Pediatric Neurology Pearls 8yo boy, with tics and Obsessive - - PowerPoint PPT Presentation

2/14/2019 1

CHILDHOOD ACUTE ONSET NEUROPSYCHIATRIC SYMPTOMS

A U D R E Y F O S T E R - B A R B E R , M D P H D P E D I A T R I C B R A I N C E N T E R O U T P A T I E N T D I R E C T O R , C H I L D N E U R O L O G Y R E S I D E N C Y D I R E C T O R , V I C E C H A I R N E U R O L O G Y U C S F K E N D A L L N A S H , M D P E D I A T R I C B R A I N C E N T E R I N P A T I E N T D I R E C T O R , A S S O C . M E D I C A L D I R E C T O R P H Y S I C I A N N E T W O R K D E V T . B E N I O F F C H I L D R E N S H O S P I T A L S

Pediatric Neurology Pearls

Case #1

 8yo boy, with tics and Obsessive Compulsive (OC)

symptoms

 Onset of simple tics 2 years prior- sniff, snort, deep

breathe, tapping fingers, palilalia

 Some obsessive character to tics, even out

movements, repeat word a certain #of times to “make it right”

 In the last month some behavior issues- easy temper,

yelling at sib, won’t touch doorknobs or drawer handles

 Query- is this PANDAS?  No ADHD signs or concerns  Eating and Sleeping well  Doing well at school  No seizures  Tics present for 2 years, vary in severity, often worse

with illness or with stress

 No recent illness symptoms  Throat culture done by Pediatrician, positive for

Group A Strep (GAS), given antibiotics

 after 10 days of antibiotics tics improved, then

worsened again a few weeks later

 No change in behavior issues, ocd symptoms

2/14/2019 2

 PMH- born at term with duodenal atresia, largyngeal

cleft s/p repair

 Development- normal milestones, bright child, aa bit

anxious but social and active in sports

 FH- Mother with Hashimoto’s thyroiditis, history of

anxiety, Father with history of a mood disorder

 SH- lives with mother and sibling, parents divorcing  Dx-Tourette Syndrome or chronic tic disorder, OCD

tendency

 Return to clinic 6 months later with concern for

“Explosive worsening” of behavior, moody, more OCD symptoms

 Tics not worse, though a few new tics added to his

repertoire

 No associated illness, primary doctor tested for Strep

by throat culture and mycoplasma by antibodies, both negative

 Did receive a Flu vaccine a few weeks to a month

prior

 New stressors- mother with new partner moving in,

with partner’s child

 Mother would prefer a PANDAS diagnosis, rather

than a diagnosis of tic disorder with mood disorder

 “PANDAS seems to have a clear treatment, whereas

the others would be a chronic disorder”

 Recommend- cognitive behavioral therapy (CBT), no

antibiotics

 6 months later, ongoing CBT with some benefit for

behavior and OCD symptoms

 Tics still present, wax and wane  Seen by Integrative Medicine doctor-

Extensive Testing-zinc, heavy metal, strep culture, MTHFR polymorphism, autoimmune screen (ANA, DS-DNA) all negative

• myocoplasma IgG+, Lyme Ab equivocal
• Cunningham panel interpreted as abnormal
• treated with 3 months of Azithromycin, patient self d/c’d

at 2 months due to GI distress

2/14/2019 3

 During the 2 months on antibiotics no tic worsening,

OCD was better already with therapy

 Mother now “not so sure” about a PANDAS

diagnosis, but feels “antibiotics are benign” so will consider them if symptoms worsen (child refused antibiotic prophylaxis)

 Plans to avoid escalation to immune therapy that

was recommended- IVIg and or pheresis

 Declined other neurologic work up (MRI and LP)

because “doing too well”

Why did PANDAS come up here?

