University of Cape Town

Massachusetts General Hospital

National Institutes of Health

Université Libre de Bruxelles

SickKids

Cincinnati Children's Hospital Medical Center

Tel Aviv Sourasky Medical Center

University of Rome Tor Vergata

Universitair Ziekenhuis Antwerpen

The University of Hong Kong

The University of Tennessee Health Science Center

University of Alberta

Boston Children's Hospital

University of Cincinnati

McGill University Health Centre

George Washington University

Medical University of Warsaw

Harvard Medical School

University of Alabama at Birmingham

UCSF University of California, San Francisco

Albert Einstein College of Medicine

University at Buffalo, The State University of New York

Pediatric Neurology publishes timely peer-reviewed clinical and research articles covering all aspects of the developing nervous system.Pediatric Neurology features up-to-the-minute publication of the latest advances in the diagnosis, management, and treatment of pediatric neurologic disorders. The journal's editor, Kenneth F. Swaiman, MD, heads an internationally recognized editorial board, ensuring the most authoritative and extensive coverage of the field. Among the topics covered are: epilepsy, mitochondrial diseases, congenital malformations, chromosomopathies, peripheral neuropathies, perinatal and childhood stroke, cerebral palsy, as well as other diseases affecting the developing nervous system.

Pediatric Neurology

The Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS), a neurodevelopmental tool for the cognitive assessment of infants and toddlers, correlates well with the Bayley Scales of Infant Development. In 1993 the Bayley Scales were revised and the second edition published (BSID-II). This study was designed to determine how well the CAT/CLAMS correlates with the BSID-II and its utility in identifying mild and severe cognitive impairment. Sixty-eight infants and toddlers (age range = 14-48 months), referred for suspected developmental delays, were administered the CAT/CLAMS and BSID-II and the results compared. The correlation between the two instruments was strong (r = 0.89, P<0.0001). The CAT/CLAMS was sensitive (81%) and specific (85%) for detecting overall cognitive impairment (BSID-II less than 70) and was even more sensitive (100%) and specific (96%) in detecting severe cognitive impairment (BSID-II less than 50). The physician using the CAT/CLAMS formulated a clinical impression of cognitive impairment that was sensitive (95%) and specific (84%) compared with formal psychologic testing. The CAT/CLAMS correlates well with the BSID-II. It is useful for detecting and quantifying mild and severe cognitive impairment. It permits the physician to formulate an accurate clinical impression of cognitive impairment consistent with possible mental retardation.

CAT/CLAMS: Its use in detecting early childhood cognitive impairment

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Tuberous sclerosis complex is highly variable in clinical presentation and findings. Disease manifestations continue to develop over the lifetime of an affected individual. Accurate diagnosis is fundamental to implementation of appropriate medical surveillance and treatment. Although significant advances have been made in the past 15 years in the understanding and treatment of tuberous sclerosis complex, current clinical diagnostic criteria have not been critically evaluated or updated since the last clinical consensus conference in 1998.
The 2012 International Tuberous Sclerosis Complex Consensus Group, comprising 79 specialists from 14 countries, was organized into 12 subcommittees, each led by a clinician with advanced expertise in tuberous sclerosis complex and the relevant medical subspecialty. Each subcommittee focused on a specific disease area with important diagnostic implications and was charged with reviewing prevalence and specificity of disease-associated clinical findings and their impact on suspecting and confirming the diagnosis of tuberous sclerosis complex.
Clinical features of tuberous sclerosis complex continue to be a principal means of diagnosis. Key changes compared with 1998 criteria are the new inclusion of genetic testing results and reducing diagnostic classes from three (possible, probable, and definite) to two (possible, definite). Additional minor changes to specific criterion were made for additional clarification and simplification.
The 2012 International Tuberous Sclerosis Complex Diagnostic Criteria provide current, updated means using best available evidence to establish diagnosis of tuberous sclerosis complex in affected individuals.

Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

Background
Tuberous Sclerosis Complex (TSC) is a multi-system disorder that includes a range of TSC-associated neuropsychiatric disorders (TAND). The lifetime prevalence rates of TAND are very high, yet surveys suggest that the majority of individuals with TSC never receive appropriate assessment or treatment for TAND. To aid systematic enquiry, a TAND Checklist was developed. Here we performed pilot validation of the TAND Checklist.

