recessive loci may play a role
in heterogeneity in language impairment in ASD, and social deficits may associate with impaired semantic processing in ASD.
The autism spectrum disorder from genes to function
Susan S. Gau, Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with a high and complex genetic basis in its
etiology. Recent CNVs investigation for rare variants, and GWA studies with endophenotype approaches for common variants
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are promising strategies to identify common genetic variants for ASD. This presentation will focus on the imaging and genetic
research related socio-communication in ASD. We explored the relationship between runs of homozygosity (ROH) and
clinical heterogeneity in 315 Han Chinese with ASD, and 1,115 healthy controls in Taiwan, and investigated the involvement
of social deficits on semantic processing in 16 ASD with severe social deficit, 16 ASD with mild social deficits, and 16 age-,
gender- and IQ-matched healthy controls. We found that one ROH region on chromosome 11 harboring 9 novel candidate
genes was significantly associated with risk of speech delay (unadjusted p=2.51 x 10-11). Regarding imaging results, both ASD
groups showed reduced activation in left anterior insula cortex (AIC), inferior frontal gyrus (IFG), and middle temporal gyrus
(MTG). There were negative correlations between AIC/IFG/MTG activations and social deficit across groups. In contrast,
the severe group showed greater activation in left superior temporal gyrus (STG) than the other groups. Left STG activation
positively correlated with social emotion deficit. These most recent findings suggest that extended recessive loci may play a role
in heterogeneity in language impairment in ASD, and social deficits may associate with impaired semantic processing in ASD.
Pediatric stroke
Advances in neuro-rehabilitation
Warren Lo, The Ohio State University and Nationwide Children’s Hospital, Columbus, Ohio, United States of America
Recent basic science observations have shown that the adult mammalian nervous system has a degree of plasticity that was
previously unexpected. These observations have changed the rehabilitation of adult stroke, and have opened new opportunities
for treatment of neurological injuries in children. The choices for motor rehabilitation have expanded rapidly, which make for
uncertainty which ones should be pursued. This presentation will address the evidence for current motor therapies. Since motor
rehabilitation is time and effort intensive, questions arise regarding who will be a good candidate for therapy. When should
interventions be pursued is uncertain, and whether there is value in repeat intervention is unknown. Much less attention has
been paid to cognitive and behavioral rehabilitation, but these are topics that often concern families more than motor function.
The limited information regarding interventions in these 2 areas will be covered in this presentation.
Background of pediatric stroke
Khalid Alahmadi, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Background: The cause of stroke in children is unknown in one-third of cases. The most common reported risk factors
in our medical institution (King Faisal Specialist Hospital & Research Centre [KFSH-RC], Riyadh, Saudi Arabia) include
cardiac disorders, sickle cell disease, coagulation disorders, arterial dissection, moyamoya, infection, and other rare genetic
disorders. Cardiac disorders are the most common cause of ischemic stroke in children and account for up to 50% of strokes
in case series. The risk of stroke in children with congenital heart disease is related to the abnormality, diagnostic and surgical
procedures, and associated genetic or acquired factors that predispose children to thrombosis. Cardiac disorders can lead
to the development of intracardiac thrombi that may embolize to the brain or can lead to thrombosis in cyanotic patients
with anemia. Blood disorders are the second most common cause of stroke in children. Neuroimaging has a crucial role in
multidisciplinary management of these patients, by avoiding under diagnosis and delays in treatment. Objectives: 1. Correlate
between the pathophysiology of ischemia and radiological findings. 2. How radiology can help in avoiding under diagnosis
and delay in treatment. 3. To list common causes of pediatric stroke. 4. How the radiological modality helps in reaching the
predisposing factor or causative agent. 5. The KFSH-RC Riyadh Neuroradiology section’s experience in pediatric stroke.
Cerebral sinovenous thrombosis
Warren Lo, The Ohio State University & Nationwide Children’s Hospital, Columbus, OH, United States of America
Cerebral sinovenous thrombosis (CSVT) is an uncommon form of cerebrovascular occlusion. The CSVT can have a wide
range of clinical presentations ranging from seizures in neonates to pseudomotor cerebri in adolescents. The availability of
sensitive non-invasive neuroimaging has made the diagnosis much easier, and may have contributed to the awareness of the
condition. This presentation will review the clinical presentation of CSVT, give several neuroimage examples, and discuss the
evaluation. This presentation will discuss the treatment guidelines, review the difficulties in diagnosis and the controversies in
treatment, and the limited information regarding outcomes.
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Pediatric stroke
Fenella Kirkham, Institute of Child Health, University College London, London, United Kingdom
Stroke and cerebrovascular disorders are an important cause of morbidity and mortality in children. Recent epidemiological
data suggest that the incidence for ischemic and hemorrhagic stroke is between 1.5 and 13 per 100,000 children. Although
outcome for stroke in children is significantly better than in adults, 20% die and 50-80% are left with significant disability.
The range of presentation, pathophysiology, investigation, and treatment of children presenting with acute hemorrhagic and
ischemic stroke syndromes is often different from adults. There are multiple risk factors and conditions predisposing to stroke.
Around half the children presenting with stroke have a previously recognized condition, most commonly congenital heart
conditions and sickle cell disease. Trauma and infection, for example, bacterial and tuberculous meningitis and Varicella,
are common triggers in the symptomatic as well as the cryptogenic group. Emergency neuroimaging should include MRI,
angiography (focal cerebral arteriopathy, moyamoya), venography (venous sinus thrombosis), and fat saturated T1-weighted
imaging of the neck (dissection). Stroke mimics include demyelination, reversible posterior leukoencephalopathy, border
zone ischemia, and metabolic conditions. Appropriate emergency management can play an important role in facilitating and
accelerating medical and surgical intervention, preventing secondary damage, and minimizing mortality and morbidity as
well as risk of recurrence. Efficient transport and intensive care are essential, and patients may require emergency treatment
for seizures and intracranial hypertension. Neurosurgical involvement may be required (drainage of intracerebral hemorrhage,
hemicraniectomy for malignant middle cerebral infarction). Urgent exchange blood transfusion for patients with stroke and
sickle cell disease is reasonable.
Risk factors and outcomes of childhood stroke
Kuang-Lin Lin, Chang Gung Children’s Hospital, Taoyuan, Taiwan
Forms of stroke due to vascular occlusion are arterial ischemic stroke and cerebral sino-venous thrombosis. In previous studies,
multiple risk factors were identified including cardiac disease, infection, vasculopathies, blood disorders, and metabolic
disorders. Interethnic differences have been demonstrated to be important. The most common vascular disorders causing
pediatric ischemic stroke are vasculitis, systemic vascular disease, vasculopathies, vasospastic disorders, and trauma. In the
group of vasculitis, primary angiitis of the CNS, meningitis, and systemic lupus erythematous are frequently seen in clinical
practice. In the vasculopathies, moyamoya disease is the most famous etiology. Dissection of the carotid or vertebral arteries
occurs in 8-20% of children with arterial ischemic stroke. Cardiac disorders account for 12-28% of children with arterial
ischemic stroke in North America and Europe, and 42% in Hong Kong Chinese children. However, in a cohort study of
Taiwan (January 1996 to July 2006), vascular disease and infection were the 2 leading etiologies. Differences in risk factor
pattern were noted in different ethnic studies. Nine percent of children die in the acute stage, and 16% children have recurrent
stroke. Infarction involving arterial ischemic stroke of anterior circulation is the most common in both the early poststroke
seizure group (61.9%) and the late poststroke seizure (57.1%). Epilepsy was the most common sequelae in both the early
poststroke seizure (38.1%) and late poststroke seizure group (100%). Poststroke seizures do not affect mortality, but there is a
significant difference in normal outcome and epilepsy between those with or without poststroke seizures.
