Managing hyperphosphatemia in patients with chronic kidney disease on dialysis with ferric citrate: latest evidence and clinical usefulness.

Ferric citrate is a novel phosphate binder that allows the simultaneous treatment of hyperphosphatemia and iron deficiency in patients being treated for end-stage renal disease with hemodialysis (HD). Multiple clinical trials in HD patients have uniformly and consistently demonstrated the efficacy of the drug in controlling hyperphosphatemia with a good safety profile, leading the US Food and Drug Administration in 2014 to approve its use for that indication. A concurrent beneficial effect, while using ferric citrate as a phosphate binder, is its salutary effect in HD patients with iron deficiency being treated with an erythropoietin-stimulating agent (ESA) in restoring iron that becomes available for reversing chronic kidney disease (CKD)-related anemia. Ferric citrate has also been shown in several studies to diminish the need for intravenous iron treatment and to reduce the requirement for ESA. Ferric citrate is thus a preferred phosphate binder that helps resolve CKD-related mineral bone disease and iron-deficiency anemia.

Ferric citrate controls phosphorus and delivers iron in patients on dialysis.

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

Cerebral hemiatrophy with superficial siderosis and PLEDs due to a germ cell tumor of the basal ganglia.

The diagnosis of basal ganglia germ cell tumors may be delayed due to slow progression and minimal early changes on magnetic resonance imaging (MRI). The cystic nature of some tumors may lead to non-diagnostic biopsies. We describe the clinical, imaging, laboratory, and postmortem findings of a basal ganglia germ cell tumor in a 19-year-old man. Clues to an early antemortem diagnosis based on MRI findings and determination of tumor markers are discussed. An early diagnosis and accurate characterization of basal ganglia germ cell tumors is essential for optimal therapy. The presence of cerebral hemiatrophy and hemorrhagic or cystic components is suggestive. Measurement of serum and cerebrospinal fluid markers such as human chorionic gonadotropin may suggest the diagnosis.

Progressive infantile axonal polyneuropathy.

Polyneuropathies are relatively uncommon in early infancy and the majority of affected children are found to have hypomyelinating neuropathies. Axonal sensorimotor neuropathies have been described in childhood but the majority of affected children present at or after 6 months of age, have nonprogressive courses, and achieve the ability to walk, albeit late. Here we present three infants with infantile progressive axonal polyneuropathy from two families with nonconsanguineous parents. Each child presented shortly after the neonatal period and with rapid progression to quadriplegia. Involvement of the lower cranial nerves, phrenic nerves, or both was present in each child. Electrophysiology was diagnostic in each child. While the diagnosis of spinal muscular atrophy was considered in each case, clinical presentation, biopsies, and genetic testing were inconsistent with this diagnosis. Recognition of this early form of progressive axonal neuropathy is important as respiratory compromise occurred early and the condition showed familial inheritance in two of our patients.

A child with reading impairment and a family history of adrenoleukodystrophy.

The clinical course of a 6-year-old boy with adrenoleukodystrophy (ALD) who underwent allogeneic stem-cell transplantation during an early clinical stage is described. Twenty-three months after transplant, he remains neurologically stable, but with moderate neurological sequelae; the serum very long chain fatty acid profile has improved, but not normalized. The indications, mechanism of action, and complications of bone marrow transplantation in ALD are discussed briefly, along with other potential therapies.

Autonomic cardiovascular control in children with obstructive sleep apnea.

