Clinical Focus

  • Leukodystrophies
  • Autoimmune Diseases of the Nervous System
  • Neurology - Child Neurology

Academic Appointments

Honors & Awards

  • Inductee, Arnold Gold Humanism Honor Society (2004)
  • Commencement Speaker, University of Rochester School of Medicine (2005)
  • Medical Student Teaching Award, Stanford Dept Neurology (2009-2010)
  • Chief Resident, Stanford Dept Neurology (2009-2010)
  • Moore Award, Honorable Mention, American Association of Neuropathology (2003)
  • PERF-CNF Scientific Award, Child Neurology Foundation (2011)

Boards, Advisory Committees, Professional Organizations

  • Founding Member, ALD Connect (2014 - Present)
  • Founding Member, The Global Leukodystrophy Initiative (GLIA) (2014 - Present)

Professional Education

  • BA, College of the Holy Cross, Chemistry (1999)
  • MD, University of Rochester School of Medicine, Medicine (2005)
  • PGY1-2 Pediatrics, Massachusetts General Hospital, Pediatrics (2007)
  • PGY3-5 Neurology, Stanford University Hospitals & Clinics, Child & Adult Neurology (2010)
  • Board Certification: Neurology - Child Neurology, American Board of Psychiatry and Neurology (2010)
  • Post-doc, Steinman & Robinson Labs, Stanford University, Neuroimmunology (2014)

Research & Scholarship

Current Research and Scholarly Interests

Our lab explores the nexus of metabolic failure and inflammation. Our approach is unique. We leverage insights from neurologic disorders with known single-gene mutations to unravel the molecular mechanisms of human neuroinflammation.

Genetic disorders offer an unparalleled vantage point for understanding human biology. Immunogenetic are particularly unique because immune tissue is both accessible and modifiable. These disorders offer a unique window into basic molecular mechanisms and make exceptional targets for stem cell and gene therapies.

Our team's goals are to:
1. build foundational knowledge in human biology
2. develop transformational therapies for each disorder we study
3. train the next generation of translational scientists

Our team draws purpose and inspiration from children and adults affected by neurodegenerative disorders. We are particularly focused on genetic and autoimmune disorders that cause damage to the myelin (the fatty insulation around the nerves) of the brain and spinal cord. X-linked adrenoleukodystrophy (genetic) and multiple sclerosis (autoimmune) are the prototypical examples of degenerative disorders of myelin; these are the two disorders we study most intensively.

One of the great obstacles to understanding and treating MS is its pathological heterogeneity. MS is currently defined solely by clinical and radiological criteria. Although MS diagnostic criteria have improved over time, abundant evidence suggests that pathophysiologic "subtypes" of MS remain clinically indistinguishable. This pathophysiologic heterogeneity poses a major confounder to the development of new therapies. To combat this heterogeneity, we use ALD as a genetic model for MS.

ALD is a rare (~1:17,00), monogenetic, X-linked disorder involving a gene (ABCD1) that encodes a peroxisomal protein. The biochemical hallmark of the disease is an accumulation of very-long chain fatty acids in several tissues, including myelin and blood. The ABCD1 mutation yields a variety of neuroendocrine symptoms, but the most feared manifestation is an inflammatory cerebral demyelinating syndrome known as "cerebral ALD" that affects ~40% of ALD boys. The absence of a clear genotype-phenotype correlation for cerebral ALD suggests a role for environmental modifiers, similar to MS.

Despite the clinical and pathogenic similarities of MS and ALD, one question stands out: Why would a metabolic disorder like ALD yield a syndrome that so closely resembles MS, the prototypic neuroimmune disorder? This is the central questions animating our lab's current work.

Clinical Trials

  • A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy Recruiting

    In this pilot study, the investigators will assess the safety of two high-dose regimens of oral vitamin D supplementation and measure the effects of vitamin D supplementation on markers of oxidative stress and inflammation in the blood and brain of study participants before, during, and after taking vitamin D supplements. The goal of the study is to establish research measures (i.e. biomarkers) and an optimal dose for vitamin D supplementation in boys with the X-linked adrenoleukodystrophy (ALD) genotype.

