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Biomedical subjects

Phillip L Pearl

Publications and source records attributed to Phillip L Pearl.

At least 19 recordsLinked to original sources
PubMed2006

The benefits of a camp designed for children with epilepsy: evaluating adaptive behaviors over 3 years.

OBJECTIVE: Children with epilepsy attending a condition-specific overnight camp were evaluated for behavioral changes over 3 consecutive years, using a modification of the Vineland Adaptive Behavioral Scale. METHODS: Trained counselors completed pre- and postcamp assessments for each camper. Repeated-measures MANOVA was used to analyze effects of the camp experience for each year, with respect to gender and age. Repeated-measures ANOVA was conducted to evaluate long-term effects from year-to-year comparisons for return campers, following three successive camp experiences. RESULTS: A significant change in social interaction was observed over 3 years. Despite some decline at the start of camp in consecutive years, the overall trend for return campers suggests a positive cumulative impact of continued camp participation, with improvements in the domains of social interaction, responsibility, and communication. CONCLUSION: A condition-specific camp designed for children with epilepsy can improve adaptive behaviors and social interactions. Overall net gains appear to increase over time, suggesting additional benefits for return campers.

Adaptation, Psychological↗
PubMed2006

Clinical experience with anticonvulsant medication in pediatric epilepsy and comorbid bipolar spectrum disorder.

Anticonvulsant drugs are first-line treatments for both bipolar mood disorder and epilepsy; however, few studies have explored treatment options when these disorders co-occur. The aim of this study was to identify bipolar disorder symptoms common in pediatric epilepsy and to determine whether anticonvulsant monotherapy might be a practical treatment consideration. A retrospective chart review identified 38 children with bipolar spectrum disorder and epilepsy comorbidity. Two mental health clinicians independently assessed psychiatric diagnoses, symptoms, and assigned retrospective CGI-I ratings for psychiatric symptoms. Common bipolar symptoms included impulsivity, psychomotor agitation, and explosive rage. Forty-two medication trials with 11 different anticonvulsants were identified. Of the 30 instances in which anticonvulsant monotherapy was attempted, carbamazepine, divalproex sodium, lamotrigine, and oxcarbazepine were associated with better psychiatric CGI-I ratings than other monotherapies (P<0.01). Results suggest that in many cases, selected anticonvulsants appeared to simultaneously treat both epilepsy and mood disorder. Controlled trials are necessary to further ascertain optimal anticonvulsant usage.

Adolescent↗
PubMed2006

Expression profiling reveals multiple myelin alterations in murine succinate semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare genetic defect of GABA degradation recently modelled in mice (SSADH(-/-) mice), manifests early absence seizures that evolve into generalized convulsive seizures and lethal status epilepticus in gene-ablated mice. Disrupted GABA homeostasis, in conjunction with the epileptic phenotype and increased gamma-hydroxybutyric acid (GHB), suggested that expression profiling with the U74Av2 Affymetrix system would reveal dysregulation of receptor genes associated with GABAergic and glutamatergic neurotransmission. Unexpectedly, we found significant downregulation for genes associated with myelin biogenesis and compaction, predominantly in hippocampus and cortex. These results were confirmed by: (1) myelin basic protein (MBP) immunohistochemistry; (2) western blotting of myelin-associated glycoprotein (MAG) and MBP; (3) qRT-PCR analyses of myelin-associated oligodendrocytic basic protein (MOBP), MAG, MBP and proteolipid protein (PLP) in hippocampus, cortex and spinal cord; (4) quantitation of ethanolamine and choline plasmalogens, all core myelin components; (5) evaluation of myelin content in brain sections employing toluidine blue staining; and (6) ultrastructural evaluation of myelin sheath thickness via electron microscopy. We speculate that increased GABA/GHB, acting through GABAergic systems, results in decreased levels of the neurosteroids progesterone and allopregnanolone [Gupta et al (2003) Ann Neurol 54(Supplement 6): S81-S90] and phosphorylation of mitogen-activated protein (MAP) kinase, with resulting myelin protein abnormalities primarily in the cortex of SSADH(-/-) mice.

Animals↗
PubMed2006

Diagnosis and treatment of neurotransmitter disorders.

