Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model.

Schizophrenia patients exhibit deficits in signaling of the M1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M1 PAMs as a novel approach for the treatment of schizophrenia.

A novel metabotropic glutamate receptor 5 positive allosteric modulator acts at a unique site and confers stimulus bias to mGlu5 signaling.

Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu5-positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu5, termed the MPEP (2-Methyl-6-(phenylethynyl)pyridine) binding site. However, one mGlu5 PAM, CPPHA (N-(4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl)-2-hydroxybenzamide), interacts with a separate allosteric site on mGlu5. Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu5 PAM from the CPPHA series termed NCFP (N-(4-chloro-2-((4-fluoro-1,3-dioxoisoindolin-2-yl)methyl)phenyl)picolinamide). NCFP binds to the CPPHA site on mGlu5 and potentiates mGlu5-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu5 subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu5 in CNS preparations. Of interest, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu5 PAMs may have similar responses in some systems, they can induce differential effects on mGlu5-mediated physiologic responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.

Brain uptake and utilization of fatty acids: recommendations for future research.

A primary goal of the international workshop "Brain Uptake and Utilization of Fatty Acids" was to identify research areas that would benefit from further investigation. The major themes for future research are presented below: (1) Elucidating the role of the developing and mature cerebrovascular endothelium (CVE) in the uptake of fatty acids (FA) into the brain. (2) Clarifying the role of diffusion and receptor-mediated uptake of FAs by various brain cell membranes and protein-mediated shuttling of FAs between the CVE and various brain cells and tissues. (3) Illuminating the mechanisms of intermediate metabolism and the roles of polyunsaturated fatty acids (PUFA) in astrocytes, neurons and oligodendrocytes. Of special interest are the long-chain omega-3 PUFA and their derivatives, such as lipoproteins, phospholipids and plasmalogens, that have been associated with various disease states (such as those listed in [5], below). (4) Elucidating the role of gene expression on long-chain omega-3 PUFA incorporation in membranes and the regulatory role these and other PUFA have on gene expression in the brain. (5) Elucidating the recently identified roles of long-chain omega-3 PUFA in mood disorders, schizophrenia, stroke, peroxisomal biogenesis disorders, Huntington's disease, other neurodegenerative disorders and disorders of oxidative stress. (6) Undertaking placebo-controlled clinical trials to assess the therapeutic potential of omega-3 PUFA in the above disorders. (7) Developing new, and utilizing existing animal models in the above studies. (8) Developing noninvasive imaging and tagging methods for quantifying the migration and distribution of PUFA and their derivatives in the brain. (9) Applying multi-disciplinary collaborations among biophysicists, physiologists and molecular biologists to the resolution of the above.

Brain uptake and utilization of fatty acids: applications to peroxisomal biogenesis diseases.

The brain is rich in diverse fatty acids saturated, monounsaturated and polyunsaturated fatty acids with chain lengths ranging from less than 16 to more than 24 carbons that make up the complex lipids present in this organ. While some fatty acids are derived from endogenous synthesis, others must come from exogenous sources. The mechanism(s) by which fatty acids enter cells has been the subject of much debate. While some investigators argue for a protein-mediated process, others suggest that simple diffusion is sufficient. In the brain, uptake is further complicated by the presence of the blood-brain barrier. Brain fatty acid homeostasis is disturbed in many human disorders, as typified by the peroxisomal biogenesis diseases. A workshop designed to bring together researchers from varied backgrounds to discuss these issues in an open forum was held in March, 2000. In addition to assessing the current state of knowledge, areas requiring additional investigation were identified and recommendations for future research were made. A brief overview of the invited talks is presented here.

Prospective study of recovery following neonatal brachial plexus injury.

The prognosis for recovery from brachial plexus injury sustained at or before birth is generally favorable. However, roughly 10% of these infants remain profoundly weak and later exhibit functional disability in the affected arm. Early identification of these at-risk infants would be helpful in selecting patients for surgical management. In our prospective study, 80 infants with brachial plexus injury were examined on a monthly basis. Complete recovery occurred in 53 (66%); in 9 (11%), mild weakness persisted. In each child, recovery to antigravity strength in the biceps, triceps, and deltoid was noted by 6 months of age. Moderate arm weakness persisted in 7 children (9%); none had antigravity strength in the deltoid at age 6 months. Eleven children (14%) had severe permanent weakness (mean follow-up: 4.4 years). At age 6 months, these individuals exhibited at best 2/5 strength proximally and typically 0-1/5 strength in the wrist and finger extensors. Our results demonstrate that detailed strength testing up to 6 months of age predicts not only complete recovery of neonatal brachial plexus injury but also those children destined for long-term severe disability.

