Social cognition in pediatric-onset multiple sclerosis (MS).

BACKGROUND: Pediatric-onset multiple sclerosis (MS) patients represent a subpopulation who are diagnosed during the course of development. Social cognitive deficits have recently been recognized in adults with MS. It is critical to identify whether these youngest patients with the disorder are also at risk. OBJECTIVE: To determine whether pediatric-onset MS is associated with social cognitive deficits. METHODS: Consecutively-recruited participants with pediatric-onset MS were compared to a group of age- and gender-matched healthy controls on Theory of Mind (ToM) task performance. Tasks measured facial affect recognition (Reading the Mind in the Eyes Test), detecting social faux pas (Faux Pas Test), and understanding the perspective of another (False Beliefs Task). RESULTS: Twenty-eight (28) pediatric-onset MS participants (median age 17 years) and 32 healthy controls (median age 16 years) completed the study. The MS participants performed worse than controls on all three ToM tasks: Reading the Mind in the Eyes Test (p = 0.008), the Faux Pas Test (p = 0.009), and the False Beliefs Task (p = 0.06). While more MS than control participants were impaired on a measure of information processing speed (the Symbol Digit Modalities Test; 38% versus 6%), it did not account for the differences in ToM performance. CONCLUSIONS: Social cognition may represent an area of cognitive functioning affected by MS in the pediatric-onset population. These processes are especially important to study in younger patients as they may have long range implications for social adjustment, employment, and well-being.

Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network.

BACKGROUND: Approximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time. OBJECTIVE: Changes in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers. METHODS: A total of 67 individuals with pediatric MS (n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8-17 years of age (mean age ± standard deviation (SD)=14.37 ± 2.02) completed initial and follow-up neuropsychological testing after an average of 1.64 ± 0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning. RESULTS: Rate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure. CONCLUSION: Findings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Parental preferences in the management of vesicoureteral reflux.

PURPOSE: Considering that there are few absolute indications for the timing and type of surgical correction of vesicoureteral reflux, we objectively measured parental choice in how the child's vesicoureteral reflux should be managed. MATERIALS AND METHODS: We prospectively identified patients 0 to 18 years old with any grade of newly diagnosed vesicoureteral reflux. All races and genders were included, and non-English speakers were excluded from analysis. Parents were shown a video presented by a professional actor that objectively described vesicoureteral reflux and the 3 treatment modalities of antibiotic prophylaxis, open ureteral reimplantation and endoscopic treatment. Then they completed a questionnaire regarding their preference for initial management, and at hypothetical followup points of 18, 36 and 54 months. Consultation followed with the pediatric urologist who was blinded to the questionnaire results. RESULTS: A total of 86 girls and 15 boys (150 refluxing units) were enrolled in the study. Mean patient age was 2.6 years old. Preferences for initial treatment were antibiotic prophylaxis in 36, endoscopic surgery in 26, open surgery in 11, unsure in 26 and no response in 2. Among those initially selecting antibiotic prophylaxis, after 18 months the preference was for endoscopic treatment, but after 36 and 54 months preferences trended toward open surgery. After consultation with the pediatric urologist 68 parents chose antibiotic prophylaxis. CONCLUSIONS: Our data show that antibiotic prophylaxis is preferred as the initial therapy for vesicoureteral reflux by 35.6% of parents. However, given persistent vesicoureteral reflux, preferences shifted toward surgery. With time the preference for open surgery increased and the preference for endoscopic surgery decreased.

Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid.

