Martha D. Carlson

Treatment of Wilson Disease With Ammonium Tetrathiomolybdate: III. Initial Therapy in a Total of 55 Neurologically Affected Patients and Follow-up With Zinc Therapy

BACKGROUND It is unclear what anticopper drug to use for patients with Wilson disease who present with neurologic manifestations because penicillamine often makes them neurologically worse and zinc is slow acting. OBJECTIVE To evaluate the frequency of neurologic worsening and drug adverse effects with ammonium tetrathiomolybdate. DESIGN Open-label study of 55 untreated patients (22 of them new) presenting with neurologic Wilson disease treated with tetrathiomolybdate varying from 120 to 410 mg/d for 8 weeks and then followed up for 3 years. Neurologic function was assessed with scored neurologic and speech tests. SETTING A university hospital referral setting. PATIENTS All untreated, newly diagnosed patients with neurologic Wilson disease. INTERVENTION Treatment with tetrathiomolybdate. MAIN OUTCOME MEASURES Neurologic function was evaluated by neurologic and speech examinations. Drug adverse effects were evaluated by complete blood cell counts and biochemical measures. RESULTS Only 2 (4%) of 55 patients treated with tetrathiomolybdate showed neurologic deterioration, compared with an estimated 50% of penicillamine-treated patients. Five of the 22 new patients exhibited bone marrow suppression and 3 had aminotransferase elevations. These numbers are higher than in the original 33 patients and appear to be due primarily to a more rapid dose escalation. CONCLUSIONS Tetrathiomolybdate shows excellent efficacy in patients with Wilson disease who present with neurologic manifestations. With rapid escalation of dose, adverse effects from bone marrow suppression or aminotransferase elevations can occur.

NMDA, AMPA, and benzodiazepine binding site changes in Alzheimer's disease visual cortex

Quantitative receptor autoradiography was used to measure the laminar distribution of [3H]glycine and [3H]glutamate binding to the N-methyl-D-aspartate (NMDA) receptor complex, [3H]D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) binding to the AMPA receptor, and [3H]flunitrazepam binding to the benzodiazepine (BDZ) receptor in three areas of visual cortex in control and Alzheimers disease (AD) postmortem human brains (primary or striate visual cortex, visual association cortex, and higher-order visual association cortex, corresponding to Brodmann Areas 17, 18, and 21, respectively). In Area 17, binding to the NMDA, AMPA, and BDZ receptors was not significantly altered in the AD brains (except in layer VI for [3H]glycine and layer III for [3H]AMPA, where binding was reduced in the AD brains). Ligand binding to the two EAA receptors in Area 18 was, however, significantly reduced in the AD brains (layers I through III for [3H]glycine and layers III through VI for [3H]AMPA). In Area 21, binding to both the NMDA and BDZ receptors but not to the AMPA receptor, was significantly reduced in almost all laminae of the AD brains (layers I through VI for [3H]glycine and layers I through V for [3H]flunitrazepam). This hierarchical pattern of laminar binding loss with increasing complexity of association visual cortices is consistent with the increasing numbers of neurofibrillary tangles found in those areas, implicating NMDA and BDZ receptor bearing cells in AD neuropathology. AMPA receptor losses do not parallel the pathology, suggesting that AMPA receptors are not directly correlated with the pathology.

Glutamate uptake into synaptic vesicles: competitive inhibition by bromocriptine.

Abstract: The ATP‐dependent uptake of l‐glutamate into synaptic vesicles has been well characterized, implicating a key role for synaptic vesicles in glutamatergic neurotransmission. In the present study, we provide evidence that vesicular glutamate uptake is selectively inhibited by the pep‐tide‐containing halogenated ergot bromocriptine. It is the most potent inhibitor of the agents tested; the IC5o was de‐termined to be 22 μM. The uptake was also inhibited by other ergopeptines such as ergotamine and ergocristine, but with less potency. Ergots devoid of the peptide moiety, however, such as ergonovine, lergotrile, and methysergide, had little or no effect. Although bromocriptine is known to elicit dopaminergic and serotonergic effects, its inhibitory effect on vesicular glutamate uptake was not mimicked by agents known to interact with dopamine and serotonin receptors. Kinetic data suggest that bromocriptine competes with glutamate for the glutamate binding site on the glutamate trans‐locator. It is proposed that this inhibitor could be useful as a prototype probe in identifying and characterizing the vesicular glutamate translocator, as well as in developing a more specific inhibitor of the transport system.