 Classic for Childhood Tic disorder-

• tics onset prepubertal, vary in type, wax and wane over time
• associated OCD (up to 50 % of patients)
• bilineal inheritance (tics, adhd, anxiety, or ocd in both parents)

 Family Concerns

• FH autoimmune disease
• hope for something treatable
• difficulty of proving associated infection, of attributing

cause/effect of antibiotic therapy

• common idea in the lay community, with integrative health

providers

History behind PANDAS

 1980s- psychiatrists noted subset of patients with

OCD who had a severe, abrupt onset of symptoms

 Temporal association with infectious triggers- strep,

varicella, mycoplasma, influenza, EBV, Lyme

 Initially called PITANDS- Pediatric infection

triggered autoimmune neurologic and psychiatric disorder

 Researchers chose to focus on GAS infection due to

ease of documentation of infection and connection to known molecular mimicry in Sydenham’s Chorea- labeled PANDAS

11

PANDAS- defined 1998

 PANDAS- pediatric autoimmune neurologic disorder

associated with Strep

 Presence of OCD and or tics- severe, interfere with

patient’s ability to function

 Age of onset 3yo to puberty  Acute onset, episodic (relapsing remitting)  Temporally related to GAS infection  Other associated neurologic (choreiform

movements) and behavioral abnormalities (sleep disturbance, enuresis, anxiety, lability, insomnia)

Swedo, SE. J Child and Adol Psychpharm, Feb 25(1)’ 2015 12

2/14/2019 4 Defining a GAS infection is tricky

 25% of the pediatric population has + strep culture

without immune reaction (carrier)

 ASO and DNAse B titers can remain elevated for months

(up to 12 mo in >50 % of kids s/p symptomatic infection)

 By age 12 years >98% of the population have positive

titers

 PANDAS research dx requires flare associated with +

culture and antibody evidence of appropriate rise in titer

• ver time, at least twice

(very rarely used clinically- diagnosis most often given with single positive culture)

Blackburn, J. Seminars in Ped Neuro. 12: 2017 13

Pediatric Acute onset Neuropsychiatric Syndrome

 2013 Consensus meeting  Back to the idea that multiple infections can trigger a

CNS response- PANS

 Mechanism may be molecular mimicry as with Strep

(pseudo-autoimmune response- Ab to strep also reacts to neuronal antigens)

 Assume also other inflammatory mechanisms  Primary focus on OCD symptoms, with other

associated symptoms secondary- behaviors and movements

14

 Abrupt, dramatic onset

• f OCD or severe food

restriction behavior

 Concurrent

neuropsychiatric symptoms: 2/7

 Anxiety  Emotional lability  Irritability, aggression,

• ppositional

 Behavioral regression  Deterioration in school

performance

 Sensory and motor

abnormalities-tics, chorea

 Somatic symptoms-

insomnia, enuresis

15

PANS PANS clinic experience

 Research clinic, must fulfill research definition

exactly

 84% documented prior illness, only 17% Strep  Primary symptom OCD or eating d/o  Tics 26%, chorea 15%  Many with severe compulsions and mood issues,

1/3 with psychosis

 Higher rate of maternal autoimmune disease,

strong FH of mood disorder

Chang, K., Frankovich, J. 2015 Journal of Child and Adol Psychopharmacology, 25(1): 2015.

2/14/2019 5 Diagnostic Assessment for PANS

 Recommend full medical and family history, detailed

neuro exam

 Note mild hypotonia and chorea sometimes seen, no

• ther specific serious neurologic signs or symptoms (no

seizures, no delirium, no focal findings)

 Strep test, other infectious titers, autoimmune labs  Commercial antibody panel- Cunningham Panel,

Moleculara Labs

• serum testing, Elisa
• anti-dopamine receptor D1 and D2L
• anti-lysoganglioside GM1
• anti-tubulin

Is the Cunningham panel helpful?

 Serum studies of autoantibodies  Sensitivity individual biomarkers for PANS dx

criteria 15-60%

 Specificity 28-92%  PPV 17-40%  NPV 44-74%  Majority of healthy controls had pathologic results  Test-retest reliability poor  Does not document neuro-inflammation

Hesselmark, E. J Neuroimmunol, Nov 15 (312): 2017.