Movement disorders
Deep brain stimulation (DBS) surgery for movement disorders in pediatric patients
Ahmed Alkhani, Department of Neurosciences, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Deep brain stimulation (DBS) is an established modality of treatment for patients with medically resistant movement disorders.
These include Parkinson disease, tremor, and dystonia. Deep brain stimulation has a proven safety and efficacy profile in both
adults and pediatric patients. In the pediatric age group, dystonia is the main indication for DBS. Since 1997, encouraging
clinical outcomes for different types of generalized dystonia treated with DBS were reported in the literature. Best results were
reported in patients with primary hereditary dystonia like DYT1. At King Faisal Specialist Hospital and Research Centre,
DBS surgery for dystonia started in 2003. Cases of primary and secondary dystonia were treated using DBS. All our patients
had their surgery under general anesthesia using MRI based stereotactic procedures targeting the internal segment of the
globus pallidus (Gpi). Clinical improvements were judged based on the Unified Dystonia Rating Scale. Our experience will be
presented and compared with the available literature. In conclusion, DBS procedures in the pediatric age group are safe and
effective for many types of dystonia.
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Dystonia - novel modalities of treatment
Jonathan W. Mink, University of Rochester Medical Center, Rochester, NY, United States of America
Dystonia is a movement disorder characterized by variably sustained involuntary muscle contraction that produces abnormal
movements and postures, often with a twisting quality. The etiologies of dystonia are many and include: single gene mutations,
structural brain injury, toxins, metabolic disorders, and idiopathic disorders. In children, dystonia is most likely secondary to
other identifiable conditions, but may be a primary genetic disorder. In a few conditions, such as dopa-responsive dystonia
due to GTP-cyclohydrolase deficiency, treatment response may be dramatic and life-long. In other conditions, response to
treatment is more variable. Treatment options include systemic pharmacotherapy, botulinum toxin injections, and surgery.
Recently, deep brain stimulation (DBS) has emerged as a promising treatment for some forms of dystonia. This lecture will
review current treatments for primary and secondary dystonias, review what is know about mechanisms of action, and present
data for emerging therapeutic strategies.
Genetics of basal ganglia and movement disorders
Russell C. Dale, The Children’s Hospital at Westmead and University of Sydney, Westmead, NSW, Australia
Movement disorders may be due to point mutations or large deletions of neurological genes. Some movement disorders are
monogenic and have mendelian patterns of inheritance. However, the genetic causes of some common movement disorders such
as Tourette syndrome remain cryptic, and suggest multiple genes and environmental factors are involved. New technologies such
as comparative genomic hybridization microarrays and whole exome sequencing have significantly improved our understanding
of genetic movement disorders. Despite the new developments in genetic technologies, the clinical phenomenology of the
abnormal movements remains paramount to diagnosis and investigation. Monogenic movement disorders can present with
pure dystonia such as DYT1 dystonia, or dystonia plus such as dopa-responsive dystonia, and myoclonus dystonia. Recent
developments in genetic movement disorders include the discovery of PRRT2 as the common cause of paroxysmal kinesigenic
dyskinesia. The presentation will provide an overview of the approach to patients with suspected movement disorders, including
clinical phenomenology, defining associated symptoms, judicious use of investigation and genetic testing. The priority to
investigation will always be to ensure treatable disorders are not missed, such as dopa-responsive conditions.
Neurotransmitter role in movement disorders
Wang-Tso Lee, Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
Cerebrospinal fluid (CSF) neurotransmitter measurement may play an important role in the diagnosis of movement
disorders. In addition to important diseases like pediatric neurotransmitter diseases, cerebral folate deficiency may also have
significant changes in CSF neurotransmitters. Pediatric neurotransmitter diseases include AR and AD guanosine triphosphate
cyclohydrolase I (GCH I) deficiency, sepiapterin reductase (SR) deficiency, tyrosine hydroxylase (TH) deficiency, aromatic
L-amino acid decarboxylase (AADC) deficiency, and dopamine transporter deficiency, and so forth. The diagnosis of pediatric
neurotransmitter diseases remains a great challenge for pediatricians and child neurologists. They can be diagnosed by clinical
manifestations, genetic analysis, plasma enzyme activity measurement, and the changes of CSF neurotransmitters. In addition
to clinical manifestations and CSF neurotransmitter measurement, neuroimaging findings may also be helpful in the diagnosis
and long-term follow-up. For patients with cerebral folate deficiency, many patients may have dyskinesia and intractable
epilepsy. Furthermore, the CSF may also play a role in diagnosis of some unusual presentations of movement disorders in
neurological diseases. By monitoring the change of CSF neurotransmitter, we can reach the correct diagnosis and give proper
treatment for the patients.
Platform Abstracts
Central nervous system inflammatory demyelinating disorders of childhood - A clinical & radiological study
from South India
P. S. Bindu, Raj. R. Divya, R. D. Bharath*, Department of Neurology, Neuroimaging and Interventional Radiology*, National
Institute of Mental Health and Neurosciences, Bangalore, India.
Background: There are only limited reports on central nervous system inflammatory demyelinating disorders of childhood
(CIDD) from India. This study describes a cohort of 56 children (age group 3-18), seen over 9 years (2003-2012) with CIDD
from a tertiary care university hospital from South India. Methods: Children who had the first episode of a demyelinating
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event before 18 years, and satisfying the consensus definitions by International Pediatric Multiple Sclerosis (IPMS) were
included in the study. Results: Among the 56 patients, a monophasic course was observed in 45 and relapsing remitting course
in 11. The first group included monophasic acute disseminated encephalitis ADEM (25), clinically isolated syndrome (CIS)
(19), neuromyelitis optica (NMO) (1). The relapsing group included MS (6), recurrent ADEM (1), and relapsing NMO (4).
In monophasic ADEM, the presenting symptoms included hemiparesis, oculomotor abnormalities, optic neuritis, cerebellar
signs, and seizures. An antecedent event was noted in 84%, the most common being a febrile illness (60%). An MRI revealed
varying combinations of hemisphere, basal ganglia, cerebellar, and brain stem involvement. Large tumefactive lesions were
observed in 6. The CIS group included optic neuritis (7) and transverse myelitis (12). Presenting manifestations in MS
included optic neuritis (1), myelitis (2), cerebellar (1), brain stem (1), right hemiparesis, and optic neuritis (1). An MRI showed
periventricular perpendicular ovoid lesions in 2. The NMO group had relapsing-remitting course in 4 and monophasic course
in one. An MRI revealed long segment spinal cord lesions in all. Conclusion: This large series of children with demyelinating
disorders provides comprehensive clinical and radiological data on childhood demyelinating disorders from India.
Clinical and neuroradiological profile of acute disseminated encephalomyelitis in 13 children at a tertiary center
in Saudi Arabia
Amal Y. Kentab,1 Mustafa A. Salih,¹ Hamdy H. Hassan,² Mohammed N. Al-Nasser,¹ Heba Y. El-Khashab,¹ Departments of
Pediatrics,¹ and Radiology,² College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Background: Acute disseminated encephalitis (ADEM) is usually a monophasic polysymptomatic inflammatory condition of
the CNS that principally involves the white matter, although the grey matter may also be affected and is often preceded by a
viral infection or vaccination. Though it is a monophasic illness, relapses are known in ADEM, making the differentiation from
multiple sclerosis crucial and important. There are scarce data on pediatric ADEM from Saudi Arabia. Objective: The aim of the
study is to present the clinical manifestations of ADEM with neuroimaging correlation, response to treatment, and outcome.
