2/14/2019
Case #1 Pediatric Neurology Pearls 8yo boy, with tics and Obsessive Compulsive (OC) symptoms Onset of simple tics 2 years prior- sniff, snort, deep CHILDHOOD ACUTE ONSET breathe, tapping fingers, palilalia NEUROPSYCHIATRIC Some obsessive character to tics, even out SYMPTOMS movements, repeat word a certain #of times to AUDREY FOSTER-BARBER, MD PHD PEDIATRIC BRAIN CENTER OUTPATIENT DIRECTOR, CHILD “make it right” NEUROLOGY RESIDENCY DIRECTOR, VICE CHAIR NEUROLOGY UCSF In the last month some behavior issues- easy temper, KENDALL NASH, MD PEDIATRIC BRAIN CENTER INPATIENT DIRECTOR, ASSOC. yelling at sib, won’t touch doorknobs or drawer MEDICAL DIRECTOR PHYSICIAN NETWORK DEVT. BENIOFF CHILDRENS HOSPITALS handles Query- is this PANDAS?
No ADHD signs or concerns No recent illness symptoms Eating and Sleeping well Throat culture done by Pediatrician, positive for Doing well at school Group A Strep (GAS), given antibiotics No seizures after 10 days of antibiotics tics improved, then worsened again a few weeks later Tics present for 2 years, vary in severity, often worse with illness or with stress No change in behavior issues, ocd symptoms
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PMH- born at term with duodenal atresia, largyngeal Return to clinic 6 months later with concern for cleft s/p repair “Explosive worsening” of behavior, moody, more Development- normal milestones, bright child, aa bit OCD symptoms anxious but social and active in sports Tics not worse, though a few new tics added to his FH- Mother with Hashimoto’s thyroiditis, history of repertoire anxiety, Father with history of a mood disorder No associated illness, primary doctor tested for Strep SH- lives with mother and sibling, parents divorcing by throat culture and mycoplasma by antibodies, both negative Dx-Tourette Syndrome or chronic tic disorder, OCD tendency Did receive a Flu vaccine a few weeks to a month prior
New stressors- mother with new partner moving in, 6 months later, ongoing CBT with some benefit for with partner’s child behavior and OCD symptoms Tics still present, wax and wane Mother would prefer a PANDAS diagnosis, rather Seen by Integrative Medicine doctor- than a diagnosis of tic disorder with mood disorder Extensive Testing-zinc, heavy metal, strep culture, MTHFR “PANDAS seems to have a clear treatment, whereas polymorphism, autoimmune screen (ANA, DS-DNA) all the others would be a chronic disorder” negative Recommend- cognitive behavioral therapy (CBT), no -myocoplasma IgG+, Lyme Ab equivocal antibiotics -Cunningham panel interpreted as abnormal -treated with 3 months of Azithromycin, patient self d/c’d at 2 months due to GI distress
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Why did PANDAS come up here?
During the 2 months on antibiotics no tic worsening, Classic for Childhood Tic disorder- OCD was better already with therapy -tics onset prepubertal, vary in type, wax and wane over time -associated OCD (up to 50 % of patients) Mother now “not so sure” about a PANDAS -bilineal inheritance (tics, adhd, anxiety, or ocd in both parents) diagnosis, but feels “antibiotics are benign” so will consider them if symptoms worsen (child refused Family Concerns antibiotic prophylaxis) -FH autoimmune disease -hope for something treatable Plans to avoid escalation to immune therapy that -difficulty of proving associated infection, of attributing was recommended- IVIg and or pheresis cause/effect of antibiotic therapy -common idea in the lay community, with integrative health Declined other neurologic work up (MRI and LP) providers because “doing too well”
History behind PANDAS PANDAS- defined 1998
1980s- psychiatrists noted subset of patients with PANDAS- pediatric autoimmune neurologic disorder OCD who had a severe, abrupt onset of symptoms associated with Strep Temporal association with infectious triggers- strep, Presence of OCD and or tics- severe, interfere with varicella, mycoplasma, influenza, EBV, Lyme patient’s ability to function Initially called PITANDS- Pediatric infection Age of onset 3yo to puberty triggered autoimmune neurologic and psychiatric Acute onset, episodic (relapsing remitting) disorder Temporally related to GAS infection Researchers chose to focus on GAS infection due to Other associated neurologic (choreiform ease of documentation of infection and connection to movements) and behavioral abnormalities (sleep known molecular mimicry in Sydenham’s Chorea- disturbance, enuresis, anxiety, lability, insomnia) labeled PANDAS Swedo, SE. J Child and Adol Psychpharm, Feb 25(1)’ 2015
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Pediatric Acute onset Neuropsychiatric Defining a GAS infection is tricky Syndrome
