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.

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.

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.

Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To provide evidence-based recommendations on the treatment of nervous system Lyme disease and post-Lyme syndrome. Three questions were addressed: 1) Which antimicrobial agents are effective? 2) Are different regimens preferred for different manifestations of nervous system Lyme disease? 3) What duration of therapy is needed? METHODS: The authors analyzed published studies (1983-2003) using a structured review process to classify the evidence related to the questions posed. RESULTS: The panel reviewed 353 abstracts which yielded 112 potentially relevant articles that were reviewed, from which 37 articles were identified that were included in the analysis. CONCLUSIONS: There are sufficient data to conclude that, in both adults and children, this nervous system infection responds well to penicillin, ceftriaxone, cefotaxime, and doxycycline (Level B recommendation). Although most studies have used parenteral regimens for neuroborreliosis, several European studies support use of oral doxycycline in adults with meningitis, cranial neuritis, and radiculitis (Level B), reserving parenteral regimens for patients with parenchymal CNS involvement, other severe neurologic symptomatology, or failure to respond to oral regimens. The number of children (> or =8 years of age) enrolled in rigorous studies of oral vs parenteral regimens has been smaller, making conclusions less statistically compelling. However, all available data indicate results are comparable to those observed in adults. In contrast, there is no compelling evidence that prolonged treatment with antibiotics has any beneficial effect in post-Lyme syndrome (Level A).

Cognitive functioning in children and adolescents with multiple sclerosis.

OBJECTIVE: To examine cognitive functioning in children with multiple sclerosis (MS). METHODS: The authors examined the neuropsychological profile of 37 children with a diagnosis of clinically definite MS and assessed the associations between cognitive function and clinical features. RESULTS: Of 37 children and adolescents evaluated, 35% demonstrated significant cognitive impairment. Cognitive functioning was strongly related to several clinical variables, including current Expanded Disability Status Scale, total number of relapses, and total disease length. The consequences of MS adversely affected academic functioning in over a third of the children. CONCLUSIONS: Cognitive deficits occur in children with multiple sclerosis. Comprehensive treatment planning should involve recognition that they may require academic accommodations for their education.

Tick-borne diseases.

Tick-transmitted infectious agents have assumed increased importance as causes of human disease in the United States. During the past two decades, Lyme borreliosis, ehrlichiosis, and babesiosis have emerged as newly described tick-borne infectious diseases of significance for pediatricians and pediatric neurologists. In fact, the highest rates of infection for Lyme disease and Rocky Mountain spotted fever (RMSF), by decade of age, are in childhood. As such, tick-borne infectious disease are of considerable public health concern, particularly for children residing in endemic regions. RMSF and human ehrlichioses can be life-threatening but are also eminently treatable when recognized early. Delays in diagnosis and treatment can lead to adverse outcomes. This article reviews the clinical and epidemiological features of Lyme borreliosis, RMSF, and ehrlichiosis, important causes of neurological illness among children, and summarizes current therapeutic and preventive strategies.

Cerebrospinal fluid findings in children with Lyme disease-associated facial nerve palsy.

OBJECTIVE: To determine the relative frequency of abnormal cerebrospinal fluid (CSF) findings in children with Lyme disease-associated facial nerve palsy. DESIGN: A clinical series. A prospective evaluation was undertaken of the condition of children seen between 1988 and 1996 at a single medical center in a Lyme disease endemic area. PATIENTS: Forty children (24 boys and 16 girls, aged 3-19 years) with new onset facial nerve palsy who met the Centers for Disease Control and Prevention case definition of Lyme disease. INTERVENTIONS: Neurologic examinations. Cerebrospinal fluid analysis. MAIN OUTCOME MEASURES: Rates of abnormal CSF findings: white blood cell count, protein level, and Borrelia burgdorferi-specific CSF assays. RESULTS: Cerebrospinal fluid white blood cell count, protein level, or both were abnormal in 27 (68%) of the children. Thirty-six (90%) of the 40 children had a CSF abnormality consistent with central nervous system infection or immune involvement by B burgdorferi. Of the 22 children with CSF pleocytosis, only 7 (32%) had headache and none had meningeal signs. CONCLUSIONS: Most children with Lyme disease-associated facial nerve palsy have CSF abnormalities. Our studies indicate that, in endemic areas, facial nerve palsy in children may be a marker of Lyme disease and occult meningitis. When Lyme disease is suspected, CSF should be examined; in some cases, it may be helpful to expand beyond routine CSF studies to look at a battery of B burgdorferi-specific assays.

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.

Pediatric neuro-AIDS. Update.

Vertically transmitted HIV-1 infection occurs in an immature developing organism. The maturational stage of the nervous and immune system when exposed to the direct or indirect effects of the virus is likely to be of utmost importance. Innumerable dynamic interactions occur between these two systems during development, and these undoubtedly interact in complex ways with HIV-1 variables. To care for these children and to design rational approaches for treatment and prevention, it is now critical to develop a better understanding of how HIV-1 affects the developing nervous system.

Neurologic status of human immunodeficiency virus 1-infected infants and their controls: a prospective study from birth to 2 years. Mothers and Infants Cohort Study.

