Why is there controversy?? Disclosures. History. Learning Objectives PANS/PANDAS. 1) tics seem to be transient and worsen with stress
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1 39 th National Conference on Pediatric Health Care March 19-22, 2018 CHICAGO Disclosures PANDAS: IT S NOT SO BLACK AND WHITE Recognizing and managing Pediatric Autoimmune Neuropsychiatric Disorder Associated with Strep in the Primary Care Setting Session 215 I have no disclosures to make Jennifer Gagnon, MSN, CPNP, FNP C Learning Objectives 1) Know the major and minor criteria for PANDAS diagnosis. 2) Know how to start treatment for PANDAS in the primary setting. 3) Identify laboratory tests that can assist in making the diagnosis and treatment plan. History Dr. Swedo conceived the idea of PANDAS in the 1980s while working at NIMH/NIH with children with Sydenham s Chorea Swedo and her team noticed a sudden onset of Tics and/or OCD in association with Group A Strep, but the child did not meet the criteria for Sydenham s Chorea Swedo was the lead author of a paper describing PANDAS in 1994 Swedo believes that children with PANDAS make up as much as 25% of kids diagnosed with OCD and/or Tourette's Swedo:.Just as Sydenham s Chorea gives you abnormal movements, PANDAS give you abnormal thoughts and behaviors PANS/PANDAS PANS An autoimmune reaction to a physiological stressor including Group A Streptococcal infections, Mycoplasma pneumonia infection, influenza, upper respiratory infections, sinusitis, and psychosocial stressors Why is there controversy?? 1) tics seem to be transient and worsen with stress PANDAS A subset of PANS where symptoms and flare ups are triggered by Group A Streptococcal Infections 2)Some feel that it is over diagnosed 1
2 Mechanism of Action: Effects of Basal Ganglia Inflammation Autoimmune process: the auto antibodies produced to fight streptococcal A infection target healthy tissue, such as neurons in the basal ganglia Within the basal ganglia autoantibodies bind and activate dopamine neurons. Too much dopamine is released and motor signals to the rest of the brain and body go haywire Dr. Agaillu s laboratory at Columbia University in conjunction with Dr. Cleary at the University of Minnesota have identified that GAS specific Th17 cells (immune cell naturally occurring in the exposed human tonsils) which produce cytokines that are known to break down the blood brain barrier Dr. Harry Chugani at Dupont Children s Hospital in Delaware is studying the use of PET scans to evaluate the amount of inflammation of the basal ganglia Basal Ganglia is a Relay Station through which Run Neurons that Control: Mood and Emotion Behavior Procedural learning Motor movements Cognition Sensory Inflammation may cause: OCD, Mood lability, Anxiety OCD, Rage, Development regression Handwriting changes, clumsiness Tics, Choreiform movements Slow processing speed, memory issues, specific Sensory and learning deficits (often math) Sensitivity to light, sounds, smells, tastes, textures Pandas ppn.org Feeding Aversions Obsessive/Compulsive Disorder Tics (no longer required) Sensory Changes Anxiety (general/severe) Sleep disturbances Academic Challenges Behavior Changes Fine/gross motor movements Urinary Symptoms CLINICAL SYMPTOMS Diagnostic criteria of PANDAS OCD: usually sudden onset from mild or no symptoms to debilitating consequences Parents can often give a particular date of this happening Helpful to use the Obsessive Compulsive Checklist and Scale (CY BCOS) to evaluate the effect on daily life Y BCOS Obsessions are unwanted ideas, images, or impulses that intrude on thinking against your wishes and efforts to resist them. They usually involve themes of harm, risk, and danger. Common obsessions are excessive fears of contamination; recurring doubts about danger; extreme concern with order, symmetry, or exactness; fear of losing important things. Compulsions are urges that people have to do something to lessen feelings of anxiety or other discomfort. Often they do repetitive, purposeful, intentional behaviors called rituals. The behavior itself may seem appropriate but it becomes a ritual when done to excess. Washing, checking, repeating, straightening, hoarding, and many other behaviors can be rituals. Some rituals are mental. For example, thinking or saying things over and over under your breath. FOOD RESTRICTIONS Various reasons for not eating adequately: Fear of vomiting Sensitivity to taste, smell, & texture Fear of food being spoiled or poisonous Can also be related to body distortion. 2