Treatments offered for PANS

 Cognitive behavioral therapy  SSRI  Antibiotics- for acute flare or daily for prevention  Steroids  NSAIDs  Plasma exchange  Intravenous Immune globulin  Rituximab  Cytoxan  Tonsillectomy, adenoidectomy

Do the Treatments for PANS work?

 Many published papers  Systematic review of the literature on PANDAS,

PANS treatment over 17 years

 3 large consensus papers- based on expert clinical

experience, no research

 One large survey of parents  12 treatment studies- only 4 RCTs  65 case series or case reports  Total 1300 patients (90 in RCTs)

• Sigra, S. Neurosci and Biobehav Rev. 86:2018.

2/14/2019 6

 Bias assessment- moderate to high risk  No control groups  Unclear randomization  Small sample size  Self selected, self reported  Mixed populations- PANDAS and PANS  Various levels of severity, mixed focus on outcomes

for OCD vs tics

 Some with multiple simultaneous treatments  Outcomes primarily short term  Overall inconclusive for evidence of efficacy for any

particular treatment

• due to lack of consistent disease definition and lack of

systemic research

 Clear adverse reactions- ranging from mild

(headache, nausea, GI distress) to serious (increased psychiatric symptoms, risk of line infection and blood clots)

Child Neurology Society Editorial Article

 Review of the literature on PANDAS and PANS  Acknowledgement of the pressure to treat even without

certainty regarding etiology or efficacy

 Caution about the lack of consensus on this controversial

dx- no accurate medical diagnostic test to rule in or rule

• ut PANS or PANDAS

 Lack of data showing efficacy of any specific antibiotic or

immune therapy

 Focus on immune tx distracts from proven therapies-

CBT and SSRIs

 Risk of missing other neurologic disease

Gilbert, Minnk, Singer. J Peds. ‘Aug, 199: 2018.

Recommendations

 Acute onset of Psychiatric Symptoms- if healthy child, mild to moderate symptoms: no testing  Acute onset Psychiatric Symptoms- if severe, disabling then stratify into 2 groups based on presence or absence of concurrent neurologic signs or symptoms

• if delirium, seizures, new non-tic movement d/o,

autonomic symptoms: full neurologic work up

• if only psychiatric symptoms, with no concurrent

neurologic symptoms: defer to psychiatry, consider based on family history, exam

2/14/2019 7 How CAN we know when to evaluate

 CANS-Childhood Acute Neuropsychiatric Symptoms

• Unusually abrupt onset of severe psychiatric symptoms

with concurrent other cognitive, behavioral or neurologic symptoms

 Likely represents multiple mechanisms

• postinfectious, autoimmune, neuroinflammatory
• toxic
• endocrine
• metabolic
• vascular
• psychogenic

Zibordi, Euro jour Ped Neuro. 22:2018.

Case #2

 11yo girl with GAS pharyngitis, treated with abx  1 week later behavior change – emotional, anxious,

difficulty sleeping (school stressors)

 PCP referred to child neurology for PANDAS  2 weeks later began having spells (4 in 24 hours)  3 ED visits (? non-epileptic spells)  admission for

expedited work up

Additional History & Clinical Exam

 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!)

Orobuccal Dyskinesia (YouTube video

• f unknown child)

2/14/2019 8 EEG monitoring

 2 focal seizures (5-10 minutes each) within 1st hour of

recording – pretty high burden!

 non-convulsive: ipsilateral nose wiping, behavioral arrest with

upward eye deviation, oral and bilateral hand automatisms

 left temporal onset

 Initial EEG background

 left T7/P3 delta slowing and frequent spike wave discharges,

normal posterior rhythm and sleep

Differential Diagnosis

 Autoimmune encephalitis (e.g. anti-NMDA receptor

encephalitis)

 Infectious encephalitis (e.g. HSV)  CNS involvement of rheumatologic disease (e.g. SLE)  Metabolic disorder (e.g. mitochondrial)  Brain tumor  Malformation of cortical development (e.g. focal

cortical dysplasia)