OBJECTIVE: To determine the timing, extent, severity, and persistence of neurologic abnormalities in children with perinatally acquired human immunodeficiency virus 1 (HIV-1) infection compared with similar uninfected children of HIV-1-infected women and control children. METHODS: Serial neurologic examinations and head circumference measurements were performed on a cohort of HIV-1-infected children born to HIV-1-infected women, seroreverting children born to HIV-1-infected women, and control children born to uninfected women. Examination data from 32 HIV-1-infected children, 99 reverters, and 116 control children were summarized by eight neurologic domains. Data were analyzed by longitudinal analysis. RESULTS: Reverter children were not different from control children in neurologic function for any of the eight domains or head circumference. HIV-1-infected children had significantly more neurologic problems than the control and reverter children for seven of the eight domains. The HIV-1-infected children were further classified by whether they had acquired immunodeficiency syndrome (AIDS)-defining clinical conditions (other than lymphoid interstitial pneumonitis) in the first 24 months of life (the AIDS-opportunistic infection group) or did not (the infected-other group). Neurologic abnormalities were early, severe, pervasive, and persistent in the AIDS-opportunistic infection group, and nearly all in this group had head circumference measurements below the 10th percentile. The infected-other group had no statistically significant differences from the uninfected children, although individual children in the infected-other group had some abnormalities. CONCLUSIONS: In utero exposure to HIV-1 without infection seems to have no negative impact on neurologic function in children in the first 2 years of life. Among children with perinatally acquired HIV-1 infection, the most severe and pervasive neurologic problems occur in those children who have early serious HIV-1 clinical disease. Most children without serious AIDS-defining clinical conditions in the first 2 years of life are also free from serious neurologic problems during that period.

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.

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.

Neurologic syndromes.

It is now well recognized that HIV-1 associated CNS disease may complicate the course of HIV-1 infection and AIDS in infants and children. It is also well recognized that the neurologic dysfunction in these young patients adds significantly to the morbidity of the disease and is often a devastating complication. It is apparent that HIV-1 CNS infection in infants and young children is complicated by numerous developmental issues. The effects, direct and indirect, of HIV-1 on the developing nervous system must be considered. The effects of HIV-1 on the immature immune system must also be considered. Moreover, the possible effects of HIV-1 on the many complex interactions between these two systems during development will clearly also require investigation. In order to care for these children and to design rational approaches for treatment and prevention, it is now critical to develop a better understanding of how HIV-1 affects the developing nervous system.

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.

MRI findings in children infected by Borrelia burgdorferi.

Cranial magnetic resonance imaging abnormalities were observed in 8 children (5 boys, 3 girls; ages 4-14 years) with neurologic problems following infection by Borrelia burgdorferi, the etiologic agent of Lyme disease. Neurologic features included headache (6), behavioral changes (5), facial palsy (2), papilledema (2), papilledema with diplopia (1), disturbance of sleep pattern (2), and carpal tunnel syndrome (1). Two MRI studies demonstrated multiple focal areas of increased signal intensity in white matter on long TR (both proton-density and T2-weighted) images.

Acquired immunodeficiency syndrome and the child's central nervous system.

Human immunodeficiency virus-1 (HIV-1) associated central nervous system disease may complicate the course of HIV-1 infection in infants and children. Neurologic dysfunction in these young patients adds significantly to the morbidity of the disease and is often a devastating complication. It is apparent that HIV-1 infection in infants and young children is complicated by numerous developmental parameters. The developmental stage of the nervous and immune systems when exposed to the virus is likely to interact in complex ways with HIV-1 variables. In order to care for these children and to design rational approaches for treatment and prevention, it is now critical to develop a better understanding of how HIV-1 affects the developing nervous system.

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.

Cerebrospinal fluid immune complexes in patients exposed to Borrelia burgdorferi: detection of Borrelia-specific and -nonspecific complexes.

We analyzed cerebrospinal fluid (CSF) from 32 patients with neurological symptoms and evidence of Borrelia burgdorferi infection (29 were seropositive as determined by enzyme-linked immunosorbent assay, 2 were cell-mediated immune positive, and 1 had been seropositive as shown by enzyme-linked immunosorbent assay 9 months previously). CSF immune complexes were found in 22 (69%) of 32 patients; in 18, there was sufficient sample to isolate immune complexes. By enzyme-linked immunosorbent assay, isolated immune complexes from 10 of these 18 patients contained antibody specific for B. burgdorferi antigens. The isotypes were IgG (n = 8), IgM (n = 3), and IgA (n = 2). By immunoblot, these antibodies were directed against B. burgdorferi 41-kDa antigen and occasionally against the 33- and 17-kDa antigens. Anti-B. burgdorferi IgM was present in patients with acute neurological symptoms, was predominantly complexed rather than free, and decreased with clinical recovery in the one serial study. Three patients were nonreactive for free CSF antibodies, but had complexed antibodies to the organism. The preliminary finding of specific B. burgdorferi components in immune complexes in CSF suggests an active process triggered by the organism, even in the absence of other CSF abnormalities.

Primary central nervous system lymphoma in a pediatric patient with acquired immune deficiency syndrome. Treatment with radiation therapy.

Primary central nervous system (CNS) lymphoma, an otherwise rare pediatric tumor, has been reported with increasing frequency in children with acquired immune deficiency syndrome (AIDS). With current therapy, the outcome of this disease is invariably fatal. The authors present a case of primary CNS lymphoma in a 3.5-year-old girl with AIDS who received treatment with total brain irradiation. After treatment, the patient's mental status improved, the seizures resolved, and she had no further progression of her neurologic symptoms until she died of pneumonia 6 months later. The autopsy revealed a necrotic mass at the site of the original tumor. The brain stem and spinal cord, unirradiated, contained lymphomatous lesions. The patient had extensive fibrinoid necrosis and leukoencephalopathy that were consistent with radiation-induced CNS damage. Coexisting AIDS encephalopathy also contributed to the patient's CNS injury. Effective palliation of CNS lymphoma in children with AIDS may be obtained with cranial irradiation. Pediatric AIDS patients may show more severe tissue effects from irradiation than unaffected children.