Neuroimaging evaluation of non-accidental head trauma with correlation to clinical outcomes: a review of 57 cases.

OBJECTIVE To review the clinical presentation and neuroimaging findings in patients with high clinical suspicion for non-accidental trauma (NAT) of the head, to investigate associations between imaging findings and long-term neurologic outcome in abused children. STUDY DESIGN A retrospective review of 57 cases of NAT of the head from a single institution was performed. Neuroimaging studies (computed tomography [CT] and magnetic resonance imaging [MRI]) were reviewed by a senior neuroradiologist, a neuroradiology fellow, and a radiology resident. Clinical history and physical findings, including retinal examination, imaging, and follow-up assessment, were reviewed. RESULTS The mean time between the patients arrival at the hospital and CT and MRI imaging was 2.9 hours and 40.6 hours, respectively. The most common clinical presentation was mental status changes, seen in 47% of patients. The most common neuroimaging finding was subdural hematoma, seen in 86% of patients. In the 47 patients who underwent both MRI and CT, 1 case of suspected NAT was missed on head CT. CT detected signs of global ischemia in all 11 patients who died (mean time after arrival at the hospital until undergoing CT, 1.1 hours). MRI detected additional signs of injury in patients who developed mild to moderate developmental delay. CONCLUSION CT was able to detect evidence of NAT of the head in 56 of 57 abused children included in our cohort and predicted severe neurologic injury and mortality. MRI was useful in detecting additional evidence of trauma, which can be helpful in risk stratification for neurologic outcomes as well in providing confirming evidence of repeated injury.

Accumulated glutamate levels in the synaptic vesicle are not maintained in the absence of active transport

We have investigated factors which may affect accumulated glutamate levels in synaptic vesicles and glutamate efflux. Agents which dissipate the electrochemical proton gradient resulted in a rapid reduction of steady-state vesicular glutamate levels, which was prevented by N-ethylmaleimide. Glutamate efflux was found to occur even in the presence of an electrochemical proton gradient, but was effectively inhibited by N-ethylmaleimide. These results suggest that accumulated glutamate levels in synaptic vesicles are not maintained unless glutamate is taken up continuously by an active transport mechanism, and they could provide an explanation for the lack of convincing evidence for the enrichment of endogenous glutamate in isolated synaptic vesicles.

Atypical childhood Wilson's disease.

Wilsons disease is a genetic disorder of copper metabolism with a hepatic or neurologic presentation. A hepatic presentation is more common in young children. Neurologic Wilsons disease often manifests as a movement disorder with dystonia, tremor, and dysarthria. Psychiatric or behavioral symptoms can also be a presenting feature of Wilsons disease. We describe an atypical neurologic presentation in a prepubertal child with minimal hepatic involvement; in which transient hemiparesis and encephalopathy dominated her initial neurologic presentation. Brain magnetic resonance imaging revealed extensive cortical and subcortical signal change, in addition to the classical basal ganglia signal abnormality observed in Wilsons disease. She was treated with oral tetrathiomolybdate anticopper therapy, followed by zinc maintenance. Her clinical status and brain imaging improved considerably at 1 year after treatment initiation. Neurologic Wilsons disease may have diverse presentations, and should be considered in children who present with cortical features and signal change on magnetic resonance imaging.

