Normocephalic sagittal craniosynostosis in young children is common and unrecognized.

OBJECTIVE: Sagittal craniosynostosis (SC) is usually diagnosed during early childhood by the presence of scaphocephaly. Recently, our group found 3.3% of children under 5 years of age with normocephalic sagittal craniosynostosis (NSC) using computed tomography (CT) scans. This paper aims to validate our preliminary findings using a larger cohort of patients, and analyze factors associated with incidental NSC. METHODS: A retrospective review of head CT scans in patients aged 0 to 71 months who presented to the emergency department of our tertiary care institution between 2008 and 2020 was completed. Patients with syndromes associated with craniosynostosis (CS), history of hydrocephalus, or other brain/cranial abnormalities were excluded. Two craniofacial surgeons reviewed the CT scans to evaluate the presence and extent of CS. Demographic information, gestational age, past medical and family history, medications, and chief complaint were recorded as covariates, and differences between patients with and without CS were analyzed. Furthermore, comparison of the prevalence of CS across age groups was studied. Additional analysis exploring association between independent covariates and the presence of CS was performed in two sub-cohorts: patients ≤ 24 months of age and patients > 24 months of age. RESULTS: A total of 870 scans were reviewed. SC was observed in 41 patients (4.71% - 25 complete, 16 incomplete), all with a normal cranial index (width/length > 0.7). The prevalence of SC increased up to 36 months of age, then plateaued through 72 months of age. Patients under 2 years of age with family history of neurodevelopmental disease had 49.32 (95% CI [4.28, 567.2]) times higher odds of developing CS. Sub-cohort of patients above 24 months of age showed no variable independently predicted developing CS. CONCLUSION: NSC in young children is common. While the impact of this condition is unknown, the correlation with family history of neurodevelopmental disease is concerning.

Global and intertuberal epileptic networks in tuberous sclerosis based on stereoelectroencephalographic (sEEG) findings: a quantitative EEG analysis in pediatric subjects and surgical implications.

OBJECTIVE: Recent evidence favors a network concept in tuberous sclerosis (TSC) with seizure generation and propagation related to changes in global and regional connectivity between multiple, anatomically distant tubers. Direct exploration of network dynamics in TSC has been made possible through intracranial sampling with stereoelectroencephalography (sEEG). The objective of this study is to define epileptic networks in TSC using quantitative analysis of sEEG recordings. We also discuss the impact of the definition of these epileptic networks on surgical decision-making. METHODS: Intracranial sEEG recordings were obtained from four pediatric patients who presented with medically refractory epilepsy secondary to TSC and subjected to quantitative signal analysis methods. Cortical connectivity was quantified by calculating pairwise coherence between all contacts and constructing an association matrix. The global coherence, defined as the ratio of the largest eigenvalue to the sum of all the eigenvalues, was calculated for each frequency band (delta, theta, alpha, beta, gamma). Spatial distribution of the connectivity was identified by plotting the leading principal component (product of the largest eigenvalue and its corresponding eigenvector). RESULTS: Four pediatric subjects with TSC underwent invasive intracranial monitoring with sEEG, comprising 31 depth electrodes and 250 contacts, for localization of the epileptogenic focus and guidance of subsequent surgical intervention. Quantitative connectivity analysis revealed a change in global coherence during the ictal period in the beta/low gamma (14-30 Hz) and high gamma (31-80 Hz) bands. Our results corroborate findings from existing literature, which implicate higher frequencies as a driver of synchrony and desynchrony. CONCLUSIONS: Coordinated high-frequency activity in the beta/low gamma and high gamma bands among spatially distant sEEG define the ictal period in TSC. This time-dependent change in global coherence demonstrates evidence for intra-tuberal and inter-tuberal connectivity in TSC. This observation has surgical implications. It suggests that targeting multiple tubers has a higher chance of seizure control as there is a higher chance of disrupting the epileptic network. The use of laser interstitial thermal therapy (LITT) allowed us to target multiple disparately located tubers in a minimally invasive manner with good seizure control outcomes.

Old herbal remedies and modern combination therapy.

The use of herbs as cures for human ailments is as old as modern man, but has now been replaced by synthetic drugs. However, the mixture of bioactive substances found in many traditional herbal remedies has similarities with modern combination therapies, like those developed by Sir John Crofton in Edinburgh for the treatment of tuberculosis. It is suggested that, in the development of these therapies, it might be possible to learn from the drug 'cocktails' found in plants.

CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis.

