Systemic juvenile idiopathic arthritis: The Great Ormond Street Hospital experience (2005-2021).

Systemic juvenile idiopathic arthritis (sJIA) is a complex, systemic inflammatory disorder driven by both innate and adaptive immunity. Improved understanding of sJIA pathophysiology has led to recent therapeutic advances including a growing evidence base for the earlier use of IL-1 or IL-6 blockade as first-line treatment. We conducted a retrospective case notes review of patients diagnosed with sJIA over a 16-year period (October 2005-October 2021) at Great Ormond Street Hospital for Children. We describe the clinical presentation, therapeutic interventions, complications, and remission rates at different timepoints over the disease course. We examined our data, which spanned a period of changing therapeutic landscape, to try and identify potential therapeutic signals in patients who received biologic treatment early in the disease course compared to those who did not. A total of 76-children (female n = 40, 53%) were diagnosed with sJIA, median age 4.5 years (range 0.6-14.1); 36% (27/76) presented with suspected or confirmed macrophage activation syndrome. A biologic disease-modifying anti-rheumatic drug (bDMARD) alone was commenced as first-line treatment in 28% (n = 21/76) of the cohort; however, at last review, 84% (n = 64/76) had received treatment with a bDMARD. Clinically inactive disease (CID) was achieved by 88% (n = 67/76) of the cohort at last review; however, only 32% (24/76) achieved treatment-free CID. At 1-year follow-up, CID was achieved in a significantly greater proportion of children who received treatment with a bDMARD within 3 months of diagnosis compared to those who did not (90% vs. 53%, p = 0.002). Based on an ever-increasing evidence base for the earlier use of bDMARD in sJIA and our experience of the largest UK single-centre case series described to date, we now propose a new therapeutic pathway for children diagnosed with sJIA in the UK based on early use of bDMARDs. Reappraisal of the current National Health Service commissioning pathway for sJIA is now urgently required.

Expression of Group I metabotropic glutamate receptors on phenotypically different cells within the nucleus of the solitary tract in the rat.

Group I metabotropic glutamate receptors (mGluRs) are G-coupled receptors that modulate synaptic activity. Previous studies have shown that Group I mGluRs are present in the nucleus of the solitary tract (NTS), in which many visceral afferents terminate. Microinjection of selective Group I mGluR agonists into the NTS results in a depressor response and decrease in sympathetic nerve activity. There is, however, little evidence detailing which phenotypes of neurons within the NTS express Group I mGluRs. In brainstem slices, we performed immunohistochemical localization of Group I mGluRs and either glutamic acid decarboxylase 67 kDa isoform (GAD67), neuronal nitric oxide synthase (nNOS) or tyrosine hydroxylase (TH). Fluoro-Gold (FG, 2%; 15 nl) was microinjected in the caudal ventrolateral medulla (CVLM) of the rat to retrogradely label NTS neurons that project to CVLM. Group I mGluRs were distributed throughout the rostral-caudal extent of the NTS and were found within most NTS subregions. The relative percentages of Group I mGluR expressing neurons colabeled with the different markers were FG (6.9+/-0.7) nNOS (5.6+/-0.9), TH (3.9+/-1.0), and GAD67 (3.1+/-1.4). The percentage of FG containing cells colabeled with Group I mGluR (13.6+/-2.0) was greater than the percent colabeled with GAD67 (3.1+/-0.5), nNOS (4.7+/-0.5), and TH (0.1+/-0.08). Cells triple labeled for FG, nNOS, and Group I mGluRs were identified in the NTS. Thus, these data provide an anatomical substrate by which Group I mGluRs could modulate activity of CVLM projecting neurons in the NTS.

CNS effects of ovarian hormones and metabolites on neural control of circulation.