3 ANXIETY Sensory Amplification 1) Generalized anxiety, which can appear to be constant 2) Age inappropriate separation anxiety All of a sudden smells, tasted, sounds, textures, brushing hair and teeth are intolerable SCREENING TOOLS: SCARED (filled out individually by parent and child: if age appropriate) MOTOR ABNORMALITIES Some children will develop vocal and/or motor tics Others may develop mild choreiform movements (chorea/choreiform movements piano fingers ) Changes in fine motor skills as well as clumsiness Usually associated with invreased dopaminergic activity What are choreiform movements? Choreiform movements are small, jerky movements occurring irregularly and arrhythmically in distal muscles. They are most easily observed by having the child stand with eyes closed and arms outstretched in front of him and fingers slightly separated (Romberg stance). After a few seconds, fine piano playing movements will be seen in the fingers, and there may be mild pronator drift of the hands. These movements are normal overflow in children younger than 5 years of age, but should be absent in children older than 6 years. Fine motor skills: before treatment and after treatment Child will demonstrate regressed behaviors Non appropriate temper tantrums Baby talk Refusal to carry out age appropriate tasks Clinginess/separation anxiety Acting younger than they are Behavioral Regression 3
4 Difficulty with visual spatial recall Poor executive functioning Poor dexterity testing Decreased processing speed Memory difficulties Difficulty in math and calculations Deterioration in School Performance Reactive rage can start instanteously and end just as quickly the child is usually remorseful Occasionally a child has no recollection of a rage episode Depression, mania, irritability, emotional liability, hyper sexuality and rage can occur during a PANDAS exacerbation MOOD DISORDERS URINARY SYMPTOMS SLEEP DISTURBANCES Polyuria (more than 3x/hour) Frequent urge to urinate Day/night secondary enuresis Need to rule out: 1) Urinary tract infection 2) Anxiety 3) OCD worries Due to separation issues, frequent co sleeping with parents is common Decreased REM sleep (can be demonstrated on polysomnography) Nightmares Prolonged transition to sleep Statistics o 1:200 children in the United States have PANDAS o Age of onset anywhere between 1yr and 14 yrs. old o Peak age at onset is 4 9 years of age o Ratio: o 2.6 boys : 1 girl o If under age 8y 4.7 boys : 1 girl Family History: 70% of families of PANDAS patients have a familial history of autoimmune illness and/or strep related illnesses Acute or gradual onset presentation Clinical Diagnosis Symptoms can also ebb and flow but there is usually a sudden onset for the first time under the age of 12 years PANS/PANDAS is a diagnosis of exclusion 4
5 Helpful items at initial appointment: 1. Pediatric Records 2. Growth Chart 3. Lab Work 4. Tests/Scans (CT, MRI, EEG, and Sleep Study) 5. Therapy Notes 6. Neuropsychological Testing 7. Current Medication List 8. Writing Samples (school notes, papers, etc) 9. Y BCOS and SCARED screening IS IT PANDAS?? Review the medical records: Has the child had a history of Group A Strep? Including strep pharyngitis, scarlet fever, vaginal or perianal strep, and impetigo? Evaluate the growth charts (any dips in growth which correlate with illness) Previous laboratory tests, work ups for other illnesses Any behavioral issues Any urinary issues Making the Diagnosis: 2 Obtain a thorough history May need to do with with child in the room, but then without the child present. Some children get very upset when they hear about things that they have done Evaluate for Group A strep (GAS) infection: Recent exposures Potential symptoms: sore throat, headaches, abdominal pain, vomiting, rashes, and perianal itching/erythema MAKING THE DIAGNOSIS: 3 PHYSICAL EXAMINATION: HEENT: swab the throat vigorously and perform a rapid strep test if negative do a hour culture; does the child have dilated pupils CARDIAC EXAM and LUNGS: need to assess for any new murmurs (if new murmur need to consider Sydenham s Chorea (by looking for other symptoms and order a cardiology consult if necessary SKIN and Genitalia: looking for scarletina rash on trunk, and rash or erythema in vaginal/anal area. Consider doing culture if questionable infection in the genital/anal area Gross motor movement as well as fine motor ability LAB TESTS FOR INITIAL WORK UP: Throat swab for GAS rapid test &/or culture ASO titer, Anti DNase titer: repeat in 2 6 weeks for antibody rise or fall CBC with differential CMP Thyroid Function Lyme titer with Western Blot Immunoglobulins 1gA, IgM, IgG with subsets 1, 2, 3, 4 Vitamin D Consider M. pneumoniae IgG, IgM Test for other infections based on history 5