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2018-19 Courses


All Publications

  • Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology Sotirchos, E. S., Bhargava, P., Eckstein, C., Van Haren, K., Baynes, M., Ntranos, A., Gocke, A., Steinman, L., Mowry, E. M., Calabresi, P. A. 2016; 86 (4): 382-390


    To study the safety profile and characterize the immunologic effects of high- vs low-dose cholecalciferol supplementation in patients with multiple sclerosis (MS).In this double-blind, single-center randomized pilot study, 40 patients with relapsing-remitting MS were randomized to receive 10,400 IU or 800 IU cholecalciferol daily for 6 months. Assessments were performed at baseline and 3 and 6 months.Mean increase of 25-hydroxyvitamin D levels from baseline to final visit was larger in the high-dose group (34.9 ng/mL; 95% confidence interval [CI] 25.0-44.7 ng/mL) than in the low-dose group (6.9 ng/mL; 95% CI 1.0-13.7 ng/mL). Adverse events were minor and did not differ between the 2 groups. Two relapses occurred, one in each treatment arm. In the high-dose group, we found a reduction in the proportion of interleukin-17(+)CD4(+) T cells (p = 0.016), CD161(+)CD4(+) T cells (p = 0.03), and effector memory CD4(+) T cells (p = 0.021) with a concomitant increase in the proportion of central memory CD4(+) T cells (p = 0.018) and naive CD4(+) T cells (p = 0.04). These effects were not observed in the low-dose group.Cholecalciferol supplementation with 10,400 IU daily is safe and tolerable in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects in MS, which include reduction of interleukin-17 production by CD4(+) T cells and decreased proportion of effector memory CD4(+) T cells with concomitant increase in central memory CD4(+) T cells and naive CD4(+) T cells.This study provides Class I evidence that cholecalciferol supplementation with 10,400 IU daily is safe and well-tolerated in patients with MS and exhibits in vivo pleiotropic immunomodulatory effects.

    View details for DOI 10.1212/WNL.0000000000002316

    View details for PubMedID 26718578

    View details for PubMedCentralID PMC4776090

  • Acute Flaccid Myelitis of Unknown Etiology in California, 2012-2015 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Van Haren, K., Ayscue, P., Waubant, E., Clayton, A., Sheriff, H., Yagi, S., Glenn-Finer, R., Padilla, T., Strober, J. B., Aldrovandi, G., Wadford, D. A., Chiu, C. Y., Xia, D., Harriman, K., Watt, J. P., Glaser, C. A. 2015; 314 (24): 2663-2671


    There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury.Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.Case incidence and infectious agent association.Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n?=?54), fever (n?=?47), and limb myalgia (n?=?41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P?<.001).In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

    View details for DOI 10.1001/jama.2015.17275

    View details for Web of Science ID 000366939800021

  • Consensus statement on preventive and symptomatic care of leukodystrophy patients MOLECULAR GENETICS AND METABOLISM Van Haren, K., Bonkowsky, J. L., Bernard, G., Murphy, J. L., Pizzino, A., Helman, G., Suhr, D., Waggoner, J., Hobson, D., Vanderver, A., Patterson, M. C. 2015; 114 (4): 516-526


    Leukodystrophies are inherited disorders whose primary pathophysiology consists of abnormal deposition or progressive disruption of brain myelin. Leukodystrophy patients manifest many of the same symptoms and medical complications despite the wide spectrum of genetic origins. Although no definitive cures exist, all of these conditions are treatable. This report provides the first expert consensus on the recognition and treatment of medical and psychosocial complications associated with leukodystrophies. We include a discussion of serious and potentially preventable medical complications and propose several preventive care strategies. We also outline the need for future research to prioritize clinical needs and subsequently develop, validate, and optimize specific care strategies.

    View details for DOI 10.1016/j.ymgme.2014.12.433

    View details for Web of Science ID 000353008900004

    View details for PubMedID 25577286

  • Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing- remitting multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) Van Haren, K., Tomooka, B. H., Kidd, B. A., Banwell, B., Bar-Or, A., Chitnis, T., Tenembaum, S. N., Pohl, D., Rostasy, K., Dale, R. C., O'Connor, K. C., Hafler, D. A., Steinman, L., Robinson, W. H. 2013; 19 (13): 1726-1733


    BACKGROUND AND OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them. METHODS: We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles. RESULTS: ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62-86%; specificity 56-79%) from MS serum (sensitivity 40-87%; specificity 62-86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides. CONCLUSIONS: Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.

