Michael R. Pranzatelli

Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder

Parkinsonism is an uncommon movement disorder in childhood. Six unusual cases of acquired parkinsonism in hospitalized children are described. Clinical manifestations included an akinetic-rigid syndrome with and without tremor, the combination of parkinsonism and dystonia, and a parkinsonism-plus syndrome. Altered mental status, mutism, dysphagia, and sialorrhea were frequent associations. Etiologies included hypoxic-ischemic encephalopathy; haloperidol treatment with and without neuroleptic malignant syndrome; toxicity of cytosine arabinoside, cyclophosphamide, amphotericin B, and methotrexate; St. Louis encephalitis and other encephalitides; and a pineal tumor with hydrocephalus. Cranial magnetic resonance imaging results ranged from normal to profound cerebral and cerebellar atrophy with chemotherapeutic toxicity. The illnesses usually were severe enough to require pharmacotherapy. Incorrect diagnoses of depression or catatonia delayed treatment or aggravated the problem. Acute treatment included amantadine, levodopa/carbidopa with or without selegiline, diphenhydramine, or benztropine. The concentration of CSF homovanillic acid was normal in a neuroleptic-associated patient, but the level was low in an encephalitic patient. All patients demonstrated dramatic improvement, including two who were not treated; some had complete resolution of symptoms and none required continued antiparkinsonian drugs despite poor scores on the Unified Parkinsons Disease Rating Scale and the Modified Hoehn and Yahr Rating Scales. The causes of parkinsonism described are more common in a general pediatric hospital than the parkinsonism associated with the popularized Segawa syndrome.

Novel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists

The 5-hydroxytryptamine1C (5-HT1C) receptor shares many features with the 5-HT2 receptor. To determine if the regulation of the sites is also similar we studied the effects of chronic treatment with drugs active at 5-HT1C/2 receptors on [3H]mesulergine-labelled 5-HT1C binding sites in spinal cord. The 5-HT receptor agonists 1-(3-chlorophenyl)piperazine (m-CPP) (-38%), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (-35%), quipazine (-27%) and m-trifluoromethylphenylpiperazine (TFMPP) (-27%) significantly down-regulated spinal 5-HT1C sites with chronic injection compared to vehicle treatment. The 5-HT receptor antagonists methiothepin (-71%), mianserin (-24%), methysergide (-21%), and cyproheptadine (-27%) also induced down-regulation, and ritanserin and metergoline further reduced [3H]mesulergine specific binding to undetectable levels. There were no significant changes in Kd to implicate presence of residual drug except for mianserin, methiothepin, and TFMPP. Pindolol and spiperone had no significant effects. In acute dose-response studies, injection of a single dose of DOI did not result in a significant change in any receptor parameters. The capacity of a drug to lower Bmax correlated significantly with its pKd (r = 0.84, P < 0.0007). This drug regulation pattern for 5-HT1C sites of down-regulation by both 5-HT1C/2 receptor agonists and antagonists is similar to that for 5-HT2 receptors and is consistent with the classification of 5-HT1C and 5-HT2 receptors in the same superfamily.

On the Molecular Mechanism of Adrenocorticotrophic Hormone in the CNS: Neurotransmitters and Receptors

A neural mechanism for the clinical efficacy of adrenocorticotrophic hormone (ACTH) independent of steroid effects in neurological disorders such as infantile spasms, myoclonic seizures in infants, and the opsoclonus-myoclonus syndrome remains controversial. This article reviews evidence that ACTH is a neurotransmitter, neuromodulator, and growth factor. It summarizes studies of anticonvulsant, antimyoclonic, and neurophysiologic effects of ACTH and ACTH fragments, the binding of ACTH in vitro to neurotransmitter receptors in brain, the chronic effects of ACTH on central neurotransmitter receptors and metabolism, effects of neurotransmitters on ACTH secretion, effects of ACTH on growth of cultured neurons, anatomic evidence for interactions of ACTH with neurotransmitters, behavioral effects and interactions of ACTH with neurotransmitter systems in vivo, and other neurochemical properties which may alter neurotransmission.

Topical Review: 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 γ-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. (J Child Neurol 1996;11:355-369).

Topical Review: Putative Neurotransmitter Abnormalities in Infantile Spasms: Cerebrospinal Fluid Neurochemistry and Drug Effects

The neuropharmacologic basis of infantile spasms and the mechanism by which adrenocorticotropic hormone (ACTH) exerts its therapeutic effects are unknown. This is a critical review of cerebrospinal fluid neurotransmitters or their metabolites in infantile spasms before and during treatment with ACTH, and of clinical drug trials with drugs acting on neurotransmission. Cerebrospinal fluid studies have shown lower γ-aminobutyric acid (GABA), ACTH, and 5-hydroxyindoleacetic acid concentrations in patients with infantile spasms compared to controls, elevated lysine and glutamate, variable or no differences in homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, norepinephrine, corticotropin-releasing hormone, and β-endorphin. Chronic treatment with ACTH in infantile spasms reduces cerebrospinal fluid GABA, β-endorphin, and somatostatin, increases norepinephrine and tyrosine, and has variable or no effect on homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, 5-hydroxyindoleacetic acid, histamine, and tryptophan. Small therapeutic trials with drugs that act through different neurotransmitters such as methysergide, α-methylparatyrosine, various benzodiazepine agonists, and vigabatrin lend some support to a role for GABA and monoamines in infantile spasms. These data, though promising, provide only a hint of potential neurotransmitter disturbances, and more basic and clinical data are needed. (J Child Neurol 1994;9:119-129).