Methods: A retrospective study to describe the characteristics of patients admitted with the clinical diagnosis of ADEM from
2000-2010 was carried out. The clinical profile, radiological findings, laboratory findings, and treatment outcome in these
children were reviewed. Diagnosis of ADEM was based on: clinical presentation of abrupt onset of multifocal neurologic signs,
evidence of patchy demyelination on MRI (cranial) not explained by any other neurologic illness. Recurrent or multiphasic
ADEM was defined as 2 distinct clinical or neuroradiologic episodes of demyelination not typical of MS, with complete
resolution of symptoms. Children with monosymptomatic episodes and those with a previous neurologic disorder as well as
those with features more in keeping with an alternative diagnosis were excluded. Results: A total of 13 patients (11 Saudis)
fulfilled the study criteria for ADEM and their data were analyzed. Male gender predominance was noted, as 53.8% of patients
were male. The mean age at presentation was (range 10 months to 11.6 years). Five patients (38.5%) presented during fall. A
history suggestive of antecedent infection was obtained in 11 children, 9 (69%) with URTI, one (7.7%) with gastroenteritis,
one (7.7%) with varicella, and one (7.7%) with hepatitis like picture. None developed ADEM post vaccination. Four of our
patients had an underlying medical problem, bronchial asthma, IDDM, autoimmune hemolytic anemia, Bare cell lymphocyte
syndrome. Polysymptomatic presentation was seen in all patients. Motor weakness (11 patients 84.6%), psychiatric symptoms
with behavioral changes (8 patients, 61.5 %), headache and vomiting (7 patients, 53.7 %), seizures, visual problem and fever
were seen in (3 patients, 23%) for each. The presenting signs were pyramidal signs (12 patients, 92%), cranial nerve palsy
(11 patients, 84.6%), altered sensorium (7 patients, 53.8%), cerebellar signs (5 patients, 38.5%), meningeal signs (5 patients,
34.5%) and spinal cord involvement (one patient, 7.7%). Of motor weakness, 5 had quadriparesis, 5 had hemiparesis, and
one had paraparesis. Of cranial nerve involvement, the most common was facial nerve palsy (5) / (1) LMN/GBS, multiple
cranial nerve palsy (4), followed by 3rd cranial nerve palsy (2; vision loss was observed in 3 patients with abnormal VEP and
no clinical evidence of optic neuritis. The duration of hospital stay was in the range of 5 days to 2 weeks for all except for 3
patients that stayed for 3-5 weeks, necessitating admission to the PICU with severe brain stem involvement. Ten patients had
initial CT scan, 6 (60%) were abnormal with multiple hypodensity within the WM. Interestingly, one presented with tumor
like mass others with hypodensity within BG and thalami, none presented with hemorrhage, 4 (40%) were normal. On MRI
of the brain, white matter changes were noted mostly in the frontal area 9 (69%), parietal area 8 (61.5%), periventricular 6
(46%) and occipital area 5 (38.5%). Brain stem 8 (61.5%), cerebellum 4 (30.7 %), deep grey matter 3 (23%), and spinal cord
lesions in 2 (out of 7 patients). Enhancement was detected in 7 (63%). Three patients achieved spontaneous clinical remission
with no treatment, and favorable outcome with steroids was observed in 10 patients. On follow up (for 12 patients) all patients
survived except for the youngest (10 months old) who died because of complicated infection related to his original illness (Bare
lymphocyte syndrome). Five patients (41.6%) had excellent recovery, 5 patients (41.6%) had mild neurologic sequel with
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high functional level, 2 patients (16.6%) had moderate to severe neurologic sequel. A relapse or multiphasic ADEM was seen
in 4 patients with interval time 2, 3, 5, 36 months from initial diagnosis, 2 of these relapses while tapering steroid therapy.
Conclusions: ADEM appears more common than previously thought, and is eminently treatable; therefore, a high index of
suspicion must be kept in children presenting with encephalopathy and sudden onset multifocal neurologic signs. Magnetic
resonance imaging remains the imaging method of choice. Even though there are no controlled trials, the dramatic recovery
seen in a large number of children with ADEM warrants therapy with corticosteroids and or IV immunoglobulin in all such
cases.
Limbic encephalitis in a child with an atypical presentation
Adel A. Mahmoud, Pediatric Neurology, King Fahad Medical City, Saudi Arabia
Background: Limbic encephalitis (LE) is a rare disorder that generally has a subacute onset evolving over days to weeks.
Patients present with a variable combination of memory loss, seizures, and psychiatric disturbance, and it is not rare for
patients to be initially misdiagnosed. Patients: We report a previously healthy 12-year-old boy who developed his first episode
of seizures at 8 years of age. He had a total of 8 prolonged focal seizure episodes, and each episode was followed by a month of
behavioral changes and short-term memory loss. There was no family history of seizures or other neurological disorders, and he
had an otherwise unremarkable neonatal and past medical history. Results: Magnetic resonance imaging during each episode
of seizures showed alternating unilateral brain hemispheric involvement consistent with LE that was followed by resolution for
a total of 6 times. Despite a negative laboratory evaluation for a large panel of paraneoplastic antibodies, the clinical scenario
and exclusion of other possible disorders made recurrent LE the most likely diagnosis. Conclusion: Limbic encephalitis is
a rare disorder that is diagnosed primarily on clinical criteria and is often associated with the presence of a paraneoplastic
antibody. However, lack of a positive paraneoplastic antibody in a patient with a triad of seizure, behavioral changes, and shortterm memory loss does not exclude the diagnosis. The unique presentation in a seronegative patient like ours may indicate a
previously unrecognized antibody. To the best of our knowledge, such a case has never been reported.
Treatment and video-EEG monitoring in children with nonconvulsive status epilepticus
Zhang Yunjian, Department of Pediatric Neurology, Children’s Hospital of Fudan University, Shanghai, China
Purpose: To explore the clinical features and VEEG monitoring of nonconvulsive status epilepticus (NCSE) in children.
Methods: Data on demographics, etiology, video-EEG (VEEG) manifestation, response to clonazepam therapy and outcomes
were analyzed. Results: Nine male and 8 females of 17 patients with NCSE ranged from 11 months to 11.4 years old. The clinical
attacks lasted a variable time from 4 hours to 3 months. Each patient had a prolonged change of consciousness, accompanied
by psychological or behavioral changes. Definite medical causes were identified in 65% of the patients. Secondary epilepsy
was the dominating cause. The characteristics of ictal VEEG in NCSE generally included slow activity and focal or generalized
δ or θ activity. After clonazepam treatment, the conditions of 12 patients were under complete control, 5 had improvement.
The time needed to control NCSE varied from 15 minutes to one week. The prognosis of CNS infection sequelae patients,
metabolism disorders and brain structural damage was poor. Conclusion: Nonconvulsive status epilepticus may present with
confusion, behavioral disturbances and psychiatric conditions. The diagnosis can be made by the ictal and interictal VEEG
monitoring. It is necessary to make the diagnosis and control the seizures as quickly as possible. Clonazepam is useful in NCSE.