Method
Mixed-methods were used across two stages. In stage 1 we gathered feedback on the Checklist from TSC ‘expert professionals’ and ‘expert parents/caregivers’. The aim was to examine face and content validity. Stage 2 involved the administration of the refined TAND Checklist to 20 parents of individuals with TSC concurrently with four widely used, validated rating scales, in order to examine external validity and to obtain qualitative feedback on face-to-face administration of the Checklist.

Results
Twenty professionals and 62 parents/caregivers from 28 countries participated in the pilot. The TAND Checklist demonstrated good face and content validity with high overall mean and median scores. Qualitative analysis highlighted concerns about the likely use of the Checklist, suggesting that family members and individuals with TSC should drive usage. Stage 2 results showed moderate to very good external validity across TAND domain and key subdomains. Internal consistency of domains and subdomains was acceptable to very good. Ninety three percent of all participants (93%) reported 4 or more lifetime TAND behavioral difficulties.

Conclusion
The pilot validation suggested that the TAND Checklist could provide a useful screening tool in clinical settings.

Pilot Validation of the Tuberous Sclerosis-Associated Neuropsychiatric Disorders (TAND) Checklist

Dyscalculia, like dyslexia, affects some 5% of schoolage children but has received much less investigative attention. In two thirds of affected children dyscalculia is associated with another developmental disorder like dyslexia, attention deficit disorder, anxiety disorder, visual/spatial disorder, or cultural deprivation. Infants, primates, some birds, and other animals are born with the innate ability, called subitizing, to tell at a glance whether small sets of scattered dots or other items differ by one or more item. This nonverbal approximate number system (ANS) extends mostly to single digit sets as visual discrimination drops logarithmically to “many” with increasing numerosity (size effect) and crowding (distance effect). Preschoolers need several years and specific teaching to learn verbal names and visual symbols for numbers and schoolagers to understand their cardinality and ordinality and the invariance of their sequence (arithmetic number line) that enables calculation. This arithmetic linear line differs drastically from the nonlinear ANS mental number line which parallels the individual number-tuned neurons in the intraparietal sulcus in monkeys and overlying scalp distribution of discrete fMRI activations by number tasks in man. Calculation is a complex skill that activates both visual/spatial and visual/verbal networks. It is less strongly left lateralized than language, with ANS activation somewhat more right- and exact number and arithmetic activation more left-sided. Maturation and increasing number skill decrease associated widespread non-numerical brain activations that persist in some cases of dyscalculia which has no single, universal neurologic cause or underlying mechanism in all affected individuals.

Dyscalculia and the Calculating Brain

Tuberous sclerosis complex (TSC) is a dominantly inherited disorder that variably affects the brain, skin, kidneys, heart, and other organs. Its neurological manifestations include epilepsy, autism, cognitive and behavioral dysfunction, and giant cell tumors. A mutation of either TSC1 or TSC2 can cause tuberous sclerosis complex. Their two gene products, hamartin and tuberin, form a physical complex which normally inhibits protein synthesis mediated through the mechanistic target or rapamycin (mTOR), so a TSC1 or TSC2 mutation results in over-activation of the mTOR cascade. In addition to their tumor suppressor roles, TSC1 and TSC2 helps to regulate cell size, neuronal migration, axon formation, and synaptic plasticity. Clinical trials of two different mTOR inhibitors have demonstrated substantial improvement of TSC-related tumors, and a recent trial also showed a benefit from the mTOR inhibitor everolimus in the treatment of refractory epilepsy due to TSC. Effective mechanism-based therapy is now available for some TSC manifestations.

The 2015 Hower Award Lecture: Applying the Lessons of Tuberous Sclerosis

Intrathecal delivery methods have been used for many decades to treat a broad range of central nervous system disorders. A literature review demonstrated that intracerebroventricular route is an established and well-tolerated method for prolonged central nervous system drug delivery in pediatric and adult populations. Intracerebroventricular devices were present in patients from 1–7156 days. The number of punctures per device ranged from 2–280. Noninfectious complication rates per patient (range, 1.0–33.0%) were similar to infectious complication rates (0.0–27.0%). Clinician experience and training and the use of strict aseptic techniques have been shown to reduce the frequency of complications.