25% of the pediatric population has + strep culture 2013 Consensus meeting without immune reaction (carrier) Back to the idea that multiple infections can trigger a ASO and DNAse B titers can remain elevated for months (up to 12 mo in >50 % of kids s/p symptomatic infection) CNS response- PANS By age 12 years >98% of the population have positive Mechanism may be molecular mimicry as with Strep titers (pseudo-autoimmune response- Ab to strep also PANDAS research dx requires flare associated with + reacts to neuronal antigens) culture and antibody evidence of appropriate rise in titer Assume also other inflammatory mechanisms over time, at least twice (very rarely used clinically- diagnosis most often given with Primary focus on OCD symptoms, with other single positive culture) associated symptoms secondary- behaviors and Blackburn, J. Seminars in Ped Neuro. 12: 2017 movements
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PANS PANS clinic experience
15 Research clinic, must fulfill research definition exactly Abrupt, dramatic onset Behavioral regression 84% documented prior illness, only 17% Strep of OCD or severe food restriction behavior Deterioration in school Primary symptom OCD or eating d/o Concurrent performance Tics 26%, chorea 15% neuropsychiatric Sensory and motor Many with severe compulsions and mood issues, symptoms: 2/7 abnormalities-tics, 1/3 with psychosis Anxiety chorea Emotional lability Higher rate of maternal autoimmune disease, Somatic symptoms- Irritability, aggression, strong FH of mood disorder oppositional insomnia, enuresis Chang, K., Frankovich, J. 2015 Journal of Child and Adol Psychopharmacology, 25(1): 2015.
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Diagnostic Assessment for PANS Is the Cunningham panel helpful?
Recommend full medical and family history, detailed Serum studies of autoantibodies neuro exam Sensitivity individual biomarkers for PANS dx Note mild hypotonia and chorea sometimes seen, no other specific serious neurologic signs or symptoms (no criteria 15-60% seizures, no delirium, no focal findings) Specificity 28-92% Strep test, other infectious titers, autoimmune labs PPV 17-40% Commercial antibody panel- Cunningham Panel, NPV 44-74% Moleculara Labs -serum testing, Elisa Majority of healthy controls had pathologic results -anti-dopamine receptor D1 and D2L Test-retest reliability poor -anti-lysoganglioside GM1 -anti-tubulin Does not document neuro-inflammation Hesselmark, E. J Neuroimmunol, Nov 15 (312): 2017.
Treatments offered for PANS Do the Treatments for PANS work?
Cognitive behavioral therapy Many published papers SSRI Systematic review of the literature on PANDAS, Antibiotics- for acute flare or daily for prevention PANS treatment over 17 years Steroids 3 large consensus papers- based on expert clinical NSAIDs experience, no research Plasma exchange One large survey of parents Intravenous Immune globulin 12 treatment studies- only 4 RCTs Rituximab 65 case series or case reports Cytoxan Total 1300 patients (90 in RCTs) Tonsillectomy, adenoidectomy -Sigra, S. Neurosci and Biobehav Rev. 86:2018.
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Bias assessment- moderate to high risk Overall inconclusive for evidence of efficacy for any No control groups particular treatment Unclear randomization -due to lack of consistent disease definition and lack of Small sample size systemic research Self selected, self reported Clear adverse reactions- ranging from mild Mixed populations- PANDAS and PANS (headache, nausea, GI distress) to serious (increased Various levels of severity, mixed focus on outcomes psychiatric symptoms, risk of line infection and for OCD vs tics blood clots) Some with multiple simultaneous treatments Outcomes primarily short term
Child Neurology Society Editorial Article Recommendations
Review of the literature on PANDAS and PANS Acute onset of Psychiatric Symptoms- if healthy child, Acknowledgement of the pressure to treat even without mild to moderate symptoms: no testing certainty regarding etiology or efficacy Acute onset Psychiatric Symptoms- if severe, disabling Caution about the lack of consensus on this controversial then stratify into 2 groups based on presence or absence of dx- no accurate medical diagnostic test to rule in or rule concurrent neurologic signs or symptoms out PANS or PANDAS Lack of data showing efficacy of any specific antibiotic or -if delirium, seizures, new non-tic movement d/o, immune therapy autonomic symptoms: full neurologic work up Focus on immune tx distracts from proven therapies- -if only psychiatric symptoms, with no concurrent CBT and SSRIs neurologic symptoms: defer to psychiatry, consider Risk of missing other neurologic disease based on family history, exam Gilbert, Minnk, Singer. J Peds. ‘Aug, 199: 2018.