Poliomyelitis-like syndrome associated with Epstein-Barr virus infection.

A 20-month-old male presented with an acute clinical syndrome resembling poliomyelitis, characterized by a flaccid monoplegia, areflexia of the involved limb, and preserved sensation. Electrophysiologic studies supported a neuronopathic localization involving the anterior horn cells. Although laboratory evidence for a poliovirus infection was absent, serologic and polymerase chain reaction studies documented an active central nervous system infection with Epstein-Barr virus, indicating that a poliomyelitis-like syndrome may be produced by infectious agents other than enteroviruses.

Outcome of surgically treated birth-related brachial plexus injuries in twenty cases.

Birth-related brachial plexus injury occurs in 0.19-2.5 per 1,000 live births, of which 70-92% improve with conservative management. With the advent of microsurgical techniques, patients who fail expectant treatment may benefit from brachial plexus exploration and reconstruction. From 1991 to 1996, 87 patients were referred to the multidisciplinary brachial plexus clinic at St. Louis Children's Hospital. Twenty patients were selected for surgical management. The average age at surgery was 10.5 months (range 3-35, median = 8), with an average follow-up of 23.9 months (range 7-45, median = 24). Two patients were lost to follow-up. Surgical procedures included neurolysis (n = 8), neurotization (n = 2), nerve grafting (n = 5), and a combination (n = 3) of the above. Two patients underwent exploration without repair. Intercostal nerves, pectoral nerves, and C4 roots were used for neurotizations, and the sural nerve was used for nerve grafting. Results from 18 patients were available for follow-up review. Fifteen patients (83% demonstrated clinical improvement postoperatively. Of the 3 patients without improvement, 2 underwent exploration without repair, and one underwent neurolysis of the axillary nerve. Of patients undergoing reconstruction, 93% had improved strength postoperatively. No subjects had worsening neurologic status, and there were no complications. These results suggest that surgery for birth-related brachial plexus injury may show favorable outcomes if patients are selected appropriately. Patients undergoing neurolysis and nerve grafting had more favorable outcomes than those undergoing neurotization.

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.

Long-term studies of metopic synostosis: frequency of cognitive impairment and behavioral disturbances.

Although the occurrence of cognitive impairment and behavioral disturbances in patients with metopic synostosis has been described, the incidence of this dysfunction has not been established. The records of 36 consecutive children with metopic synostosis followed at one craniofacial center from 1978 to 1993 were reviewed and parental questionnaires were completed to establish the frequency of mental retardation, learning disabilities, and behavioral problems associated with this synostosis. Documentation of syndromes, abnormal karyotype, and central nervous system anomalies also was done. The study group consisted of 27 males and 9 females. The average age at most recent follow-up was 7 years and 1 month (range 6 months to 22 years). Two patients had chromosomal abnormalities (9p syndrome and trisomy 21). On the basis of CT and MRI scans, intracranial anomalies were identified for only one patient having an absent corpus callosum. Thirty-two of the study patients had adequate information for longitudinal assessment. Twenty patients have normal development without apparent disability. Of these, those of school age are at appropriate grade level. Eight patients have mild to moderate learning disabilities or behavioral problems, including attention deficit/hyperactivity disorder and impaired language development. Four patients have significant mental impairment. Impaired cognitive development was not limited to children with abnormal karyotype or central nervous system anomaly. Cognitive and behavioral abnormalities occur in at least a third of patients with metopic synostosis. The, at times, subtle nature of these abnormalities mandates longitudinal developmental and neurologic evaluation for infants with metopic synostosis.

Fast spin-echo magnetic resonance imaging for radiological assessment of neonatal brachial plexus injury.

Neurosurgical management of birth-related brachial plexus palsy involves observing the patient for a period of several months. Operative intervention is usually undertaken at 3 to 6 months of age or more in infants who have shown little or no improvement in affected muscle groups. Ancillary tests such as electromyography and nerve conduction studies are occasionally useful. No radiological study has been consistently helpful in operative planning, except for contrast computerized tomography (CT) myelography, which requires general anesthesia in infants. This is because the infant's small size exceeds the functional resolution of the imaging modalities. This report describes the use of a special sequence of magnetic resonance (MR) imaging entitled "fast spin echo" (FSE-MR). Unlike CT myelography, this technique provides high-speed noninvasive imaging that allows clinicians to evaluate preganglionic nerve root injuries without the use of general anesthesia and lumbar puncture. The utility of this technique is illustrated in three cases, two involving either infraclavicular exploration or a combination of infraclavicular and supraclavicular exposure based on FSE-MR findings. The FSE-MR imaging offers an excellent alternative to contrast CT myelography in evaluation of infants with birth-related brachial plexus injuries.