OBJECTIVE: To describe the relationship between symptomatology and time to diagnosis of an institutional series of patients with CNS germ cell tumor (CNSGCT) over a 16-year period. METHODS: Thirty consecutive patients newly diagnosed with CNSGCT (mean age 10.9 years; range 6 to 17 years; 70% boys) were evaluated at our institution between 1990 and 2006. RESULTS: Duration of symptoms prior to diagnosis ranged from 5 days to 3 years (mean 8.4 months). Tumor location included pineal (14), suprasellar (8), pineal/suprasellar (3), pineal/thalamic (4), and basal ganglionic/thalamic (3). Five patients had disseminated disease at the time of diagnosis. Features including headache, nausea, vomiting, and visual changes led to earlier diagnosis. Symptoms including movement disorders, enuresis, anorexia, and psychiatric complaints delayed diagnosis in 9 of 30 patients, diagnosed 7 months to 3 years (mean 22.3 months) from symptom onset. In 7 of 9 patients with delayed diagnosis, enuresis was present. Seventeen of 30 patients had signs of endocrine dysfunction at presentation that included diabetes insipidus (4), hypothyroidism (8), and growth hormone deficiency (4). Ophthalmologic findings of decreased visual acuity, visual field deficits, or ocular abnormalities were present in 13 patients. Duration of symptoms did not correlate with tumor subtype or event-free survival. In three patients with basal ganglionic/temporal lobe, thalamic, or pineal/suprasellar signal abnormalities on MRI, neuroradiographic diagnosis was difficult. CONCLUSIONS: Diagnosis of CNS germ cell tumor is often delayed, and presentation may include movement disorders or mimic psychiatric disease. MRI interpretation can be challenging and may require serum/CSF markers and biopsy for diagnosis.

Use of audiotaped patient consultations in a head and neck oncology clinic and survey of patient attitudes to this facility.

The overall quality and delivery of patient care is becoming increasingly important, especially in those diagnosed with cancer. Multidisciplinary clinics are a valuable adjunct to this, but patients may not fully understand or comprehend all that is said to them. The use of audiotaping consultations has been studied in some settings, but not in head and neck cancer clinics. We report on a series of 50 consecutive head and neck patients to determine their views on the value of this facility. Thirty-nine patients (78 per cent) utilized the opportunity, of which 36 patients (92 per cent) found it beneficial. Over three quarters of the patients who used the facility thought that medical staff could benefit and learn from the tape recording. We recommend that audiotaping becomes a standard part of the multidisciplinary head and neck oncology clinic, helping to improve the overall quality of patient care.

The cytotoxic T-cell response to herpes simplex virus type 1 infection of C57BL/6 mice is almost entirely directed against a single immunodominant determinant.

Many virus infections give rise to surprisingly limited T-cell responses directed to very few immunodominant determinants. We have been examining the cytotoxic T-lymphocyte (CTL) response to herpes simplex virus type 1 (HSV-1) infection. Previous studies have identified the glycoprotein B-derived peptide from residues 498 to 505 (gB(498-505)) as one of at least three determinants recognized by HSV-1-specific CTLs isolated from C57BL/6 mice. We had previously found that in vitro-derived CTLs directed to gB(498-505) show a characteristic pattern of T-cell receptor (TCR) usage, with 60% of gB(498-505)-specific CD8(+) T cells expressing BV10(+) TCR beta chains and a further 20% expressing BV8S1. In this report, we confirm that this TCR V-region bias is also reflected in the ex vivo response to HSV-1 infection. A high proportion of activated CD8(+) draining lymph node cells were found to express these dominant V regions, suggesting that a substantial number of in vivo responding T cells were directed to this one viral determinant. The use of an HSV-1 deletion mutant lacking the gB(498-505) determinant in combination with accurate intracellular gamma interferon staining allowed us to quantify the extent of gB-specific T-cell dominance. Together, these results suggested that between 70 and 90% of all CD8(+) HSV-1-specific T cells target gB(498-505). While deletion of this determinant resulted in an attenuated CD8(+) T-cell response, it also permitted the emergence of one or more previously unidentified cryptic specificities. Overall, HSV-1 infection of C57BL/6 mice results in an extremely focused pattern of CD8(+) T-cell selection in terms of target specificity and TCR expression.

Paracrine regulation of colony-stimulating factor-1 in medulloblastoma: implications for pathogenesis and therapeutic interventions.