Pregnant women often experience orthostatic hypotension, and pregnancy is associated with increased susceptibility to hemorrhagic hypotension. Experiments evaluating arterial baroreflex control of efferent sympathetic nerve activity in virgin and term-pregnant rats revealed that arterial baroreflex sympathoexcitation is attenuated, while sympathoinhibitory responses are well-maintained or potentiated. Following a hypotensive challenge, pregnant animals exhibit attenuated Fos expression in the rostral ventrolateral medulla (RVLM), suggesting that unloading of arterial baroreceptors results in less excitation of presympathetic neurons in the brain stem. Other experiments, in which afferent baroreceptor discharge was recorded, suggest that this was not due to differences in afferent baoreceptor function. GABAergic mechanisms are responsible for tonic inhibition of sympathoexcitatory neurons in the RVLM and the major metabolite of progesterone, 3 alpha-OH-dihydro-progesterone (3 alpha-OH-DHP), which is elevated in pregnancy, is the most potent endogenous positive modulator of CNS GABAA receptor function. Additional experiments revealed that acutely administered 3 alpha-OH-DHP, either intravenously or directly into the RVLM, mimicked the effects of pregnancy on baroreflex control of efferent sympathetic nerve activity and potentiated pressure sensitivity of spinally projecting RVLM neurons. Preliminary experiments using semiquantitative RT-PCR, evaluated the relative expression of three subunits (alpha 1-3) of the GABAA receptor, and suggest that chronic exposure to elevated levels of ovarian hormones can result to changes in GABAA receptor subunit composition. It is likely that changes in control of sympathetic outflow in pregnancy are related to complex interactions between genomic and nongenomic actions of ovarian hormones and metabolites.

Thyroid status influences baroreflex function and autonomic contributions to arterial pressure and heart rate.

The effect of thyroid status on arterial baroreflex function and autonomic contributions to resting blood pressure and heart rate (HR) were evaluated in conscious rats. Rats were rendered hyperthyroid (Hyper) or hypothyroid (Hypo) with triiodothyronine and propylthiouracil treatments, respectively. Euthyroid (Eut), Hyper, and Hypo rats were chronically instrumented to measure mean arterial pressure (MAP), HR, and lumbar sympathetic nerve activity (LSNA). Baroreflex function was evaluated with the use of a logistic function that relates LSNA or HR to MAP during infusion of phenylephrine and sodium nitroprusside. Contributions of the autonomic nervous system to resting MAP and HR were assessed by blocking autonomic outflow with trimethaphan. In Hypo rats, the arterial baroreflex curve for both LSNA and HR was shifted downward. Hypo animals exhibited blunted sympathoexcitatory and tachycardic responses to decreases in MAP. Furthermore, the data suggest that in Hypo rats, the sympathetic influence on HR was predominant and the autonomic contribution to resting MAP was greater than in Eut rats. In Hyper rats, arterial baroreflex function generally was similar to that in Eut rats. The autonomic contribution to resting MAP was not different between Hyper and Eut rats, but predominant parasympathetic influence on HR was exhibited in Hyper rats. The results demonstrate baroreflex control of LSNA and HR is attenuated in Hypo but not Hyper rats. Thyroid status alters the balance of sympathetic to parasympathetic tone in the heart, and the Hypo state increases the autonomic contributions to resting blood pressure.

Comparison of MRI and MRA findings in children with a variety of neurologic conditions.

The role of MRA in the evaluation of children is evolving. We compared MRA and MRI in children with a variety of neurologic conditions to determine when MRA provides positive, cost-beneficial information. A total of 114 patients were retrospectively studied. MRA and MRI were performed and compared. MRA was abnormal in 34 (30%) of 114 patients: five (83%) of six with Menkes' disease, four (33%) of 12 with sickle cell disease, 12 (38%) of 32 with vascular malformations, one (6%) of 17 with headaches, seven (24%) of 24 with new focal deficits, one (10%) of 10 with seizures, and four (31%) of 13 with miscellaneous diagnoses. MRA and MRI were concordant in 73 (64%) of 114. Maximum concordance was in patients with Menkes' disease (100%) and minimum in those with new focal deficits (50%). The best MRA cost/benefit ratios were obtained in patients with Menkes' disease, vascular malformations, and sickle cell disease. A normal MRI usually forecasted a normal MRA. However, abnormal MRI findings did not always predict MRA abnormalities. Positive, cost-beneficial information is provided by MRA mostly in conditions known to involve the cerebral vasculature. Indications to perform MRA should be based on the neurologic diagnosis and MRI findings.