Triopia: craniofacial malformation with prosencephalic duplication.

A case of ocular duplication with complex craniofacial and central nervous system anomalies is described. The anomaly is termed triopia because the child's most overt and distinguishing feature was three eyes: the left orbit contained two globes with independent ocular adnexa; the right orbit contained one normal appearing and functioning globe. Computer assisted medical imaging was used to define, in vivo, the intra- and extracranial soft and hard tissue anomalies: the cerebral hemisphere ipsilateral to the ocular duplication was also duplicated. Possible bases for this anomaly include duplication of primordia for the eye and secondary prosencephalon.

Changes in hip migration after selective dorsal rhizotomy for spastic quadriplegia in cerebral palsy.

Selective dorsal rhizotomy is increasingly used for management of spastic quadriplegic cerebral palsy but rates of hip stability following the operation have not been reported. Determining hip stability by radiographic measurement of lateral migration of the femoral head beyond a lateral edge of the acetabulum after dorsal rhizotomy allows an objective assessment of the outcome of the operation. This prospective study examined the effect of selective dorsal rhizotomy on lateral migration of the femoral head in 45 children with spastic quadriplegic cerebral palsy. The children ranged in age from 2 to 9 years (average 5 years 1 month) and were grouped according to their ages with 23 children in the 2- to 4-year-old group and 22 children in the 5- to 9-year-old group. Postoperative follow up ranged from 7 to 50 months (average 20 months). The Reimers migration percentage (MP), a measure of the lateral migration of the femoral head, was calculated from anteroposterior hip radiographs taken prior to the operation and at the last follow-up examination. Of the 90 hips involved, 9% improved, 80% remained unchanged, and 11% worsened, yielding a radiographic stability rate of 89%. The hips with postrhizotomy worsening of the MP had an average preoperative MP of 14% (range 9% to 38%) and an average postoperative increase in MP of 18% (range 11% to 37%). Of the 45 children, four subsequently underwent unilateral derotational femoral osteotomies for persistent or worsening hip subluxation. There was a significant tendency for the MP to worsen in patients with lower prerhizotomy MP values (chi 2 = 20.74, df = 4, p = 0.001), but the age of patients and their ambulatory status at the time of rhizotomy had no bearing on postoperative hip stability. The data indicate that selective dorsal rhizotomy prevents progressive lateral migration of the femoral head in the majority of children who undergo the operation for spastic quadriplegia.

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)

Prolonged absence status epilepticus associated with carbamazepine therapy, increased intracranial pressure, and transient MRI abnormalities.

We describe an adolescent epileptic patient who presented in nonconvulsive status epilepticus that appeared to be related to treatment with carbamazepine. The absence status, which was resistant to multiple anticonvulsants, produced increased intracranial pressure and transient abnormalities observed on MRI.

Seizures in children with congenital hydrocephalus: long-term outcome.

We documented seizures in 33 of 68 (48.5%) children with congenital hydrocephalus not associated with myelomeningocele. Mental retardation (MR) and CNS malformations correlated with seizure occurrence; age at shunt insertion and number of shunt revisions and infections were not significant variables in predicting seizures. Of 11 patients seizure free for 2 or more years on medication, six had therapy discontinued without seizure recurrence. Among those 33 children with seizures, 14 (42.4%), including five who had failed withdrawal of medication, have adequately controlled seizures on anticonvulsants. Frequent convulsions despite treatment occur in 13 (39.4%) of the 33 children with seizures. Absence of MR, older age and nonparoxysmal EEG at seizure onset, and absence of CNS malformation correlated with seizure remission. Longer time without seizures while on medication did not predict successful discontinuation of therapy. In contrast, MR correlated significantly with seizure recurrence following cessation of treatment. Our study indicates that medication can be safely discontinued in children with congenital hydrocephalus who are of normal intelligence and have been seizure free on anticonvulsants for 3 years.

Prognosis for seizure control and remission in children with myelomeningocele.

A combined retrospective and prospective study was designed to determine the incidence of seizures in 140 children with myelomeningocele, as well as the potential for seizure control and remission. The incidence of seizures in 109 patients with myelomeningocele and hydrocephalus was 16.5 per cent, and 19.4 per cent in a further 31 patients without hydrocephalus. Mental retardation, often in combination with cerebral malformations, was significantly more common in children with seizures, regardless of presence or absence of hydrocephalus. Of the 24 patients with convulsion, three-quarters had anti-epileptic medication discontinued, without recurrence of seizures. An additional five children's seizures are well controlled with medication. Mental retardation was the only significant predictor of long-term outcome. These results indicate that children with myelomeningocele have an excellent prognosis for seizure control and subsequent remission off medication.