Intracerebroventricular Delivery as a Safe, Long-Term Route of Administration

Poliosis is defined as decrease or absence of melanin in the hair and appears as a patch of white hair. It may affect various regions of the body such as the scalp, eyelashes, eyebrow, and beard. Neurological disorders causing poliosis are rare and have previously been reported with tuberous sclerosis, Vogt-Koyanagi-Harada disease, neurofibroma and trigeminal neuralgia. This is the first case of poliosis associated with ganglioglioma. Poliosis can be a symptom and initial presentation of an underlying disease before other more characteristic manifestation appears. Underlying mechanism for poliosis in ganglioglioma remains unclear although it may be mediated via cytotoxic T-cells as seen in other diseases. Removal of the underlying pathology leads to spontaneous resolution of poliosis.

Poliosis With a Rare Association

Incident breakthrough seizures, serum MMP-9 and perfusion MRI parameters in a cohort of children and adolescents with neurocysticercosis: a longitudinal observational study

Myotonia congenita is a nondystrophic muscle disorder characterized by muscle stiffness and muscle hypertrophy. The disorder can be inherited in an autosomal-dominant (Thomsen disease) or autosomal-recessive (Becker disease) manner. Both forms of myotonia congenita are attributable to mutations in the CLCN1 gene. Treatment with a variety of medications has led to long-term improvement in the clinical course of affected individuals. We describe a Honduran boy with myotonia congenita and a novel p.L287I mutation in the CLCN1 gene. The patient's unaffected father carries the same mutation, most likely reflecting autosomal-recessive myotonia congenita, with an inability to find a second mutation. The patient received carbamazepine treatment for 1 year, resulting in decreased muscle stiffness, increased strength, and improved quality of life in school and with peers.

Novel CLCN1 Mutation in Carbamazepine-Responsive Myotonia Congenita

Craniofrontonasal syndrome is characterized by coronal craniosynostosis, hypertelorism, telecanthus, a broad grooved nasal tip, dental anomalies, mild syndactyly, and broad thumbs. It involves an X-linked malformation syndrome with a variable phenotype that is caused by mutations in the ephrin-B1 gene. Detailed phenotypic analysis indicates that females are more severely affected than males, a highly unusual characteristic for an X-linked disorder. We review the literature on this genetic paradox, and discuss the pattern of inheritance and genetic counseling.

Diverse Clinical and Genetic Aspects of Craniofrontonasal Syndrome

Over the past two decades, cerebral visual impairment has been recognized as a principal deficit in preterm children, and in particular those with cerebral palsy. We review the current knowledge of visual processing deficits in these children, and provide an overview of the tools for assessing cerebral visual impairment. Commercially available instruments are usually directed at evaluating visuospatial skills rather than detecting object recognition difficulties. Particularly in children aged 3 years or younger and in children with multiple handicaps, cerebral visual impairment is difficult to diagnose. This difficulty may be attributable to limitations specific to the instrument, such as a test that is inappropriate for age, or to child-specific limitations such as motor impairment or speech delay. We therefore include an overview of relevant neuroimaging findings reported in these children, focusing on the most recent imaging modalities. Novel techniques such as diffusion tensor imaging may provide sensitive markers of cerebral visual impairment in situations where clinical diagnosis is difficult, and such approaches may allow for early intervention.

Visual Perception in Preterm Children: What Are We Currently Measuring?

To determine if there is a relationship between low serum ferritin and sleep disturbance in children with autism spectrum disorder, an 8-week open-label treatment trial with oral iron supplementation was conducted as a pilot study. At baseline and posttreatment visits, parents completed a Sleep Disturbance Scale for Children and a Food Record. Blood samples were obtained. Thirty-three children completed the study. Seventy-seven percent had restless sleep at baseline, which improved significantly with iron therapy, suggesting a relationship between sleep disturbance and iron deficiency in children with autism spectrum disorder. Sixty-nine percent of preschoolers and 35% of school-aged children had insufficient dietary iron intake. Mean ferritin increased significantly (16 microg/L to 29 microg/L), as did mean corpuscular volume and hemoglobin, suggesting that low ferritin in this patient group resulted from insufficient iron intake. Similar prevalence of low ferritin at school age as preschool age indicates that children with autism spectrum disorder require ongoing screening for iron deficiency.