West syndrome in tuberous sclerosis complex.

West syndrome occurs commonly in children with tuberous sclerosis complex and is associated with a grave prognosis for cognitive and seizure outcomes. We sought to determine the epilepsy outcome of children with tuberous sclerosis complex and West syndrome and whether EEG, MRI, or steroid therapy duration were different in those whose epilepsy improved compared with those with intractable seizures. Seventeen patients with tuberous sclerosis complex and West syndrome were identified. For each patient, two sets of clinical evaluations, EEG and MRI data, and treatment information separated by at least 12 months were obtained. The patients were divided into two seizure outcome groups. EEG, MRI, and treatment data were compared between the groups. The intellectual deficiency was either severe (76%) or moderate (24%). Seizure control improved in 10 and worsened in seven, without mortality (follow-up range = 12-216 months). No significant differences in EEG background, MRI findings, or steroid treatment duration were evident between the groups. The difference in EEG-sleep approached statistical significance (P = 0.06). Our findings did not confirm reports of high mortality and poor epilepsy outcome in intellectually deficient children with West syndrome and tuberous sclerosis complex. EEG sleep was the best indicator of seizure control and approached statistical significance. The duration of steroid therapy had no influence on seizure control.

The ketogenic diet in refractory epilepsy: the experience of Children's Hospital of Pittsburgh.

The ketogenic diet appears to be effective in reducing seizure frequency in patients with epilepsy refractory to antiepileptic drug therapy. Reported seizure frequencies before and after the diet was initiated were obtained for 48 patients started on the ketogenic diet between December 1994 and January 1998 at Children's Hospital of Pittsburgh. The majority of patients (71%) were able to achieve > or = 50% reduction in seizure activity. Of these, more than half (53%) had > 90% reduction in seizures after 45 days of diet therapy. Complications included gastrointestinal complaints and infrequent lipid abnormalities. The ketogenic diet appears to be an effective method of treatment for children with epilepsy refractory to drug therapy.

Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging.

Tuberous sclerosis complex is a disease that affects many organs, including the central nervous system. Nervous system involvement in the form of hamartomas often results in seizures. In this study we wanted to determine the outcome of epilepsy in tuberous sclerosis complex and determine whether interictal electroencephalograms (EEGs) and hamartoma burden as seen with magnetic resonance imaging (MRI) are predictive of degree of seizure control. The study population consisted of 30 patients. For each patient two sets of EEG and MRI data, separated by at least 12 months, and information on seizure frequency at time of data collection were obtained. Sensitivity, specificity, and positive and negative predictive values of various EEG and MRI findings were determined. Seizure control improved in 20 and worsened in 10 patients. In relation to seizure control, the specificity of an abnormal sleep EEG and the positive predictive value of normal sleep EEG were 100%. MRI and EEG background were neither sensitive nor specific for predicting seizure control. A majority of children with tuberous sclerosis complex can achieve good seizure control. The sleep EEG is helpful in predicting eventual seizure control.

Long-term computer-assisted outpatient electroencephalogram monitoring in children and adolescents.

The aims of this study were (1) to define the role of long-term computer-assisted outpatient electroencephalographic monitoring (COEEG) in children and adolescents with known or suspected epilepsy, and (2) to compare COEEG data with routine interictal electroencephalograms (EEG). We performed 18-channel COEEG in 84 children and adolescents with diagnosed (group 1, n = 49) or suspected (group 2, n = 35) epilepsy. Mean recording time was 1.4 days. Overall, COEEG was useful in 87% of patients. In group 1, events were recorded in 73% of patients and were electrographic seizures in 45%. In group 2, events were detected in 86% of patients and were electrographic seizures in 17%. Nocturnal and partial seizures predominated. Seizure diagnosis and classification by COEEG was concordant with interictal EEG findings in 19% and discordant in 63% of patients. COEEG is a useful technique for the diagnosis of epileptic and nonepileptic events among selected children and adolescents. When compared to routine interictal EEG, COEEG could offer additional accuracy in the classification of seizures in pediatric patients.