Epileptic spasms beyond infancy: Electroclinical, neuroimaging, and the role of epilepsy surgery
Fahad A. Bashiri, Pediatric Neurology Unit, Faculty of Medicine & King Khalid University Hospital, King Saud University ,
Riyadh, Saudi Arabia
Objective: Epileptic spasm beyond infancy is poorly understood, with only a few reports describing this condition. In this
report, we describe clinical, neurophysiological, neuroimaging, and modality of treatment of this rare epileptic syndrome.
Methods: We retrospectively reviewed the EEG and epilepsy data of patients with epileptic spasms documented by video EEG
monitoring at the Children’s Hospital of British Columbia, Vancouver, BC, Canada from January 1999 - July 2010. Results:
Fourteen patients were identified: 8 males, age of seizure onset from one month to 14.4 years; mean age 14.95 years, age at
video EEG recording from 2.8-17.2 years. Anomalies of brain development represented 66.6%, 4 patients were cryptogenic,
2 had cingulate tumor, one had perinatal asphyxia, and one had chromosomal abnormalities. Interictal EEG revealed two-
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thirds with normal background, the majority with delta, and theta slowing. Ictal EEG showed suppression followed by
fast beta activity in the majority with delta activity in some patients. Eight patients had surgical intervention preceded by
intracranial electrocorticography in 7 out of 8. Among those who had surgery, 62.5% became seizure free. All patients had
neuropsychology evaluation, which was normal in 5 patients (35.7%). Conclusion: Epileptic spasms beyond infancy is a rare
condition, interictal EEG is poorly localizing. Video EEG recording helps in recognizing the condition. Anomalies of brain
development are an important etiology. Epilepsy surgery has a roll in treating this condition with favorable outcome compared
with conventional treatment.
Lennox-Gastaut syndrome associated with dysgenesis of corpus callosum
A. Bruce Janati, Center for Neurology in Fairfax, VA, United States of America
Introduction: Lennox-Gastaut syndrome (LGS) is an electro-clinical syndrome composed of the triad of mental retardation,
multiple seizure types, and the characteristic generalized slow spike-wave complexes in the EEG. In this article, we report on
2 patients with LGS who’s brain MRI showed dysgenesis of the corpus callosum (CC). We review the literature and stress the
role of CC in the genesis of secondary bilateral synchrony (SBS). Methods: This was a clinical study conducted at King Khalid
Hospital. Results: The EEG was consistent with LGS in patient one and unilateral slow spike-wave complexes in patient 2.
The MRI showed hypoplasia of the splenium of CC in patient one, and global hypoplasia of CC combined with Joubert
syndrome in patient 2. Conclusion: Based on the data, we proffer the following hypotheses: 1-Hypoplasia of CC interferes
with functional integrity of this structure. 2-The genu of CC plays a pivotal role in the genesis of secondary bilateral synchrony.
3-Electrodecremental seizures in LGS emanate from pacemakers generated in the brain stem, in particular the mesencephalon
projecting abnormal signals to the cortex via thalamic nuclei. 4-Unilateral slow spike-wave complexes in the context of mental
retardation and multiple seizure types may represent a variant of LGS, justifying neuroimaging studies.
Rosiglitazone attenuates NMDA-induced excitotoxicity in hippocampus and not through PPAR gamma
activation
Shi-Bing Wong, Pediatrics, Buddhist Tzu Chi General Hospital, Taipei branch, Taiwan
Mesial temporal lobe epilepsy (MTLE) accounts for 30-35% patients with epilepsy. The MTLE is strongly correlated to
hippocampal sclerosis. Low-Mg2+ artificial cerebrospinal fluid (ACSF) will induce ictal and interictal-like epileptiform
discharges in CA1, CA3, entorhinal cortex in hippocampal slice preparations, which can be regarded as an in vitro model
of temporal lobe epilepsy. Peroxisome proliferators-activated receptor gamma (PPARγ) is a nuclear hormone receptor. Drugs
targeting the PPARγ receptor have been studied in various CNS diseases, including Alzheimer’s disease and multiple sclerosis.
In this study, we aimed to evaluate the neuroprotective and anti-convulsive effects of rosiglitazone, a synthetic PPARγ
agonist. At first, we applied kainic acid 25 μM or NMDA 40 μM to 7-8 DIV hippocampal slice cultures and treated with
rosiglitazone 1μM or 10 μM. Both concentrations had no protection on kainic acid-treated slices. But in NMDA-treated
slices, rosiglitazone 10 μM significantly attenuated NMDA-induced excitotoxicity over dentate gyrus, CA3, and CA1. Then
we applied rosiglitazone in different concentrations over hippocampal Schaffer collateral EPSP. Rosiglitazone 1uM and 10uM
had no effect on Schaffer collateral-CA1 synaptic transmission, which was mainly AMPA-transmitted. But they suppressed the
amplitude of population spikes induced by magnesium-free ACSF. Lastly, we induced epileptiform discharges in hippocampus
by Mg-free ACSF, and treated with rosiglitazone in different concentrations. Rosiglitazone 10 μM significantly deceased the
epileptiform discharges to 30% of baseline. In conclusion, PPARγ agonist rosiglitazone could protect hippocampal slice from
NMDA excitotoxicity, and may arise from blockade of NMDA synaptic transmission directly.
Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings
Brahim Tabarki-Melaiki, Amel Al-Hashem, Shatha Al-Shafi, Saad Al-Shahwan, Divisions of Pediatric Neurology and Genetics,
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
Background: Biotin responsive basal ganglia disease (BBGD) also called thiamine transporter-2 deficiency, is a treatable
autosomal recessive neurometabolic condition resulting from mutations in the SLC19A3 gene. Objective: To investigate the
clinical, genetic, and neuroradiologic data of BBGD and clarify the disease spectrum. Methods: We first investigated all patients
attending the Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia with a genetically
proven diagnosis of BBGD between 2009 and 2012. All patients underwent a detailed medical history and clinical examination,
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extensive laboratory investigations including genetic tests, and brain MRI. Finally, we conducted a systematic review of the
literature. Results: We enrolled 15 patients meeting the diagnostic criteria for BBGD, and analyzed the data on 16 patients
from 5 previous reports. The BBGD occurred predominantly in preschool/school-aged patients in the Saudi population, but
it was also observed in other ethnic groups. The typical clinical picture consisted of recurrent subacute encephalopathy leading
to coma, seizures, and extrapyramidal manifestations. The brain MRI typically showed symmetric and bilateral lesions in the
caudate nucleus and putamen, infra- and supratentorial brain cortex, and in the brainstem. Vasogenic edema characterized
the acute crises as demonstrated by diffusion-weighted imaging/apparent diffusion coefficient MRI. Atrophy and gliosis in the
affected regions were observed in patients with chronic disease. Early treatment with a combination of biotin and thiamine
resulted in clinical and neuroradiologic improvement. Death and neurologic sequelae including dystonia, mental retardation,
and epilepsy were observed in those who were not treated or were treated late. Conclusions: Biotin responsive basal ganglia
disease is an under diagnosed pan-ethnic treatable condition. Clinicians caring for patients with unexplained encephalopathy
and neuroimaging showing vasogenic edema in the bilateral putamen and caudate nuclei, infra- and supratentorial cortex, and
brainstem should consider this disorder early in the hospital course because a therapeutic trial with biotin and thiamine can be
lifesaving. Our study also provides new insights into the disease: 1/the neuroimaging features of the disease, 2/thiamin is main
treatment of the disease and not biotin.