OBJECTIVE: Colony-stimulating factor (CSF)-1, a chemotactic and mitogenic factor for macrophages and microglia, is expressed in a variety of nervous system tumors and when present in nonneural malignancies, is associated with marked inflammatory infiltrates, dissemination, and poorer prognosis. This study investigated the paracrine effects of CSF-1 production by medulloblastoma cells on the macrophage/microglial lineage. METHODS: A recurrent metastatic desmoplastic medulloblastoma was isolated from a 26-year-old man and propagated in tissue culture. Cellular phenotype and proliferation were assessed by immunocytochemical techniques; transcript expression for CSF-1, granulocyte macrophage-CSF, interleukin-3, and c-fms (the receptor for CSF-1) was examined with reverse transcriptase-polymerase chain reaction; and conditioned media and coculture paradigms were used to study cytokine effects on cellular proliferation. RESULTS: Serially passaged cells were uniformly immunoreactive for two lineage-independent neuroepithelial markers, nestin and vimentin. A subpopulation of cells with morphological characteristics of early differentiation stained for neurofilament 66 (7%) and microtubule-associated protein (5%) (markers of early neuronal precursors and postmitotic neurons, respectively) and for the Yp subunit of glutathione-S-transferase (3%) (a marker of early oligodendroglial progenitors). Tumor cells expressed transcripts for CSF-1, but not for granulocyte macrophage-CSF, interleukin-3, or c-fms. Treatment of microglia with serum-free medulloblastoma-conditioned media significantly increased proliferation (P < 0.001), suggesting the secretion of CSF-1. Coculture of medulloblastoma cells and microglia significantly increased proliferation of both cell types (each condition, P < 0.01). CONCLUSION: These observations suggest that CSF-1 mediates important paracrine interactions between transformed cells and the immune system, resulting in increased growth rate and metastatic potential. Future therapeutic goals need to include immunotherapeutic protocols to modulate this interaction.

Stopping dialysis of an incompetent patient over the family's objection: is it ever ethical and legal?

Decisions to stop dialysis or other life-sustaining treatments for incompetent patients are among the most difficult ethical problems faced by physicians and families. This observation is verified by the large number of court cases and the increasing frequency of ethics consultations on these issues. In such instances, in the absence of an advance directive, the usual practice for physicians is to turn to the patient's family for direction on whether to start, continue, or withdraw the treatment. They do so on the presumption that the family best represents the patient's interests. This presumption may not always be correct. A case is presented in which the family's insistence on continued dialysis was contrary to the patient's previously expressed wishes and the treating physician's assessment of the patient's best interests. It is asserted that, in such situations, after thorough conversation with the family, consultation, documentation, and an unsuccessful attempt to transfer the patient's care to another physician, nephrologists have an ethical obligation and legal right to override the family's decision and to stop dialysis. The ethical obligation is supported by the principles of respect for persons, beneficence, and nonmaleficence. The legal right is grounded in common law and state statutes.

Silicone allergy in ventriculoperitoneal shunts.

Reported are the cases of three hydrocephalic patients who developed a clinically heterogenous entity with an allergic rejection of their silicone ventriculoperitoneal shunts. All of the patients had an original presentation indicative of a shunt infection, but laboratory analysis revealed sterile cerebrospinal fluid in all three cases. The typical course included recurrent skin breakdowns over the shunt tract, subsequent infections and development of fungating granulomas. Treatment, with successful resolution of the symptoms, included changing the shunt material from silicone to polyurethane, with immunosuppression in one patient and removal of the shunt altogether in the other two patients. The roles of the immune system and silicone in the pathophysiology of this condition are discussed.

Basic fibroblast growth factor and epidermal growth factor exert differential trophic effects on CNS neurons.

Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) are potent mitogenic proteins capable of inducing cell division in a wide variety of cell types. In addition to their mitogenic properties, both proteins have recently been shown to enhance survival and process outgrowth from neurons of central nervous system origin. The full spectrum of neuronal subtypes responding to these factors has not been elucidated. In the present study, EGF was found to enhance survival and process outgrowth of primary cultures of cerebellar neurons of neonatal rat brain. This effect was dose-dependent and was observed with EGF concentrations as low as 100 pg/ml. In marked contrast, bFGF was ineffective in enhancing survival or neurite elongation from cerebellar neurons when tested in the range of 0.1 to 10.0 ng/ml. However, within this concentration range, bFGF did prove effective in stimulating an increase in [3H]thymidine incorporation into primary cultures of cerebellar astrocytes, demonstrating that bFGF was active and that cells in the cerebellum do respond to bFGF. These results suggest that EGF or an EGF-like peptide may act as a neurite elongation and maintenance factor for cerebellar neurons. EGF has now been shown to support striatal, cortical, and cerebellar neurons, suggesting that this factor may have trophic activity throughout the central nervous system. bFGF, in contrast, appears to exert its effects on limited populations of neurons.

Enchondroma protuberans of the rib.

Enchondroma protuberans of the rib may be indistinguishable from osteochondroma or chondrosarcoma. The problems of needle biopsy and the confusion which arose in the preoperative and intraoperative evaluation of two previous cases from the literature were avoided in the present case by total resection of the lesion. Where possible, total resection is recommended for accurate diagnosis.