    View details for DOI 10.1177/1352458513485653

    View details for PubMedID 23612879

  • Identification of Naturally Occurring Fatty Acids of the Myelin Sheath That Resolve Neuroinflammation SCIENCE TRANSLATIONAL MEDICINE Ho, P. P., Kanter, J. L., Johnson, A. M., Srinagesh, H. K., Chang, E., Purdy, T. M., Van Haren, K., Wikoff, W. R., Kind, T., Khademi, M., Matloff, L. Y., Narayana, S., Hur, E. M., Lindstrom, T. M., He, Z., Fiehn, O., Olsson, T., Han, X., Han, M. H., Steinman, L., Robinson, W. H. 2012; 4 (137)


    Lipids constitute 70% of the myelin sheath, and autoantibodies against lipids may contribute to the demyelination that characterizes multiple sclerosis (MS). We used lipid antigen microarrays and lipid mass spectrometry to identify bona fide lipid targets of the autoimmune response in MS brain, and an animal model of MS to explore the role of the identified lipids in autoimmune demyelination. We found that autoantibodies in MS target a phosphate group in phosphatidylserine and oxidized phosphatidylcholine derivatives. Administration of these lipids ameliorated experimental autoimmune encephalomyelitis by suppressing activation and inducing apoptosis of autoreactive T cells, effects mediated by the lipids' saturated fatty acid side chains. Thus, phospholipids represent a natural anti-inflammatory class of compounds that have potential as therapeutics for MS.

    View details for DOI 10.1126/scitranslmed.3003831

    View details for Web of Science ID 000305075700005

    View details for PubMedID 22674551

    View details for PubMedCentralID PMC3953135

  • Safety, tolerability, and efficacy of fluoxetine as an antiviral for acute flaccid myelitis. Neurology Messacar, K., Sillau, S., Hopkins, S. E., Otten, C., Wilson-Murphy, M., Wong, B., Santoro, J. D., Treister, A., Bains, H. K., Torres, A., Zabrocki, L., Glanternik, J. R., Hurst, A. L., Martin, J. A., Schreiner, T., Makhani, N., DeBiasi, R. L., Kruer, M. C., Tremoulet, A. H., Van Haren, K., Desai, J., Benson, L. A., Gorman, M. P., Abzug, M. J., Tyler, K. L., Dominguez, S. R. 2018


    OBJECTIVE: To determine the safety, tolerability, and efficacy of fluoxetine for proven or presumptive enterovirus (EV) D68-associated acute flaccid myelitis (AFM).METHODS: A multicenter cohort study of US patients with AFM in 2015-2016 compared serious adverse events (SAEs), adverse effects, and outcomes between fluoxetine-treated patients and untreated controls. Fluoxetine was administered at the discretion of treating providers with data gathered retrospectively. The primary outcome was change in summative limb strength score (SLSS; sum of Medical Research Council strength in all 4 limbs, ranging from 20 [normal strength] to 0 [complete quadriparesis]) between initial examination and latest follow-up, with increased SLSS reflecting improvement and decreased SLSS reflecting worsened strength.RESULTS: Fifty-six patients with AFM from 12 centers met study criteria. Among 30 patients exposed to fluoxetine, no SAEs were reported and adverse effect rates were similar to unexposed patients (47% vs 65%, p = 0.16). The 28 patients treated with >1 dose of fluoxetine were more likely to have EV-D68 identified (57.1% vs 14.3%, p < 0.001). Their SLSS was similar at initial examination (mean SLSS 12.9 vs 14.3, p = 0.31) but lower at nadir (mean SLSS 9.25 vs 12.82, p = 0.02) and latest follow-up (mean SLSS 12.5 vs 16.4, p = 0.005) compared with the 28 patients receiving 1 (n = 2) or no (n = 26) doses. In propensity-adjusted analysis, SLSS from initial examination to latest follow-up decreased by 0.2 (95% confidence interval [CI] -1.8 to +1.4) in fluoxetine-treated patients and increased by 2.5 (95% CI +0.7 to +4.4) in untreated patients (p = 0.015).CONCLUSION: Fluoxetine was well-tolerated. Fluoxetine was preferentially given to patients with AFM with EV-D68 identified and more severe paralysis at nadir, who ultimately had poorer long-term outcomes.CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with EV-D68-associated AFM, fluoxetine is well-tolerated and not associated with improved neurologic outcomes.

    View details for DOI 10.1212/WNL.0000000000006670

    View details for PubMedID 30413631

  • Pediatric Bickerstaff brainstem encephalitis: a systematic review of literature and case series JOURNAL OF NEUROLOGY Santoro, J., Lazzareschi, D. V., Campen, C., Van Haren, K. P. 2018; 265 (1): 141?50


    To characterize the phenotype of pediatric Bickerstaff's brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures.We systematically reviewed PubMed, Web of Science, and SCOPUS databases as well as medical records at the Lucile Packard Children's Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ? 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia.We reviewed 682 manuscripts, identifying a total of 47 pediatric BBE cases. We also describe five previously unreported cases. The phenotype of these pediatric patients was similar to previously published literature. Sixty-eight percent of patients demonstrated positive anti-GQ1b antibody titers, yet the presence of these antibodies was not associated with longer times to recovery. Patients with neuroimaging abnormalities featured a longer median time to recovery, but this was not statistically significant (p = 0.124). Overall, patients treated with any form of immunotherapy (intravenous immunoglobulin, steroids, or plasmapheresis) demonstrated shorter median time to resolution of symptoms compared to supportive therapy, although this trend was not statistically significant (p = 0.277). Post-hoc t tests revealed a trend towards use of immunotherapy against supportive care alone (p = 0.174).Our study identified clinical, radiologic, and treatment features that may hold prognostic value for children with BBE. The role of immunotherapy remains under investigation but may prove of utility with further, randomized controlled studies in this rare disease.