PURPOSE: Children in whom nonsurgical management for vesicoureteral reflux fails are considered candidates for surgical intervention. An option is endoscopic treatment with Deflux(R). We reviewed our experience with febrile urinary tract infections in children following initial successful treatment of vesicoureteral reflux with Deflux and identified factors predictive of post-Deflux urinary tract infections. We also analyzed the incidence of delayed vesicoureteral reflux recurrence in these patients. MATERIALS AND METHODS: We performed a retrospective chart review of all children from 2002 to 2006 diagnosed with grades I to IV vesicoureteral reflux who were treated with Deflux and who had a negative initial followup voiding cystourethrogram at 2 to 5 months. Patients were categorized into post-Deflux infection and infection-free groups. Predictive factors, including the number of preoperative febrile urinary tract infections, dysfunctional elimination and renal cortical defects on dimercapto-succinic acid scan, were analyzed and compared. RESULTS: Of the patients 45 met all study inclusion and exclusion criteria. A total of 12 patients (27%) who were diagnosed with a culture documented febrile urinary tract infection were categorized into the infection group. Of 12 children in the post-Deflux infection group 11 (92%) had multiple predictors compared to 14 of 33 (42%) who remained infection-free (p = 0.005). Ten of these 12 patients (92%) were found to have evidence of vesicoureteral reflux when evaluated with voiding cystourethrogram/radionuclide cystogram after infection. CONCLUSIONS: This study demonstrates that up to 27% of patients treated endoscopically may have a febrile urinary tract infection after an initial negative postoperative voiding cystourethrogram/radionuclide cystogram at 2 to 5 months and up to 92% of those will demonstrate delayed vesicoureteral reflux recurrence. Children with a history of 2 or more predictive factors, including multiple febrile urinary tract infections, dysfunctional elimination and/or renal cortical defects on dimercapto-succinic acid scan, may not be optimal candidates for Deflux. If endoscopic treatment is chosen, these patients require more vigilant followup, including late voiding cystourethrogram.

Simultaneous expression of Borrelia OspA and OspC and IgM response in cerebrospinal fluid in early neurologic Lyme disease.

Lyme disease is the major tick-borne disease, caused by Borrelia burgdorferi (Bb). Neurological involvement is common in all stages. In vivo expression of Bb antigens (Ags) and the immune response to them has not been well investigated in the cerebrospinal fluid (CSF). Upregulation of outer surface protein (Osp) C and concomitant downregulation of OspA before tick inoculation of the spirochete has been reported in skin and blood in animals. CSF OspA Ag in early disease suggests otherwise in CSF. Early Ag expression and IgM response in human CSF was investigated here. Paired CSF and serum was collected from 16 early, predominantly erythema migrans Lyme disease patients with neurologic problems, 13 late Lyme disease patients, and 19 other neurologic disease (OND) controls. Samples were examined for IgM reactivity to recombinant Bb-specific Osps using ELISA and immunoblot. Of 12 early Lyme disease patients with neurologic involvement with both CSF and serum IgM against OspC, 7 (58%) had IgM to OspA (n = 5) or OspB (n = 2) that was restricted to the CSF, not serum. Overall, 12 of 16 (75%) of these early Lyme disease patients with neurologic involvement had CSF and serum IgM against OspC. Only 3 of 13 (23%) late Lyme disease patients and none of 19 OND controls had CSF IgM directed against OspC. In conclusion, in CSF, OspC and OspA can be coexpressed, and IgM response to them occurs in early Lyme disease patients with neurologic involvement. This biologic finding may also provide a discriminating marker for CNS infection in Lyme disease.

Evaluating the association of allergies with multiple sclerosis susceptibility risk and disease activity in a pediatric population.

BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

The "flowerpot" sign: inference of poor renal function in high grade vesicoureteral reflux by calyceal orientation.