Autonomic cardiorespiratory control changes with sleep-wake states and is influenced by sleep-related breathing disorders. Power spectrum (PS) analysis of instantaneous fluctuations in heart rate (HR) is used to investigate the role of the autonomic nervous system (ANS) in cardiorespiratory control. The two spectral regions of interest are the low frequency component (LF) and high frequency component (HF). The aim of the present study was to investigate the autonomic cardiorespiratory control in children with obstructive sleep apnea (OSA) syndrome. We studied 10 children with OSA versus 10 normal children. All subjects underwent whole night polysomnography. Spectral analysis of the HR and breathing signals was performed for 256 second long, artifact-free epochs in each sleep-wake state. The LF power was higher in the OSA group compared with control subjects for all states, reflecting enhanced sympathetic activity in OSA subjects. The results indicated sympathetic predominance during REM sleep in all subjects and parasympathetic predominance in slow wave sleep only in controls. The autonomic balance (LF/HF) was significantly higher in OSA patients than in control subjects, at all stages during night sleep, and while awake before sleep onset. An index of overall autonomic balance (ABI) was computed for each subject and correlated well with the measured respiratory disturbance index (RDI).

Bone marrow transplantation for the treatment of alpha-mannosidosis.

We report successful bone marrow transplantation in a child with a severe form of alpha-mannosidosis, type I. There was complete resolution of the recurrent sinopulmonary disease and organomegaly, improvement in the bony disease, and stabilization of neurocognitive function.

Sleep apnea in patients receiving growth hormone.

Among 145 patients treated with recombinant human growth hormone (GH), four developed sleep apnea (two obstructive, two mixed) associated with tonsillar and adenoidal hypertrophy in three. These four patients had no local risk factors predisposing to upper airway obstruction (i.e., frequent pharyngitis or sinusitis). Clinical and/or polysomnographic features of sleep apnea improved following cessation of GH therapy in one patient, and following tonsillectomy and adenoidectomy in all patients. The present observations indicate that, albeit rarely, obstructive and/or central sleep apnea may occur in children treated with GH. Polysomnography should be considered if symptoms of snoring, interrupted sleep, daytime somnolence-particularly if associated with tonsillar hypertrophy-appear in children during GH therapy.

Sleep disorders in school-age children.

This article on school age children reviews relevant issues in sleep physiology, the classification of sleep disorders, their clinical and laboratory assessment, some common sleep disorders, the sleep-epilepsy relationship, as well as the impact of daytime sleepiness on higher cortical functions.

Excessive daytime sleepiness in a 13-year-old.

Included in the large group of children referred for attention deficit evaluations, several less common entities can be found. Careful history will enable the identification of these atypical cases of attention deficit and allow more precise diagnosis and treatment.

The laboratory assessment of daytime sleepiness in childhood.

Excessive daytime sleepiness is a disabling symptom of diverse etiologies. This article reviews the various, currently available diagnostic techniques that can be applied in the evaluation of childhood hypersomnolence, along with their merits and limitations. Normal polysomnographic data of children differ from those of adults. Serial studies may be required in evolving childhood narcolepsy for establishing a definitive diagnosis.

Myeloradicular features as the initial presentation of sarcomas of childhood.

Sarcomas (chondrosarcoma, Ewing sarcoma, rhabdomyosarcoma, and undifferentiated sarcoma) generally present with nonneurologic symptoms at the onset. Five children with sarcomas who presented with spinal cord compression or radiculopathy as their initial problems are described. These patients appear to be older than those with the more commonly encountered neuroblastoma-related spinal cord compression. Our patients had a favorable neurologic recovery initially, but ultimately succumbed to systemic complications from spread of the sarcoma.

Narcolepsy in children.

Childhood narcolepsy is frequently under-diagnosed. Hypersomnolence may not always be accompanied by cataplexy, sleep paralysis, or hypnagogic hallucinations in the early stages. Pathophysiologic considerations revolve around an altered central nervous system catecholamine-acetylcholine balance. Both idiopathic and symptomatic forms have been described. Serial polysomnography and multiple sleep latency tests may be required to establish a definitive diagnosis. The long-term management requires the provision of both pharmacological and non-pharmacological forms of therapy.

Fluctuations in autonomic nervous activity during sleep displayed by power spectrum analysis of heart rate variability.