    View details for DOI 10.1007/s00415-017-8684-8

    View details for Web of Science ID 000419777000019

    View details for PubMedID 29177548

  • Neonatal detection of Aicardi Goutieres Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots MOLECULAR GENETICS AND METABOLISM Armangue, T., Orsini, J. J., Takanohashi, A., Gavazzi, F., Conant, A., Ulrick, N., Morrissey, M. A., Nahhas, N., Helman, G., Gordish-Dressman, H., Orcesi, S., Tonduti, D., Stutterd, C., van Haren, K., Toro, C., Iglesias, A. D., van der Knaap, M. S., Mansky, R., Moser, A. B., Jones, R. O., Vanderver, A. 2017; 122 (3): 134?39
  • CD141 Monocyte Transcriptomes from Multiple Sclerosis Patients Enrolled in a Clinical Trial of Vitamin D Highlights Metabolic Pathways Relevant to Immune Regulation Van Haren, K., Schubert, S., Eid, R., Kirloskar, K., Cho, Y., Mowry, E., Calabresi, P. WILEY. 2017: S277
  • Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings JOURNAL OF CHILD NEUROLOGY Song, H., Haeri, S., Vogel, H., van der Knaap, M., Van Haren, K. 2017; 32 (10): 867?70


    We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care.The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories.Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening.These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders.

    View details for DOI 10.1177/0883073817712588

    View details for Web of Science ID 000407901800002

    View details for PubMedID 28597716

  • Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies MOLECULAR GENETICS AND METABOLISM Adang, L. A., Sherbini, O., Ball, L., Bloom, M., Darbari, A., Amartino, H., DiVito, D., Eichler, F., Escolar, M., Evans, S. H., Fatemi, A., Fraser, J., Hollowell, L., Jaffe, N., Joseph, C., Karpinski, M., Keller, S., Maddock, R., Mancilla, E., McClary, B., Mertz, J., Morgart, K., Langan, T., Leventer, R., Parikh, S., Pizzino, A., Prange, E., Renaud, D. L., Rizzo, W., Shapiro, J., Suhr, D., Suhr, T., Tonduti, D., Waggoner, J., Waldman, A., Wolf, N. I., Zerem, A., Bonkowsky, J. L., Bernard, G., van Haren, K., Vanderver, A., Global Leukodtystrophy Initiative 2017; 122 (1-2): 18?32


    Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

    View details for DOI 10.1016/j.ymgme.2017.08.006

    View details for Web of Science ID 000413134800003

    View details for PubMedID 28863857

  • Decision Making in Adrenoleukodystrophy: When Is a Good Outcome Really a Good Outcome? JAMA neurology Van Haren, K., Engelen, M. 2017

    View details for DOI 10.1001/jamaneurol.2017.0095

    View details for PubMedID 28418445

  • Arresting and Relapsing Cerebral Adrenoleukodystrophy, A Treatable Mimic of Multiple Sclerosis Carlson, A. M., Huffnagel, I. C., Engelen, M., Van Haren, K. SAGE PUBLICATIONS LTD. 2017: 27
  • Acute flaccid myelitis: A clinical review of US cases 2012-2015. Annals of neurology Messacar, K., Schreiner, T. L., Van Haren, K., Yang, M., Glaser, C. A., Tyler, K. L., Dominguez, S. R. 2016; 80 (3): 326-338


    This review highlights clinical features of the increasing cases of acute flaccid paralysis associated with anterior myelitis noted in the United States from 2012 to 2015. Acute flaccid myelitis refers to acute flaccid limb weakness with spinal cord gray matter lesions on imaging or evidence of spinal cord motor neuron injury on electrodiagnostic testing. Although some individuals demonstrated improvement in motor weakness and functional deficits, most have residual weakness a year or more after onset. Epidemiological evidence and biological plausibility support an association between enterovirus D68 and the recent increase in acute flaccid myelitis cases in the United States. Ann Neurol 2016.