Prevalence and Etiology of Intracranial Hemorrhage in Term Children Under the Age of Two Years: A Retrospective Study of Computerized Tomographic Imaging and Clinical Outcome in 798 Children

RATIONALE AND OBJECTIVES The purposes of this study were to retrospectively identify various etiologies underlying intracranial hemorrhages (ICHs) in term infants aged <2 years and their respective prevalence in this population and to describe the long-term clinical outcomes in these patients. MATERIALS AND METHODS A retrospective review of the medical records and computed tomographic studies of the head in 798 term infants aged 0 to 24 months with suspected or known ICHs was conducted. RESULTS ICHs were present in 195 of the 798 infants (24%). More than one type of ICH was present in 32%. Subdural hemorrhage was the most frequent type of ICH, occurring in 63% of the infants. Good clinical outcomes were present in 49% of the infants but varied depending on the location, etiology, and timing of the ICH. CONCLUSION The incidence of various etiologies of ICH depended on the ages of the infants. The overall clinical outcomes were good, with no long-term sequelae in half of the infants presenting with ICHs. In infants aged >4 weeks presenting with ICHs, special attention should be given to the possibility of nonaccidental trauma etiology, because this is common and has worse long-term outcomes.

Chiari I malformation with syrinx

The Chiari I congenital malformation is characterized by caudal displacement of the cerebellar tonsils through the cervical canal. Although this malformation is often asymptomatic, coexisting syringomyelia can result in neurologic symptoms. We report a case of progressive ataxia with brainstem dysfunction in an adolescent female manifesting a severe Chiari I malformation with syrinx. Chiari decompression 4 years after initial presentation led to rapid improvement in most of her long-term symptoms. This case demonstrates the importance of consideration of Chiari I with syringomyelia in the differential diagnosis of progressive ataxia and brainstem symptoms.

Neonatal Sleep–Wake Analyses Predict 18-month Neurodevelopmental Outcomes

Objectives The neurological examination of critically ill neonates is largely limited to reflexive behavior. The exam often ignores sleep-wake physiology that may reflect brain integrity and influence long-term outcomes. We assessed whether polysomnography and concurrent cerebral near-infrared spectroscopy (NIRS) might improve prediction of 18-month neurodevelopmental outcomes. Methods Term newborns with suspected seizures underwent standardized neurologic examinations to generate Thompson scores and had 12-hour bedside polysomnography with concurrent cerebral NIRS. For each infant, the distribution of sleep-wake stages and electroencephalogram delta power were computed. NIRS-derived fractional tissue oxygen extraction (FTOE) was calculated across sleep-wake stages. At age 18-22 months, surviving participants were evaluated with Bayley Scales of Infant Development (Bayley-III), 3rd edition. Results Twenty-nine participants completed Bayley-III. Increased newborn time in quiet sleep predicted worse 18-month cognitive and motor scores (robust regression models, adjusted r2 = 0.22, p = .007, and 0.27, .004, respectively). Decreased 0.5-2 Hz electroencephalograph (EEG) power during quiet sleep predicted worse 18-month language and motor scores (adjusted r2 = 0.25, p = .0005, and 0.33, .001, respectively). Predictive values remained significant after adjustment for neonatal Thompson scores or exposure to phenobarbital. Similarly, an attenuated difference in FTOE, between neonatal wakefulness and quiet sleep, predicted worse 18-month cognitive, language, and motor scores in adjusted analyses (each p < .05). Conclusions These prospective, longitudinal data suggest that inefficient neonatal sleep-as quantified by increased time in quiet sleep, lower electroencephalogram delta power during that stage, and muted differences in FTOE between quiet sleep and wakefulness-may improve prediction of adverse long-term outcomes for newborns with neurological dysfunction.

Acute Unilateral Ophthalmoplegia as the Presenting Sign of Acute Myeloid Leukemia in a 15-Month-Old Girl

Central nervous system manifestations of acute myeloid leukemia are rare at presentation. Acute cranial nerve findings on neurologic examination can be indications for brain imaging. Magnetic resonance imaging can highlight cranial nerves emerging from the brainstem, particularly if they are gadolinium-enhanced or thickened. We describe a 15-month-old girl with acute unilateral ophthalmoplegia as the presenting sign of acute myeloid leukemia. Her presentation emphasizes the importance of appropriate laboratory and radiographic evaluation in a toddler with new-onset strabismus, which may be discounted as a previously unrecognized or benign finding.