The neurotransmitter disorders represent an enigmatic and enlarging group of neurometabolic conditions caused by abnormal neurotransmitter metabolism or transport. A high index of clinical suspicion is important, given the availability of therapeutic strategies. This article covers disorders of monoamine (catecholamine and serotonin) synthesis, glycine catabolism, pyridoxine dependency, and gamma-aminobutyric acid (GABA) metabolism. The technological aspects of appropriate cerebrospinal fluid (CSF) collection, shipment, study, and interpretation merit special consideration. Diagnosis of disorders of monoamines requires analysis of CSF homovanillic acid, 5-hydroxyindoleacetic acid, ortho-methyldopa, BH4, and neopterin. The delineation of new disorders with important therapeutic implications, such as cerebral folate deficiency and PNPO deficiency, serves to highlight the value of measuring CSF neurotransmitter precursors and metabolites. The impressive responsiveness of Segawa fluctuating dystonia to levodopa is a hallmark feature of previously unrecognized neurologic morbidity becoming treatable at any age. Aromatic amino acid decarboxylase and tyrosine hydroxylase deficiency have more severe phenotypes and show variable responsiveness to levodopa. Glycine encephalopathy usually has a poor outcome; benzoate therapy may be helpful in less affected cases. Pyridoxine-dependent seizures are a refractory but treatable group of neonatal and infantile seizures; rare cases require pyridoxal-5-phosphate. Succinic semialdehyde dehydrogenase deficiency is relatively common in comparison to the remainder of this group of disorders. Treatment directed at the metabolic defect with vigabatrin has been disappointing, and multiple therapies are targeted toward specific but protean symptoms. Other disorders of GABA metabolism, as is true of the wide spectrum of neurotransmitter disorders, will require increasing use of CSF analysis for diagnosis, and ultimately, treatment.

Journal Article↗
PubMed2005

Inherited disorders of neurotransmitters in children and adults.

Inherited disorders of neurotransmitters are a group of neurometabolic syndromes attributable to a primary disturbance of neurotransmitter metabolism or transport. This is an enlarging group of recognized disorders requiring specialized diagnostic procedures for detection. This review considers clinical disorders of biopterin, catecholamines, serotonin, glycine, pyridoxine, and GABA metabolism. Newly described syndromes such as cerebral folate deficiency and pyridoxal-5-phosphate dependency are included. The disorders of the metabolic pathways of biopterin, catecholamines, and serotonin are linked due to their common synthetic components. Glycine encephalopathy represents an enlarging phenotype related to abnormalities of the glycine degradative cleavage system. Both pyridoxine and pyridoxal-5-phosphate dependency need to be considered in refractory neonatal seizures. The most common disorder of GABA metabolism is SSADH deficiency, which has a broad phenotype of mental retardation, epilepsy, ataxia, and hyporeflexia and which invokes the combined problems of elevated brain GABA and GHB.

Adult↗
PubMed2005

Seizures and metabolic disease.

Seizures represent an important clinical manifestation of inborn errors of metabolism. The presence of myoclonic seizures and very early onset are clues to a metabolic disorder. Specific correlations between age of seizure onset and electroencephalogram patterns with inborn errors of metabolism are discussed. The explosion of information in neurogenetics and metabolism mandates increasing awareness of appropriate metabolic diagnostic and therapeutic strategies in the setting of certain epilepsies. Specific laboratory, imaging, and treatment considerations are included to present updated material in a field that continues to expand rapidly.

Anticonvulsants↗
PubMed2005

Pediatric sleep disorders.

Pediatric sleep disorders represent a heterogeneous collection of disturbances that require varied intervention strategies. The diagnosis of some sleep disorders (eg, OSAS, narcolepsy, PLMD) require PSG, whereas others can be diagnosed during an office visit with a thorough medical,psychiatric, and sleep history. Sleep disorders place children at risk for school failure, accidents, and social problems, and can place a significant burden on families and the parent-child relationship.

Child↗
PubMed2005

Methylphenidate HCl: therapy for attention deficit hyperactivity disorder.

Methylphenidate is a first-line therapy for attention deficit hyperactivity disorder, the most prevalent neuropsychiatric disorder of childhood. The compound is a piperidine and the D-threo-isomer is considered the biologically active form. The compound is available in multiple short- and long-acting preparations, having different delivery systems leading to varying kinetics without clear superiority in efficacy or tolerability at the group level. Common adverse effects are insomnia, appetite disturbance, stomach ache, headache and dizziness. Its mechanism of action is linked to the monoamines dopamine and norepinephrine. The compound appears to predominantly increase the synaptic concentration of dopamine, presumably via inhibition of the dopamine transporter DAT1. There also appears to be effects on presynaptic vesicular trafficking and distribution of dopamine. Both immediate- and sustained-release preparations of methylphenidate have proven efficacy in children and adults with attention deficit hyperactivity disorder. Analysis of the National Institutes of Health-sponsored multimodal treatment study of attention deficit hyperactivity disorder supports a combined medication and behavioral therapy approach.