    View details for DOI 10.1002/ana.24730

    View details for PubMedID 27422805

  • Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology Pohl, D., Alper, G., Van Haren, K., Kornberg, A. J., Lucchinetti, C. F., Tenembaum, S., Belman, A. L. 2016; 87 (9): S38-45


    Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti-myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies.

    View details for DOI 10.1212/WNL.0000000000002825

    View details for PubMedID 27572859

  • Magnetic Resonance Imaging Spectrum of Succinate Dehydrogenase-Related Infantile Leukoencephalopathy ANNALS OF NEUROLOGY Helman, G., Caldovic, L., Whitehead, M. T., Simons, C., Brockmann, K., Edvardson, S., Bai, R., Moroni, I., Taylor, J. M., Van Haren, K., Taft, R. J., Vanderver, A., van der Knaap, M. S. 2016; 79 (3): 379-386


    Succinate dehydrogenase-deficient leukoencephalopathy is a complex II-related mitochondrial disorder for which the clinical phenotype, neuroimaging pattern, and genetic findings have not been comprehensively reviewed.Nineteen individuals with succinate dehydrogenase deficiency-related leukoencephalopathy were reviewed for neuroradiological, clinical, and genetic findings as part of institutional review board-approved studies at Children's National Health System (Washington, DC) and VU University Medical Center (Amsterdam, the Netherlands).All individuals had signal abnormalities in the central corticospinal tracts and spinal cord where imaging was available. Other typical findings were involvement of the cerebral hemispheric white matter with sparing of the U fibers, the corpus callosum with sparing of the outer blades, the basis pontis, middle cerebellar peduncles, and cerebellar white matter, and elevated succinate on magnetic resonance spectroscopy (MRS). The thalamus was involved in most studies, with a predilection for the anterior nucleus, pulvinar, and geniculate bodies. Clinically, infantile onset neurological regression with partial recovery and subsequent stabilization was typical. All individuals had mutations in SDHA, SDHB, or SDHAF1, or proven biochemical defect.Succinate dehydrogenase deficiency is a rare leukoencephalopathy, for which improved recognition by magnetic resonance imaging (MRI) in combination with advanced sequencing technologies allows noninvasive diagnostic confirmation. The MRI pattern is characterized by cerebral hemispheric white matter abnormalities with sparing of the U fibers, corpus callosum involvement with sparing of the outer blades, and involvement of corticospinal tracts, thalami, and spinal cord. In individuals with infantile regression and this pattern of MRI abnormalities, the differential diagnosis should include succinate dehydrogenase deficiency, in particular if MRS shows elevated succinate. Ann Neurol 2016 ANN NEUROL 2016;79:379-386.

    View details for DOI 10.1002/ana.24572

    View details for Web of Science ID 000371896800005

    View details for PubMedID 26642834

  • Emerging Treatments for Pediatric Leukodystrophies PEDIATRIC CLINICS OF NORTH AMERICA Helman, G., Van Haren, K., Escolar, M. L., Vanderver, A. 2015; 62 (3): 649-?


    The leukodystrophies are a heterogeneous group of inherited disorders with broad clinical manifestations and variable pathologic mechanisms. Improved diagnostic methods have allowed identification of the underlying cause of these diseases, facilitating identification of their pathologic mechanisms. Clinicians are now able to prioritize treatment strategies and advance research in therapies for specific disorders. Although only a few of these disorders have well-established treatments or therapies, a number are on the verge of clinical trials. As investigators are able to shift care from symptomatic management of disorders to targeted therapeutics, the unmet therapeutic needs could be reduced for these patients.

    View details for DOI 10.1016/j.pcl.2015.03.006

    View details for Web of Science ID 000356999800008

    View details for PubMedID 26022168

  • A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study LANCET INFECTIOUS DISEASES Greninger, A. L., Naccache, S. N., Messacar, K., Clayton, A., Yu, G., Somasekar, S., Federman, S., Stryke, D., Anderson, C., Yagi, S., Messenger, S., Wadford, D., Xia, D., Watt, J. P., Van Haren, K., Dominguez, S. R., Glaser, C., Aldrovandi, G., Chiu, C. Y. 2015; 15 (6): 671-682