Children With Autism: Effect of Iron Supplementation on Sleep and Ferritin

This case report describes a child with a severe autistic syndrome worsened by hypersexual behavior consisting of compulsive masturbatory activity. Selective serotonin reuptake inhibitors have been reported to be beneficial in reducing hypersexual behaviors. A treatment with mirtazapine improved the entire clinical autistic picture with the disappearance of masturbation. This result suggests that selective serotonin reuptake inhibitors could be useful and promising tools in the treatment of hypersexual behaviors in children with autistic disorders. Moreover, the general, and in some ways unexpected, improvement of the social interaction, communication, and imagination, the dramatic reduction of aloof mannerisms, stereotypes, aggressiveness, and inappropriate emotional response to frustrations, as well as the first appearance of the pragmatic use of language and a strong impetus to emotional development disclosed a new spectrum of possible applications of these drugs, and mirtazapine in particular, suggesting the need for new and more extensive studies on the pharmacotherapy of autism.

Compulsive Masturbation in Infantile Autism Treated by Mirtazapine

This report describes the case of a 4 1/2-year-old female with developmental delay and tonic-clonic seizures, persistently elevated serum alkaline phosphatase activity, and low serum pyridoxal 5'-phosphate. Born at term to consanguineous parents, she was dysmorphic and delayed at 5 months. At 11 months, seizures and microcephaly were evident but skeletal and cerebral imaging, karyotyping, and genetic metabolic tests were unremarkable. Serum alkaline phosphatase activity, however, was elevated (1.3 +/- 0.6 times greater than the upper limit of normal) on seven occasions between 5 months and 4(1/2) years of age. Hyperphosphatasia with neurologic deficit (MIM #239300), a rare autosomal recessive disorder, was diagnosed. The low serum levels of pyridoxal 5'-phosphate (6 nmol/L; normal >20 nmol/L) prompted a pyridoxine challenge. A clinically significant but paradoxical response was observed. On electroencephalography, diffuse delta slow waves (1-2 Hz) were observed, suggestive of stage 3 or 4 slow-wave sleep. With daily administration of 100 mg pyridoxine and withdrawal of phenobarbital, seizures were not evident. We suggest that serum alkaline phosphatase should be measured in cases of seizures with paradoxical electroencephalographic response to pyridoxine. Conversely, pyridoxine challenge should be considered in cases of hyperphosphatasia with seizures and neurologic deficit.

Hyperphosphatasia With Neurologic Deficit: A Pyridoxine-Responsive Seizure Disorder?

Dystonia is a state of continuous contraction of groups of agonist and antagonist muscles resulting in a sustained abnormal posture. Dopa-responsive dystonia was first described in 1976 by Segawa. Patients typically have diurnal variation of their symptoms with worsening at the end of the day and a dramatic response to low-dose L-dopa. This report presents five consecutive children with dopa-responsive dystonia who were misdiagnosed initially as spastic diplegic cerebral palsy, intractable epilepsy, hereditary spastic paraplegia, or a neurodegenerative disorder. There were two males and three females aged 3-13 years (mean 8.6 years). They were monitored for up to 2 years (mean 14.8 months). One had focal, one axial, one segmental, and two generalized dystonia. The dystonia was paroxysmal in two (tiptoe walking and opisthotonus), and all had a progressive course. All children responded dramatically to L-dopa (mean 200 mg/day), including three who were wheelchair-bound for several years. The difficulties in early diagnosis, variability of clinical presentation, and dramatic response to L-dopa will be illustrated. To conclude, dopa-responsive dystonia should be considered in any child who presents with paroxysmal or progressive hypertonia of unknown etiology, because it responds so dramatically to L-dopa.

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