10/27/2013. Funding from the Autoimmune Encephalitis Alliance. Heather Van Mater, MD MS October 27, 2013
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1 Funding from the Alliance Heather Van Mater, MD October 27, Aviv, et al. MR imaging and angiography of primary CNS of childhood. AJNR Am J Neuroradiol. 2006; 27: Aviv, et al. of primary central nervous system angiitis of childhood: conventional angiogram versus magnetic resonance angiogram at presentation. AJNR Am J Neuroradiol, 2007: Benseler, et al. primary central nervous system in children: a newly recognized inflammatory central nervous system disease. Arthritis Rheum.2005;52: Benseler, et al. central nervous system in children. Arthritis Rheum.2006; 54: Bien, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 2012; 135: Cellucci, et al. von Willebrand factor antigen- a novel biomarker of disease activity in childhood CNS [abstract]. Arthritis Rheum. 2009; 60(suppl.10): S573-S574. Dalmau, et al. Clinical experience and laboratory investigation in patients with anti-r. Lancet Neurol 2011; 10: Eleftherlou, et al. Investigation of childhood central nervous system : magnetic resonance angiography vserus catheter cerebral angiography. Dev Med Child Neurol. 2010; 52: Hutchinson, et al. Treatment of small vessel primary CNS in children: an open label cohort study. Lancet Neurol. 2010; 9: Lancaster, et al. and antibodies to synaptic and neuronal cell surface proteins. Neurology 2011; 77: Sen, et al. Treatment of primary angiitis of the central nervous system in children with mycophenolate mofetil. Rheumatology. 2010; 49: Salvarani, et al. central nervous system : analysis of 101patients. Ann. Neurol. 2007; 62: Titular, et al. Treatment and prognostic factors for long-term outcome in patients with anti- receptor : an observational cohort study. Lancet Neurol 2013 Feb;12(2): Twilt M and Benseler S. The spectrum of CNS in children and adults. Nat Rev Rheumatol 2012;8: Zuliani, et al. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry 2012; 83: Provide a conceptual framework of inflammatory brain disease Recognize the variable and overlapping presentations Review a basic approach to evaluation and treatment year old previously healthy female develops: Social withdraw Academic decline Chronic headaches Increasing paranoia Hallucinations Strong family history of schizophrenia Diagnosed with schizophrenia and treated for 2 years with haloperidol up to 15mg twice daily, with no significant improvement No able to go to school, in psychiatric day program 1
2 Broad category of diseases characterized by brain dysfunction secondary to an autoimmune mediated process May be secondary to or encephalomyelitis/ Not new diseases, just new names reflecting a new understanding Old Name. Pediatric stroke viral / NOS Recurrent Atypical Refractory epilepsy New Name. angiitis of the CNS Anti- receptor Hashimoto s Neuromyelitis Optica (anti-) Antibody mediated autoimmune 7 8 In 2001, a total of 36 children were documented in the literature with childhood primary angiitis of the CNS (cpacns) Anti- described 2002 Anti- receptor antibody described 2006 Many more antibody mediated syndromes: GABA,, LGI Variable presentation Symptoms Locations Severity Progression Responsiveness to treatment Makes it very difficult to diagnose Any new onset neurologic deficit or psychiatric disease Seizures Weakness Cognitive decline/regression Psychosis Catatonia Insomnia
3 Often with a prodromal illness with flu-like symptoms Initial neuropsychiatric symptoms may be mild and intermittent mild vision changes headaches weakness behavior changes cognitive decline 13 cpacns Headache, cognitive impairment and behavior changes Headaches usually start as low intensity and then progress to more debilitating Focal symptoms often a later finding Behavior changes/psychosis (hallucinations, paranoia, OCD ) Seizures Cognitive decline, Loss of speech Bensler, et al. Arthritis and Rheum 2006 Benseler, et al. Arthritis&Rheum 2005 Dalmau, Lancet Neurol 2011 Titular, Lancet Neurol Rarely reported separately in studies Represent a major disease manifestation Everyone with psychiatric disease does not have inflammatory brain disease but some do Broad differential of conditions to consider Neurologic Infectious Metabolic Rheumatologic Oncologic Hematologic Psychiatric Neurologic Rheumatologic Infectious Neoplastic Metabolic Endocrine Vascular Hematologic Toxic Differential of s Migraines with vasospasm, Multiple Sclerosis, lupus erythematosis, Behcet's, osis, Central nervous system angiitis (CNS ), ANCA associated HSV, Mycoplasma, Lyme, Bartonella, Arboviruses, EBV, CMV, HHV6, HIV, Post-varicella Leptomeningeal Carcinaomatosis (Leukemia, Lymphoma), disease (teratoma) Amino acidopathies, Organic academia, Urea cycle defects, Mitochondrial disorders, Disorders of fatty acid oxidation, Lysosomal storage disorders Thyroid disease (Hashimoto s ) Stroke, Reversible Cerebral Vasoconstriction Syndrome, Moyamoya, Fibromuscular dysplasia Thromboembolic events, Sickle cell disease Recreational drugs (Cocaine), Heavy metals, Inhalants/solvents Broad differential of conditions to consider Neurologic Infectious Metabolic Rheumatologic Oncologic Hematologic Psychiatric Need to work across disciplines to ensure thorough and appropriate work up and treatment 18 3