    Enterovirus D68 was implicated in a widespread outbreak of severe respiratory illness across the USA in 2014 and has also been reported sporadically in patients with acute flaccid myelitis. We aimed to investigate the association between enterovirus D68 infection and acute flaccid myelitis during the 2014 enterovirus D68 respiratory outbreak in the USA.Patients with acute flaccid myelitis who presented to two hospitals in Colorado and California, USA, between Nov 24, 2013, and Oct 11, 2014, were included in the study. Additional cases identified from Jan 1, 2012, to Oct 4, 2014, via statewide surveillance were provided by the California Department of Public Health. We investigated the cause of these cases by metagenomic next-generation sequencing, viral genome recovery, and enterovirus D68 phylogenetic analysis. We compared patients with acute flaccid myelitis who were positive for enterovirus D68 with those with acute flaccid myelitis but negative for enterovirus D68 using the two-tailed Fisher's exact test, two-sample unpaired t test, and Mann-Whitney U test.48 patients were included: 25 with acute flaccid myelitis, two with enterovirus-associated encephalitis, five with enterovirus-D68-associated upper respiratory illness, and 16 with aseptic meningitis or encephalitis who tested positive for enterovirus. Enterovirus D68 was detected in respiratory secretions from seven (64%) of 11 patients comprising two temporally and geographically linked acute flaccid myelitis clusters at the height of the 2014 outbreak, and from 12 (48%) of 25 patients with acute flaccid myelitis overall. Phylogenetic analysis revealed that all enterovirus D68 sequences associated with acute flaccid myelitis grouped into a clade B1 strain that emerged in 2010. Of six coding polymorphisms in the clade B1 enterovirus D68 polyprotein, five were present in neuropathogenic poliovirus or enterovirus D70, or both. One child with acute flaccid myelitis and a sibling with only upper respiratory illness were both infected by identical enterovirus D68 strains. Enterovirus D68 viraemia was identified in a child experiencing acute neurological progression of his paralytic illness. Deep metagenomic sequencing of cerebrospinal fluid from 14 patients with acute flaccid myelitis did not reveal evidence of an alternative infectious cause to enterovirus D68.These findings strengthen the putative association between enterovirus D68 and acute flaccid myelitis and the contention that acute flaccid myelitis is a rare yet severe clinical manifestation of enterovirus D68 infection in susceptible hosts.National Institutes of Health, University of California, Abbott Laboratories, and the Centers for Disease Control and Prevention.

    View details for DOI 10.1016/S1473-3099(15)70093-9

    View details for Web of Science ID 000354638000032

    View details for PubMedID 25837569

  • Disease specific therapies in leukodystrophies and leukoencephalopathies MOLECULAR GENETICS AND METABOLISM Helman, G., Van Haren, K., Bonkowsky, J. L., Bernard, G., Pizzino, A., Braverman, N., Suhr, D., Patterson, M. C., Fatemi, S. A., Leonard, J., van der Knaap, M. S., Back, S. A., Damiani, S., Goldman, S. A., Takanohashi, A., Petryniak, M., Rowitch, D., Messing, A., Wrabetz, L., Schiffmann, R., Eichler, F., Escolar, M. L., Vanderver, A. 2015; 114 (4): 527-536


    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.

    View details for DOI 10.1016/j.ymgme.2015.01.014

    View details for Web of Science ID 000353008900005

    View details for PubMedCentralID PMC4390468

  • Disease specific therapies in leukodystrophies and leukoencephalopathies. Molecular genetics and metabolism Helman, G., Van Haren, K., Bonkowsky, J. L., Bernard, G., Pizzino, A., Braverman, N., Suhr, D., Patterson, M. C., Ali Fatemi, S., Leonard, J., van der Knaap, M. S., Back, S. A., Damiani, S., Goldman, S. A., Takanohashi, A., Petryniak, M., Rowitch, D., Messing, A., Wrabetz, L., Schiffmann, R., Eichler, F., Escolar, M. L., Vanderver, A. 2015; 114 (4): 527-536


    Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.

    View details for DOI 10.1016/j.ymgme.2015.01.014

    View details for PubMedID 25684057

  • De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy HUMAN MUTATION Lee, J., Srour, M., Kim, D., Hamdan, F. F., Lim, S., Brunel-Guitton, C., Decarie, J., Rossignol, E., Mitchell, G. A., Schreiber, A., Moran, R., Van Haren, K., Richardson, R., Nicolai, J., Oberndorff, K. M., Wagner, J. D., Boycott, K. M., Rahikkala, E., Junna, N., Tyynismaa, H., Cuppen, I., Verbeek, N. E., Stumpel, C. T., Willemsen, M. A., de Munnik, S. A., Rouleau, G. A., Kim, E., Kamsteeg, E., Kleefstra, T., Michaud, J. L. 2015; 36 (1): 69-78


    KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

    View details for DOI 10.1002/humu.22709

    View details for Web of Science ID 000347076700011

    View details for PubMedID 25265257

  • Acute Flaccid Paralysis with Anterior Myelitis - California, June 2012-June 2014 MMWR-MORBIDITY AND MORTALITY WEEKLY REPORT Ayscue, P., Van Haren, K., Sheriff, H., Waubant, E., Waldron, P., Yagi, S., Yen, C., Clayton, A., Padilla, T., Pan, C., Reichel, J., Harriman, K., Watt, J., Sejvar, J., Nix, W. A., Feikin, D., Glaser, C. 2014; 63 (40): 903-906


    In August 2012, the California Department of Public Health (CDPH) was contacted by a San Francisco Bay area clinician who requested poliovirus testing for an unvaccinated man aged 29 years with acute flaccid paralysis (AFP) associated with anterior myelitis (i.e., evidence of inflammation of the spinal cord involving the grey matter including anterior horn cell bodies) and no history of international travel during the month before symptom onset. Within 2 weeks, CDPH had received reports of two additional cases of AFP with anterior myelitis of unknown etiology. Testing at CDPH's Viral and Rickettsial Disease Laboratory for stool, nasopharyngeal swab, and cerebrospinal fluid (CSF) did not detect the presence of an enterovirus (EV), the genus of the family Picornaviridae that includes poliovirus. Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients. To identify other cases of AFP with anterior myelitis and elucidate possible common etiologies, CDPH posted alerts in official communications for California local health departments during December 2012, July 2013, and February 2014. Reports of cases of neurologic illness received by CDPH were investigated throughout this period, and clinicians were encouraged to submit clinical samples for testing. A total of 23 cases of AFP with anterior myelitis of unknown etiology were identified. Epidemiologic and laboratory investigation did not identify poliovirus infection as a possible cause for the observed cases. No common etiology was identified to explain the reported cases, although EV-D68 was identified in upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines.

    View details for Web of Science ID 000342955700006

    View details for PubMedCentralID PMC4584614

  • National Variation in Costs and Mortality for Leukodystrophy Patients in US Children's Hospitals PEDIATRIC NEUROLOGY Brimley, C. J., Lopez, J., Van Haren, K., Wilkes, J., Sheng, X., Nelson, C., Korgenski, E. K., Srivastava, R., Bonkowsky, J. L. 2013; 49 (3): 156-162


    Inherited leukodystrophies are progressive, debilitating neurological disorders with few treatment options and high mortality rates. Our objective was to determine national variation in the costs for leukodystrophy patients and to evaluate differences in their care.We developed an algorithm to identify inherited leukodystrophy patients in deidentified data sets using a recursive tree model based on International Classification of Disease, 9th Edition, Clinical Modification, diagnosis and procedure charge codes. Validation of the algorithm was performed independently at two institutions, and with data from the Pediatric Health Information System (PHIS) of 43 US children's hospitals, for a 7-year period between 2004 and 2010.A recursive algorithm was developed and validated, based on six International Classification of Disease, 9th Edition, Clinical Modification, codes and one procedure code that had a sensitivity up to 90% (range 61-90%) and a specificity up to 99% (range 53-99%) for identifying inherited leukodystrophy patients. Inherited leukodystrophy patients comprise 0.4% of admissions to children's hospitals and 0.7% of costs. During 7 years, these patients required $411 million of hospital care, or $131,000/patient. Hospital costs for leukodystrophy patients varied at different institutions, ranging from two to 15 times more than the average pediatric patient. There was a statistically significant correlation between higher volume and increased cost efficiency. Increased mortality rates had an inverse relationship with increased patient volume that was not statistically significant.We developed and validated a code-based algorithm for identifying leukodystrophy patients in deidentified national datasets. Leukodystrophy patients account for $59 million of costs yearly at children's hospitals. Our data highlight potential to reduce unwarranted variability and improve patient care.

    View details for DOI 10.1016/j.pediatrneurol.2013.06.006

    View details for Web of Science ID 000323588800003

    View details for PubMedID 23953952

    View details for PubMedCentralID PMC3748620

  • Case Report of Subdural Hematoma in a Patient With Sturge-Weber Syndrome and Literature Review: Questions and Implications for Therapy JOURNAL OF CHILD NEUROLOGY Lopez, J., Yeom, K. W., Comi, A., Van Haren, K. 2013; 28 (5): 672-675


    Sturge-Weber syndrome is a neurocutaneous disorder associated with vascular abnormalities in the skin, eye, and brain leading to both acute and chronic cerebral hypoperfusion and, in some affected children, brain injury. Aspirin can reduce stroke-like events and seizure episodes and prevent further brain injuries in these patients. Although a few cases of intracranial hemorrhage in patients with Sturge-Weber syndrome have been reported, prior reports have not discussed this complication with regard to particular therapies. The authors present a toddler with Sturge-Weber syndrome who developed a subdural hematoma in the setting of a mechanical fall with minor head trauma. They discuss the possible role of aspirin in contributing to, or perhaps protecting against, intracranial hemorrhage in patients with Sturge-Weber syndrome. Further data are needed to establish the utility of aspirin in Sturge-Weber syndrome.