Cardiovascular response to group I metabotropic glutamate receptor activation in NTS.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus tractus solitarius (NTS). Exogenous glutamate in the NTS activates neurons through ionotropic and metabotropic glutamate receptors (mGluRs). This study tested the hypothesis that group I mGluRs in the NTS produce depressor, bradycardic, and sympathoinhibitory responses. In urethan-anesthetized rats, unilateral 30-nl microinjections of the group I-selective mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The dose of drug that produced 50% of the maximal response (ED50) was 50-100 microM. The response to microinjection of equal concentrations of DHPG or the general mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) produced similar cardiovascular effects. The cardiovascular response to injection of DHPG or ACPD was abolished by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid did not attenuate the response to DHPG or ACPD injection. These data suggest that DHPG and ACPD activate mGluRs in the NTS and do not require ionotropic glutamate receptors to produce their cardiovascular response. In the NTS the group I mGluRs produce responses that are consistent with excitation of neurons involved in reducing sympathetic outflow, heart rate, and arterial pressure.

Glutamate in the nucleus of the solitary tract activates both ionotropic and metabotropic glutamate receptors.

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus of the solitary tract (NTS). Blockade of ionotropic glutamate receptors with kynurenic acid blocks the arterial baroreflex but, paradoxically, does not abolish the response to exogenous glutamate. This study tested the hypothesis that exogenous glutamate in the NTS activates both ionotropic and metabotropic glutamate receptors (mGluRs). In urethan-anesthetized rats, unilateral microinjections of glutamate into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The cardiovascular response to injection of glutamate was not altered by NTS blockade of mGluRs with alpha-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid attenuated the response to glutamate injection. After combined NTS injection of MCPG and kynurenic acid, the response to glutamate was blocked. These data suggest that exogenous glutamate microinjected into the NTS acts at both ionotropic glutamate receptors and mGluRs. In addition, blockade of both classes of glutamate receptors is required to block the cardiovascular response to microinjection of glutamate in the NTS.

Attenuated baroreflex control of sympathetic nerve activity after cardiovascular deconditioning in rats.

The effect of cardiovascular deconditioning on baroreflex control of the sympathetic nervous system was evaluated after 14 days of hindlimb unloading (HU) or the control condition. Rats were chronically instrumented with catheters and sympathetic nerve recording electrodes for measurement of mean arterial pressure (MAP) and heart rate (HR) and recording of lumbar (LSNA) or renal (RSNA) sympathetic nerve activity. Experiments were conducted 24 h after surgery, with the animals in a normal posture. Baroreflex function was assessed using a logistic function that related HR and LSNA or RSNA to MAP during infusion of phenylephrine and nitroprusside. Baroreflex influence on HR was not affected by HU. Maximum baroreflex-elicited LSNA was significantly reduced in HU rats (204 +/- 11.9 vs. 342 +/- 30.6% baseline LSNA), as was maximum reflex gain (-4.0 +/- 0.6 vs. -7.8 +/- 1.3 %LSNA/mmHg). Maximum baroreflex-elicited RSNA (259 +/- 10.8 vs. 453 +/- 28.0% baseline RSNA), minimum baroreflex-elicited RSNA (-2 +/- 2.8 vs. 13 +/- 4.5% baseline RSNA), and maximum gain (-5.8 +/- 0.5 vs. -13.6 +/- 3.1 %RSNA/mmHg) were significantly decreased in HU rats. Results demonstrate that baroreflex modulation of sympathetic nervous system activity is attenuated after cardiovascular deconditioning in rodents. Data suggest that alterations in the arterial baroreflex may contribute to orthostatic intolerance after a period of bedrest or spaceflight in humans.