Spectrum of neuro degeneration in children
Tipu Sultan, Department of Neurology, The Childrens Hospital & Institute of Child Health, Lahore, Pakistan
Objective: To investigate the spectrum of diagnosis, clinical presentation, and role of neuroimmaging in neurodegenerative
disorders of childhood. Design: Descriptive study. Place and duration of study: Department of Neurology, Children’s
Hospital, Lahore, Pakistan from June 1, 2006 to May 31, 2009. Subjects & Methods: A total of 6273 patients were admitted
to the Neurology Department in the study period. Out of these, 166 children fulfilled the inclusion criteria. History, clinical
examination, and relevant investigations were carried out and proformas were filled. Results: The male to female ratio was 1.4:1.
Age range was 1-12 years. Metachromatic leukodystrophy was the predominant type (21%), followed by adrenoleukodystrophy
(16%), SSPE (12%), 10% had Wilson Disease, 4% of lipidosis, Gaucher disease, (3%) of each Alexander disease, Pantothenate
kinase-associated neurodegeneration, one case each of multiple sclerosis and ataxia telangiectasia. In 6 cases, a final diagnosis
could not be made. Conclusion: Degenerative brain diseases are a common entity in the pediatric population. The most
common presentation is regression of milestones. The presentation is quite variable. Physicians must investigate when dealing
with children with regression of milestones to obtain an early diagnosis. Because of limited diagnostic modalities, brain imaging
has significant value. Facilities for enzyme studies should be available at tertiary care hospitals.
Biotin responsive basal ganglia disease (BBGD): Unusual presentation with spinal cord involvement
Fahad A. Bashiri,¹ Muddathir H. Hamad,¹ Heba Y. El-Khashab,¹ Saeed M. Hassan,¹ Hamdy H. Hassan,² Mustafa A. Salih,¹
Division of Pediatric Neurology,1 Department of Pediatrics, Division of Radiology,² College of Medicine, King Saud University,
Riyadh, Saudi Arabia.
Biotin responsive basal ganglia disease (BBGD) is a recessively inherited disorder, which manifests as subacute encephalopathy.
It is a rare disorder related to thiamine transporter-2 deficiency and is caused by a mutation in the SLC19A3 gene. Administration
of high dose of biotin and thiamine results in significant clinical and radiological improvement. Here, we report 2 cases of
BBGD with different clinical presentations, one had cervical spinal involvement. Case 1: A 13-year-old girl who was previously
healthy presented at the age of 11 years with seizures, confusion, and abnormal gait. Analysis of CSF was normal. An MRI
brain was significant for multiple variable size lesions of high signal intensity symmetrically involving the basal ganglia, cerebral,
and cerebellar white matter with alterations in signal intensity of the cervical spine. She was diagnosed initially as acute
disseminated encephalomyelitis (ADEM), received IVIG and methylprednisolone with initial improvement but 2 further
recurrences. A DNA test identified a mutation in SLC19A3 gene, administration of high dose biotin and thiamine reversed the
symptoms. Case 2: A 2-year-old girl who presented with a 5-day history of unsteady gait, which progressed to inability to walk.
Her brother died aged 2 years and was suspected to have mitochondrial disease. Her clinical examination showed dystonia.
Laboratory investigations revealed normal amino acids and urine organic acids profile. A brain MRI demonstrated high signal
intensity in subcortical white matter, red nuclei, and basal ganglia bilaterally. The DNA confirmed the diagnosis of BBGD.
She responded dramatically to a high dose of biotin and thiamine. Conclusion: Biotin responsive basal ganglia disease is a rare
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disorder that should be suspected in patients who present with features of ADEM or acute dystonia, as early recognition and
treatment prevent serious complications and death.
Megalencephaly and white matter diseases in infancy and childhood
L. Mansour,* E. Fateen,** M. Rashed,** S. Ezzat,*** S. Mohamed,*** A. Badr,* L. Tarek,* Cairo University,* National
Research Centre,** Ein Shams University,*** Cairo, Egypt
Introduction: Canavan disease is an autosomal recessive disorder due to a defective ASPA gene. Objective: To highlight the
clinical manifestations of Canavan disease, among cases with macrocephaly and white matter diseases, the diagnostic work up,
molecular and prenatal diagnosis. Methods: We included 22 cases presenting with macrocephaly and MRI findings of white
matter disease. Ages ranged from 6 months to 10 years. All patients were subjected to history, neurological examination, and
urine organic acid profile. Quantitative N-acetyl aspartic acid in urine was found in 5 cases, MRS in 7 cases, aryl sulfatase and
hexoseaminidase A activity in one case. The DNA sequence analysis of the ASPA gene (NM0049.2) for 2 Canavan cases and
prenatal diagnosis for one pregnant mother. Results: Cases were classified into Canavan disease 12 cases, megaloencephalic
leukoencephalopathy with subcortical cysts in 4 cases, glutaric aciduria type 1, Tay-Sachs disease, and vanishing white matter
disease in one case each, and 3 cases required further work up. Canavan cases (6 ms-54 ms) presented with psychomotor delay,
defective vision (5 cases), and seizures (7 cases). The DNA sequence analysis of the ASPA gene (2 cases) showed homozygous
for c.244 dup A (p.mct82 Asnfs X 8) mutation confirming the diagnosis of Canavan disease. Prenatal diagnosis revealed a fetus
heterozygous for the same mutation. Conclusion: An MRI is important for the diagnosis of white matter diseases. The urine
organic acid profile helps with the diagnosis of Canavan disease, and glutaric aciduria type I. The DNA sequence analysis for
ASPA gene is required for the diagnosis and prenatal diagnosis of Canavan disease. Hexoseaminidase activity is needed for the
diagnosis of Tay-Sachs disease.
The ketogenic diet experience at King Fahad Medical City, Riyadh, Saudi Arabia
Adel A. Mahmoud, Pediatric Neurology, King Fahad Medical City, Saudi Arabia
Purpose: Few centers in the Middle East offer ketogenic diet for epilepsy treatment. Anecdotal data shows that the ratio of
the diet needed to reach the state of ketosis might differ in different races. Unpublished data from India claimed that some
patients may reach ketosis at ratios of 1:1, which is different from the known belief that ketosis is usually reached at ratios
higher than that. This lead to thinking that there might be racial differences in to response to the diet. In King Fahad Medical
City, Riyadh, Saudi Arabia, the ketogenic diet program was initiated in 2008. We evaluated this issue and effect of diet on
seizure control, alertness, ambulation, and continuation of antiepileptic drugs. We aimed to document any differences between
our patients in Saudi Arabia and those reported internationally. Methods: We conducted a retrospective analysis on ketogenic
diet since November 2008. Thirty patients were included. Ages ranged from 10 months to 11 years with intractable epilepsy.
Follow up was for at least 6 months. Results: Twenty-four patients continued on the diet, 6 discontinued (3 no improvement,
one had persistent hypokalemia, one developed lipoid pneumonia, and one for social reasons) Of the 24 patients, 8 (33%)
became seizure free, 6 (25%) had 90% improvement, 6 (25%) had more than 50% improvement, and 4 (16%) had no clear
improvement in seizures. In 9 out of 24 (37%), the family reported better ambulation after the diet. Sixteen patients (66%)
showed better alertness and became calmer on the diet. The dose and number of AEDs were decreased, and 2 patients went
off medications.
