Objectives Describe the relatively common but only recently - - PDF document

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Objectives Describe the relatively common but only recently - - PDF document

2/13/2014 Approach to Pediatric Autoimmune Encephalitis Eyal Muscal , MD, MS Immunology, Allergy, and Rheumatology Co-Appointment in Child Neurology Amber Stocco MD Medical Director Pediatric Movement Disorder Clinic Medical Co-Director


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Approach to Pediatric Autoimmune Encephalitis

Amber Stocco MD

Medical Director Pediatric Movement Disorder Clinic Medical Co-Director Cerebral Palsy Clinic Blue Bird Pediatric Neurology Clinic

Eyal Muscal , MD, MS

Immunology, Allergy, and Rheumatology Co-Appointment in Child Neurology

Pediatrics

Objectives

Describe the relatively common but only recently discovered entity: NMDA Receptor Antibody Encephalitis (NMDAR) Brief overview of other common pediatric autoimmune encephalitis antibodies: GAD, Voltage-gated K channel (VGKC), Anti-Thyroid Abs, anti-glycine, anti-dopamine Recognize clinically and medically the typical semiology of associated movement disorders of NMDAR: dystonia, chorea, myoclonus, ataxia, and stereotypies Detail long term prognosis and prolonged care needed for NMDAR (and perhaps other less prevalent autoimmune encephalitides) Pediatrics

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Previously healthy 13 mon Hispanic F Acute onset irritability Regression of speech and gait Jerky eye and body movements No seizures

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Pediatrics Although semiology is distinctive no single antibody yet identified Strong association in children with neural crest tumors Ongoing surveillance for tumors Although movements improve there is guarded outcome developmentally and behaviorally

Opsoclonus Myoclonus

Pediatrics

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Previously healthy 8 yr old Hispanic male 3 days PTA had HA, developed intractable seizures and lapsed into prolonged coma T2 hyperintense bilateral temporal lobe signal changes (limbic) Marked dystonia, myoclonus, and seizures Developed severe “rage attacks” and regression that has persisted

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2 major isotopes identified Rare association in children with malignancy Seizures are a major feature Although movements improve there is guarded outcome developmentally

Voltage Gated K Channel Encephalopathies

Pediatrics

Vignette #3

Previously healthy 3 yr old Hispanic male 3 days PTA had myalagias, HA, N/V Given Abx for serum WBC 29, proteinuria Day of admit: insomnia, confusion, hallucinations, slurred speech, ataxia, expressive aphasia IgM mycoplasma + (IgG neg) A few days later seizures and then chorea

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EEG: sz, slow background, & left post temp spikes Extensive autoimmune/infectious work up CSF - WNL NMDA IgG AB + Treatment: Steroids then IVIG Multiple Relapses BNZ, Tetrabenazine, and Keppra symptomatically

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Pediatrics IgG to NMDA receptor Discovered in 2005 in women with

  • varian teratomas

Recognized as the most prevalent autoimmune encephalitis Prevalence of NMDAR surpassed viral encephalitides in one epidemiology study

NMDAR Encephalitis

Gable MS et al. Clinical Infectious Diseases. 2012; 54: 899-904

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MRI brain normal 67% (33% w/ nonspecific T2 changes) EEG abnormal 90% (slowing or epileptiform) CSF abnormal 79% (mild pleocytosis, elevated protein) CSF NMDAR + in 100% (Serum NMDAR +, only 85%)

NMDAR Encephalitis

Pediatrics

AMS Sz Movements Time to onset of immuno-modulation is key to recovery. Usually requires intensive, first line therapy: steroids/IVIG and/or Pex 12 % chance of relapse rate, less in those who had 2nd line therapy Prolonged recovery time up to 18 mo

Take Home Points from Vignette #3

Pediatrics

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Previously healthy 13 yr old AAF 7 days PTA c/o leg “heaviness”, “looked confused”, “laughing and singing hysterically” Went to ER x 2 and discharged Day of admit: neighbors called police because of hallucinations/agitation Given Geodon for agitation obtunded

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Most common movement disorder associated with NMDAR Encephalitis Stereotyped and purposeless Movement Fragment Semi-volitional ?

