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Biomedical subjects

M R Pranzatelli

Publications and source records attributed to M R Pranzatelli.

At least 19 recordsLinked to original sources
PubMed1998

Monoaminergic effects of high-dose corticotropin in corticotropin-responsive pediatric opsoclonus-myoclonus.

Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Cerebrospinal fluid free choline in movement disorders of paediatric onset.

We measured free choline in cerebrospinal fluid (CSF) of 78 patients with movement disorders of paediatric onset and various controls as a putative index of central phospholipid metabolism. Most of the disorders studied were myoclonic disorders, such as progressive myoclonus epilepsy, the opsoclonus-myoclonus syndrome, and essential myoclonus, but other movement disorders, interictal seizure disorders, and different neurological and nonneurological disorders were also included. There were no significant differences in CSF choline concentrations in myoclonic disorders or other movement disorders compared with controls. The CSF choline levels were lowest in children with seizure disorders including progressive myoclonus epilepsy. In progressive myoclonus epilepsy, the CSF choline values resembled other epileptic disorders rather than other myoclonic disorders. When all the data were analysed collectively, no significant relation of CSF choline was found to patient age, gender, aliquot of CSF measured, or the length of time the sample was stored at -70 degrees C. Separate analyses of data from children and adults showed a trend toward a biphasic relation between patient age and CSF choline which could be pursued in developmental studies of normal subjects. Reduced CSF choline may indicate increased choline incorporation into brain phospholipids, disturbances of choline metabolism, decreased choline release, or non-neural factors.

Acetylcholine↗
PubMed1997

Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: an analysis of antigenic targets in neural tissues.

OBJECTIVE: Opsoclonus-myoclonus (OM) is a rare neurologic syndrome affecting children and adults. In children it occurs as a parainfectious process or a paraneoplastic syndrome in association with neuroblastoma. Evidence for an immune mechanism includes the presence of serum autoantibodies to several neural antigens and improvement of symptoms with immunosuppressive therapy. We studied the neural antigenic targets of serum IgM and IgG autoantibodies from nine children with OM. DESIGN: We studied sera from nine children with OM, three with associated neuroblastoma and six with a prodromal viral illness. Control subjects (n = 77) included four children with neuroblastoma but not OM, 32 children with other neurologic disorders, and 41 with nonneurologic illnesses. We studied the neural antigenic targets of serum IgM and IgG autoantibodies by the following methods: (1) immunostaining of human cerebellar sections and peripheral nerve, and (2) Western blot analysis with human brain fractions including white matter, gray matter, and cerebellar Purkinje cells and nuclei. RESULTS: Sera from all nine children with OM had IgM and IgG binding to the cytoplasm of cerebellar Purkinje cells and to some axons in white matter. In peripheral nerve, IgM and IgG from all nine OM sera bound to large and small axons. Western blot analysis showed a distinctive pattern of binding to several neural proteins, including a 210 kd antigen identified as the high molecular weight subunit of neurofilament. No control serum showed a similar pattern of reactivity. CONCLUSION: Opsoclonus-myoclonus syndrome in childhood is associated with a distinctive pattern of serum IgM and IgG binding to neural tissues and antigens.

Adolescent↗
PubMed1997

Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1.

Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable approximately 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.

Base Sequence↗
PubMed1996

A controlled trial of 5-hydroxy-L-tryptophan for ataxia in progressive myoclonus epilepsy.

To study the role of serotonin in the ataxia of progressive myoclonus epilepsy, eight patients received oral 5-hydroxy-L-tryptophan (L-5-HTP) or placebo plus carbidopa for 1 month in a controlled, double-blinded, dose-ranging, cross-over, add-on study. Ataxia was evaluated using objective and subjective scales. All of the subjects had significantly slower motor performance on timed, repetitive tasks than controls and had moderately severe ataxia. L-5-HTP was not efficacious for ataxia or speed of motor performance. Serotonergic drugs that work through mechanisms different than L-5-HTP may be more effective in correcting the abnormal serotonergic neurotransmission suggested by reduction of serotonin metabolites in cerebrospinal fluid in patients with progressive myoclonus epilepsy.

5-Hydroxytryptophan↗
PubMed1996

The immunopharmacology of the opsoclonus-myoclonus syndrome.