Further Evaluation

 Brain MRI with contrast – normal  Serum labs – no indication of infection or underlying

rheumatologic disorder

 Lumbar Puncture

 6 WBCs (lymphocyte predominant), normal protein/glucose  HSV PCR negative  3 oligoclonal bands  +NMDAR abs in CSF (and serum)

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

 Antibody-mediated autoimmune encephalitis (AE)  Abs form against extracellular NR1 subunit of

NMDA receptor

 Known immunologic triggers:

 Tumor (usually ovarian teratoma)  HSV encephalitis  Unknown in about 50% of patients

2/14/2019 9 Demographics

 Female predominance: 81% female  Affects young individuals: 37% < 18 yrs (95% < 45 yrs)  About 50% with a tumor, usually ovarian teratoma (not always, esp > 45)  Sex ratio and detection of ovarian teratoma is age dependent  Adults: largely young women, ovarian teratoma common  Children < 12: sex ratio more equal, ovarian teratoma rare

Titulaer et al, Treatment and prognostic factors for long-term

• utcome in patients with anti-NMDAR encephalitis: an
• bservational cohort study. Lancet Neurology, 2013.

Association with HSV encephalitis

 20-30% of patients with HSV encephalitis can

develop HSV-induced AE (most commonly anti- NMDAR encephalitis)

 Occurs within 2 months following HSV infection  Similar clinical phenotype

Armange et al, Lancet Neurology 2018

VERY IMPORTANT TO TEST FOR ANTI-NMDAR IN CASES OF HSV ENCEPHALITIS RELAPSE!

Clinical Features

 Half of children/young adults have a non-specific viral prodrome  Symptoms- new onset

 Behavior (psychiatric) and cognitive dysfunction – anxiety, agitation, bizarre

behavior, hallucinations, delusions, disordered thinking

 Speech dysfunction  Memory deficits  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!

Initial symptoms by age

Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-NMDAR encephalitis: an observational cohort study. Lancet Neurology, 2013.

Behavior change and seizures are most common presenting symptoms in all ages

• Behavior more common in adults
• Seizures/movement disorder more common in

children (< 12)

2/14/2019 10 Poly-symptomatic Disease

 87% developed ≥ 4 symptoms

within 4 weeks

 1% had only one symptom  Most common:

behavior/cognitive changes, memory deficits, speech disorder, seizures, movement disorder

 Children: movement disorder,

speech disorder Adults: memory deficits and central hypoventilation

 Rare sxs: ataxia and hemiparesis

(seen mainly in young children)

Titulaer et al, Treatment and prognostic factors for long-term outcome in patients with anti-NMDAR encephalitis: an observational cohort study. Lancet Neurology, 2013.

Findings in anti-NMDAR encephalitis

 Brain MRI – often normal or shows transient FLAIR

• r contrast-enhancing abnormalities in cortical and

subcortical regions

 CSF – often abnormal with pleocytosis  EEG – usually focal or diffuse slowing

 More sensitive than brain MRI or CSF studies (cell

count/protein)  Diagnosis is confirmed with + IgG antibodies to

NMDAR in CSF or serum

 CSF testing is important given higher sensitivity (100%) than

serum (85%)

What do we know about treatment?

 No prospective randomized trials  Observational studies  Largest study: retrospective, 501 patients (177 children)

 Nearly all (94%) treated with first-line immunotherapy/tumor

removal

 53% improved within 4 weeks  Of those who didn’t improve, 57% received second-line

immunotherapy  higher likelihood of good outcome (mRS 0-2)  Tenets of treatment:

 responsive to immune therapy  early treatment better than late  if no/limited response to first-line therapy move on to second-line

therapy

Standard Disease Treatment

 Tumor removal  Immunotherapy

 First-line: High-dose steroids, IVIg, plasma exchange  Typically solumedrol x 5 days AND either IVIg or plasma exchange  Second-line: Rituximab, cyclophosphamide  Typically start with rituximab in children, but if severe consider

dual-therapy

 Questions/challenges

 IVIg versus PLEX?  When to move on to second-line therapy?  Need novel therapies

2/14/2019 11 Symptom Management

 Goal: minimize morbidity & complications from critical illness  Psychosis/agitation/delirium