Orobuccal Stereotypies

Pediatrics

Myorythemia

Rhythmic Oscillatory Slower then tremor (< 1 Hertz) Purposeless Sometimes suppressible Does not carry the volitional connotation of stereotypy

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MRI brain: subtle tempoparietal hyperintensity EEG: slowing and sz CSF: cell count/ protein/glucose WNL Agitated, nonverbal, apneas intubation and trach Negative systemic autoimmune and infectious work up NMDA IgG AB + Steroids, IVIG, Pex, rituxan, then monthly cytoxan and IVIG (BNZ and Keppra symptomatically) Stimulants for promoting wakefulness

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video

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Pediatrics Hemiparesis and ataxia more common in pediatrics (often presenting symptom) Autonomic instability Symptoms improve in the reverse order, usually movements going away first. 80% improve with proper treatment but course prolonged ADHD-like symptoms may persist

Take Home Points from Vignette #4

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  • video

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Chorea

Involuntary / insuppressable Non-rhythmic (random) Purposeless, Sudden Spreading/migrating (one body part to another) Motor-impersistence Hypotonia Hung-up Reflexes

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Age: 5 to 15 yrs Gender: F > M Typical 4 - 8 wks s/p Group A Strep May be unilateral in up to 30% Typically lasts 2 - 6 mos, almost always < 2 yrs Comorbid Psych: OCD, ADHD, Anxiety, Depression Exacerbations/Recurrences: 20 - 60% Re-infection, OCPs, Pregnancy (ChoreaGravidarum) Lab: +ANA, +/- ASO, +/- Anti-DNAase MRI: Normal to BG Enlargement/T2 Changes

Syndenham’ ’ ’ ’s Chorea

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Pediatrics AMS, most have seizures then chorea vs. myorythemia In children most cancer associations are rare Initial ovarian or testicular ultrasound as only screening Recent discussion that older girls may need semi-annual MRI evaluations Only 1 of 14 patients at TCH with a teratoma (11 yr old; pubertal)

NMDA Encephalitis in the younger child

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Pediatrics Involuntary / Insuppressable Stereotyped (opposite of chorea) Twisting (hyperextension) Generalized or task specific Exacerbated by movement or emotion Hypertonia during movement Reflexes range: normal to increased

Dystonia

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Ataxia

Dysmetria

  • Finger to chin
  • Heel to shin

Unsteady

  • Wide-based gait

Impaired Dysdiadochokinesia Scanning Speech Unlike other “BG” movements, usually cerebellar in etiology Pediatrics

Myoclonus

Sudden, “shock-like” May be:

Epileptic (cortical) Non-Epileptic (subcortical) Physiologic (e.g. sleep myoclonus)

Many Etiologies:

Benign Myoclonic Syndromes Epileptic Myoclonic Encephalopathies Post Anoxic (Lance-Adams Syndrome) Myoclonic Dystonia (DYT-11) Opsoclonus Myoclonus Pediatrics ADEM 50 NMDAR 14 patients Hashimoto’s Encephalopathy 5 Opsoclonus Myoclonus 3 Anti-GAD 3 Anti-VGKC 2

Autoimmune Encephalitis TCH 2009-2013

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  • SLE-spectrum disorders?
  • CNS vasculitides?
  • Other systemic autoimmune dx?
  • Immunosuppression anyone?

Why Rheumatology?

Pediatrics

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CNS Deficit in a Child or Adolescent I

Twilt M et al. Nature Rev Rheum 2012.

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CNS Deficit in a Child or Adolescent II

  • Change in behavior
  • Seizures
  • Movement disorder

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Mechanisms Clinical Features Diagnostic Measures Treatment Approaches

thecontinentalblog.wordpress.com

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Where are Ab’ ’ ’ ’s From?

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Where Do Antibodies Go?

Pediatrics

What Do Antibodies Do?

Pediatrics

What Do Antibodies Do?