INTRODUCTION/OBJECTIVE: Modern radiographic advances have allowed for detailed and accurate imaging of not only urologic anatomy but also urologic function. The art of observational inference of subtle anatomic features and function from a static radiograph is being traded for new, more precise, and more expensive modalities. While the superiority of these methods cannot be denied, the total information provided in simpler tests should not be ignored. The relationship between high grade vesicoureteral reflux with the dilated calyces arranged cephalad to a dilated funnel-shaped renal pelvis on VCUG and reduced differential renal function has not been previously described, but has been anecdotally designated a "flowerpot" sign by our clinicians. We hypothesize that the appearance of a "flowerpot" kidney as described herein is an indicator of poor renal function in the setting of high grade VUR. STUDY DESIGN: IRB approval was obtained and 315 patients were identified from system-wide VCUG reports from 2004-2012 with diagnosed "high grade" or "severe" vesicoureteral reflux. Inclusion into the study required grade IV or V VUR on initial VCUG and an initial radionuclide study for determination of differential function. Patients with a solitary kidney, posterior urethral valve, multicystic dysplastic kidney, renal ectopia, or duplex collecting systems were excluded. Grade of reflux, angle of the inferior-superior calyceal axis relative to the lumbar spine, and differential uptake were recorded along with presence of the new "flowerpot" sign. Variables were analyzed using the Mann-Whitney U test to determine statistical significance. RESULTS: Fifty seven patients met inclusion criteria with 11 being designated as "flowerpot" kidneys. These "flowerpot" kidneys could be objectively differentiated from other kidneys with grade IV and/or grade V VUR both by inferior-superior calyceal axis (median angle, 52° [37-66] vs. 13° [2-37], respectively p < 0.001) and by differential renal uptake (median, 23% [5-49] vs. 45% [15-81], respectively p < 0.001). Likewise, there was no difference between either calyceal axis (median angle, 13° [3-20] vs. 13° [2-37]) or differential function (median, 48% [24-81] vs. 40% [15-66], p = 0.129) when comparing kidneys with grade IV and grade V VUR, respectively, that did not demonstrate the "flowerpot" sign. DISCUSSION/CONCLUSION: Grading of VUR is used to provide a common language for scientific discussion and determine prognosis for children with similar attributes. The dysmorphic calyceal system in the "flowerpot" kidneys supports the theory of abnormal renal blastema induction associated with abnormal differentiation of the ureteral bud. Even in the absence of urinary tract infections and/or pyelonephritis, renal abnormalities and decreased differential function can be observed on renal scintigraphy. This study also confirms the male predominance and functional similarities between grade 4 and 5 refluxing renal units. Recognizing this is a limited observational study based on imaging alone, the "flowerpot" sign is an indicator of the most severe form of grade 5 VUR but is only one factor in predicting long term overall renal prognosis. However, 14% (8/57) of our cohort had a relative uptake of less than 20% with 5 of these exhibiting the "flowerpot" sign. The "flowerpot" sign on VCUG can be used as indirect evidence of poor differential renal function and, therefore, useful in guiding parental expectations prior to formal functional imaging.

Progressive multifocal leukoencephalopathy in HIV-1-infected children.

OBJECTIVE: To describe the clinical and pathologic features of two HIV-1-infected children with progressive multifocal leukoencephalopathy (PML). DESIGN: Case report. SETTING: University-affiliated, public-health trust hospital. METHODS: Two HIV-1-infected children with PML are described. A 13-year-old girl, presumed to be congenitally infected with HIV-1, presented with dysarthria and paresthesias of the tongue and chin that evolved rapidly to dementia, muteness and severe spastic quadriparesis. The other patient, a 10-year-old boy who developed HIV-1 infection from a blood transfusion at the age of 3 years, presented with a facial palsy with subsequent development of right hemiparesis and aphasia. RESULTS: Brain biopsy in the first child and autopsy in the second confirmed the diagnosis of PML. In both patients, the CD4 T-lymphocyte count was less than 100 x 10(6)l at the time of neurological presentation. CONCLUSION: Despite seroepidemiological studies suggesting that the majority of individuals are infected with JC virus during childhood, PML is rare in children with impaired cell-mediated immunity. Our patients illustrate that PML is among the neurological complications of HIV-1 infection in children.

Neurologic manifestations in children with North American Lyme disease.

To delineate the spectrum of neurologic manifestations and the relative frequencies of different syndromes associated with North American Lyme disease, we describe 96 children referred for neurologic problems in the setting of Borrelia burgdorferi infection. The most frequent neurologic symptom was headache, and the most common sign was facial palsy. Less common manifestations were sleep disturbance, and papilledema associated with increased intracranial pressure. Signs and symptoms of peripheral nervous system involvement were infrequent. The most common clinical syndromes were mild encephalopathy, lymphocytic meningitis, and cranial neuropathy (facial nerve palsy). In contrast with adult patients with neurologic Lyme disease, meningoradiculitis (Bannwarth's syndrome) and peripheral neuropathy syndromes were rare. However, a "pseudotumor cerebri-like" syndrome seems to be unique to North American pediatric Lyme disease.