6 GATHERING MORE INFORMATION: Strep pneumonia titers (if thought necessary) (suspect immunocompromise) Confirm Lyme findings (if concerned about co infections) Cunningham Panel Polysomnography Evaluation of Growth Chart WHAT IS THE CUNNINGHAM PANEL? Developed bymadeline Cunningham, Ph.D. from University of Oklahoma Health Science Center and her team Investigating anti neuronal autoantibodies and their mechanisms of action on movement and behavioral disorders including PANS/PANDAS Assessing the correlation of autoantibodies and immune responses with disease onset and symptoms in defining movement and behavioral disorders including PANS/PANDAS Allows autoantibodies to be identified that are directed against specific neurologic receptors which can assist in making an accurate diagnosis 5 different tests: neuronal antigens CUNNINGHAM PANEL Allows autoantibodies to be identified that are directed against specific neurologic receptors which can assist in making an accurate diagnosis 5 different tests: neuronal antigens 1. Anti Dopamine receptor (D1) 2. Anti Dopamine receptor (D2) D1 & D2 are responsible for fine motor control, cognition, and other forms o behavior 3. Anti lysoganglioside (GM1) associated with degenerative neuro. conditions 4. Anti tubulin (associated with autoimmune thyroid conditions) 5. CamKinase II (elevation may be associated with an infection triggered autoimmune condition UPDATED 2017 GUIDELINES FOR DIAGNOSING PANDAS Now you have gathered all of this information, does the patient have PANDAS? Remember it is a diagnosis made by exclusion. Guidelines: 1) Presence of OCD and/or tics (complex, multiple, unusual) [tics are no longer required 2) Age of presentation is between age 3 years of age and puberty 3) Acute onset with episodic course 4) Association with GAS infection 5) Association with neurological abnormalities New classifications of Disease Trajectory Per 2017 Clinical Management Guidelines New Onset or Acute Flares Relapsing remitting Chronic static or chronic progressive MANAGEMENT of MILD SYMPTOMS Mild symptoms tend not to interfere with daily activities for more than a couple of hours a day. Treatment may consist of Antibiotics Corticosteroid Anti inflammatories Cognitive Behavioral Therapy???Adenoidectomy: no hard evidence; however still recommended for obstructive sleep apnea and treatment of chronic GAS When antibiotics are given 1 3 days after symptom onset, there tends to be a faster response in symptoms. It is also important to recognize that some symptoms will resolve without intervention. 6
7 2017 GUIDELINES FOR MANAGEMENT of PANS/PANDAS Individualized treatment plan medical and social Safety concerns School Accommodation: 504 or IEP Family support and education Psychologists/counselors 2017 GUIDELINES: OCD: Cognitive Behavioral Therapy (CBT) and Exposure Response Prevention (ERP) teaches how to adjust family s accommodations However during an acute phase the child may not be able to grasp the concepts being discussed If treatment is started early, there usually is good success Pharmaceutical management of OCD can take weeks before any benefit is seen SSRIs are the preferred treatment for OCD But it is important to START LOW & GO SLOW The dose is usually started with a dosage of ¼ of the typical dose, with upward titration every 2 weeks If OCD is incapacitating antipsychotic medications can be used 2017 GUIDELINES: Restriction of food/fluid intake Other disorders need to be ruled out Focus on maintaining adequate nutrition and hydration while treating brain inflammation (NG feeds or PPN may be necessary) Assessment includes physical exam, orthostatic vital signs, EKG, electrolytes, magnesium, phosphorus, and monitoring for refeeding syndrome OT can help with high anxiety situations and compulsive behavior 2017 GUIDELINES: Attention Deficit and Hyperactivity Disorder Interruption of classroom setting Stimulants can be used Methylphenidate usually is more beneficial than amphetamines since amphetamines can increase compulsive behaviors Alomoxetine is a 2 nd line medication but does have anti inflammatory effect. Other 2017 GUIDELINES: SLEEP DISTURBANCES: Causes Separation anxiety OCD Bedtime rituals Enuresis Nightmares Temperature dysregulation Sleep apnea (enlarged tonsils) Decreased REM sleep (can be an adverse effect of SSRIs) SLEEP DISTURBANCES CONTINUED Initiation of good sleep hygiene If behavioral changes don t help: pharmaceuticals can be used Lower doses usually are beneficial with lower side effects 7