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“Epidemiology”

phrei.org

Pediatrics

Dalmau 2011

  • 100/400 in case series are pediatric
  • Less than 40% of pedi cases have tumors

Pediatrics

Dalmau 2013

  • 177/ 577 in case series are pediatric
  • 40% of 12-17 yr old girls have tumors
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What Did We Know in 2011?

  • In 2011 most of outcome data was adult based

Pediatrics

beaconcompanies.com

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Treatment Algorithm: 2011

Pediatrics

Toronto Sick Kids Protocol

Pediatrics

“EBM”: TCH 2012

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“EBM”: TCH 2012

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http://faithrichardson.com/images/pharmacology.gif

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Steroids

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IVIG

Kazatchkine et al. NEJM, 345 (10): 2001, 237-245

Pediatrics

TPE

/www.apheresis.com/img/substitution.gif

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Rituxan

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Cytoxan

http://www.pharmgkb.org/search/pathway/cyclophos/cyclophos-pk.jsp

Pediatrics

beaconcompanies.com

Pediatrics

  • Crunching data (n=8?)
  • Diagnosis within 4 weeks (62%?)
  • Max Follow up 2 years (most <1 yr)
  • No Flares !!!!
  • All back in school
  • Deficits? Frontal? “ADAHD”

So How Are We Doing?

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elisteincartoons.com

Pediatrics

  • 48% flunk 1st line Tx!
  • At 24 mon f/u 81% had good outcome

(mRS 0-2)

  • Improvement continued at 18 mon
  • 2nd line works when 1st line fails
  • pedi and adult pooled data

Dalmau 2013

Pediatrics

Outcomes: Dalmau 2013

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Outcomes: Dalmau 2013 II

Pediatrics

  • No ICU stay
  • Tx within first 4 weeks of onset
  • 2nd line Tx (multi-variable analysis)
  • Predictors of effect and magnitude of 2nd

line effect were similar in children

Dalmau 2013: Predictors of Success

Pediatrics

Relapse Lower with 2nd Line Tx?

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Gaps in Knowledge 2013

  • True NP deficits at: 12, 18 and 24 months?
  • Utility of psychotropic medications?
  • Early roles of PM+R and psychiatry?
  • Utilization of decision tools in EMR?
  • Are other autoimm. Encephalitides to be

treated the same? Pediatrics

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References

Treatment and prognostic factors for long-term

  • utcome in patients with anti-NMDA receptor

encephalitis: an observational cohort study. Titulaer, M, Dalmau J, et al Lancet Neurol. 2013 Jan;12:157-65 Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Lancet Neurol. 2011 Jan;10(1):63-74. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. J Neurosci. 2010 Apr 28;30(17):5866-75.

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References

Clinical Features, Treatment, and Outcome

  • f 500 Patients with Anti-NMDA Receptor

Encephalitis. March 14, 2012 Lecture AAN, Maarten Titulaer, MD, PhD Auto-Immune Encephalopathies. Feb 5, 2012 Lecture TNS Winter Conf, Amy Pruitt MD Movement Disorder Emergencies, K. Poston MD, S. Frucht MD, J Neurology , 2008; 4:2-13 Continuum (Lifelong Learning in Neurology), “Movement Disorders”, Vol 13, Number 1,

  • Feb. 2007. American Academy of Neurology,

Lippincott Williams & Wilkins, Hagerstown, MD. Clinical experience and laboratory Investigations in patients with anti-NMDAR

  • encephalitis. Dalmau J, Lancaster E,

Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R.Lancet Neurol. 2011 Jan;10(1):63-74.

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References

A Comprehensive Review of Movement Disorders for the Clinical Practitioner, Vol. 3, July 30-31 2006. Stanley Fahn MD, Joseph Jankovic MD, Mark Hallett MD, Peter Jenner Principles and Practice of Movement Disorders, Stanley Fahn MD, Joseph Jankovic MD, Mark Hallett MD, Peter Jenner PhD. Churchill Livingstone, Philadelphia, PA: 2007. Chorea in Fifty Consecutive Patients with Rheumatic Fever. F. Cardoso MD, C. Eduardo MD, AP Silva MD, CC Mota MD. IN: Movement Disorders, 1997; 12:701-703.