    View details for DOI 10.1177/0883073812449514

    View details for Web of Science ID 000317683900018

    View details for PubMedID 22805242

  • Vitamin D Status as a Risk Factor for Cerebral Demyelination in X-Linked Adrenoleukdystrophy Van Haren, K., Mowry, E., Raymond, G., Moser, A., Steinman, L. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Therapeutic Advances in Pediatric Multiple Sclerosis. The Journal of pediatrics 2013

    View details for DOI 10.1016/j.jpeds.2013.04.028

    View details for PubMedID 23726542

  • Fahr's Disease: Pediatric Presentation of a Rare Neurodegenerative Disorder Singhal, N., Van Haren, K., Wu, Y. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Fahr's Disease: Pediatric Presentation of a Rare Neurodegenerative Disorder Singhal, N., Van Haren, K., Wu, Y. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Immune response in Leukodystrophies PEDIATRIC NEUROLOGY Eichler, F., Van Haren, K. 2007; 37 (4): 235-244


    Although the genetics and biochemistry of leukodystrophies have been extensively explored, the immune response in these disorders has received relatively little attention. Both the disease course and its response to treatment may be highly dependent on the immune system. In this review, we compare three common leukodystrophies, each with a different immune response: (1) X-linked adrenoleukodystrophy, which demonstrates a severe, lymphocytic inflammatory response; (2) metachromatic leukodystrophy, which yields a histiocytic response; and (3) vanishing white-matter disease, in which no inflammation is typically seen. We highlight the biochemical, pathologic, and clinical differences, while focusing on the immune response in each disease. We also review the response of leukodystrophies to immunomodulatory therapies and interventions such as hematopoietic stem-cell transplantation. Future studies may delineate specific inflammatory markers as possible candidates for therapeutic intervention.

    View details for DOI 10.1016/j.pediatrneurol.2007.06.011

    View details for Web of Science ID 000250295000001

    View details for PubMedID 17903666

  • The unfolded protein response in vanishing white matter disease JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY van der Voorn, J. P., van Kollenburg, B., Bertrand, G., Van Haren, K., Scheper, G. C., Powers, J. M., van der Knaap, M. S. 2005; 64 (9): 770-775


    Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocytes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2alpha (eIF2alphaP) and combined immunohistochemical and Western blot analysis of the downstream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.

    View details for Web of Science ID 000231781300004

    View details for PubMedID 16141786

  • The life and death of Oligodendrocytes in vanishing white matter disease 79th Annual Meeting of the American-Association-of-Neuropathologists Van Haren, K., van der Voorn, J. P., PETERSON, D. R., van der Knaap, M. S., Powers, J. M. LIPPINCOTT WILLIAMS & WILKINS. 2004: 618?30


    Vanishing white matter disease (VWM) is a progressive cavitating disease of central white matter due to a deficiency of the translation initiation factor eIF2B. Oligodendrocytes appear to be numerically increased in some white matter areas, while decreased in others. We compared oligodendrocytes of cerebral, cerebellar, and pontine white matter from 5 VWM patients with those of age-matched controls by light microscopy and immunohistochemistry using antibodies to activated caspase-3, bak, bax, bcl-2, survivin, and Ki-67, as well as by the TUNEL technique. Oligodendrocytes were identified morphologically and quantified using an ocular grid. We observed statistically significant increases in their densities at all sites; Ki-67-labeled oligodendrocytes were identified in 2 of 5 patients. Apoptotic oligodendrocytes were documented in 3 of 5 patients, while bcl-2 and survivin labeling was observed in 2 of 5 and 2 of 2 patients, respectively. There was a trend toward an increase in apoptotic labeling of oligodendrocytes that was strongest in the cerebrum, the major locus of VWM, in the youngest and most severely affected patients. These data conclusively demonstrate increased oligodendrocytic densities in VWM; the increase is not an artifact of white matter contraction. Our data also document that oligodendrocytes undergo apoptosis, perhaps in conjunction with major neurologic crises, and that a subset of oligodendrocytes are able to persist and proliferate. Conflicting proliferative, cell-death, and survival signals impact the oligodendrocytes of VWM.

    View details for Web of Science ID 000221897100006

    View details for PubMedID 15217090

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