Animals↗
PubMed2004

Pediatric neurotransmitter diseases.

The pediatric neurotransmitter disorders represent a challenging group of rare neurometabolic disorders classified on the basis of alterations in neurotransmitter metabolic pathways. The disorders are currently classified into disturbances of monoamine and gamma-aminobutyric acid (GABA) metabolism, although disorders of other neurotransmitters, such as glutamate and melatonin, may well be recognized in future investigations. This review summarizes the clinical and laboratory features of selected pediatric neurotransmitter disorders that have been partially delineated. Of the monoamine group, these are Segawa disease or guanosine triphosphate-cyclohydrolase I deficiency, aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency. Of the GABA disorders, these are pyridoxine-dependent epilepsy, GABA transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. As proper collection, handling, and interpretation of cerebrospinal fluid is required for assessment of most of these disorders, we end by summarizing important considerations for obtaining cerebrospinal fluid samples.

Biogenic Monoamines↗
PubMed2004

Imaging data in autism: from structure to malfunction.

During the last two decades, neuroimaging studies have improved our knowledge of brain development and contributed to our understanding of disorders involving the developing brain. Differences in cerebral anatomy have been determined in autism spectrum disorder (ASD). Morphological studies by magnetic resonance imaging have provided evidence of structural differences in ASD compared with the normal population. This has enhanced our view of autism as a neurobiological disorder corresponding with different stages and events in brain development. Alterations in volume of the total brain and specifically the cerebellum, frontal lobe, and limbic system have been identified. There appears to be a pattern of increased and then decreased rate of brain growth over time. We integrate these observations with neurobehavioral findings to provide a developmental hypothesis of the pathophysiology of autism.

Autistic Disorder↗
PubMed2004

Clinical aspects of the disorders of GABA metabolism in children.

PURPOSE OF REVIEW: There has been increased recognition of the pediatric neurotransmitter disorders. This review focuses on the clinical disorders of GABA metabolism. RECENT FINDINGS: The known clinical disorders of GABA metabolism are pyridoxine dependent epilepsy, GABA-transaminase deficiency, SSADH deficiency, and homocarnosinosis. Pyridoxine dependent epilepsy is diagnosed clinically but potentially more common presentations, with later and atypical features, widen the spectrum. No gene locus has been confirmed; the pathophysiology may involve alterations in PLP transport, binding to GAD, or other PLP-dependent pathways. SSADH deficiency is associated with developmental delay, prominent language deficits, hypotonia, ataxia, hyporeflexia, and seizures. Increased detection is reported when specific ion monitoring is used for GHB on urine organic acids. The most consistent MRI abnormality is increased signal in the globus pallidus. MR spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare but require CSF for detection, thus allowing for the possibility that these entities, as in the other pediatric neurotransmitter disorders, are underrecognized. SUMMARY: The disorders of GABA metabolism require an increased index of clinical suspicion. Pyridoxine dependent epilepsy is a treatable condition with a potentially widening clinical spectrum, but with a prognosis dependent on early intervention. SSADH deficiency has a heterogeneous spectrum and requires careful urine organic acid testing for screening, followed by enzymatic confirmation allowing appropriate prognostic and genetic counseling.

4-Aminobutyrate Transaminase↗
PubMed2004

22q13 deletion syndrome with central diabetes insipidus: a previously unreported association.

We describe a two-year-old girl with 22q13 deletion syndrome (MIM # 606232), 46, XX, de l (22) (q13.31). ish del (22) (q13.31) (TUPLE 1+,ARSA-). The patient has hypotonia, normal growth, severe expressive language delay, mild mental retardation, and minor dysmorphic facial features. In addition, she had central diabetes insipidus that was diagnosed at age two days and resolved at age 27 months. To our knowledge, this association has not been reported previously. Infants with hypotonia, or those suspected to have this syndrome should have high-resolution chromosome analysis and fluorescent in situ hybridization (FISH) studies or molecular analysis, since the chromosomal deletion may be subtle and may go undetected on routine cytogenetic studies. The association of 22q13 deletion syndrome with central diabetes insipidus is reported for the first time.

Abnormalities, Multiple↗
PubMed2003

Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria).

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as gamma-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients.

Adult↗