The opsoclonus-myoclonus syndrome (OMS) is a potentially devastating paraneoplastic or paraviral syndrome. Although it is a rare disorder, it has major implications for cancer, virology, immunology, developmental neurobiology, and molecular pharmacology. The mechanism of brain injury in OMS is unknown, but evidence suggests immune system dysregulation. This article surveys recent clinical and laboratory evidence for the autoimmune theory and discusses how some current therapies for OMS may exert their effects through immunomodulation. Specific testable hypotheses on the immunologic defect in OMS involving both B cells and T cells, the nature and mechanisms of brain injury, and their clinical correlations are proffered. The current therapeutic armamentarium provides a broad spectrum of nonselective immunotherapies, including noncytotoxic and cytotoxic drugs, intravenous immunoglobulins, and plasma exchange, some selected for induction and others for maintenance. The use of combination immunotherapies may allow steroid sparing, targeting of more than one immunologic effector pathway, and a mixture of early- and late-acting drugs. More selective immunotherapies, now available or in preclinical and clinical trials, have great potential for the treatment of OMS but require precise information on the underlying immunological problem. These data provide possible new directions for immunologic research and therapy in OMS.

Adult↗
PubMed1996

Human brainstem serotonin receptors: characterization and implications for subcortical myoclonus.

The immediate serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (L-5-HTP), is an investigational treatment for myoclonic disorders. Its mechanism of action in humans is incompletely understood. We measured the density of subtypes of 5-HT1 and 5-HT2 receptors and the affinity of 5-HT and L-5-HTP in vitro in the human brainstem and cortex, regions associated with subcortical and cortical myoclonus, respectively. In the cortex, the rank order of 5-HT receptor subtype Bmax was 5-HT2A (low-affinity), 5-HT1A, 5-HT uptake sites, 5-HT1D, 5-HT2C, 5-HT1E/F, and 5-HT2A (high-affinity) sites. In the brainstem, the rank order was 5-HT uptake sites, 5-HT1D, 5-HT2C, 5-HT1A, and 5-HT2A(L) sites. Specific binding at 5-HT1E/F and high-affinity 5-HT2A sites was too low for characterization. In competition studies, 5-HT had high affinity for 5-HT1A and 5-HT2C sites in the brainstem and cortex, but L-5-HTP was > 1,000-fold less active. These data support the hypothesis that in humans L-5-HTP stimulates 5-HT receptors in the CNS only after conversion to 5-HT. They also indicate in the human brainstem a prominence of 5-HT1A sites and paucity of 5-HT1D, 5-HT1E/F, and 5-HT2A sites, which has implications for brainstem-mediated myoclonus and response to serotonergic drugs.

5-Hydroxytryptophan↗
PubMed1996

Oral pharmacotherapy for the movement disorders of cerebral palsy.

Movement disorders are a well-recognized feature of some patients with cerebral palsy and often require treatment. However, treatments have been symptomatic and empiric, and there have been few pharmacologic studies. The major movement disorders in cerebral palsy are dystonia and the hyperkinesias choreoathetosis and myoclonus. They may occur in combination, often accompanied by spasticity and sometimes by epilepsy. Some drugs are useful treatments for all of these problems, but others may improve one while worsening another. Pitfalls in management include not diagnosing metabolic/degenerative disorders, which may mimic cerebral palsy, or not recognizing reversible complications of cerebral palsy, which may exacerbate symptoms. This review attempts to summarize empiric drug use and recommendations for therapy, drug studies in extrapyramidal cerebral palsy, and prospects for new drugs or models for the problem. Many new pharmacologic agents are available for study in cerebral palsy. Better methods of detecting basal ganglia injury after perinatal injury in asymptomatic infants may allow early intervention in the biologic process of recovery and adaptation.

Administration, Oral↗
PubMed1996

Antidyskinetic drug therapy for pediatric movement disorders.

The pharmacologic armamentarium used to treat dyskinesias in childhood is increasing. Anticonvulsant drugs as a class are still some of the broadest-spectrum antidyskinetic agents, probably because the class includes so many differently acting drugs or because dyskinesias are manifestations of subcortical electrical events. This group is enhanced by recent developments in gamma-aminobutyric acid and glutamate receptor pharmacology, which promise new antidyskinetic drugs. Other drugs acting at receptors for monoamines (dopamine, norepinephrine, and serotonin), acetylcholine, opioids, or histamine may provide symptomatic improvement. Fewer pharmacotherapies address the underlying pathophysiology of movement disorders. Of these, drugs or biologicals for immunomodulation are the most developed, but the group also includes antioxidants, cofactors, metabolic inhibitors, and chelators. There is potential for drugs that block the neurotoxic effects of glutamate to treat movement disorders and reverse or prevent brain injury. Peripheral blockade of focal dyskinesias through botulinum toxin offers a useful alternative to drugs in some patients.

Child↗
PubMed1996

Plastic responses of neonatal 5-hydroxytryptamine1B receptors to 5,7-dihydroxytryptamine lesions mapped by quantitative autoradiography.