EEG and brain death determination in children.

In a retrospective study involving several medical centers we identified 52 patients under age 5 years who met the adult clinical criteria for brain death and had at least one EEG with electrocerebral silence. Of the 52 patients, 31 died spontaneously and 21 were disconnected from the respirator. Repeat EEGs were obtained in 28 patients, and in all electrocerebral silence persisted. The study suggests that clinical criteria similar to those used for adults in the determination of brain death can also be applied to children above age 3 months and that a single EEG with electrocerebral silence is sufficient to confirm brain death in this age group.

Spinal cord pathology in pediatric acquired immunodeficiency syndrome.

We examined the spinal cords from 15 consecutive autopsies of infants and children with AIDS using a battery of histochemical and immunocytochemical stains, and in four cases, electron microscopy. Corticospinal tract (CST) signs were a notable clinical finding in 14; however, the age of onset, rate of progression, severity of dysfunction, and duration varied among patients. Ten cases had pathologic changes in the CST. In four of the ten cases, the changes were consistent with an "axonopathy" since axons and myelin were both diminished in the CST. These cases may represent CST wallerian degeneration, since they had marked injury to cerebral white matter in the form of chronic inflammation with multinucleated cells, gliosis, and myelin pallor. In five cases, with an average age at death of 31 months, the CST showed poor myelination with relative preservation of axons. These cases may represent delayed myelination or possibly cytokine-mediated injury to newly formed myelin since the CST is one of the last tracts to myelinate in the spinal cord. One child with primary CNS lymphoma had a complicated pattern of spinal injury due to unilateral CST wallerian degeneration possibly superimposed upon delayed myelination, in addition to patchy areas of demyelination associated with perivascular lymphomatous infiltrates. Four children with mild CST signs, ranging in age from 5 to 6 months, had CST myelin pallor that was consistent with the degree of myelination expected for age. We did not find vacuolar myelopathy similar to that seen in adult AIDS, but did note focal vacuolar changes in the thoracic posterior columns in the oldest child.

Detection of Borrelia burgdorferi-specific antigen in antibody-negative cerebrospinal fluid in neurologic Lyme disease.

OBJECTIVE: To determine the potential of detection in CSF of specific Borrelia burgdorferi antigen, OspA, as a marker of infection in neurologic Lyme disease and compare this with the detection of antibody. DESIGN: CSF from 83 neurologic patients in an area highly endemic for Lyme disease was examined prospectively for (1) OspA by antigen capture ELISA and Western blot employing monoclonal antibodies, and for (2) B burgdorferi antibodies by ELISA. RESULTS: Of the 35 of 83 (42%) patients who were positive for OspA antigen in their CSF, 15 (43%) were antigen positive despite being antibody-negative in CSF. Seven of these 15 (47%) had otherwise normal routine CSF analyses. Six of these 15 (40%) patients met strict CDC surveillance criteria for Lyme disease; four (27%) patients had seroconversion coincident with new neurologic problems; and three (20%) with characteristic syndromes for Lyme disease were seronegative, but had complexed antibody to B burgdorferi. The final two patients (13%) were seropositive and had unexplained neurologic problems not characteristic of Lyme disease. CONCLUSIONS: B burgdorferi antigen can be detected in CSF that is otherwise normal by conventional methodology, and can be present without positive CSF antibody. Since CSF antigen implies intrathecal seeding of the infection, the diagnosis of neurologic infection by B burgdorferi should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.

AIDS: calcification of the basal ganglia in infants and children.

CT or postmortem examination demonstrated calcification of the basal ganglia in eight infants and children with acquired immune deficiency syndrome. Serial CT studies documented progression of both bilateral symmetric calcium densities and cerebral atrophy. Clinical features included progressive encephalopathy with dementia, and pyramidal tract signs. Postmortem examination of four children revealed variable degrees of calcific vasopathy of the basal ganglia, involving predominantly the putamen and globus pallidus.

Detection of Borrelia burgdorferi antigens in cerebrospinal fluid.