OBJECTIVE: The use of an efficient noninvasive method to investigate the autonomic nervous system and cardiovascular control during sleep. BACKGROUND: Beat-to-beat heart rate variability displays two main components: a low-frequency (LF) one representing sympathetic and parasympathetic influence and a high-frequency (HF) component of parasympathetic origin. Sympathovagal balance can be defined as LF/HF ratio. METHODS/DESIGN: We reviewed normal, standardly staged all-night polysomnograms from 10 healthy children aged 6 to 17 years. Recorded 256-second traces of heart rate and respiration were sampled. Power spectra of instantaneous heart rate and respiration were computed using a fast Fourier transform method. RESULTS: The study revealed a decrease in LF during sleep, with minimal values during non-REM slow-wave sleep and elevated levels similar to those of wakefulness during REM. HF increased with sleep onset, reaching maximal values during slow-wave sleep, and behaved as a mirror image of LF. LF/HF ratio displayed changes similar to those in LF. CONCLUSION: The sympathetic predominance that characterizes wakefulness decreases during non-REM sleep, is minimal in slow-wave sleep, and surges toward mean awake levels during REM sleep. The autonomic balance is shifted toward parasympathetic predominance during slow-wave sleep. This noninvasive method used to outline autonomic activity achieves results that are in complete agreement with those obtained with direct invasive tools.

Sleep abnormalities in patients with severe cerebral palsy.

The all-night polysomnographic findings of nine patients with spastic quadriparesis (mean age 36.7 months) were analysed retrospectively and compared with those of nine age-matched controls (mean age 37.4 months). The cerebral palsy group had significantly more respiratory disturbances per hour of sleep, with five of nine being diagnosed as having obstructive sleep apnea. They also had fewer changes in body position during the night. Interictal epileptiform discharges averaged 23.3 per cent of the total arousals in the cerebral palsy group. Obstructive apnea, decreased ability to change body position, and interictal epileptiform discharges are prevalent in the sleep of patients with severe cerebral palsy, and contribute towards its disruption.

Ependymal abnormalities in lissencephaly/pachygyria.

The ependyma was examined in eight children with neuroblast migratory disorders of diverse origin: three cases of lissencephaly type 1 with severe to mild degrees of agyria/pachygyria, four cases of lissencephaly type 2 in Fukuyama muscular dystrophy and the Walker-Warburg syndrome, and one case of hemimegalencephalic pachygyria. Morphological and immunohistochemical abnormalities of the ependyma were strikingly similar in all. Discontinuities were disproportionate to the degree of ventriculomegaly. In some regions, the ependyma remained a pseudostratified columnar epithelium, though basal processes were absent. The poles of the horns of the lateral ventricles were replaced by extensive heterotopic ependymal rosettes. Rosettes and rows of ependyma also were in other subventricular sites. Subependymal nodules of large astrocytes and their processes bulged into the ventricular lumen after infancy. Ependymal cells did not express glial fibrillary acidic protein, but showed persistent expression of S-100 protein, cytokeratin CK-904 and sometimes vimentin long after these proteins normally disappear. An abnormal ependyma in lissencephaly/pachygyria may contribute to disturbances in neuronogenesis, guidance of axonal projections and neuroblast migrations; it may be a primary factor in pathogenesis.

Syringomyelia presenting as cricopharyngeal pseudostricture.

A 14-year-old boy was referred for evaluation of a cervical esophageal "stricture" diagnosed by upper gastrointestinal radiograph, which had been performed for evaluation of dysphagia and dysphonia of several months' duration. Neurological examination revealed several cranial nerve abnormalities and hyperreflexia, raising the suspicion of a cervicomedullary junction lesion. However, computed tomography of the head, neck, and spine was completely normal. Findings on the swallowing videofluoroscopy were interpreted as consistent with a stricture (a "tight constriction distal to the pyriform sinus"). However, no evidence for this was found by either esophagoscopy or esophageal manometry, which revealed a low-pressure cervical esophageal sphincter. Neurologic evaluation was pursued with magnetic resonance imaging, which revealed a large syrinx extending from C2 to T2 segments. We report this case to point out the importance of considering neurologic disease in the differential diagnosis of "stricture" of the cervical esophagus.