8 2017 GUIDELINES: Irritability and Aggression Unprovoked violent behavior Safety plan needs to be in place (for family and child) OK to call (establish a relationship with local law enforcement and EMTs with an explanation of illness) For some reason the presence of an authority figure (other than a parent) can help diffuse the situation Benzodiazepams: safest and most effective Antipsychotics or mood stabilizers: decrease the frequency and intensity 2017 GUIDELINES: Separation Anxiety Can be exhausting and respite is needed CBT is helpful for both the child as well as the individual involved Generalized and separation anxiety School needs to be aware (have a safe person ) Consider medication In the treatment of PANDAS Remember: One size does not fit all! TREATING the Child after diagnosis: Management per 2017 Guidelines Treat infection appropriately Immunizations Role of Adenotonsillectomy Role of Probiotics Vitamin D Supplements It takes a Village Choosing an antibiotic 5 Medical Fields Pediatrics Neuropsychiatry Rheumatology Immunology Infectious Disease Beta lactams Most effective in treating GAS infections Cephalosporins Erythromycin, Azithromycin, and Clindamycin can be used but need to know resistance rate in practice area 8
9 ANTIBIOTICS PENCILLINS PENICILLIN ALLERGIC Penicillin V Cephalexin Amoxicillin Cefadroxil Benzathine (Pen G IM) Clindamycin Augmentin Azithromycin Clarithromycin oral Use of Anti inflammatories Steroidal Non steroidal Ibuprofen intravenous Naproxen Celebrex Antibiotics Management of Moderate symptoms Moderate symptoms could be: significant anxiety OCD occupying more than 50% of their awake hours. May be missing school for multiple reasons. If treatment has never been initiated prior to this severity of symptoms: Antibiotics, Anti inflammatories, & Corticosteroids should be considered prior to IVIG especially since it has been noted that antibiotics can produce remission within 2 3 weeks CBT should be started as soon as the child can tolerate it, and SSRIs may need to be considered BUT MUST BE STARTED AT A VERY LOW DOSE. MANAGEMENT OF SEVERE SYMPTOMS These children have neuro psychiatric symptoms that could have life threatening consequences; including those with significant weight loss due to food aversions, impulsive behaviors, suicidal ideation. More than 80% of the child s waking hours are plagued with severe anxiety and obsessional thoughts. Consider the treatment for mild and moderate symptoms, but due to the severity of case it may be necessary to consider plasmapheresis or Rituximab. Children with co morbidities need to have those managed as well. Moderate/Severe Symptoms IVIG (OFF LABEL) How does it work? high dose 1.5g 2g/kg (max 70g) split over 2 days. Hydration prior and after, prevent headaches with medication or drink fluids. Can repeat again if no improvement within 4 6 months Commonly done in an outpatient setting Common SE: flu like symptoms, migraines, pain in joints & extremities, muscle pain, hives, etc. Does have possible serious side effects TREATMENT OF SEVERE or INTRACTABLE PANDAS SYMPTOMS Plasmapheresis Plasmapheresis is the removal of auto antibodies that circulate through the blood attacking healthy cells, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulation. Inpatient, 4 5 days in the hospital, higher risk of complications: infection, blood clotting. allergic reaction More serious but uncommon risks include bleeding Plasmapheresis may not be an appropriate treatment if someone is hemodynamically unstable or can t tolerate central line placement Usually short lived and needs to be repeated 9
10 Mainstays of Treatment Rituximab (OFF LABEL) Immuno modulatory agent Anti CD20 monoclonal antibody Depletes B cells and therefore interferes with humoral immunity Appears to be effective in the treatment of autoimmune neurological disorders Immune system takes 6 12 months to recover 2017 Guidelines 1. Treatment of the immunologic and infectious process 2. Psychoeducation approach 3. Psychotherapy 4. Cognitive Behavioral Therapy 5. Family 6. School based Assistance 7. Pharmacological interventions THE 2013 CONSORTIUM Fortunately, many of the individuals with PANS/PANDAS will recover completely and symptomatic treatments can be discontinued. Thienemann, et The 2013 Guidelines have been created by physicians at the following institutions: Stanford University: School of Medicine Columbia University: Mailman School of Public Health University of South Florida University of Missouri: School of Medicine University of North Carolina, School of Medicine University of Oklahoma College of Medicine Massachusetts General Hospital National Institute of Mental Health Latimer Neurology Center more institutions and physicians are part of 2017 Helpful Resources o National Institutes of Health o Pandasnetwork.org o Pandas/Pans advocacy support o PANDAS and PANS in the School Setting (book) o Moleculera labs o Pandas physician network o In a Pickle over PANDAS (children s book) o PANS, CANS & Automobiles (book) o My Kid is Not Crazy (documentary by Tim Sorel) 10
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