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How CAN we know when to evaluate Case #2
CANS-Childhood Acute Neuropsychiatric Symptoms 11yo girl with GAS pharyngitis, treated with abx -Unusually abrupt onset of severe psychiatric symptoms with concurrent other cognitive, behavioral or neurologic 1 week later behavior change – emotional, anxious, symptoms difficulty sleeping (school stressors) PCP referred to child neurology for PANDAS Likely represents multiple mechanisms -postinfectious, autoimmune, neuroinflammatory 2 weeks later began having spells (4 in 24 hours) -toxic 3 ED visits (? non-epileptic spells) admission for -endocrine expedited work up -metabolic -vascular -psychogenic
Zibordi, Euro jour Ped Neuro. 22:2018.
Orobuccal Dyskinesia (YouTube video Additional History & Clinical Exam of unknown child)
Withdrawn (decreased speech output), endorsed small abnormal mouth movements “Type A kid,” but symptoms new and atypical
Normal vitals and general exam Normal neurologic exam except: Mental Status: suddenly agitated, paces around room “I know what’s going on, I have to go home” Very rare subtle orobuccal dyskinesia (easily could be missed!)
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EEG monitoring Differential Diagnosis
2 focal seizures (5-10 minutes each) within 1st hour of Autoimmune encephalitis (e.g. anti-NMDA receptor recording – pretty high burden! encephalitis) non-convulsive: ipsilateral nose wiping, behavioral arrest with Infectious encephalitis (e.g. HSV) upward eye deviation, oral and bilateral hand automatisms CNS involvement of rheumatologic disease (e.g. SLE) left temporal onset Metabolic disorder (e.g. mitochondrial) Initial EEG background left T7/P3 delta slowing and frequent spike wave discharges, Brain tumor normal posterior rhythm and sleep Malformation of cortical development (e.g. focal cortical dysplasia)
Anti-N-methyl-D-aspartate receptor Further Evaluation (NMDAR) encephalitis
Brain MRI with contrast – normal Serum labs – no indication of infection or underlying Antibody-mediated autoimmune encephalitis (AE) rheumatologic disorder Abs form against extracellular NR1 subunit of Lumbar Puncture NMDA receptor 6 WBCs (lymphocyte predominant), normal protein/glucose Known immunologic triggers: HSV PCR negative Tumor (usually ovarian teratoma) HSV encephalitis 3 oligoclonal bands Unknown in about 50% of patients +NMDAR abs in CSF (and serum)
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Demographics Association with HSV encephalitis
Female predominance: 81% female 20-30% of patients with HSV encephalitis can Affects young individuals: 37% < 18 yrs (95% < 45 yrs) develop HSV-induced AE (most commonly anti- About 50% with a tumor, usually ovarian teratoma (not always, esp > 45) Sex ratio and detection of ovarian teratoma is age dependent NMDAR encephalitis) Adults: largely young women, ovarian teratoma common Occurs within 2 months following HSV infection Children < 12: sex ratio more equal, ovarian teratoma rare Similar clinical phenotype Armange et al, Lancet Neurology 2018
VERY IMPORTANT TO TEST FOR ANTI-NMDAR IN CASES OF HSV ENCEPHALITIS RELAPSE!
Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-NMDAR encephalitis: an observational cohort study. Lancet Neurology, 2013.
Clinical Features Initial symptoms by age
Half of children/young adults have a non-specific viral prodrome Behavior change and seizures are most common presenting Symptoms- new onset symptoms in all ages Behavior (psychiatric) and cognitive dysfunction – anxiety, agitation, bizarre behavior, hallucinations, delusions, disordered thinking • Behavior more common in adults Speech dysfunction • Seizures/movement disorder more common in Memory deficits children (< 12) Seizures Movement disorders: orofacial dyskinesias, choreoathetosis, dystonia, akathisia, rigidity Decreased level of consciousness Autonomic instability
Sleep disturbance also common Hx in kids: “my child is having tantrums and talking baby talk again” (regression) - not normal! Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-NMDAR encephalitis: an observational cohort study. Lancet Neurology, 2013.