Follow up study of 26 gene-confirmed Chinese patients with vanishing white matter disease and role of unfolded
protein response in the pathogenesis
Ye Wu, Department of Pediatrics, Peking University First Hospital, Beijing, China
Vanishing white matter disease (VWM) is one of the common hereditary leukoencephalopathies in childhood. Mutations in
EIF2B1-5, encoding α-ε subunits of eukaryotic translation initiation factor 2B (eIF2B), are identified in more than 90% of
VWM patients. Since the first VWM patient was diagnosed in mainland China in 2006, 26 Chinese patients were confirmed
by EIF2B1-5 gene analysis. The prevalence of EIF2B3 mutations in Chinese was much higher than Caucasian patients (42.3%
versus 4%), which is probably due to a founder mutation (p.IIe346Thr) in EIF2B3. This mutation was detected in 75% of
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patients with EIF2B3 mutations. Follow-up study was performed on 26 gene-confirmed patients. Compared with reported
Caucasian patients, the regression was more rapid. On the basis of onset age, all patients are classified as early childhood form,
except for one infantile form. Episodic aggravation in the case of stress was common (73%). High prevalence of episodic
aggravation in VWM is supposed to be related with ER stress. We transfected lentivirus vectors carrying wild type or mutant
eIF2Bγ (EIF2B3-p.IIe346Thr) into human oligodendrocytes line. The mutant showed increasing levels of UPR (unfolded
protein response) markers, including p-eIF2α, ATF4, CHOP, GADD34, all of which is located in the PERK pathway of UPR.
The apoptosis ratio is higher in mutant cells at 48 and 72 hours after ER stress inducement. Under basic or ER stress conditions
during different time course, the mutant cell line displayed lower cell viability. Apoptosis induced by UPR after ER stress may
account for the pathogenesis and deterioration of VWM.
Infantile ascending spastic paralysis caused by a novel ALS2 mutation identified by homozygosity mapping
Salma Majid, Genotyping Laboratory, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
Mutations in the alsin gene are causative for 3 clinically distinct motor neuron diseases, infantile ascending spastic paralysis,
juvenile primary lateral sclerosis, and juvenile amyotrophic lateral sclerosis. A total of 23 different ALS2 mutations have been
described for such disorders. Most of these mutations are predicted to result in frameshift leading to premature truncation of
the alsin protein. We report a novel ALS2 truncating mutation (c. 2761C>T) in 2 infants affected by infantile ascending spastic
paralysis (IAHSP) with bulbar muscles involvement. This mutation resides in the pleckstrin domain, a characteristic of GEFs
for the Rho GTPase family involved in overall neuronal development or maintenance. This study highlights the importance of
using homozygosity mapping combined with candidate gene analysis to identify the underlying genetic defect as in this small
Saudi consanguineous family. This study will help in genetic screening and consideration of preimplantation genetic diagnosis
in such families.
Immediate effects on the motor function of spastic cerebral palsy by restraint of a dominant hand
Shigeru Hanaoka, Tokyo Metropolitan Medical Rehabilitation Center for the Disabled, Tokyo, Japan
Introduction: The brain has many interesting control systems. In a process to treat cerebral palsy, in an attempt to enhance the
function of a subordinate hand, we noticed an interesting phenomenon, which can be called immediate effects. We report here
the phenomenon with a hypothesis. Methods: The subjects were 16 cases of the spastic type of cerebral palsy, 13 hemiplegia
(9 cases could walk), 2 spastic diplegia (none could walk) and one spastic tetraplegia; 11 males, 5 females, from the age of 3-9
years. We restrained their dominant hands with bandages to keep them grasping with their thumbs inside, and observed the
change just before and after this maneuver on muscle tonus, use of affected hand, posture, and walking pattern. The age of the
first trial of this maneuver was from 0.68-9.1 years old. Results: In all cases, decrease of the muscle tonus of the unrestrained
hands and arms were observed. In 7 of 9 cases, hemiplegic walking pattern became milder. These effects were enhanced by
tighter bandages, and disappeared by at least the morning after the release from bandage. Conclusions: Restraint of the
dominant hand has immediate effects on muscle tonus and movements of extremities on the subordinate side, and makes
spastic symptoms milder. This simple maneuver makes spastic symptoms milder, and it influences not only upper extremities
but trunks and lower extremities. This phenomenon suggests the possibility that restraint of the dominant hand suppresses
control of the dominant hemisphere and release of the latent potential of the subordinate hemisphere.
Preclinical assessment of clinic ready compounds for the treatment of spinal muscular atrophy
Faraz Farooq, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease, which is characterized by the loss of a motor
neurons resulting in progressive muscle atrophy. The loss of functional survival motor neuron (SMN) protein due to mutations
or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels of the SMN
protein originating from the copy gene SMN2, which could compensate in part for the absence of the functional SMN1 gene.
We have shown a novel therapeutic strategy for SMA treatment through the activation of the p38 and STAT5 kinase pathway
activating clinic ready compounds. Celecoxib (p38 activating drug) and Prolactin (STAT5 activator) demonstrate a clear
promise for use in SMA clinical trial studies as they increase SMN protein levels, ameliorate disease phenotype in SMA mouse
model, have blood brain barrier penetration and also have FDA approved status. We are currently working with clinicians
to design clinical trials for SMA with celecoxib, which already have approval from Health Canada. Spinal muscle atrophy is
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the most common genetic cause of infant death and is currently untreatable. This study will address a number of unanswered
questions of PRL treatment, which will make a strong case for its introduction into phase 1 trials for SMA. This study will also
help in the identification of other clinic ready STAT5 and p38 pathway activators as new candidates for SMA treatment. We
believe it shall bring effective treatments closer to reality for SMA.
PLA2G6 associated neurodegeneration (PLAN): A phenotypic, electrophysiological, radiological and
histopathological study from South India
P. S. Bindu, M. A. Shah,*** A. Mahadevan,* N. Gayathri,* T. C. Yasha,* S. Sinha, M. Nagappa, R. D. Bharath,** A. Kumar,***
A. B. Taly, Department of Neurology, Neuropathology,* Neuroimaging and Interventional Radiology,** National Institute of
Mental Health & Neurosciences, Department of Molecular Reproduction, Development and Genetics,*** Indian Institute of
Science, Bangalore, India
Background: There are only limited reports on PLA2G6 associated neurodegeneration (PLAN), an important cause of
progressive cerebral degeneration in children, from India. Patient and Methods: The study included 6 patients (age range
1-10 years, male: female ratio = 1:1) seen over 5 years (2008-2012). Their diagnosis was confirmed by molecular genetic
analysis. Results: Clinical phenotypes included infantile neuroaxonal dystrophy (INAD) in 5 and dystonia-parkinsonism in
one. Consanguinity was observed in 4 and family history in none. Salient clinical features included developmental delay (5),
regression of milestones (6), involuntary movement (3), optic atrophy (3), oculomotor disturbances (4), macrocephaly (4),
hypotonia (5), brisk stretch reflexes (5), extensor plantar (5), and dystonia and bradykinesia in one. Nerve conduction study
(n=6) revealed axonal neuropathy in 2. Evoked potential studies (n=6) showed abnormality in all. Electroencephalogram (n=6)
showed high amplitude beta fast activity only in one. The MRI (n=6) was abnormal in all cases, the most frequent abnormality
being cerebellar vermian atrophy (4). The patient with dystonia-parkinsonism showed mineralization of globus pallidus and
substantia nigra along with cerebellar atrophy. Muscle biopsy (n=6) showed characteristic axonal dilatation and spheroids in 5
patients of INAD. Genetic testing revealed both known and novel mutations in all. Conclusions: This is the first ever report of
a genetically confirmed case series of PLAN patients from India. Presence of combined upper and lower motor neuron signs,
macrocephaly, and cerebellar atrophy in a child with neuroregression may provide clues to the diagnosis.