Regional differences in the ontogeny of 5-hydroxytryptamine-1C binding sites in rat brain and spinal cord

Developmental profiles of [3H]mesulergine-labelled central 5-HT1c binding sites differed regionally in the rat during the first 5 weeks postnatal. At birth, cortical 5-HT1c sites were 24-32% of adult levels and increased significantly by 14-21 days. In brainstem, the majority of 5-HT1c sites were already present at birth and increased further by 10 days, which was earlier than in other regions. A pattern of increasing binding site density was also found in hippocampus, diencephalon, and spinal cord. Cerebellar 5-HT1c sites remained at low levels throughout. A mature pattern of regional differences was apparent by 21-28 days with a new rank order: cortex, diencephalon > spinal cord, brainstem, hippocampus > cerebellum. These trends were seen whether Bmax was expressed according to brain weight or protein concentration. The regional contrast in the ontogeny of 5-HT1c binding sites may be relevant to the proposed role of 5-HT as a growth factor in brain development.

Dissociation of the plasticity of 5-HT1A sites and 5-HT transporter sites.

To study the early effects of neonatal 5,7-dihydroxytryptamine lesions on 5-hydroxytryptamine1A (5-HT1A) receptors, we measured regional [3H]8-OH-DPAT-labeled 5-HT1A sites in binding assays and compared them to our previous studies of [3H]paroxetine-labeled 5-HT transporter sites during the first month in the same rats. While there were significant time- and dose-dependent effects of 5,7-DHT on 5-HT transporter sites, there were no significant changes in 5-HT1A sites in cortex, hippocampus, diencephalon, brainstem, cerebellum, or spinal cord. 5,7-DHT lesions also did not alter the Ki of Gpp(NH)p at brainstem 5-HT1A sites or the Ki of 5-HT in cortex or brainstem in the presence or absence of GTPγS or Gpp(NH)p. There were significant regional differences between the density of 5-HT1A sites and 5-HT transporter sites. The ontogeny of brainstem 5-HT1A sites was a pattern of increases until three weeks postnatal, and 5,7-DHT lesions did not alter the ontogeny of 5-HT1A sites. These data suggest differential plasticity of 5-HT1A and 5-HT transporter binding sites during the first month after neonatal 5,7-DHT lesions.

Ontogeny of [125I]iodocyanopindolol-labelled 5-hydroxytryptamine1B-binding sites in the rat CNS.

Little is known about the ontogeny of the 5-hydroxytryptamine1B (5-HT1B) receptor, a putative terminal autoreceptor in the CNS. To learn more about the regional development of 5-HT1B sites and how early these sites may become functional, we studied [125I]iodocyanopindolol ([125I]ICYP)-labelled central 5-HT1B sites in developing postnatal rat brain and spinal cord. Significant ontogenic changes in Bmax were found in neocortex, hippocampus, striatum and brainstem. Maximum binding-site density was reached by 21 days in hippocampus and cortex, but not until 28 days in striatum. The rank order of binding site density changed with rat age, but Bmax was consistently high in brainstem and low in cerebellum. The percent increases in Bmax also varied with brain region, ranging from a 2-fold increase in brainstem up to 8-fold increases in cortex and striatum. In competition studies, the Ki for 5-HT and for RU 24969 was the same in 5-day-old and adult rat brain. These data indicate regional differences in the ontogeny of 5-HT1B-binding sites and suggest that 5-HT1B receptors are functional early in the postnatal period.

Serotonin receptors in human neuroblastoma : a possible biologic tumor marker

We used saturation radioligand binding to measure nine types of serotonin receptors in 13 neuroblastomas from children. 5-HT1E and 5-HT3 sites were found in neuroblastomas with receptor density and affinity similar to human or rat brain. No 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, or 5-HT uptake sites were found in any of the tumors, although all were detected in human or rat brain. These data demonstrate that human neuroblastomas possess 5-HT receptors found in human brain and relevant to human myoclonus. We speculate that 5-HT receptors in human neural crest-derived tumors may have clinical and neurobiological significance.

Acute dyskinesias in young asthmatics treated with theophylline

Two young children, 5 and 30 months of age, developed acute transient dyskinesias. The novel features of these patients were classic orobuccal-lingual dyskinesias, their young ages, and the association with asthma and theophylline. The movements resembled tardive dyskinesias of older patients on neuroleptics, but neither patient had any exposure to neuroleptic drugs. Choreiform movements were moderately severe and remitted several hours after discontinuation of theophylline or over days in the patient who remained on the drug. No symptomatic treatment of dyskinesia was required. Both infants otherwise had normal neurologic examinations with no clinical evidence of meningoencephalitis, seizures, or stroke. Both infants required hospitalization for respiratory distress, but not intensive care. The highest theophylline levels measured in these patients were 22 and 25 micrograms/ml and levels determined closest to the appearance of dyskinesias were lower. Urine toxicology screen for other drugs and routine blood work were normal. The infants, examined subsequently for 1 1/2-2 years for asthma, have demonstrated no reappearance of dyskinesias or other neurologic abnormalities. We propose an interaction of theophylline, hypoxemia, or other factors related to asthma in the pathophysiology of reversible dyskinesia in our patients.