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Poly-symptomatic Disease Findings in anti-NMDAR encephalitis
87% developed ≥ 4 symptoms Brain MRI – often normal or shows transient FLAIR within 4 weeks or contrast-enhancing abnormalities in cortical and 1% had only one symptom Most common: subcortical regions behavior/cognitive changes, memory deficits, speech CSF – often abnormal with pleocytosis disorder, seizures, movement disorder EEG – usually focal or diffuse slowing More sensitive than brain MRI or CSF studies (cell Children: movement disorder, count/protein) speech disorder Adults: memory deficits and central Diagnosis is confirmed with + IgG antibodies to hypoventilation Titulaer et al, Treatment and prognostic factors for NMDAR in CSF or serum Rare sxs: ataxia and hemiparesis long-term outcome in patients with anti-NMDAR (seen mainly in young children) encephalitis: an observational cohort study. Lancet CSF testing is important given higher sensitivity (100%) than Neurology, 2013. serum (85%)
What do we know about treatment? Standard Disease Treatment
No prospective randomized trials Tumor removal Observational studies Immunotherapy Largest study: retrospective, 501 patients (177 children) First-line: High-dose steroids, IVIg, plasma exchange Nearly all (94%) treated with first-line immunotherapy/tumor removal Typically solumedrol x 5 days AND either IVIg or plasma exchange 53% improved within 4 weeks Second-line: Rituximab, cyclophosphamide Of those who didn’t improve, 57% received second-line Typically start with rituximab in children, but if severe consider immunotherapy higher likelihood of good outcome (mRS 0-2) dual-therapy Tenets of treatment: Questions/challenges responsive to immune therapy IVIg versus PLEX? early treatment better than late When to move on to second-line therapy? if no/limited response to first-line therapy move on to second-line therapy Need novel therapies
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Symptom Management Outcomes
Goal: minimize morbidity & complications from critical illness No difference between children and adults
Psychosis/agitation/delirium During hospitalization: 75% are admitted to ICU Delirium precautions At 2 yrs, 81% of patients “good” outcome (mRS 0-2), 6% Clonidine/dexmedetomidine Low-dose anti-psychotics only with caution (risk of NMS) died Sleep disruption Melatonin, clonidine, others Improvement up to 18 months after symptom onset Movements Predictors of good outcome Difficult to treat - goal is to minimize morbidity (self-harm, rhabdo), not to stop the movements Earlier treatment with immunotherapy/tumor removal Benzodiazepines, others No need for ICU stay Vigilant attention to oral care Titulaer et al, Treatment and prognostic factors for long- Seizures 12% relapse in first 2 yrs term outcome in patients with anti-NMDAR encephalitis: an observational cohort study. Lancet Neurology, 2013. Consider avoiding levetiracetam given risk of worsening irritability Dysautonomia/hypoventilation NEOS score (1-5) -> associated with functional status at 1 year Cardio-respiratory monitoring Balu et al, Neurology 2019
Clinical Approach to Diagnosis of Autoimmune Encephalitis (Graus et al, Lancet Neurol 2016) Case #3
Goal: early treatment Graus criteria validated 10yo boy with recent onset MRI-negative focal epilepsy before ab test returns in separate cohort of Presents to ED with new spells of non-stereotyped children (Ho et al, Dev Med and Child Neuro 2017) extremity movements, gait instability, and 29 patients anti-NMDAR, anxiety 74 other encephalitides EEG: non-epileptic movements Graus anti-NMDAR Dx: non-epileptic spells, conversion disorder (for the gait), and criteria 90% sensitive anxiety disorder and 96% specific Parents bring him back to ED couple days later with Median time to meet worsening anxiety (“I’d rather be dead”) and episode of criteria 2 weeks “shaking with LOC” Transferred for further evaluation/cEEG monitoring
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Additional HX & Clinical Examination Diagnostic Evaluation/Outcome
Family reported (and patient endorsed) fidgety leg EEG monitoring: movements, spells of stiffening, and Very frequent focal seizures Normal background initially, transitioned to diffuse slowing withdrawal/anxiety over past few weeks -> atypical Brain MRI with contrast normal Examination: CSF Normal vitals and general exam 2 WBC, normal glucose and protein Normal neurologic exam except: Screen for tumor - negative Distressed, readily brought to tears in between spells, “please help me”, fluent but decreased speech output Fulfilled 4/6 sxs for Graus criteria – empiric RX started Subtle leg akathisia +NMDAR ab in CSF and serum Several beats ankle clonus bilaterally Complete recovery after first-line therapy, no relapse
Take-Home Points Take-Home Points
PANDAS/PANS remains a controversial diagnosis, and Anti-NMDAR encephalitis is a severe antibody- treatments are unproven mediated disease responsive to immunotherapy and Children with concurrent onset of acute psychiatric and clinically recognizable neurologic symptoms deserve a full neurologic diagnostic Young children initially present with movement evaluation disorder or seizures more often than adults, and Treatment should include evidence based psychiatric young girls/boys nearly equally affected care (CBT and SSRIs) In all patients, important to probe about Antibiotics or immune modulation treatment should be behavior/psych symptoms, changes in speech, subtle discussed on a case by case basis, ideally based on abnormal movements, “spells” we need to ask, objective findings of infection or neuro-inflammation listen, and promptly evaluate when indicated CANS/Childhood Acute Neuropsychiatric Symptoms have a much broader differential diagnosis Goal is early therapy to improve outcome
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Thank you
For your attention! For our collaborators Emmanuelle Waubant Carla Francisco Jeffrey Gelfand Michael Wilson Bennett Leventhal Khyati Brahmbatt Josep Dalmau
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