Type III spinal muscular atrophy mimicking muscular dystrophies
Abdulaziz S. Alsaman, Pediatric Neurology, King Fahad Medical City, Riyadh, Saudi Arabia
Types III and IV spinal muscular atrophy represent a diagnostic challenge due to the great variability in their presentation.
We report a series of 8 patients with type III spinal muscular atrophy who were followed for a long time for possible muscular
dystrophy or myopathy, confirming its clinical heterogeneity, and propensity to delayed diagnosis. Clinical examination
revealed heterogeneous findings, where the diagnosis of type III spinal muscular atrophy was not immediately apparent in
many patients as their clinical and laboratory abnormalities were consistent with muscular dystrophy or myopathy. The
presence of dystrophic features such as hypertrophy of the calves, weakness of the limb girdle, high serum creatine kinase
levels, and myopathic histopathology should not divert attention from the possibility of spinal muscular atrophy. It is strongly
recommended to give variable presentations enough thought and to consider the autosomal recessive type III spinal muscular
atrophy in the diagnostic evaluation.
The era of pediatric neuromuscular disorder genetics
Mustafa A. Salih, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
The magnitude of neuromuscular disorders (NMD), mostly inherited as autosomal recessive (AR), is apparently large in the
Arabian Peninsula and North Africa due to the high rate of consanguinity. The prevalence rate of anterior horn cell diseases,
including Werdnig-Hoffman disease, was 133 and 177 per million in 2 studies, compared to 12 per million from the World
Survey. The frequency of severe childhood autosomal recessive muscular dystrophy (MD) was found to be equivalent to, and
higher than, Duchenne MD in Tunisia and Saudi Arabia, respectively. The corresponding genes were identified including
alpha-sarcoglycan (or Adhalin gene, from the Arabic word Adhal for muscle). The same founder mutation of one form of
congenital muscular dystrophy (MDC1A) was detected in families from Saudi Arabia and Sudan. Utilizing the power of familybased genetic studies combined with emerging DNA technology, new NMD were identified in populations of Arab descent.
Those with gene identification included: 1. Salih myopathy: Autosomal recessive titinopathy causing early onset myopathy/
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dystrophy with dilated cardiomyopathy (http://www.ncbi.nlm.nih.gov/books/NBK83297/). 2. Charcot-Marie-Tooth Disease
Type 4B1 (OMIM 601382). 3. Horizontal gaze palsy and progressive scoliosis (OMIM 607313). 4. Bosley-Salih-Alorainy
syndrome (OMIM 601536). 5. A novel form of congenital myasthenic syndrome due to AL2G2 gene mutations. 6. A novel
form of congenital muscular dystrophy due to B3GALNT2 gene mutations. These advances of pediatric neurogenetics made
possible the choice of life-saving drugs in congenital myasthenic syndromes, as will be demonstrated, and made feasible
presymptomatic, prenatal, and pre-implantation genetic diagnoses for affected families.
Lack of a right diagnosis of rigid spine muscular dystrophy, leading to tragic stories. Case Series.
Fouad A. Alghamdi, Pediatric Neurology, King Fahad Medical City, Riyadh, Saudi Arabia
We present 3 cases of genetically confirmed rigid spine muscular dystrophy with SEPN1 gene mutation. These 3 unrelated
patients had a tragic history due to lack of diagnosis. Patient one developed frequent attacks of behavioral changes, which
were secondary to undiscovered severe respiratory failure and carbon dioxide accumulation. She improved on ventilator use,
but required antipsychotic medication. Patient 2 had unexplained difficult ventilator extubation with normal chest x-ray for
2 months, which could not be explained by his H1N1 infection. Patient 3 accused his treating physician of malpractice after
being ventilator dependant following a chest infection. All these manifestations were understood after reaching a diagnosis of
rigid spine muscular dystrophy, which is associated with respiratory difficulty.
Genotype/phenotype analysis in Chinese laminin deficient congenital muscular dystrophy patients
Hui Xiong, Department of Pediatrics, Peking University First Hospital, Beijing, China
Laminin-α2 (merosin) deficiency is an autosomal recessive disorder characterized by severe muscular dystrophy associated
with typical abnormal white matter signal on brain MRI. It contributes to approximately half of the congenital muscular
dystrophy (CMD) cases in the western world, but there are only a few clinical cases reported in China. To determine the
clinical and molecular genetic characteristics of merosin deficient congenital muscular dystrophy 1A (MDC1A), we studied
40 CMD patients with typical white matter abnormality and complete or partial deficiency of laminin-α2 diagnosed by
immunohistochemistry staining. Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes,
LAMA2 gene mutation analysis was performed using PCR-DNA direct sequencing. After detecting only partial mutation by
direct DNA sequencing, we performed multiplex ligation-dependent probe amplification (MLPA) to check the exon deletion
or duplication. Then, the relationships between genotype and phenotype were analyzed. We identified 72 mutations in LAMA2
of all 40 patients (90%). Among these mutations, most of them are compound heterozygous. We found 14 known and 32
previously undescribed mutations spanning all protein domains. Most of them were nonsense or splicing site or frame shift
mutation causing laminin-α2 absence. Among all of the mutations, 18.1% had one or more than one exon deletion. According
to our research we further defined the clinical manifestation and molecular genetic characteristics of a cohort of 40 Chinese
patients with laminin-α2 deficient CMD, and our data suggest that the majority of laminin-α2 deficient patients in China
showed LAMA2 gene mutations. Genetic characterization of affected families is valuable in prenatal diagnosis.
Knowledge, attitudes, and practices of pediatricians towards developmental screening
Kathryn B. Braganza, Philippine Children’s Medical Center, Manilla, Philippines
Background: This study aims to provide a venue for further optimizing childcare in our country by identifying the needs
that should be focused in empowering the primary care services in providing early identification and intervention. Objective:
This research aims to determine the knowledge, attitudes, and practices of pediatricians towards developmental screening. An
association of the findings with the age, year of practice, and location of practice will be vital in determining the population
that should be further educated. Methods: This is an analytical cross-sectional study using a validated self-administered
questionnaire completed by 175 pediatricians and those who are primarily involved in child care. A non-probability sampling
was carried out. Multiple methods, which included correspondents directly handing the questionnaires, and electronic mail
was used to gather data for this study. Results: Among the respondents, 94% rely on nonstandardized methods and 16.5% use
a standardized screening instrument to detect developmental problems. The mean of direct referral to intervention program
was 36%. Significant associations were noted between attitude scores and region and age of subjects, and the practice scores
with age of subjects. Conclusion: This study showed that the majority of the respondents follow the PPS recommendation of
developmental surveillance on each child visit. Minority practices standardized screening tool (16.5%) and the mean of direct
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referral to intervention programs was 36%. Considering the barriers cited, pediatricians should be trained to use a brief and
concise screening tool and information on the intervention programs and its services should be disseminated.
Does the neurological outcome differ between 2 cohorts of preterm patients with isolated PVL and severe IVH?