We examined CSF for Borrelia burgdorferi antigens using antigen-capture ELISA and Western (immuno) blot. Antigen-capture ELISA was positive in 38 of 77 (49%) CSF samples obtained from neurologic patients with presumed B burgdorferi infection, compared with one of 34 (3%) CSF samples obtained from other neurologic disease controls who came from a region endemic for Lyme disease. Western immunoblot was positive for B burgdorferi antigens in 12 of 22 (55%) CSF samples from the B burgdorferi infected groups, compared with none of 11 CSF samples from the control group. CSF antigen detection should prove helpful in evaluating patients for suspected neurologic Lyme disease.

Primary vesicoureteral reflux in the black child.

Primary vesicoureteral reflux is a polygenic abnormality due to a deficiency of the ureterovesical junction which allows urine in the bladder to ascend into the ureter and kidney. Fifty-one black children with primary vesicoureteral reflux were evaluated and treated at Children's Hospital from 1976 to 1986. The results of the evaluation and treatment were compared with those of 493 white patients with primary vesicoureteral reflux seen during the same time interval. The general approach to management was nonsurgical. There were no radical differences in the mode of presentation, age at presentation, and age at resolution. The distribution of reflux by maximum grade was not affected by race. Overall, 19 (37%) black children experienced spontaneous resolution of reflux. The mean duration of reflux in black children who had spontaneous resolution was 14.6 months. This duration was statistically significantly shorter than that in white patients with spontaneous resolution of vesicoureteral reflux (P less than .005). Surgical correction was believed to be required in 8 (16%) patients and 8 (16%) were lost to follow-up. Renal scarring demonstrated by intravenous pyelogram or renal scan was initially present in 12 (23%) black patients compared with 65 (13%) white patients. This was due to a higher percentage of renal scarring in black girls which was not explained by distribution of grades of reflux. There was no progression of scarring in our black patients, whereas 3 (0.6%) white patients had progression of scarring. Although vesicoureteral reflex is rarely seen in black patients (9% of series), it has similar demographic features.(ABSTRACT TRUNCATED AT 250 WORDS)

Testicular histology in the adolescent with a varicocele.

A varicocele is a common cause of adult male infertility, and surgical ligation is a generally accepted mode of therapy. However, the guidelines for management of the adolescent with a varicocele are not clearly defined. Herein, we describe histologic abnormalities noted on testis biopsy in nine of 24 boys with moderate to large varicoceles. Surgical ligation of the varicocele is recommended when there is volume loss of the testis ipsilateral to the varicocele. All others should be reexamined periodically, and an attempt should be made to obtain a baseline semen analysis.

Computed tomographic demonstration of cerebral edema in a child with galactosemia.

An eight-day-old male infant with galactosemia presented with signs of increased intracranial pressure and no evidence of intracranial infection or hemorrhage. Computed tomographic scans demonstrated the presence of diffuse cerebral edema. With treatment, the edema gradually resolved, although it persisted longer within the white matter and was associated with transient bilateral pyramidal tract signs.

Neurologic manifestations of Schoenlein-Henoch purpura: report of three cases and review of the literature.

Three patients developed prominent neurologic symptoms and signs associated with Schoenlein-Henoch purpura. A 7 1/2-year-old boy was seen with status epilepticus after a 2-week history of generalized headaches, irritability, and intermittent colicky abdominal pain. A left hemiparesis and a left homonymous hemianopia with a right gaze preference that were present on initial examinations gradually resolved, but a mild left arm paresis persisted. Cutaneous, renal, and joint involvement followed initial CNS manifestations. The second patient, a 7-year-old girl, had a complex partial seizure with secondary generalization and a postictal hemiparesis seven days after presentation with classic signs of Schoenlein-Henoch purpura. Behavioral changes were noted during the acute phase of the illness. The third patient, a 13-year-old boy, developed signs of a left brachial plexopathy and transient weakness of his right leg during a complicated course of Schoenlein-Henoch purpura. Review of the world literature indicates that headaches and mental status changes are the most frequent neurologic complications of Schoenlein-Henoch purpura, followed by seizures, focal neurologic deficits, mononeuropathies, and polyradiculoneuropathies. The vasculitis of Schoenlein-Henoch purpura can involve the nervous system and may add significantly to the morbidity of the illness.