4 Imaging: CT very poor at picking up abnormalities (30-40%) MRI with gadolinium parenchymal disease (T2, FLAIR, gad enhancement, ischemia) leptomeningeal enhancement vessel wall enhancement extent of involvement MRA/V, CTA, conventional angiogram as indicated Aviv, Am J Nueroradiol 2006 Eleftheriou, Deve Med &Child Neuro 2010 Zuliani,J Neurol Neurosurg Psychiatry 2012 Twilt. Nat Rev Rheumatol CBC, ESR, CRP von Willebrand factor antigen Immunoglobulin Serologies: Anti-ds DNA, ENABs, ANCA, ACE Anti-phospholipids Thyroid antibodies (anti-microsomal and antithyroglobulin) Anti-neuronal (paraneoplastic panel, anti-, ) Thyroid function tests Metabolic and infectious work up Zuliani, J Neurol Neurosurg Psychiatry 2012 Twilt. Nat Rev Rheumatol Cellucci, Arthritis Rheum Lumbar Puncture Cell counts, Protein Opening pressure ACE, anti-neuronal antibodies Oligoclonal bands, IgG index Infectious workup EEG Diffuse slowing Epileptiform activity Zuliani,J Neurol Neurosurg Psychiatry 2012 Twilt. Nat Rev Rheumatol Almost always abnormal in cpacns 98% of those with angiography 100% in those reported with angiography positive disease This is in contrast to autoimmune Half of patients with normal MRI Bensler, et al. Arthritis and Rheum 2006 Benseler, et al. Arthritis&Rheum 2005 Aviv, Am J Nueroradiol 2006 Eleftheriou, Deve Med &Child Neuro 2010 Zuliani,J Neurol Neurosurg Psychiatry
5 MRI positive cpacns Inflammatory markers usually normal CSF usually normal cpacns At least one abnormal inflammatory marker in 76% of children (may only be mild abnormality) CSF abnormal in 90% Abnormal MRI Vessel imaging (CTA, MRA/V, angiogram) Negative Serologies Negative Normal MRI more likely Serologies SO.normal labs and LP results do not rule out CNS cpacns Brain Biopsy Bensler, et al. Arthritis and Rheum 2006 Benseler, et al. Arthritis&Rheum Negative cpacns 26 cpacns Monthly IV Cyclophosphamide x7 doses High dose steroids Maintenance therapy with MMF for a total treatment course of 2 years positive cpacns No trials : anti-coagulation +/- steroids : treat similar to angiography disease Group of diseases associated with both intracellular and cell surface antigens Limbic (anti-, now anti-lgi1) Anti- receptor Neuromyelitis optica (AQP4) Hashimoto s Anti- (Stiffman/) Can be paraneoplastic, but majority are not in children Consider ultrasound of ovary/testes Associated with paraneoplastic conditions T-cell mediated autoimmunity Causes neuronal death Therefore less responsive to immunotherapy Cell Surface Less commonly associated with neoplasms B-cell/plasma cell infiltrates Disrupt cell signaling More responsive to immunotherapy 29 Bien, Brain
6 anti-neuronal antibody Prompt diagnosis and initiation of therapy antigen Onconeuronal Escalation to second line therapy in autoimmune if little response after one month (, LG1, GABA) (Hu, MA) Overall very good outcomes Corticosteroids, IVIG, plasmapheresis Response Treat Oncologic disease Full recovery can take up to 18 to 24 months No Response Rituximab Cyclophosphomide Chronic Immunosuppression Benseler, Arthritis & Rheum 2005 Salvarani, Ann Neurol 2007 Titular,Lancet Neurol 2013 Hutchinson, Lancet Neurol 2010 Lancaster E et al., Neurology Multidisciplinary approach Symptomatic treatment of neurologic and psychiatric manifestations Multidisciplinary approach Symptomatic treatment of neurologic and psychiatric manifestations Seizures Movement disorders Agitation Anorexia Impulsivity Disinhibition Hypersexuality Hyperphagia Seizures Movement disorders Agitation Anorexia Impulsivity Disinhibition Hypersexuality Hyperphagia Failure of first line treatments wrong diagnosis vs Vasculitis Elevated vwf antigen, ESR Angiogram Lesional brain biopsy: inconclusive no demyelination perivascular hemosiderin deposition Diagnosed with small vessel cpacns Treatment: cyclophosphamide and steroids Response: Dramatic improvements in MRI Returned to school, more interactive Has not returned to baseline cognitive function, ongoing issues with peer relations Inflammatory brain disease increasingly recognized as etiology of new onset neuropsychiatric manifestations Two broad categories Vasculitis Hard to diagnose Broad spectrum of symptoms No single test Takes a team to diagnose and treat Treatments very effective, especially when started early and escalated if poor initial response
7 Co-conspirator: Bill Gallentine Fabulous and supportive division: Jeff Dvergsten, Egla Rabinovich and Laura Schanberg Past and present fellows: Elisa Wershba, Eveline Wu, Laura Lewandowski, Angela Bryan. Alliance Our Patients and families 37 7
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