We previously found different effects on behavior, serotonin (5-HT) concentrations, 5-HT uptake sites, and 5-HT1A binding sites of neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions depending on the route of 5,7-DHT injection. To study the impact of early lesions on 5-HT1B sites as putative 5-HT terminal autoreceptors, we labelled them autoradiographically with [3H]5-HT 4 months after intraperitoneal (i.p.) or intracisternal (i.c.) 5,7-DHT injection during the first postnatal week and quantitated specific binding in 22 brain regions. Changes were confined to the subiculum and substantia nigra, regions with the most 5-HT1B-specific binding and projection areas of structures with high mRNA expression. Both routes of 5,7-DHT injection were associated with increases in specific binding in subiculum (24% for i.p. and 47% for i.c. route). In contrast, there was a 32% increase in specific binding in the substantia nigra in rats with lesions made i.c. but not i.p. No significant differences were found in nucleus accumbens, caudate-putamen or other brain areas. In saturation homogenate binding studies of 5-HT1B sites using [125I]iodocyanopindolol 1 month after i.p. injections, neonatal 5,7-DHT lesions did not significantly alter Bmax or Kd in the neocortex, striatum, diencephalon or brainstem. These data indicate the differential effects of the route of neonatal 5,7-DHT injections on plasticity of 5-HT1B receptor recognition sites and suggest the presence of a subpopulation of post-synaptically located 5-HT1B sites which increases in response to denervation. The data also suggest that sprouting of 5-HT neurons after neonatal 5,7-DHT lesions does not involve 5-HT1B sites.

5,7-Dihydroxytryptamine↗
PubMed1995

Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in the pediatric opsoclonus-myoclonus syndrome.

To study the purported role of central monoamine disturbances in the pathophysiology of the opsoclonus-myoclonus syndrome, the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid were measured in cerebrospinal fluid samples from 27 affected children and 47 age- and gender-matched control subjects by high-pressure liquid chromatography with electrochemical detection. 5-Hydroxyindoleacetic acid and homovanillic acid concentrations in the cerebrospinal fluid were approximately 30 to 40% lower in opsoclonus-myoclonus patients compared to control subjects, and the normal inverse correlation between age and monoamine metabolite concentrations in the cerebrospinal fluid of control subjects was not found in opsoclonus-myoclonus patients. Patients with the lowest values were less than 4 years old, and a subgroup had extremely low levels, but differences in older children were not significant. Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid were more positively correlated in control subjects than in opsoclonus-myoclonus patients. None of the patients exhibited high levels of monoamine metabolites. Homovanillic acid levels were slightly lower in the cerebrospinal fluid of patients receiving corticotropin or steroids at the time of lumbar puncture. Clinical variables that could be excluded were paraneoplastic etiology, anesthetic for lumbar puncture, syndrome duration, age at onset, gender, response to steroids, length of time until initiation of corticotropin or steroids, presence of seizures, opsoclonus, and functional impairment. These data suggest a disturbance and possible altered ontogeny of serotonin or dopamine neurotransmission in a subpopulation of children with opsoclonus-myoclonus with low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1995

Encephalopathy with parkinsonian features in children following bone marrow transplantations and high-dose amphotericin B.

Encephalopathy, leukoencephalopathy, and secondary parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high-dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis that did not involve the nervous system. Treatment included high-dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal ganglia atrophy, as well as frontal and temporal lobe white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment. The third succumbed to non-central nervous system Epstein-Barr virus-lymphoproliferative disease and had autopsy-confirmed leukoenephalopathy.

Adolescent↗
PubMed1995

Neurobehavioral and psychosocial functioning of children with opsoclonus-myoclonus syndrome.

Childhood opsoclonus-myoclonus syndrome (OMS) is a movement disorder which typically strikes children in the early preschool years, seriously affecting intellectual, social-emotional and general adaptive development. This series of 13 cases with well-documented neurological histories, aged 1.7 to 16.3 years, provides an initial systematic evaluation of these children's neuropsychological, psychosocial and adaptive status. As expected, children with OMS had significantly reduced intelligence and severe speech and motor output problems; however, most of them also demonstrated a range of preserved neurocognitive abilities and impressive goal-directedness and communicative effort. Psychosocial problems included mild behavioral impairment on the Achenbach Child Behavior Checklist, and severe adaptive limitations on the Vineland Adaptive Behavior Scales despite relatively strong social skills. Developmental factors and likelihood of subcortical localization are discussed, and practical guidelines are provided for behavioral and educational management of these children.

Adolescent↗
PubMed1995

Neuropharmacology of progressive myoclonus epilepsy: response to 5-hydroxy-L-tryptophan.

Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lündborg disease (U-L), mitochondrial encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L-5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (< 20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondrial encephalomyopathy developed status epilepticus during treatment with L-5-HTP. As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.