Muhammad T. Alrifai, Pediatric Neurology, King Abdulaziz Medical City - National Guard Health Affairs, Riyadh, Saudi
Arabia
Objective: To compare the neurological outcome of isolated PVL (iPVL) and severe IVH in 2 cohorts of patients at one center
in Saudi Arabia. Methods: The study included all preterm neonates with iPVL and severe IVH (grade III and IV) documented
with at least 2 imaging modalities; one of which is cranial ultrasound, and the other is either brain CT scan or brain MRI. The
neurological outcome of developmental delay and cerebral palsy was compared between the 2 groups. Results: A total of 21
cases of iPVL and 27 cases of severe IVH (grade III and IV) were identified. One case of each group died in hospital from the
IVH group and soon after discharge in the iPVL group. Of 20 cases of iPVL, 9 (45%) had good developmental outcome and
11 (55%) had bad developmental outcome. Of 26 cases with severe IVH, 14 (54%) had good developmental outcome and
12 (46%) had bad outcome (p=0.7666). Distribution of the neurological outcome according to the PVL grade was: Grade I
showed 6/8 good neurological outcome and 2/8 had bad outcome; while PVL grade II showed 3/4 good outcome and 1/4 had
bad outcome; and all cases (n=8) of PVL grade III had bad outcome (p=0.0014). Severe motor neurological deficit affecting
function is distributed as follows: 11/20 in the iPVL group, and 7/26 in the severe IVH group (p=0.0324). Conclusion:
Approximately half of the cases of iPVL and severe IVH had poor developmental outcome; however, the severity of cerebral
palsy was greater in the iPVL patients.
Early intervention of children with deaf blindness: Bangladesh experience
Shamim Ferdous, Bangladesh Protibondhi Foundation, Dhaka, Bangladesh
Deaf blindness is a very rare disability causing extreme developmental disadvantage. It affects all areas of development,
including the formation of very early parent-child relationships, communication, cognition, motor, perceptual development,
social, and emotional development. Early intervention has been recognized as a means of ameliorating the developmental
constraints associated with deaf blindness. The deaf blind are very easily misassessed; there is a need to look beyond the
child’s overt behavior, and to search for incongruities in development. An understanding of the developmental implications
of deaf blindness, and how it manifests in children’s behavior, is essential to this process. Knowledge of specialist teaching
approaches, also, is vital for those providing intervention. Therefore, developmental consequences of deaf blindness indicate
a need for early intervention that involves families, a need for specialist intervention, and a need for co-coordinated services.
Deaf blind children are fragile learners, whose development can easily be harmed by unskilled teaching. Due to lack of
proper understanding of the complex nature of this dual sensory impairment, and limited expertise in the area, these children
have remained invisible with regards to public policy, specialized services, and excluded from the disabilities movement in
Bangladesh. The present paper will briefly discuss the situation of the services developed in Bangladesh and the outcome of the
service provided by trained interveners, in conjunction with other forms of support, an appropriate model for the delivery of
early intervention for children with dual sensory impairments with a focus in programming on assessment and training in the
use of vision and audition as well as development of other senses.
Best Poster Presentations
Urbanization influence on the prevalence and common co-morbidities of epilepsy in children and adolescents:
Analysis of National Health Insurance database in Taiwan
Kuo-Liang Chiang, Division of Pediatrics, Kuang-Tien General Hospital, Taichung, Taiwan
Background and Objectives: Epilepsy is one of the most prevalent pediatric neurologic diseases. In addition, children with
epilepsy may have co-morbidities that may result in significant disability. The epidemiology information for pediatric patients
with epilepsy in Taiwan is limited. In this study, prescription data from the National Health Insurance (NHI) research database
provides the urbanization influence on the prevalence and the common co-morbidities of childhood epilepsy. Methods: In
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the NHI database, patients aged less than 20 years old with ICD code 345.xx with at least one AED were classified as epilepsy
cases. In addition, co-morbidities were also studied in accordance with these epilepsy cases. Finally, patients were grouped
based on the urbanization level to provide insight into the differences between rural and urban areas of Taiwan. Results: The
estimated prevalence of children with epilepsy was 0.4% of the pediatric population (0.4% for women, and 0.5% for men).
The most common co-morbidities are cerebral palsy, mental deficit, and ADHD. Furthermore, males have a higher risk of
epilepsy than females. Discussion: Our estimated prevalence and associated co-morbidities ratio of children with epilepsy
through the NHI system has high reliability, and is close to the true prevalence of childhood epilepsy in Taiwan. Using the
NHI database, we also can investigate whether there are significant differences in the prevalence and co-morbidity rate of
children with epilepsy between the rural and urban areas.
High frequency oscillations measured on the scalp. A new horizon for non-invasive brain research
Tetsuro Nagasawa,1,2 Hiroshi Terashima,2 Akiko Shibata,2 Aki Ando,2 Hirofumi Kashii,2 Masaya Kubota,2, Department of
Pediatrics,1 Tokyo Metropolitan Fuchu Medical Center for the Disabled, Division of Neurology,2 National Center for Child
Health and Development, Tokyo, Japan
Background: Recently, high frequency oscillations (HFOs) measured on the cerebral cortex have been used in epilepsy surgery
as well as physiological studies. The HFOs are considered to be reliably detected with intracranial EEG alone, but some studies
showed HFOs using electrodes on the scalp. This study aims to confirm the existence of scalp HFOs. Methods: A total of six
patients with focal epilepsy were included. Three females, age range: 8-14 years (average 9.8 years). Scalp EEG was recorded
with sampling frequency at 1,000 Hz in each patient. Time-frequency analysis (10 to 200 Hz; -500 to +500ms) of focal spikes
was designed to evaluate HFOs associated with the peak of spikes. At each time-frequency bin (5Hz X 10ms) the percent
change in amplitude (averaged across 20-30 spikes) relative to the reference period was calculated and also tested for statistical
significance. Results: Four out of 6 patients showed HFOs over 100 Hz in accord with the peak of spikes. The patterns of the
HFOs were similar between patients and different from artifact or harmonics resonance. The electrodes that showed HFOs
were more pervasive than the electrodes with spikes. Discussion: Considering that the chance of intracranial EEG is so rare,
HFOs on the scalp EEG have great potential for both epileptic and physiological studies. Further analyses, however, are needed
to determine the optimal conditions to detect HFOs, the difference between patients with and without HFOs, and so forth.
Conclusion: The HFOs measured on the scalp are reliable and useful to some degree.
Resective epilepsy surgery in children with bilateral MRI lesion
Rita Yu, Severance Children’s Hospital, Seoul, South Korea
Through a retrospective review of 468 cases and 388 patients who underwent epilepsy surgery at Severance Children’s Hospital
from 2003 to August 2011, 102 patients had bilateral lesions on pre-operative MRI according to the neuro-radiology reports.
From these, 62.7% (64/102) of the patients had palliative surgeries, such as total corpus callosotomy or vagus nerve stimulator
(VNS) insertions, and 37.3% (38/102) underwent resective surgery. After a mean follow up period of 3 years, only 25.5%
(26/102) of bilateral lesion patients reported Engel class I outcome, while 26.5% reported Engel class III, and 42.2% reported
Engel class IV results postoperatively. However, when surgical modalities are taken into account, the outcome of those who
went through unilateral resective surgery is much higher, with 47.4% (18 out of 38) of Engel class I results, in contrast to
19% or 0% of Engel class I amongst patients who went through palliative surgery. According to this study, resective surgery
is a possible treatment option with moderate outcome, especially when compared to palliative surgeries, which has been the
conventional choice for intractable epilepsy conditions.
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