Ultrasound-tailored functional hemispherectomy for surgical control of seizures in children.

Functional hemispherectomy techniques have been designed to minimize the long-term complications of anatomical resection without reducing the effectiveness of seizure control. The authors have used an ultrasound-guided approach tailored to combine temporal lobectomy with frontal and occipital disconnections with a central topectomy of the lateral, insular, and interhemispheric cortex. This technique achieves a comprehensive functional disconnection and minimizes entrance and manipulation within the body of the lateral ventricle. Eight patients ranging in age from 10 months to 23 years with congenital paresis and medically intractable seizures underwent functional hemispherectomy via this technique. The average surgical time was 4.5 hours, and blood loss ranged from 90 to 400 ml. All but one patient was discharged after 5 days. Postoperative fever syndromes, aseptic meningitis, and infection were avoided. On long-term follow-up evaluation (range 18-60 months, mean 38 months), seven of eight patients remain seizure free and were not on a course of anticonvulsant agents. Advantages of this technique include avoiding entrance into the ventricle, a more predictable postoperative period, and reduced postoperative complications.

Diagnostic value of pediatric outpatient video-EEG.

Outpatient video-electroencephalography (OVEEG) was performed in 100 infants, children, and adolescents with diagnosed (group I, n = 64) or suspected (group II, n = 36) epilepsy. Median monitoring duration was 4 hours. Indications for OVEEG in group I were classification of seizures, reported seizure exacerbation, or onset of new signs. OVEEG indications in group II were repetitive paroxysmal and stereotyped signs of myoclonic movements, fixed gaze, abnormal behavior, or nonmyoclonic motor activity. In group I patients, symptomatic events were recorded in 89%, half of which were seizures. Among group II patients, events were recorded in 67% and were seizures in 22%. Overall, OVEEG was successful in 83% of patients. Compared to a 24-hour inpatient admission for video-EEG monitoring, OVEEG represented cost reductions of 55-80% per patient. We conclude that OVEEG is a cost-effective, useful alternative to continuous inpatient video-EEG monitoring in the investigation of selected infants, children, and adolescents with diagnosed or suspected epilepsy.

The epileptiform significance of intermittent rhythmic delta activity in childhood.

Intermittent rhythmic delta activity is reported in various disorders and is classified as a nonspecific abnormal electroencephalographic pattern. We have investigated its clinical and electroencephalographic features in childhood. Intermittent rhythmic delta activity was identified in 54 children over a period of 48 months. Epilepsy was present in 81%, 4% had only a single generalized tonic-clonic seizure, and 15% had no seizures. Generalized seizures were more common than partial seizures (83% versus 13%; 4% were mixed). The largest group of patients had idiopathic epilepsy. Epileptiform features were present in 70%. No patient identified prospectively has had a space-occupying lesion. Intermittent rhythmic delta activity should be considered an epileptiform pattern in children, most commonly occurring as an interictal pattern in primary generalized epilepsy.

Cerebral edema causing death in children with maple syrup urine disease.

Four children with the classic form of maple syrup urine disease (MSUD) died of cerebral edema during an intercurrent infection that caused severe dehydration and acidosis. The diagnosis of MSUD had been established during the neonatal period in all four patients, on day 1 of life in three of them. All were in satisfactory control before the intercurrent illness. Two patients underwent peritoneal dialysis. Signs of brain-stem compression occurred after treatment, when biochemical abnormalities were improving. Computed tomography of the head, which was done in two patients, revealed cerebral edema; one of these patients also had subarachnoid hemorrhage. Autopsy in one case revealed cerebral edema with herniation. Our experience documents that cerebral edema may occur in the older child with MSUD as well as in the neonate. The pathogenesis of cerebral edema in MSUD remains unclear. Early treatment of dehydration and acidosis may prevent the catastrophic consequences that we have observed.

Value of plasmapheresis in hepatic encephalopathy.

Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.