5-Hydroxytryptophan↗
PubMed1995

Mechanism of action of antiepileptic and antimyoclonic drugs.

Most drugs used to treat myoclonus are also antiepileptic. The main drugs are the benzodiazepines, valproate, and barbituates. Advances in the understanding of antiepileptic drug mechanisms of action have revealed two main patterns: increasing inhibition either through GABA or glycine, or decreasing excitation due to glutamate. Anticonvulsants such as the benzodiazepines, barbiturates, vigabatrin, tiagabine, or progabide act through GABA. New prototype anticonvulsants such as dizocilpine and remacemide target glutamate receptors or associated ion channels. For some antimyoclonic drugs such as piracetam, many effects are reported but no mechanism of action has been established. Many newer anticonvulsants have not been tested in human myoclonic disorders but efficacy against PTZ-induced seizures suggests antimyoclonic activity. Our ability to improve the treatment of myoclonus requires greater knowledge of the molecular mechanisms of myoclonus and more exact delineation of its relation to epilepsy. Better drugs also will result from refinements from prototype drugs and new concepts about brain function. Most of the discussion has been focused on the use of drugs as symptomatic treatment, but drugs such as glutamate blockers are already having a role in the treatment of degenerative neurological disorders, an important cause of some myoclonic disorders. It also may be possible to improve treatment by focusing on selective regional effects of drugs or drug delivery. The CNS penetration of drugs is often no uniform. For many antimyoclonic and antiepileptic drugs, regional studies have not been performed, especially in humans. Lack of efficacy could therefore be due to lack of drug delivery to myoclonic generators or suppression structures. It is conceivable that drug effects in different brain regions also may be opposing, such as in forebrain and hindbrain structures. Stimulation of the same receptor subtype may have different implications for myoclonus if the sites are pre- or postsynaptically located (as in 5-HTIA sites), or predominantly cerebellar versus hippocampal (as in BDZ I vs II sites). Molecular genetic abnormalities in neurological disease may affect neurotransmission and the action of drug either directly at the receptor site or in other ways such as transduction, translation, or expression. Further insights into these abnormalities may provide new targets for pharmacotherapy. Most antiepileptic and antimyoclonic drugs developed to date have aimed at broad-spectrum treatment of the symptoms, rather than treatment of regional problems such as in the forebrain or the hindbrain. Because of this, the currently available drugs have broad side effects such as cognitive impairment, tremors, teratogenicity, etc. To develop more region-specific and more efficacious drugs, we need to develop a better understanding of local central nervous system problems in myoclonus and epilepsy. The development and application of molecular biological techniques have increased our knowledge of receptors and transporters immensely. It is conceivable that in the near future we will be able to determine whether small mutations affect the structure and function of these molecules. In addition, the glimpses into the process of cell death and sprouting by remaining neurons in the epileptic brain, and perhaps the myoclonic brain, raise the possibility of designing regionally oriented drugs with greater efficacy and fewer side effects. The current developments in the understanding of the central neurons should allow for the development of exciting new pharmacotherapies in the future.

Animals↗
PubMed1994

Quantitative autoradiography of 5-hydroxytryptamine1A binding sites in rats with chronic neonatal 5,7-dihydroxytryptamine lesions.

We recently reported that rats with elevated brainstem serotonin (5-HT) concentration and 5-HT transporter binding site density after neonatal 5,7-dihydroxytryptamine (5,7-DHT) lesions made by intraperitoneal (i.p.) injection exhibited more myoclonic supersensitivity to the 5-HT1A agonist 8-OH-DPAT than those with decreased brainstem 5-HT and 5-HT transporter sites following intracisternal 5,7-DHT (i.c.) injection. To investigate the role of 5-HT1A receptors in these differences, we labelled 5-HT1A binding sites autoradiographically with [3H]8-OH-DPAT 4 months after i.p. or i.c. 5,7-DHT or saline in the first week postnatal. The regional distribution of 5-HT1A sites conformed to previous reports of highest receptor densities in hippocampus (CA1, dentate gyrus), septal nuclei, dorsal and median raphe, mammillary body, and certain cortical regions (cingulum, claustrum). 5-HT1A binding was significantly decreased (-87%) in the dorsal raphe after i.c.-made 5,7-DHT lesions. No reductions were found after lesions made by i.p. injection compared to controls, but rather a 246% increase in area of 5-HT1A binding extending from the dorsal raphe was observed. These changes in 5-HT1A binding sites in the dorsal raphe in the chronic phase of 5,7-DHT lesions may contribute to the different behavioral consequences of the route of neonatal 5,7-DHT injection.

5,7-Dihydroxytryptamine↗