Delirium precautions



Clonidine/dexmedetomidine



Low-dose anti-psychotics only with caution (risk of NMS)  Sleep disruption



Melatonin, clonidine, others  Movements



Difficult to treat - goal is to minimize morbidity (self-harm, rhabdo), not to stop the movements



Benzodiazepines, others



Vigilant attention to oral care  Seizures



Consider avoiding levetiracetam given risk of worsening irritability  Dysautonomia/hypoventilation



Cardio-respiratory monitoring

Outcomes

 No difference between children and adults  During hospitalization: 75% are admitted to ICU  At 2 yrs, 81% of patients “good” outcome (mRS 0-2), 6%

died

 Improvement up to 18 months after symptom onset  Predictors of good outcome

 Earlier treatment with immunotherapy/tumor removal  No need for ICU stay

 12% relapse in first 2 yrs

 NEOS score (1-5) -> associated with functional status at 1 year

Balu et al, Neurology 2019 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 Approach to Diagnosis of Autoimmune Encephalitis (Graus et al, Lancet Neurol 2016)

 Goal: early treatment

before ab test returns

 Graus criteria validated

in separate cohort of children (Ho et al, Dev Med and Child

Neuro 2017)

 29 patients anti-NMDAR,

74 other encephalitides

 Graus anti-NMDAR

criteria 90% sensitive and 96% specific

 Median time to meet

criteria 2 weeks

Case #3

 10yo boy with recent onset MRI-negative focal epilepsy  Presents to ED with new spells of non-stereotyped

extremity movements, gait instability, and anxiety

 EEG: non-epileptic movements  Dx: non-epileptic spells, conversion disorder (for the gait), and

anxiety disorder  Parents bring him back to ED couple days later with

worsening anxiety (“I’d rather be dead”) and episode of “shaking with LOC”

 Transferred for further evaluation/cEEG monitoring

2/14/2019 12 Additional HX & Clinical Examination

Family reported (and patient endorsed) fidgety leg movements, spells of stiffening, and withdrawal/anxiety over past few weeks -> atypical Examination:

 Normal vitals and general exam  Normal neurologic exam except:  Distressed, readily brought to tears in between spells,

“please help me”, fluent but decreased speech output

 Subtle leg akathisia  Several beats ankle clonus bilaterally

Diagnostic Evaluation/Outcome

 EEG monitoring:

 Very frequent focal seizures  Normal background initially, transitioned to diffuse slowing

 Brain MRI with contrast

 normal

 CSF

 2 WBC, normal glucose and protein

 Screen for tumor - negative  Fulfilled 4/6 sxs for Graus criteria – empiric RX started

 +NMDAR ab in CSF and serum  Complete recovery after first-line therapy, no relapse

Take-Home Points

 PANDAS/PANS remains a controversial diagnosis, and

treatments are unproven

 Children with concurrent onset of acute psychiatric and

neurologic symptoms deserve a full neurologic diagnostic evaluation

 Treatment should include evidence based psychiatric

care (CBT and SSRIs)

 Antibiotics or immune modulation treatment should be

discussed on a case by case basis, ideally based on

• bjective findings of infection or neuro-inflammation

 CANS/Childhood Acute Neuropsychiatric Symptoms

have a much broader differential diagnosis

Take-Home Points

 Anti-NMDAR encephalitis is a severe antibody-

mediated disease responsive to immunotherapy and clinically recognizable

 Young children initially present with movement

disorder or seizures more often than adults, and young girls/boys nearly equally affected

 In all patients, important to probe about

behavior/psych symptoms, changes in speech, subtle abnormal movements, “spells”  we need to ask, listen, and promptly evaluate when indicated

 Goal is early therapy to improve outcome

2/14/2019 13 Thank you

 For your attention!  For our collaborators

 Emmanuelle Waubant  Carla Francisco  Jeffrey Gelfand  Michael Wilson  Bennett Leventhal  Khyati Brahmbatt  Josep Dalmau